Does intensive follow-up increase days alive and well out of hospital in heart failure?

151 Figure 1Day after discharge from hospitalDid you feel well today?Please write yes or no.Weight, kg123456789101112131415161718192021222324252627282930 151 Table 1Baseline characteristicsBaseline characteristicsStandard Follow-UpN=9Intensive Follow-UpN=17Age (years)78 [69,81]74 [65,82]Gender [number of females (%)] 2 (22%)7 (41%)Rockwood Frailty Score (2 weeks pre admission) 3 [3,5]5 [3,5]Left Ventricular Systolic Function (%)Preserved 34%Mildly impaired 11%Moderately impaired 33%Severely impaired 22%Preserved 35%Mildly impaired 12%Moderately impaired 18%Severely impaired 35%NTproBNP ng/L4772 [2883,4859]9 88 [4333,14876]eGFR on discharge, ml/min/1.73m246 [35,63]51 [30,82]Comorbidity Number (in addition to HF)3 [2,4]5 [3,6]SBP, mmHg108 [106,111]110 [103,120]Number of people known COVID positive (%)0%6%Descriptive statistics are expressed as Median [IQR] or N (%).Abbreviations: eGFR: Estimated Glomerular Filtration Rate, HF: Heart failure, IQR: Inter-Quartile Range, NTproBNP: N-terminal prohormone of brain natriuretic peptide, SBP: Systolic Blood Pressure. 151 Table 2Effectiveness of intensive follow-upStandard Follow-UpIntensive Follow-UpDays alive and well out of hospital12 [8,25]22 [15,28]Days with weight recorded27 [14,30]27 [7,30]ACEi, ARB, or entresto (%)6 (67%)14 (82%)Beta-Blocker (%)8 (89%)16 (94%)% max. dose of Beta-Blocker 44 [25,53]50 [34,100]MRA%5 (56%)9 (53%)Dose of MRA, mg25 [25,25]25 [25, 25]SGLT2 inhibitor (on Dapaglifozin or empaglifozin) (%)5 (56%)14 (82%)Total number of Disease Modifying Agents (max 4)3 [2,4]3 [3,4]Descriptive statistics are expressed as Median [IQR] or N (%).Abbreviations: ACEi: Angiotensin Converting Enzyme Inhibitor, ARB: Angiotensin Receptor Blocker, IQR: Inter-Quartile Range, MRA: Mineralocorticoid receptor antagonist, SGLT2 inhibitors: Sodium-glucose cotransporter-2 inhibitors.Conflict of InterestNone

Regenerative medicine: postnatal approaches.

Paper 2 of the paediatric regenerative medicine Series focuses on recent advances in postnatal approaches. New gene, cell, and niche-based technologies and their combinations allow structural and functional reconstitution and simulation of complex postnatal cell, tissue, and organ hierarchies. Organoid and tissue engineering advances provide human disease models and novel treatments for both rare paediatric diseases and common diseases affecting all ages, such as COVID-19. Preclinical studies for gastrointestinal disorders are directed towards oesophageal replacement, short bowel syndrome, enteric neuropathy, biliary atresia, and chronic end-stage liver failure. For respiratory diseases, beside the first human tracheal replacement, more complex tissue engineering represents a promising solution to generate transplantable lungs. Genitourinary tissue replacement and expansion usually involve application of biocompatible scaffolds seeded with patient-derived cells. Gene and cell therapy approaches seem appropriate for rare paediatric diseases of the musculoskeletal system such as spinal muscular dystrophy, whereas congenital diseases of complex organs, such as the heart, continue to challenge new frontiers of regenerative medicine.

Coronaviruses exploit a host cysteine-aspartic protease for replication.

Highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus 2 (refs. 1,2) (SARS-CoV-2), Middle East respiratory syndrome coronavirus3 (MERS-CoV) and SARS-CoV-1 (ref. 4), vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture5-7 and in patient tissues8-10, suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that caspase-6, a cysteine-aspartic protease of the apoptosis cascade, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid proteins, generating fragments that serve as interferon antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss in golden Syrian hamsters infected with SARS-CoV-2 and improves the survival of mice expressing human DPP4 that are infected with mouse-adapted MERS-CoV. Our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.

A bipotential organoid model of respiratory epithelium recapitulates high infectivity of SARS-CoV-2 Omicron variant.

The airways and alveoli of the human respiratory tract are lined by two distinct types of epithelium, which are the primary targets of respiratory viruses. We previously established long-term expanding human lung epithelial organoids from lung tissues and developed a 'proximal' differentiation protocol to generate mucociliary airway organoids. However, a respiratory organoid system with bipotential of the airway and alveolar differentiation remains elusive. Here we defined a 'distal' differentiation approach to generate alveolar organoids from the same source for the derivation of airway organoids. The alveolar organoids consisting of type I and type II alveolar epithelial cells (AT1 and AT2, respectively) functionally simulate the alveolar epithelium. AT2 cells maintained in lung organoids serve as progenitor cells from which alveolar organoids derive. Moreover, alveolar organoids sustain a productive SARS-CoV-2 infection, albeit a lower replicative fitness was observed compared to that in airway organoids. We further optimized 2-dimensional (2D) airway organoids. Upon differentiation under a slightly acidic pH, the 2D airway organoids exhibit enhanced viral replication, representing an optimal in vitro correlate of respiratory epithelium for modeling the high infectivity of SARS-CoV-2. Notably, the higher infectivity and replicative fitness of the Omicron variant than an ancestral strain were accurately recapitulated in these optimized airway organoids. In conclusion, we have established a bipotential organoid culture system able to reproducibly expand the entire human respiratory epithelium in vitro for modeling respiratory diseases, including COVID-19.

What are the effects of covid-19 on heart failure admission rates and mortality?

119 Table 1ConclusionThe number of consecutive episodes of HF admissions has increased compared with the pre-COVID era. There were no changes in mortality between the pre-COVID era and the first wave however there was a statistically significant increase in mortality with the second wave.Conflict of InterestNone

Human liver organoid derived intra-hepatic bile duct cells support SARS-CoV-2 infection and replication.

Although the main route of infection for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the respiratory tract, liver injury is also commonly seen in many patients, as evidenced by deranged parenchymal liver enzymes. Furthermore, the severity of liver damage has been shown to correlate with higher mortality. Overall, the mechanism behind the liver injury remains unclear. We showed in this study that intra-hepatic bile duct cells could be grown using a human liver organoid platform. The cholangiocytes were not only susceptible to SARS-CoV-2 infection, they also supported efficient viral replication. We also showed that SARS-CoV-2 replication was much higher than SARS-CoV. Our findings suggested direct cytopathic viral damage being a mechanism for SARS-CoV-2 liver injury.

Gut microbiota composition is associated with SARS-CoV-2 vaccine immunogenicity and adverse events.

OBJECTIVE: The gut microbiota plays a key role in modulating host immune response. We conducted a prospective, observational study to examine gut microbiota composition in association with immune responses and adverse events in adults who have received the inactivated vaccine (CoronaVac; Sinovac) or the mRNA vaccine (BNT162b2; BioNTech; Comirnaty). DESIGN: We performed shotgun metagenomic sequencing in stool samples of 138 COVID-19 vaccinees (37 CoronaVac and 101 BNT162b2 vaccinees) collected at baseline and 1 month after second dose of vaccination. Immune markers were measured by SARS-CoV-2 surrogate virus neutralisation test and spike receptor-binding domain IgG ELISA. RESULTS: We found a significantly lower immune response in recipients of CoronaVac than BNT162b2 vaccines (p<0.05). Bifidobacterium adolescentis was persistently higher in subjects with high neutralising antibodies to CoronaVac vaccine (p=0.023) and their baseline gut microbiome was enriched in pathways related to carbohydrate metabolism (linear discriminant analysis (LDA) scores >2 and p<0.05). Neutralising antibodies in BNT162b2 vaccinees showed a positive correlation with the total abundance of bacteria with flagella and fimbriae including Roseburia faecis (p=0.028). The abundance of Prevotella copri and two Megamonas species were enriched in individuals with fewer adverse events following either of the vaccines indicating that these bacteria may play an anti-inflammatory role in host immune response (LDA scores>3 and p<0.05). CONCLUSION: Our study has identified specific gut microbiota markers in association with improved immune response and reduced adverse events following COVID-19 vaccines. Microbiota-targeted interventions have the potential to complement effectiveness of COVID-19 vaccines.

Epidemiology of paediatric orthopaedic-related trauma injuries sustained across a lockdown period during the COVID-19 pandemic.

OBJECTIVES: Lockdowns have been implemented by countries to slow down SARS-CoV-2 transmission. Singapore's lockdown was enforced between 7 April 2020 and 1 June 2020. The objective of this study was to compare the epidemiology of paediatric orthopaedic trauma injuries during and immediately after the lockdown, with a non-pandemic period in 2019. METHODS: All paediatric outpatients and inpatients seen in our hospital following an orthopaedic-related traumatic injury from the 8-week lockdown and 8 weeks post-lockdown were evaluated. Cases for matched periods in 2019 were identified retrospectively for baseline comparison. Patient demographics, venue of injury, anatomic location of injury, caregiver supervision and location of procedures performed in the hospital were assessed. RESULTS: 968 and 2810 injuries were observed in 2020 and 2019, respectively. While the proportion of injuries sustained by pre-schoolers and toddlers increased, those sustained by primary and secondary school children decreased in 2020 (p < 0.001). Majority of the injuries during the lockdown were sustained at home compared to schools or public recreational facilities (p < 0.001). Hand (26.2%) and elbow (20.8%) injuries were the most common during the lockdown. The proportion of procedures performed in the Children's Emergency during the lockdown was more than twice that of the same period in 2019 (p < 0.001). CONCLUSION: Our study showed a 2.9-fold decrease in orthopaedic-related injuries seen during the peri-lockdown period compared to a non-pandemic period. Pre-schoolers seem to be most vulnerable to injuries during the lockdown. Hand and elbow injuries were most common.

Uncovering Clinical Risk Factors and Predicting Severe COVID-19 Cases Using UK Biobank Data: Machine Learning Approach.

BACKGROUND: COVID-19 is a major public health concern. Given the extent of the pandemic, it is urgent to identify risk factors associated with disease severity. More accurate prediction of those at risk of developing severe infections is of high clinical importance. OBJECTIVE: Based on the UK Biobank (UKBB), we aimed to build machine learning models to predict the risk of developing severe or fatal infections, and uncover major risk factors involved. METHODS: We first restricted the analysis to infected individuals (n=7846), then performed analysis at a population level, considering those with no known infection as controls (ncontrols=465,728). Hospitalization was used as a proxy for severity. A total of 97 clinical variables (collected prior to the COVID-19 outbreak) covering demographic variables, comorbidities, blood measurements (eg, hematological/liver/renal function/metabolic parameters), anthropometric measures, and other risk factors (eg, smoking/drinking) were included as predictors. We also constructed a simplified (lite) prediction model using 27 covariates that can be more easily obtained (demographic and comorbidity data). XGboost (gradient-boosted trees) was used for prediction and predictive performance was assessed by cross-validation. Variable importance was quantified by Shapley values (ShapVal), permutation importance (PermImp), and accuracy gain. Shapley dependency and interaction plots were used to evaluate the pattern of relationships between risk factors and outcomes. RESULTS: A total of 2386 severe and 477 fatal cases were identified. For analyses within infected individuals (n=7846), our prediction model achieved area under the receiving-operating characteristic curve (AUC-ROC) of 0.723 (95% CI 0.711-0.736) and 0.814 (95% CI 0.791-0.838) for severe and fatal infections, respectively. The top 5 contributing factors (sorted by ShapVal) for severity were age, number of drugs taken (cnt_tx), cystatin C (reflecting renal function), waist-to-hip ratio (WHR), and Townsend deprivation index (TDI). For mortality, the top features were age, testosterone, cnt_tx, waist circumference (WC), and red cell distribution width. For analyses involving the whole UKBB population, AUCs for severity and fatality were 0.696 (95% CI 0.684-0.708) and 0.825 (95% CI 0.802-0.848), respectively. The same top 5 risk factors were identified for both outcomes, namely, age, cnt_tx, WC, WHR, and TDI. Apart from the above, age, cystatin C, TDI, and cnt_tx were among the top 10 across all 4 analyses. Other diseases top ranked by ShapVal or PermImp were type 2 diabetes mellitus (T2DM), coronary artery disease, atrial fibrillation, and dementia, among others. For the "lite" models, predictive performances were broadly similar, with estimated AUCs of 0.716, 0.818, 0.696, and 0.830, respectively. The top ranked variables were similar to above, including age, cnt_tx, WC, sex (male), and T2DM. CONCLUSIONS: We identified numerous baseline clinical risk factors for severe/fatal infection by XGboost. For example, age, central obesity, impaired renal function, multiple comorbidities, and cardiometabolic abnormalities may predispose to poorer outcomes. The prediction models may be useful at a population level to identify those susceptible to developing severe/fatal infections, facilitating targeted prevention strategies. A risk-prediction tool is also available online. Further replications in independent cohorts are required to verify our findings.

Exploring Drugs and Vaccines Associated with Altered Risks and Severity of COVID-19: A UK Biobank Cohort Study of All ATC Level-4 Drug Categories Reveals Repositioning Opportunities.

Effective therapies for COVID-19 are still lacking, and drug repositioning is a promising approach to address this problem. Here, we adopted a medical informatics approach to repositioning. We leveraged a large prospective cohort, the UK-Biobank (UKBB, N ~ 397,000), and studied associations of prior use of all level-4 ATC drug categories (N = 819, including vaccines) with COVID-19 diagnosis and severity. Effects of drugs on the risk of infection, disease severity, and mortality were investigated separately. Logistic regression was conducted, controlling for main confounders. We observed strong and highly consistent protective associations with statins. Many top-listed protective drugs were also cardiovascular medications, such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), calcium channel blocker (CCB), and beta-blockers. Some other drugs showing protective associations included biguanides (metformin), estrogens, thyroid hormones, proton pump inhibitors, and testosterone-5-alpha reductase inhibitors, among others. We also observed protective associations by influenza, pneumococcal, and several other vaccines. Subgroup and interaction analyses were also conducted, which revealed differences in protective effects in various subgroups. For example, protective effects of flu/pneumococcal vaccines were weaker in obese individuals, while protection by statins was stronger in cardiovascular patients. To conclude, our analysis revealed many drug repositioning candidates, for example several cardiovascular medications. Further studies are required for validation.

Targeting highly pathogenic coronavirus-induced apoptosis reduces viral pathogenesis and disease severity.

Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R-like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2- and SARS-CoV-induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2-inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.

Online action planning forums to develop a roadmap to mitigate the impact of COVID-19 on the delivery of global children's surgical care.

PURPOSE: We aimed to understand the challenges facing children's surgical care providers globally and realistic interventions to mitigate the catastrophic impact of COVID-19 on children's surgery. METHODS: Two online Action Planning Forums (APFs) were organized by the Global Initiative for Children's Surgery (GICS) with a geographically diverse panel representing four children's surgical, anesthesia, and nursing subspecialties. Qualitative analysis was performed to identify codes, themes, and subthemes. RESULTS: The most frequently reported challenges were delayed access to care for children; fear among the public and patients; unavailability of appropriate personal protective equipment (PPE); diversion of resources toward COVID-19 care; and interruption in student and trainee hands-on education. To address these challenges, panelists recommended human resource and funding support to minimize backlog; setting up international, multi-center studies for systematic data collection specifically for children; providing online educational opportunities for trainees and students in the form of large and small group discussions; developing best practice guidelines; and, most importantly, adapting solutions to local needs. CONCLUSION: Identification of key challenges and interventions to mitigate the impact of the COVID-19 pandemic on global children's surgery via an objective, targeted needs assessment serves as an essential first step. Key interventions in these areas are underway.

Human Intestinal Organoids Recapitulate Enteric Infections of Enterovirus and Coronavirus.

Enteroviruses, such as EV-A71 and CVA16, mainly infect the human gastrointestinal tract. Human coronaviruses, including SARS-CoV and SARS-CoV-2, have been variably associated with gastrointestinal symptoms. We aimed to optimize the human intestinal organoids and hypothesize that these optimized intestinal organoids can recapitulate enteric infections of enterovirus and coronavirus. We demonstrate that the optimized human intestinal organoids enable better simulation of the native human intestinal epithelium, and that they are significantly more susceptible to EV-A71 than CVA16. Higher replication of EV-A71 than CVA16 in the intestinal organoids triggers a more vigorous cellular response. However, SARS-CoV and SARS-CoV-2 exhibit distinct dynamics of virus-host interaction; more robust propagation of SARS-CoV triggers minimal cellular response, whereas, SARS-CoV-2 exhibits lower replication capacity but elicits a moderate cellular response. Taken together, the disparate profile of the virus-host interaction of enteroviruses and coronaviruses in human intestinal organoids may unravel the cellular basis of the distinct pathogenicity of these viral pathogens.

A Comparison Between Chinese Children Infected with Coronavirus Disease-2019 and with Severe Acute Respiratory Syndrome 2003.

OBJECTIVES: To compare the clinical and laboratory features of severe acute respiratory syndrome 2003 (SARS) and coronavirus disease 2019 (COVID-19) in 2 Chinese pediatric cohorts, given that the causative pathogens and are biologically similar. STUDY DESIGN: This is a cross-sectional study reviewing pediatric patients with SARS (n = 43) and COVID-19 (n = 244) who were admitted to the Princess Margaret Hospital in Hong Kong and Wuhan Children's Hospital in Wuhan, respectively. Demographics, hospital length of stay, and clinical and laboratory features were compared. RESULTS: Overall, 97.7% of patients with SARS and 85.2% of patients with COVID-19 had epidemiologic associations with known cases. Significantly more patients with SARS developed fever, chills, myalgia, malaise, coryza, sore throat, sputum production, nausea, headache, and dizziness than patients with COVID-19. No patients with SARS were asymptomatic at the time of admission, whereas 29.1% and 20.9% of patients with COVID-19 were asymptomatic on admission and throughout their hospital stay, respectively. More patients with SARS required oxygen supplementation than patients with COVID-19 (18.6 vs 4.7%; P = .004). Only 1.6% of patients with COVID-19 and 2.3% of patients with SARS required mechanical ventilation. Leukopenia (37.2% vs 18.6%; P = .008), lymphopenia (95.4% vs 32.6%; P < .01), and thrombocytopenia (41.9% vs 3.8%; P < .001) were significantly more common in patients with SARS than in patients with COVID-19. The duration between positive and negative nasopharyngeal aspirate and the length in hospital stay were similar in patients with COVID-19, regardless of whether they were asymptomatic or symptomatic, suggesting a similar duration of viral shedding. CONCLUSIONS: Children with COVID-19 were less symptomatic and had more favorable hematologic findings than children with SARS.

Haematological and immunological data of Chinese children infected with coronavirus disease 2019.

Haematological and immunological data of children with COVID-19 infection is lacking. Between 21st January and 20th March 2020, 244 children who were confirmed to have COVID-19 infection and admitted to the Wuhan Children's Hospital, China were retrospectively reviewed. 193 children were considered as symptomatic, which was defined as having either the presence of clinical symptoms or the presence of CT thorax abnormalities. Their haematological and immunological profiles, including complete blood counts, lymphocyte subsets (T, B and NK cell counts), immunoglobulin (Ig) profiles (IgG, IgA and IgM) and cytokine profiles were analysed and compared between the symptomatic and asymptomatic groups. The median values and the interquartile ranges were calculated. Comparison was made using the Mann-Whitney U test. Children with symptomatic COVID-19 infection had significantly lower haemoglobin levels, but higher absolute lymphocyte and monocyte counts, IgG and IgA levels, as well as interleukin 6 (IL-6), IL-10, tumour necrosis factor alpha and interferon gamma levels. The obtained data will be utilized for further studies in comparing children and adults with COVID-19 infections in other parts of the world and with different severity .

Infection of bat and human intestinal organoids by SARS-CoV-2.

A novel coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-emerged in humans in Wuhan, China, in December 2019 and has since disseminated globally1,2. As of April 16, 2020, the confirmed case count of coronavirus disease 2019 (COVID-19) had surpassed 2 million. Based on full-genome sequence analysis, SARS-CoV-2 shows high homology to SARS-related coronaviruses identified in horseshoe bats1,2. Here we show the establishment and characterization of expandable intestinal organoids derived from horseshoe bats of the Rhinolophus sinicus species that can recapitulate bat intestinal epithelium. These bat enteroids are fully susceptible to SARS-CoV-2 infection and sustain robust viral replication. Development of gastrointestinal symptoms in some patients with COVID-19 and detection of viral RNA in fecal specimens suggest that SARS-CoV-2 might cause enteric, in addition to respiratory, infection3,4. Here we demonstrate active replication of SARS-CoV-2 in human intestinal organoids and isolation of infectious virus from the stool specimen of a patient with diarrheal COVID-19. Collectively, we established the first expandable organoid culture system of bat intestinal epithelium and present evidence that SARS-CoV-2 can infect bat intestinal cells. The robust SARS-CoV-2 replication in human intestinal organoids suggests that the human intestinal tract might be a transmission route of SARS-CoV-2.