Covid-19 Pandemic Strategy for Treatment of Acute Uncomplicated Appendicitis with Antibiotics- Risk Categorization and Shared Decision-Making.

BACKGROUND: During the Coronavirus disease 2019 (COVID-19) pandemic, a protocol was adopted by our department on antibiotics treatment for Acute Uncomplicated Appendicitis (AUA). Our study aimed to determine the feasibility and safety of non-operative treatment (NOT), compared to upfront laparoscopic appendectomy (LA), for AUA in children during the pandemic. METHOD: Our prospective comparative study was conducted from May 1, 2020 to January 31, 2021. Patient selection criteria included: age ≥5 years, abdominal pain duration ≤48 h, ultrasound (US)/Computered Tomography scan confirmation of AUA, US appendiceal diameter 6-11 mm with no features of perforation/abscess collection and no faecolith. For NOT patients, intravenous antibiotics were administered for 24-48 h followed by oral for 10-day course. Comparison was performed between patients whose parents preferred NOT to those who opted for up-front appendectomy. Primary outcomes were NOT success at index admission, early and late NOT failure rates till 27 months. Secondary outcomes were differences in complication rate, hospital length of stay (LOS) and cost between groups. RESULTS: 77 patients were recruited: 43 (55.8%) underwent NOT while 34 (44.2%) patients opted for LA. Success of NOT at index admission was 90.7% (39/43). Overall, NOT failure rate at 27 months' follow-up was 37.2% (16/43). Of the NOT failures, 1 appendix was normal on histology while only 1 was perforated. There were no significant differences in secondary outcomes between both groups except for LOS of late NOT failure. Cost for upfront LA was nearly thrice that of NOT. CONCLUSION: Our stringent COVID protocol together with shared decision-making with parents is a safe and feasible treatment option during a crisis situation. LEVEL OF EVIDENCE: Treatment study, Level II.

Conservative antibiotic treatment of pediatric acute uncomplicated appendicitis during the COVID-19 pandemic: a prospective comparative cohort study.

BACKGROUND: Our study aimed to compare the clinical outcomes and cost-efficiency of antibiotic management versus laparoscopic appendectomy for acute uncomplicated appendicitis (AUA) in children during the COVID-19 pandemic when resources were limited and transmission risks uncertain. METHOD: In this prospective comparative cohort study, we analyzed the data of 139 children diagnosed with AUA meeting the following inclusion criteria: 5-18 years of age, symptoms duration of ≤ 48 h, appendix diameter ≤ 11 mm and no appendicolith. Treatment outcomes between non-operative management group (78/139) and upfront laparoscopic appendectomy group (61/139) were compared. Antibiotic regimes were intravenous ceftriaxone/metronidazole or amoxicillin/clavulanic acid for 48 h, followed by oral antibiotics to complete total 10-days course. RESULTS: 8/78 (10.3%) children had early failure (within 48 h) requiring appendectomy. 17/70 (24.3%) patients experienced late recurrence within mean follow-up time of 16.2 ± 4.7 months. There were no statistical differences in peri-operative complications, negative appendicectomy rate, and incidence of perforation and hospitalization duration between antibiotic and surgical treatment groups. Cost per patient in upfront surgical group was significantly higher ($6208.5 ± 5284.0) than antibiotic group ($3588.6 ± 3829.8; p = 0.001). CONCLUSION: Despite 24.3% risk of recurrence of appendicitis in 16.2 ± 4.7 months, antibiotic therapy for AUA appears to be a safe and cost-effective alternative to upfront appendectomy.

Subtyping of major SARS-CoV-2 variants reveals different transmission dynamics based on 10 million genomes.

SARS-CoV-2 continues to evolve, causing waves of the pandemic. Up to May 2022, 10 million genome sequences have accumulated, which are classified into five major variants of concern. With the growing number of sequenced genomes, analysis of the big dataset has become increasingly challenging. Here we developed systematic approaches based on sets of correlated single nucleotide variations (SNVs) for comprehensive subtyping and pattern recognition of transmission dynamics. The approach outperformed single-SNV and spike-centric scans. Moreover, the derived subtypes elucidate the relationship of signature SNVs and transmission dynamics. We found that different subtypes of the same variant, including Delta and Omicron exhibited distinct temporal trajectories. For example, some Delta and Omicron subtypes did not spread rapidly, while others did. We identified sets of characteristic SNVs that appeared to enhance transmission or decrease efficacy of antibodies for some subtypes. We also identified a set of SNVs that appeared to suppress transmission or increase viral sensitivity to antibodies. For the Omicron variant, the dominant type in the world, we identified the subtypes with enhanced and suppressed transmission in an analysis of eight million genomes as of March 2022 and further confirmed the findings in a later analysis of ten million genomes as of May 2022. While the "enhancer" SNVs exhibited an enriched presence on the spike protein, the "suppressor" SNVs are mainly elsewhere. Disruption of the SNV correlation largely destroyed the enhancer-suppressor phenomena. These results suggest the importance of fine subtyping of variants, and point to potential complex interactions among SNVs.

Conservative Antibiotic Treatment of Pediatric Uncomplicated Appendicitis During Covid-19 Pandemic– a Case Control Study (preprint)

Background Our study aimed to compare the clinical outcomes and cost-efficiency of antibiotic management versus laparoscopic appendectomy for acute uncomplicated appendicitis (AUA) in children during the COVID-19 pandemic when resources were limited and transmission risks uncertain.Method In this prospective case-control study between Apr 2020 to Jan 2022, we analyzed the data of 139 children diagnosed with AUA meeting the following inclusion criteria: symptoms duration of ≤48 hours, appendix diameter ≤11 mm and no appendicolith. 78/139 cases were treated with antibiotics while 61 matched controls underwent upfront laparoscopic appendectomy. Antibiotic regimes were intravenous Ceftriaxone/Metronidazole or Amoxicillin/Clavulanic acid for 48 hours, followed by oral antibiotics to complete total 10-days course.Results 8/78 (10.3%) children had early failure (within 48hours) requiring appendectomy. 17/78 patients (21.8%) experienced late recurrence within mean follow-up time of 16.2±4.7 months. There were no statistical differences in peri-operative complications, negative appendicectomy rate, incidence of perforation and hospitalization duration between antibiotic and surgical treatment groups. Cost per patient in upfront surgical group was significantly higher ($6208.5±5284.0) than antibiotic group ($3588.6±3829.8; p = 0.001).Conclusion Despite 21.9% risk of recurrence of appendicitis in 16.2±4.7 months, antibiotic therapy for AUA appears to be a safe and cost-effective alternative to upfront appendectomy.

A booster dose of Delta × Omicron hybrid mRNA vaccine produced broadly neutralizing antibody against Omicron and other SARS-CoV-2 variants.

BACKGROUND: With the continuous emergence of new SARS-CoV-2 variants that feature increased transmission and immune escape, there is an urgent demand for a better vaccine design that will provide broader neutralizing efficacy. METHODS: We report an mRNA-based vaccine using an engineered "hybrid" receptor binding domain (RBD) that contains all 16 point-mutations shown in the currently prevailing Omicron and Delta variants. RESULTS: A booster dose of hybrid vaccine in mice previously immunized with wild-type RBD vaccine induced high titers of broadly neutralizing antibodies against all tested SARS-CoV-2 variants of concern (VOCs). In naïve mice, hybrid vaccine generated strong Omicron-specific neutralizing antibodies as well as low but significant titers against other VOCs. Hybrid vaccine also elicited CD8+/IFN-γ+ T cell responses against a conserved T cell epitope present in wild type and all VOCs. CONCLUSIONS: These results demonstrate that inclusion of different antigenic mutations from various SARS-CoV-2 variants is a feasible approach to develop cross-protective vaccines.

Air Sampling for Fungus around Hospitalized Patients with Coronavirus Disease 2019.

The risk of developing coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) depends on factors related to the host, virus, and treatment. However, many hospitals have modified their existing rooms and adjusted airflow to protect healthcare workers from aerosolization, which may increase the risk of Aspergillus exposure. This study aimed to quantitatively investigate airborne fungal levels in negative and slightly negative pressure rooms for COVID-19 patients. The air in neutral pressure rooms in ordinary wards and a liver intensive care unit with high-efficiency particulate air filter was also assessed for comparison. We found the highest airborne fungal burden in recently renovated slightly negative air pressure rooms, and a higher airborne fungal concentration in both areas used to treat COVID-19 patients. The result provided evidence of the potential environmental risk of CAPA by quantitative microbiologic air sampling, which was scarcely addressed in the literature. Enhancing environmental infection control measures to minimize exposure to fungal spores should be considered. However, the clinical implications of a periodic basis to determine indoor airborne fungal levels and further air sterilization in these areas remain to be defined.

Considerations for developing and implementing an online community-based exercise intervention with adults living with HIV: a qualitative study.

OBJECTIVES: To describe the need for, and utility of, online community-based exercise (CBE) interventions with adults living with HIV and identify factors to consider in developing and implementing an online CBE intervention with adults living with HIV. DESIGN: Qualitative descriptive study using web-based semistructured interviews. PARTICIPANTS: We recruited adults representing at least one of five stakeholder groups with experience in CBE and/or HIV: (1) adults living with HIV, (2) rehabilitation professionals, (3) fitness personnel, (4) educators with eLearning experience and (5) representatives from HIV community-based organisations (CBOs). DATA COLLECTION: We asked participants to describe their experiences with online CBE, need and utility for online CBE and factors in developing and implementing online CBE interventions. We analysed data using a group-based thematic analytical approach. RESULTS: Among the 11 participants, most had experience working with adults living with HIV (73%) or with telehealth/rehabilitation/coaching in HIV or other chronic conditions (91%). Participants (eight women; two men; one non-binary; median age: 49 years), identified the need and utility for online CBE interventions to increase accessibility and continuity of care with adults living with HIV. Six factors to consider in developing and implementing online CBE included: (1) person-specific considerations (episodic nature of HIV, stigma, HIV disclosure), (2) accessibility of programme (physical space to exercise, reliable internet, access to devices, digital literacy), (3) programme delivery and technology (live vs prerecorded online classes, multiple online platforms for delivery, physical activity tracking, troubleshooting technology), (4) attributes of programme personnel (working with CBOs, relatable instructors, diverse staff), (5) programme content and design (tailored exercise classes, educational sessions) and (6) building community (shared experiences, peer support, social opportunities). CONCLUSIONS: There is a need and utility for online CBE in the context of HIV. Considerations for development and implementation span individual, structural and technical, and community dimensions. Results can inform the future development and implementation of online CBE with adults living with HIV and other chronic episodic conditions.

Vaccinia virus-based vaccines confer protective immunity against SARS-CoV-2 virus in Syrian hamsters.

COVID-19 in humans is caused by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that belongs to the beta family of coronaviruses. SARS-CoV-2 causes severe respiratory illness in 10-15% of infected individuals and mortality in 2-3%. Vaccines are urgently needed to prevent infection and to contain viral spread. Although several mRNA- and adenovirus-based vaccines are highly effective, their dependence on the "cold chain" transportation makes global vaccination a difficult task. In this context, a stable lyophilized vaccine may present certain advantages. Accordingly, establishing additional vaccine platforms remains vital to tackle SARS-CoV-2 and any future variants that may arise. Vaccinia virus (VACV) has been used to eradicate smallpox disease, and several attenuated viral strains with enhanced safety for human applications have been developed. We have generated two candidate SARS-CoV-2 vaccines based on two vaccinia viral strains, MVA and v-NY, that express full-length SARS-CoV-2 spike protein. Whereas MVA is growth-restricted in mammalian cells, the v-NY strain is replication-competent. We demonstrate that both candidate recombinant vaccines induce high titers of neutralizing antibodies in C57BL/6 mice vaccinated according to prime-boost regimens. Furthermore, our vaccination regimens generated TH1-biased immune responses in mice. Most importantly, prime-boost vaccination of a Syrian hamster infection model with MVA-S and v-NY-S protected the hamsters against SARS-CoV-2 infection, supporting that these two vaccines are promising candidates for future development. Finally, our vaccination regimens generated neutralizing antibodies that partially cross-neutralized SARS-CoV-2 variants of concern.

Rapid generation of mouse model for emerging infectious disease with the case of severe COVID-19.

Since the pandemic of COVID-19 has intensely struck human society, small animal model for this infectious disease is in urgent need for basic and pharmaceutical research. Although several COVID-19 animal models have been identified, many of them show either minimal or inadequate pathophysiology after SARS-CoV-2 challenge. Here, we describe a new and versatile strategy to rapidly establish a mouse model for emerging infectious diseases in one month by multi-route, multi-serotype transduction with recombinant adeno-associated virus (AAV) vectors expressing viral receptor. In this study, the proposed approach enables profound and enduring systemic expression of SARS-CoV-2-receptor hACE2 in wild-type mice and renders them vulnerable to SARS-CoV-2 infection. Upon virus challenge, generated AAV/hACE2 mice showed pathophysiology closely mimicking the patients with severe COVID-19. The efficacy of a novel therapeutic antibody cocktail RBD-chAbs for COVID-19 was tested and confirmed by using this AAV/hACE2 mouse model, further demonstrating its successful application in drug development.

CpG-adjuvanted stable prefusion SARS-CoV-2 spike protein protected hamsters from SARS-CoV-2 challenge.

The COVID-19 pandemic presents an unprecedented challenge to global public health. Rapid development and deployment of safe and effective vaccines are imperative to control the pandemic. In the current study, we applied our adjuvanted stable prefusion SARS-CoV-2 spike (S-2P)-based vaccine, MVC-COV1901, to hamster models to demonstrate immunogenicity and protection from virus challenge. Golden Syrian hamsters immunized intramuscularly with two injections of 1 µg or 5 µg of S-2P adjuvanted with CpG 1018 and aluminum hydroxide (alum) were challenged intranasally with SARS-CoV-2. Prior to virus challenge, the vaccine induced high levels of neutralizing antibodies with 10,000-fold higher IgG level and an average of 50-fold higher pseudovirus neutralizing titers in either dose groups than vehicle or adjuvant control groups. Six days after infection, vaccinated hamsters did not display any weight loss associated with infection and had significantly reduced lung pathology and most importantly, lung viral load levels were reduced to lower than detection limit compared to unvaccinated animals. Vaccination with either 1 µg or 5 µg of adjuvanted S-2P produced comparable immunogenicity and protection from infection. This study builds upon our previous results to support the clinical development of MVC-COV1901 as a safe, highly immunogenic, and protective COVID-19 vaccine.

AI detection of mild COVID-19 pneumonia from chest CT scans.

OBJECTIVES: An artificial intelligence model was adopted to identify mild COVID-19 pneumonia from computed tomography (CT) volumes, and its diagnostic performance was then evaluated. METHODS: In this retrospective multicenter study, an atrous convolution-based deep learning model was established for the computer-assisted diagnosis of mild COVID-19 pneumonia. The dataset included 2087 chest CT exams collected from four hospitals between 1 January 2019 and 31 May 2020. The true positive rate, true negative rate, receiver operating characteristic curve, area under the curve (AUC) and convolutional feature map were used to evaluate the model. RESULTS: The proposed deep learning model was trained on 1538 patients and tested on an independent testing cohort of 549 patients. The overall sensitivity was 91.5% (195/213; p < 0.001, 95% CI: 89.2-93.9%), the overall specificity was 90.5% (304/336; p < 0.001, 95% CI: 88.0-92.9%) and the general AUC value was 0.955 (p < 0.001). CONCLUSIONS: A deep learning model can accurately detect COVID-19 and serve as an important supplement to the COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test. KEY POINTS: • The implementation of a deep learning model to identify mild COVID-19 pneumonia was confirmed to be effective and feasible. • The strategy of using a binary code instead of the region of interest label to identify mild COVID-19 pneumonia was verified. • This AI model can assist in the early screening of COVID-19 without interfering with normal clinical examinations.

Analysis of genomic distributions of SARS-CoV-2 reveals a dominant strain type with strong allelic associations.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID 19, continues to evolve since its first emergence in December 2019. Using the complete sequences of 1,932 SARS-CoV-2 genomes, various clustering analyses consistently identified six types of the strains. Independent of the dendrogram construction, 13 signature variations in the form of single nucleotide variations (SNVs) in protein coding regions and one SNV in the 5' untranslated region (UTR) were identified and provided a direct interpretation for the six types (types I to VI). The six types of the strains and their underlying signature SNVs were validated in two subsequent analyses of 6,228 and 38,248 SARS-CoV-2 genomes which became available later. To date, type VI, characterized by the four signature SNVs C241T (5'UTR), C3037T (nsp3 F924F), C14408T (nsp12 P4715L), and A23403G (Spike D614G), with strong allelic associations, has become the dominant type. Since C241T is in the 5' UTR with uncertain significance and the characteristics can be captured by the other three strongly associated SNVs, we focus on the other three. The increasing frequency of the type VI haplotype 3037T-14408T-23403G in the majority of the submitted samples in various countries suggests a possible fitness gain conferred by the type VI signature SNVs. The fact that strains missing one or two of these signature SNVs fail to persist implies possible interactions among these SNVs. Later SNVs such as G28881A, G28882A, and G28883C have emerged with strong allelic associations, forming new subtypes. This study suggests that SNVs may become an important consideration in SARS-CoV-2 classification and surveillance.

Pharmacokinetics and Pharmacodynamics of Vancomycin in Severe COVID-19 Patients: a Preliminary Study in a Chinese Tertiary Hospital (preprint)

Vancomycin plays an important role in the treatment of concurrent infections in severe coronavirus disease 2019 (COVID-19) patients. However, few is known about its pharmacokinetics (PK) in these patients. Here we performed therapeutic drug monitoring (TDM) of intravenous vancomycin with or without nasal administration in these patients. Drug dosage was adjusted depending on vancomycin concentration. A population PK model was developed using NONMEM software. Therapeutic effects, and vancomycin-related adverse events were monitored. A total of 63 samples from 8 patients were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry. The mean trough and peak concentration were 13.79±6.61 (4.63-34.2) mg/L (n=36) and 30.97±9.71 (17-49.9) mg/L (n=27), respectively. 25.4% of serum vancomycin concentration was beyond optimal range. Dose adjustments were made for 3 patients. The PK of vancomycin was consistent with two-compartment model, with the clearance and distribution volume in the central compartment of 4.3 L/h and 2.0 L, respectively. The AUC0-24/MIC of vancomycin was 848±566 h. Target infection was clinically cured in all patients, and no vancomycin-associated nephrotoxicity was detected during the TDM process. In conclusion, the PK studies of vancomycin in COVID-19 patients are needed to optimize drug dosage. Based on our PK model, the clearance of vancomycin was 4.3 L/h. 

Abnormalities of peripheral blood system in patients with COVID-19 in Wenzhou, China.

BACKGROUND: In December 2019, coronavirus disease 2019 (COVID-19) was first found in Wuhan, China and soon was reported all around the world. METHODS: All confirmed cases with COVID-19 in Wenzhou from January 19 to February 20, 2020, were collected and analyzed. Of the 116 patients with COVID-19, 27 were diagnosed as severe cases. Among severe cases, 9 were treated in ICU. The data of blood routine examination were analyzed and compared among common patients (as common group), severe patients admitted to intensive care unit (as severe ICU group) and severe patients not admitted to ICU (as severe non-ICU group). The blood routine examination results were dynamically observed in the above groups after admission. RESULTS: Patients with COVID-19 have lower counts of leucocytes, lymphocytes, eosinophils, platelets, and hemoglobin, but have higher neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR), which were compared with controls (P < 0.001). In severe ICU group, patients have the lowest count of lymphocytes, but the highest neutrophil count and NLR among the above three groups (all P values < 0.05); NLR and MLR indicators were combined for diagnostic efficacy analysis of severe COVID-19, and its area under the curve reached 0.925. The odds ratio of the delay in days to the start of the increase of eosinophil count for predicting the outcome of patients with severe COVID-19 was 2.291 after age adjusted. CONCLUSIONS: Patients with COVID-19 have abnormal peripheral blood routine examination results. Dynamic surveillance of peripheral blood system especially eosinophils is helpful in the prediction of severe COVID-19 cases.