Global disparities in mortality and liver transplantation in hospitalised patients with cirrhosis: a prospective cohort study for the CLEARED Consortium

Summary Background Cirrhosis, the end result of liver injury, has high mortality globally. The effect of country-level income on mortality from cirrhosis is unclear. We aimed to assess predictors of death in inpatients with cirrhosis using a global consortium focusing on cirrhosis-related and access-related variables. Methods In this prospective observational cohort study, the CLEARED Consortium followed up inpatients with cirrhosis at 90 tertiary care hospitals in 25 countries across six continents. Consecutive patients older than 18 years who were admitted non-electively, without COVID-19 or advanced hepatocellular carcinoma, were enrolled. We ensured equitable participation by limiting enrolment to a maximum of 50 patients per site. Data were collected from patients and their medical records, and included demographic characteristics;country;disease severity (MELD-Na score);cirrhosis cause;medications used;reasons for admission;transplantation listing;cirrhosis-related history in the past 6 months;and clinical course and management while hospitalised and for 30 days post discharge. Primary outcomes were death and receipt of liver transplant during index hospitalisation or within 30 days post discharge. Sites were surveyed regarding availability of and access to diagnostic and treatment services. Outcomes were compared by country income level of participating sites, defined according to World Bank income classifications (high-income countries [HICs], upper-middle-income countries [UMICs], and low-income or lower-middle-income countries [LICs or LMICs]). Multivariable models controlling for demographic variables, disease cause, and disease severity were used to analyse the odds of each outcome associated with variables of interest. Findings Patients were recruited between Nov 5, 2021, and Aug 31, 2022. Complete inpatient data were obtained for 3884 patients (mean age 55·9 years [SD 13·3];2493 (64·2%) men and 1391 (35·8%) women;1413 [36·4%] from HICs, 1757 [45·2%] from UMICs, and 714 [18·4%] from LICs or LMICs), with 410 lost to follow-up within 30 days after hospital discharge. The number of patients who died while hospitalised was 110 (7·8%) of 1413 in HICs, 182 (10·4%) of 1757 in UMICs, and 158 (22·1%) of 714 in LICs and LMICs (p<0·0001), and within 30 days post discharge these values were 179 (14·4%) of 1244 in HICs, 267 (17·2%) of 1556 in UMICs, and 204 (30·3%) of 674 in LICs and LMICs (p<0·0001). Compared with patients from HICs, increased risk of death during hospitalisation was found for patients from UMICs (adjusted odds ratio [aOR] 2·14 [95% CI 1·61–2·84]) and from LICs or LMICs (2·54 [1·82–3·54]), in addition to increased risk of death within 30 days post discharge (1·95 [1·44–2·65] in UMICs and 1·84 [1·24–2·72] in LICs or LMICs). Receipt of a liver transplant was recorded in 59 (4·2%) of 1413 patients from HICs, 28 (1·6%) of 1757 from UMICs (aOR 0·41 [95% CI 0·24–0·69] vs HICs), and 14 (2·0%) of 714 from LICs and LMICs (0·21 [0·10–0·41] vs HICs) during index hospitalisation (p<0·0001), and in 105 (9·2%) of 1137 patients from HICs, 55 (4·0%) of 1372 from UMICs (0·58 [0·39–0·85] vs HICs), and 16 (3·1%) of 509 from LICs or LMICs (0·21 [0·11–0·40] vs HICs) by 30 days post discharge (p<0·0001). Site survey results showed that access to important medications (rifaximin, albumin, and terlipressin) and interventions (emergency endoscopy, liver transplantation, intensive care, and palliative care) varied geographically. Interpretation Inpatients with cirrhosis in LICs, LMICs, or UMICs have significantly higher mortality than inpatients in HICs independent of medical risk factors, and this might be due to disparities in access to essential diagnostic and treatment services. These results should encourage researchers and policy makers to consider access to services and medications when evaluating cirrhosis-related outcomes. Funding National Institutes of Health and US Department of Veterans Affairs.

COVID-19 myocarditis and long-term heart failure sequelae.

PURPOSE OF REVIEW: The clinical syndrome of coronavirus disease 2019 (COVID-19) has become a global pandemic leading to significant morbidity and mortality. Cardiac dysfunction is commonly seen in these patients, often presenting as clinical heart failure. Accordingly, we aim to provide a comprehensive review on COVID-19 myocarditis and its long-term heart failure sequelae. RECENT FINDINGS: Several suspected cases of COVID-19 myocarditis have been reported. It is often not clear if the acute myocardial dysfunction is caused by myocarditis or secondary to generalized inflammatory state of cytokine release or microvascular thrombotic angiopathy. Ischemia may also need to be ruled out. Regardless, myocardial dysfunction in these patients is associated with poor overall prognosis. Laboratory testing, echocardiography, cardiac magnetic resonance imaging, and even endomyocardial biopsy may be needed for timely diagnosis. Several treatment strategies have been described, including both supportive and targeted therapies. SUMMARY: COVID-19 can cause a spectrum of ventricular dysfunction ranging from mild disease to fulminant myocarditis with hemodynamic instability. Future research is needed to understand the true prevalence of COVID-19 myocarditis, as well as to better define various diagnostic protocols and treatment strategies.

Four thermostatic steps: A novel CRISPR-Cas12-based system for the rapid at-home detection of respiratory pathogens.

The outbreak of coronavirus disease 2019 (COVID-19) in 2019 has severely damaged the world's economy and public health and made people pay more attention to respiratory infectious diseases. However, traditional quantitative real-time polymerase chain reaction (qRT-PCR) nucleic acid detection kits require RNA extraction, reverse transcription, and amplification, as well as the support of large-scale equipment to enrich and purify nucleic acids and precise temperature control. Therefore, novel, fast, convenient, sensitive and specific detection methods are urgently being developed and moving to proof of concept test. In this study, we developed a new nucleic acid detection system, referred to as 4 Thermostatic steps (4TS), which innovatively allows all the detection processes to be completed in a constant temperature device, which performs extraction, amplification, cutting of targets, and detection within 40 min. The assay can specifically and sensitively detect five respiratory pathogens, namely SARS-CoV-2, Mycoplasma felis (MF), Chlamydia felis (CF), Feline calicivirus (FCV), and Feline herpes virus (FHV). In addition, a cost-effective and practical small-scale reaction device was designed and developed to maintain stable reaction conditions. The results of the detection of the five viruses show that the sensitivity of the system is greater than 94%, and specificity is 100%. The 4TS system does not require complex equipment, which makes it convenient and fast to operate, and allows immediate testing for suspected infectious agents at home or in small clinics. Therefore, the assay system has diagnostic value and significant potential for further reducing the cost of early screening of infectious diseases and expanding its application. KEY POINTS: • The 4TS system enables the accurate and specific detection of nucleic acid of pathogens at 37 °C in four simple steps, and the whole process only takes 40 min. •A simple alkali solution can be used to extract nucleic acid. • A small portable device simple to operate is developed for home diagnosis and detection of respiratory pathogens.

Safety and immunogenicity of heterologous ChAdOx1-nCoV19 and BNT162b2 vaccination: A meta-analysis of the heterologous COVID-19 vaccination outcomes.

INTRODUCTION: Here, we systematically assessed the safety and immunogenicity of the heterologous ChAd/BNT vaccination regimens. MATERIALS AND METHODS: We evaluated the immunogenicity by the geometric mean titers ratio (GMTR) of the neutralizing antibody and anti-spike IgG. The safety of heterologous ChAd/BNT vaccination was evaluated using the pooled risk ratios (RRs) calculated by the random-effects model about the adverse events. Our study was registered with PROSPERO, CRD42021265165. RESULTS: Eleven studies were included in the analyses. Compared to the homologous ChAd/ChAd vaccination, the heterologous ChAd/BNT vaccination showed significantly higher immunogenicity in terms of the neutralizing antibody and GMTR of anti-spike IgG, but at the same time displayed higher incidence of total adverse reactions, especially for the local adverse reactions. Moreover, heterologous ChAd/BNT vaccination showed similar immunogenicity to the homologous BNT/BNT vaccination (GMTR of neutralizing antibody and anti-spike IgG) and similar safety. DISCUSSION: Heterologous ChAd/BNT vaccination showed robust immunogenicity and tolerable safety.

Assessment of integrated patterns of human-animal-environment health: a holistic and stratified analysis.

BACKGROUND: Data-driven research is a very important component of One Health. As the core part of the global One Health index (GOHI), the global One Health Intrinsic Drivers index (IDI) is a framework for evaluating the baseline conditions of human-animal-environment health. This study aims to assess the global performance in terms of GOH-IDI, compare it across different World Bank regions, and analyze the relationships between GOH-IDI and national economic levels. METHODS: The raw data among 146 countries were collected from authoritative databases and official reports in November 2021. Descriptive statistical analysis, data visualization and manipulation, Shapiro normality test and ridge maps were used to evaluate and identify the spatial and classificatory distribution of GOH-IDI. This paper uses the World Bank regional classification and the World Bank income groups to analyse the relationship between GOH-IDI and regional economic levels, and completes the case studies of representative countries. RESULTS: The performance of One Health Intrinsic Driver in 146 countries was evaluated. The mean (standard deviation, SD) score of GOH-IDI is 54.05 (4.95). The values (mean SD) of different regions are North America (60.44, 2.36), Europe and Central Asia (57.73, 3.29), Middle East and North Africa (57.02, 2.56), East Asia and Pacific (53.87, 5.22), Latin America and the Caribbean (53.75, 2.20), South Asia (52.45, 2.61) and sub-Saharan Africa (48.27, 2.48). Gross national income per capita was moderately correlated with GOH-IDI (R2 = 0.651, Deviance explained = 66.6%, P < 0.005). Low income countries have the best performance in some secondary indicators, including Non-communicable Diseases and Mental Health and Health risks. Five indicators are not statistically different at each economic level, including Animal Epidemic Disease, Animal Biodiversity, Air Quality and Climate Change, Land Resources and Environmental Biodiversity. CONCLUSIONS: The GOH-IDI is a crucial tool to evaluate the situation of One Health. There are inter-regional differences in GOH-IDI significantly at the worldwide level. The best performing region for GOH-IDI was North America and the worst was sub-Saharan Africa. There is a positive correlation between the GOH-IDI and country economic status, with high-income countries performing well in most indicators. GOH-IDI facilitates researchers' understanding of the multidimensional situation in each country and invests more attention in scientific questions that need to be addressed urgently.

Analysis of Pathogenic Bacteria and Drug Resistance Among Girls with Bacterial Vaginitis.

Objective: The aim of this study was to analyze the prevalence of vaginal flora and drug resistance in bacterial vaginitis among girls. Methods: A total of 3099 girls (0-10 years old) with vaginitis who visited the Beijing Children's Hospital from January 2020 to December 2021 were included in the present study. The clinical data, results of bacterial culture of vaginal secretions, and drug sensitivity reports of the subjects were collected and analyzed. Results: Of the 3099 girls with vaginitis, 399 girls had a positive bacterial culture of vaginal secretions. Nineteen types of bacteria were cultured from the vaginal secretions of these 399 girls, with a total of 419 strains. The top three infective bacteria were Haemophilus influenzae (127 strains, 30.31%), Staphylococcus aureus (66 strains, 15.75%), and Streptococcus agalactiae (32 strains, 7.64%). Additionally, 20 girls were simultaneously infected with two types of bacteria. Staphylococcus aureus, Group G Streptococcus, Haemophilus parainfluenzae, and Pseudomonas aeruginosa more frequently occurred in mixed infections. The number and bacterial detection rate among school-age girls were higher than those of preschool-age girls. We found seasonal variation in infection rates, and vaginitis among girls was higher in summer. Recurrence of vaginitis in girls was not related to the type of pathogenic bacteria in the infection. Drug sensitivity analyses showed that the resistance rates of clindamycin and erythromycin were generally high, 70-100%. After the coronavirus disease 2019 outbreak, the resistance rates of some antibiotics had decreased to varying degrees. Conclusion: Improving the understanding of vaginal flora and drug resistance in girls with vaginitis will facilitate the selection of highly effective and sensitive antibacterial drugs and reduce the production of drug-resistant strains.

Evaluation of In Vitro and In Vivo Antiviral Activities of Vitamin D for SARS-CoV-2 and Variants.

The COVID-19 pandemic has brought about unprecedented medical and healthcare challenges worldwide. With the continual emergence and spread of new COVID-19 variants, four drug compound libraries were interrogated for their antiviral activities against SARS-CoV-2. Here, we show that the drug screen has resulted in 121 promising anti-SARS-CoV-2 compounds, of which seven were further shortlisted for hit validation: citicoline, pravastatin sodium, tenofovir alafenamide, imatinib mesylate, calcitriol, dexlansoprazole, and prochlorperazine dimaleate. In particular, the active form of vitamin D, calcitriol, exhibits strong potency against SARS-CoV-2 on cell-based assays and is shown to work by modulating the vitamin D receptor pathway to increase antimicrobial peptide cathelicidin expression. However, the weight, survival rate, physiological conditions, histological scoring, and virus titre between SARS-CoV-2 infected K18-hACE2 mice pre-treated or post-treated with calcitriol were negligible, indicating that the differential effects of calcitriol may be due to differences in vitamin D metabolism in mice and warrants future investigation using other animal models.

Safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster following three doses of CoronaVac: a multicentre, open-label, phase 4, randomised trial.

BACKGROUND: Aerosolised Ad5-nCoV is the first approved mucosal respiratory COVID-19 vaccine to be used as a booster after the primary immunisation with COVID-19 vaccines. This study aimed to evaluate the safety and immunogenicity of aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, or inactivated COVID-19 vaccine CoronaVac given as the second booster. METHODS: This is an open-label, parallel-controlled, phase 4 randomised trial enrolling healthy adult participants (≥18 years) who had completed a two-dose primary immunisation and a booster immunisation with inactivated COVID-19 vaccines (CoronaVac only) at least 6 months before, in Lianshui and Donghai counties, Jiangsu Province, China. We recruited eligible participants from previous trials in China (NCT04892459, NCT04952727, and NCT05043259) as cohort 1 (with the serum before and after the first booster dose available), and from eligible volunteers in Lianshui and Donghai counties, Jiangsu Province, as cohort 2. Participants were randomly assigned at a ratio of 1:1:1, using a web-based interactive response randomisation system, to receive the fourth dose (second booster) of aerosolised Ad5-nCoV (0·1 mL of 1·0 × 1011 viral particles per mL), intramuscular Ad5-nCoV (0·5 mL of 1·0 × 1011 viral particles per mL), or inactivated COVID-19 vaccine CoronaVac (0·5 mL), respectively. The co-primary outcomes were safety and immunogenicity of geometric mean titres (GMTs) of serum neutralising antibodies against prototype live SARS-CoV-2 virus 28 days after the vaccination, assessed on a per-protocol basis. Non-inferiority or superiority was achieved when the lower limit of the 95% CI of the GMT ratio (heterologous group vs homologous group) exceeded 0·67 or 1·0, respectively. This study was registered with ClinicalTrials.gov, NCT05303584 and is ongoing. FINDINGS: Between April 23 and May 23, 2022, from 367 volunteers screened for eligibility, 356 participants met eligibility criteria and received a dose of aerosolised Ad5-nCoV (n=117), intramuscular Ad5-nCoV (n=120), or CoronaVac (n=119). Within 28 days of booster vaccination, participants in the intramuscular Ad5-nCoV group reported a significantly higher frequency of adverse reactions than those in the aerosolised Ad5-nCoV and intramuscular CoronaVac groups (30% vs 9% and 14%, respectively; p<0·0001). No serious adverse events related to the vaccination were reported. The heterologous boosting with aerosolised Ad5-nCoV triggered a GMT of 672·4 (95% CI 539·7-837·7) and intramuscular Ad5-nCoV triggered a serum neutralising antibody GMT of 582·6 (505·0-672·2) 28 days after the booster dose, both of which were significantly higher than the GMT in the CoronaVac group (58·5 [48·0-71·4]; p<0·0001). INTERPRETATION: A heterologous fourth dose (second booster) with either aerosolised Ad5-nCoV or intramuscular Ad5-nCoV was safe and highly immunogenic in healthy adults who had been immunised with three doses of CoronaVac. FUNDING: National Natural Science Foundation of China, Jiangsu Provincial Science Fund for Distinguished Young Scholars, and Jiangsu Provincial Key Project of Science and Technology Plan.

The Effect of Future Time Perspective on Internet Dependence Among College Students in Pandemic Time: A Moderated Mediation Analysis.

Purpose: Social isolation during the COVID-19 pandemic has greatly increased the probability of Internet dependence. This study sought to examine the relation between future time perspective and college students' Internet dependence, as well as the mediating role of boredom proneness and the moderating effect of self-control in the link between boredom proneness and Internet dependence. Materials and Methods: A questionnaire survey was carried out among college students from two universities in China. A sample of 448 participants varying from freshmen to seniors completed questionnaires on future time perspective, Internet dependence, boredom proneness and self-control. Results: Results indicated that college students with high future time perspective were less likely to fall into Internet dependence and boredom proneness mediated this relationship. The relation between boredom proneness and Internet dependence was moderated by self-control. Boredom proneness had a greater impact on Internet dependence for students with low self-control. Conclusion: Future time perspective could influence Internet dependence through the mediating role of boredom proneness, which is moderated by self-control. The results advanced our understanding of how future time perspective affected college students' Internet dependence, revealing that intervention strategies which could improve students' self-control would be instrumental in reducing Internet dependence.

Enhanced Interfacial H-Bond Networks Promote Glycan-Glycan Recognition and Interaction.

H-bond networks at heterogeneous interfaces play crucial roles in bioseparation, biocatalysis, biochip array profiling, and functional nanosystem self-assembly, but their precise modulation and enhancement remain challenging. In this study, we have discovered that interfacial hydrophobic hydration significantly enhances H-bond networks at the interface between a glycan-modified adsorbent and a methanol-water-acetonitrile ternary solution. The enhanced H-bond networks greatly promote the adsorbent-solution heterogeneous glycan-glycan recognition and interaction. This novel hydrophobic hydration-enhanced hydrophilic interaction (HEHI) strategy improves the affinity and efficiency of intact glycopeptide enrichment. Compared with the commonly used hydrophilic-interaction enrichment strategy, 23.5 and 48.5% more intact N- and O-glycopeptides are identified, and the enrichment recoveries of half of the glycopeptides are increased >100%. Further, in-depth profiling of both N- and O-glycosylation occurring on SARS-CoV-2 S1 and hACE2 proteins has been achieved with more glycan types and novel O-glycosylation information involved. Interfacial hydrophobic hydration provides a powerful tool for the modulation of hydrophilic interactions in biological systems.

The colonic interleukin-19 aggravates the dextran sodium sulfate/stress-induced comorbidities due to colitis and anxiety.

Comorbidities due to inflammatory bowel disease (IBD) and anxiety are commonly acknowledged; however, their underlying basis is unclear. In the current study, we first conducted a clinical retrospective analysis to identify the enhancive incidence rate of IBD before or after the epidemic of Corona Virus Disease 2019 (COVID-19), with higher Generalized Anxiety Disorder-7 (GAD-7), as well as poorer Gastrointestinal Quality of Life Index (GIQLI). Then, the dextran sodium sulfate (DSS) and chronic unpredictable stress (CUS)-induced IBD and anxiety comorbid models were established with the correlational relations between symptoms of IBD and anxiety-related behaviors. We found dysfunctional up-regulation of a new inflammatory factor interleukin (IL)-19 in the colon of DSS/CUS treated mice. Overexpression of IL-19 in colon induced anxious phenotypes, and accelerated the anxious condition and symptoms of colitis in the DSS/CUS model by promoting the expression of inducible nitric oxide synthase (iNOS), IL-1ß, and IL-6 pro-inflammatory factors, and activating signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon. Furthermore, overexpression of IL-19 in the colon also reduced the expression levels of brain-derived neurotrophic factor (BDNF), extracellular signal-regulated kinase (ERK), and cAMP-response element binding protein (CREB) signaling pathways activity in the hippocampus. These results suggest that IL-19 was a pivotal player in DSS/CUS-induced comorbidities of colitis and anxiety with different signaling pathways for the colon and hippocampus, which provides a candidate gene to explore the pathophysiology of comorbidities due to colitis and anxiety.

Analysis of Factors Influencing Air Quality in Different Periods during COVID-19: A Case Study of Tangshan, China.

This study aimed to analyze the main factors influencing air quality in Tangshan during COVID-19, covering three different periods: the COVID-19 period, the Level I response period, and the Spring Festival period. Comparative analysis and the difference-in-differences (DID) method were used to explore differences in air quality between different stages of the epidemic and different years. During the COVID-19 period, the air quality index (AQI) and the concentrations of six conventional air pollutants (PM2.5, PM10, SO2, NO2, CO, and O3-8h) decreased significantly compared to 2017-2019. For the Level I response period, the reduction in AQI caused by COVID-19 control measures were 29.07%, 31.43%, and 20.04% in February, March, and April of 2020, respectively. During the Spring Festival, the concentrations of the six pollutants were significantly higher than those in 2019 and 2021, which may be related to heavy pollution events caused by unfavorable meteorological conditions and regional transport. As for the further improvement in air quality, it is necessary to take strict measures to prevent and control air pollution while paying attention to meteorological factors.