Long-term immune responses in patients with confirmed novel coronavirus disease-2019: a 9-month prospective cohort study in Shanghai, China.

BACKGROUND: The duration of antibodies against SARS-CoV-2 in Covid-19 patients remains uncertain. Longitudinal serological studies are needed to prevent disease and transmission of the virus. METHODS: In 2020, 414 blood samples were tested, obtained from 157 confirmed Covid-19 patients, in a prospective cohort study in Shanghai. RESULTS: The seropositive rate of IgM peaked at 40.5% (17/42) within 1 month after illness onset and then declined. The seropositive rate of IgG was 90.6% (58/64) after 2 months, remained above 85% from 2 to 9 months and was 90.9% (40/44) after 9 months. Generalized estimating equations models suggested that IgM (P < 0.001) but not IgG significantly decreased over time. Age ≥ 40 years (adjusted odds ratio [aOR] 4.531; 95% confidence interval [CI] 1.879-10.932), and cigarette smoking (aOR 0.344; 95% CI 0.124-0.951) were associated with IgG, and age ≥ 40 years (aOR 2.820; 95% CI 1.579-5.036) was associated with IgM. After seroconversion, over 90% and 75.1% of subjects were estimated to remain IgG-positive 220 and 254 days, respectively. Of 1420 self-reported symptoms questionnaires, only 5% reported symptoms 9 months after onset. CONCLUSIONS: In patients with a history of natural infection, anti-SARS-CoV-2 IgG is long-lived, being present for at least 9 months after illness onset. The long duration of natural immunity can mitigate and eliminate Covid-19 and the ongoing pandemic.

Epidemiological and clinical characteristics of 161 discharged cases with coronavirus disease 2019 in Shanghai, China.

BACKGROUND: In December 2019, the outbreak of coronavirus disease 2019 (COVID-19) began in Wuhan, China, and rapidly spread to other regions. We aimed to further describe the epidemiological and clinical characteristics of discharged COVID-19 cases and evaluate the public health interventions. METHODS: We collected epidemiological and clinical data of all discharged COVID-19 cases as of 17 February 2020 in Shanghai. The key epidemiological distributions were estimated and outcomes were also compared between patients whose illness were before 24 January and those whose illness were after 24 January. RESULTS: Of 161 discharged COVID-19 cases, the median age was 45 years, and 80 (49.7%) cases were male. All of the cases were categorized as clinical moderate type. The most common initial symptoms were fever (85.7%), cough (41.0%), fatigue (19.3%), muscle ache (17.4%), sputum production (14.9%), and there were six asymptomatic cases. 39 (24.2%) cases got infected in Shanghai, and three of them were second-generation cases of Shanghai native cases. The estimated median of the time from onset to first medical visit, admission, disease confirmation, and discharge for 161 cases was 1.0 day (95% CI, 0.6-1.2), 2.0 days (95% CI, 1.5-2.6), 5.2 days (95% CI, 4.6-5.7), 18.1 days (95% CI, 17.4-18.8), respectively. The estimated median of the time from admission to discharge was 14.0 days (95% CI, 13.3-14.6). The time from onset to first medical visit, admission and disease confirmation were all shortened after the Shanghai's first-level public health emergency response. In Cox regression model, the significant independent covariates for the duration of hospitalization were age, the time from onset to admission and the first-level public health emergency response. CONCLUSIONS: Local transmission had occurred in Shanghai in late January 2020. The estimated median of the time from onset to discharge of moderate COVID-19 was 18.1 days in Shanghai. Time intervals from onset to first medical visit, admission and disease confirmation were all shortened after the Shanghai's first-level public health emergency response. Age, the first-level public health emergency response and the time from onset to admission were the impact factors for the duration of hospitalization.

Three infection clusters related with potential pre-symptomatic transmission of coronavirus disease (COVID-19), Shanghai, China, January to February 2020.

We report three clusters related with potential pre-symptomatic transmission of coronavirus disease (COVID-19) between January and February 2020 in Shanghai, China. Investigators interviewed suspected COVID-19 cases to collect epidemiological information, including demographic characteristics, illness onset, hospital visits, close contacts, activities' trajectories between 14 days before illness onset and isolation, and exposure histories. Respiratory specimens of suspected cases were collected and tested for SARS-CoV-2 by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) assay. The interval between the onset of illness in the primary case and the last contact of the secondary case with the primary case in our report was 1 to 7 days. In Cluster 1 (five cases), illness onset in the five secondary cases was 2 to 5 days after the last contact with the primary case. In Cluster 2 (five cases) and Cluster 3 (four cases), the illness onset in secondary cases occurred prior to or on the same day as the onset in the primary cases. The study provides empirical evidence for transmission of COVID-19 during the incubation period and indicates that pre-symptomatic person-to-person transmission can occur following sufficient exposure to confirmed COVID-19 cases. The potential pre-symptomatic person-to-person transmission puts forward higher requirements for prevention and control measures.

Avian Influenza A Viruses among Occupationally Exposed Populations, China, 2014-2016.

To determine the seroprevalence and seroconversion of avian influenza virus (AIV) antibodies in poultry workers, we conducted a seroepidemiologic study in 7 areas of China during December 2014-April 2016. We used viral isolation and reverse transcription PCR to detect AIVs in specimens from live poultry markets. We analyzed 2,124 serum samples obtained from 1,407 poultry workers by using hemagglutination inhibition and microneutralization assays. We noted seroprevalence of AIV antibodies for subtypes H9N2, H7N9, H6N1, H5N1-SC29, H5N6, H5N1-SH199, and H6N6. In serum from participants with longitudinal samples, we noted seroconversion, with >4-fold rise in titers, for H9N2, H7N9, H6N1, H5N1-SC29, H6N6, H5N6, and H5N1-SH199 subtypes. We found no evidence of H10N8 subtype. The distribution of AIV antibodies provided evidence of asymptomatic infection. We found that AIV antibody prevalence in live poultry markets correlated with increased risk for H7N9 and H9N2 infection among poultry workers.

Rapid decrease of serum alpha-fetoprotein and tumor volume predicts outcome in children with hepatoblastoma treated with neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy is given to children with unresectable hepatoblastoma to increase the rate and safety of curative complete surgical resection. Elevated levels of serum alpha-fetoprotein (sAFP) decline with tumor shrinkage. In this single-institution retrospective study, we determined early dynamic changes of sAFP levels and tumor volume in children during therapy for unresectable hepatoblastoma. METHODS: We correlated early dynamic changes of sAFP levels and tumor volume and the sum of the longest primary tumor and measurable metastatic disease diameters as per RECIST 1.1 criteria with patient outcome. RESULTS: There were 34 patients, 7 of whom died of disease. Patients with ≥ 90% (≥ 1 log10) decrease in sAFP levels after two chemotherapy courses had a better event-free survival (P = 0.039) and overall survival (OS; P = 0.045) than those with < 90% decrease. During this treatment interval, average tumor volume decreased from 481 mL (± 254 mL) to 268 mL (± 258 mL; P < 0.001) which was associated with OS (P = 0.029). Relative change in sAFP levels or tumor volume in between course 2 and pre-surgery or response as per RECIST 1.1 was not associated with OS. CONCLUSION: Early decline of sAFP levels and tumor volume, but not response as per RECIST 1.1 may predict survival in children with unresectable hepatoblastoma. This finding could be useful to identify therapy non-responders for whom alternative interventions may be required for cure. Confirmation of the finding using larger patient cohorts will be necessary before this strategy is incorporated into prospective trials.

Clusters of Human Infections With Avian Influenza A(H7N9) Virus in China, March 2013 to June 2015.

Multiple clusters of human infections with novel avian influenza A(H7N9) virus have occurred since the virus was first identified in spring 2013. However, in many situations it is unclear whether these clusters result from person-to-person transmission or exposure to a common infectious source. We analyzed the possibility of person-to-person transmission in each cluster and developed a framework to assess the likelihood that person-to-person transmission had occurred. We described 21 clusters with 22 infected contact cases that were identified by the Chinese Center for Disease Control and Prevention from March 2013 through June 2015. Based on detailed epidemiological information and the timing of the contact case patients' exposures to infected persons and to poultry during their potential incubation period, we graded the likelihood of person-to-person transmission as probable, possible, or unlikely. We found that person-to-person transmission probably occurred 12 times and possibly occurred 4 times; it was unlikely in 6 clusters. Probable nosocomial transmission is likely to have occurred in 2 clusters. Limited person-to-person transmission is likely to have occurred on multiple occasions since the H7N9 virus was first identified. However, these transmission events represented a small fraction of all identified cases of H7N9 human infection, and sustained person-to-person transmission was not documented.

A phase II trial evaluating the feasibility of adding bevacizumab to standard osteosarcoma therapy.

Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received two courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab-related targeted toxicity (grade 4 hypertension, proteinuria or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2-4 major wound complications). Thirty-one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4-year event-free survival (EFS) rate and overall survival rate were 57.5 ± 10.0% and 83.4 ± 7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (<5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma.

In-bag enzymatic splenic digestion: a novel alternative to manual morcellation?

BACKGROUND: Contained in-bag spleen morcellation is a conventional extraction technique for safe spleen removal during laparoscopic splenectomy. Existing data for the use of in-bag enzymatic splenic digestion as an alternative to morcellation are lacking. This proof-of-concept study sought to evaluate the effectiveness of single and combinatorial enzyme digestion of murine spleens. MATERIALS AND METHODS: Murine spleens were digested with collagenase alone or with combinations of commercially available enzymes (collagenase, elastase, hyaluronidase, neutral protease) to determine their degradation effect. The primary end point was the percentage of mass reduction at 15 and 30 min. RESULTS: For collagenase alone (n = 15), the mean reduction in mass was 14 ± 10% (range: 2%-31%) at 15 min and 30 ± 25% (range: 7%-100%) at 30 min. Using combinatorial dissolution with collagenase, hyaluronidase, and elastase (n = 8), the mean reduction in mass was 27 ± 16% (range: 6%-42%) at 15 min and 48 ± 27% (range: 3%-100%) at 30 min. Injecting the enzyme solution into whole spleens (n = 9) yielded a mean reduction in mass of 22 ± 13% (range: 9%-42%) at 15 min and 55 ± 31% (range: 9%-100%) at 30 min; mean reduction was 9 ± 13% (range: 0%-39%) at 15 min and 23 ± 13% (range: 3%-53%) with no injection (n = 12). CONCLUSIONS: We provide the first demonstration of successful enzymatic murine spleen digestion as an alternative method for in-bag spleen removal during laparoscopic splenectomy. However, the significant cost and quantities of commercial enzyme required for clinical application dampens the enthusiasm for this novel approach.

Avian influenza virus in pregnancy.

The unprecedented epizootic of avian influenza viruses, such as H5N1, H5N6, H7N1 and H10N8, has continued to cause disease in humans in recent years. In 2013, another novel influenza A (H7N9) virus emerged in China, and 30% of those patients died. Pregnant women are particularly susceptible to avian influenza and are more likely to develop severe complications and to die, especially when infection occurs in the middle and late trimesters. Viremia is believed to occur infrequently, and thus vertical transmission induced by avian influenza appears to be rare. However, avian influenza increases the risk of adverse pregnancy outcomes, including spontaneous abortion, preterm birth and fatal distress. This review summarises 39 cases of pregnant women and their fetuses from different countries dating back to 1997, including 11, 15 and 13 infections with H7N9, H5N1 and the 2009 pandemic influenza (H1N1), respectively. We analysed the epidemic features, following the geographical, population and pregnancy trimester distributions; underlying diseases; exposure history; medical timelines; human-to-human transmission; pathogenicity and vertical transmission; antivirus treatments; maternal severity and mortality and pregnancy outcome. The common experiences reported in different countries and areas suggest that early identification and treatment are imperative. In the future, vigilant virologic and epidemiologic surveillance systems should be developed to monitor avian influenza viruses during pregnancy. Furthermore, extensive study on the immune mechanisms should be conducted, as this will guide safe, rational immunomodulatory treatment among this high-risk population. Most importantly, we should develop a universal avian influenza virus vaccine to prevent outbreaks of the different subtypes. Copyright © 2016 John Wiley & Sons, Ltd.

Comparison of (18) F-FDG-PET-CT and Bone Scintigraphy for Evaluation of Osseous Metastases in Newly Diagnosed and Recurrent Osteosarcoma.

BACKGROUND: Bone scintigraphy (BS) is used to detect osseous metastases in osteosarcoma. (18) F-fluorodeoxyglucose-positron emission tomography-computed tomography ((18) F-FDG-PET-CT) is being increasingly used for staging. We compared the sensitivity, specificity, and diagnostic accuracy of (18) F-FDG-PET-CT and BS for detecting osseous metastases in osteosarcoma. METHODS: We retrospectively reviewed 39 patients with osteosarcoma who had paired PET-CT and BS at diagnosis and/or first recurrence from 2003 to 2012. Imaging studies were reviewed by two pediatric imaging specialists who were blinded to results of the opposing modality and reference standard. Reviewers categorized lesions as benign, malignant, or indeterminate. Reference standard for lesion histology was biopsy or clinical follow-up. Diagnostic performance of PET-CT, BS, and combined modalities were determined. RESULTS: There were 40 examinations from 39 patients and 65 distant lesions were evaluated. Median age was 12 years (range 5-19 years). Four patients had 15 osseous metastases at diagnosis (two biopsied and 13 clinically), and two had five osseous metastases at recurrence (one biopsied and five clinically). For distant sites, sensitivity, specificity, and diagnostic accuracy were 79%, 89% and 86% for PET-CT, 32%, 96%, and 77% for BS, and 95%, 85%, and 88% for PET-CT/BS combined. Sensitivity of PET-CT was superior to BS (P = 0.035); combined imaging modalities were superior to BS (P < 0.001) but not better than PET-CT alone (P = 0.25). Specificity for BS approached significance compared to combined imaging (P = 0.063). Examination-based analysis yielded similar results between individual and combined imaging modalities. CONCLUSIONS: (18) F-FDG-PET-CT demonstrated superior sensitivity over BS for detecting osseous metastases, supporting the use of (18) F-FDG-PET-CT for staging of osteosarcoma.

Feasibility of Pegylated Interferon in Children and Young Adults With Resected High-Risk Melanoma.

BACKGROUND: Pegylated interferon α-2b (IFN α-2b) improves disease-free survival in adults with resected stage III melanoma. We conducted a study to determine the feasibility and safety of incorporating pegylated IFN α-2b as adjuvant therapy in the treatment of children and adolescents with high-risk melanoma. Pharmacokinetic studies of IFN α-2b and neuropsychological and quality of life (OL) assessments were performed. PATIENT AND METHODS: Eligible patients with resected American Joint Committee on Cancer Stage IIC, IIIA, and IIIB cutaneous melanoma received nonpegylated IFN α-2b 20 million units/m(2) /day intravenously 5 days per week for 4 weeks (induction) followed by pegylated IFN α-2b 1 µg/kg/dose weekly subcutaneously (SQ) for 48 weeks (maintenance). RESULTS: Twenty-three patients (15 females, median age 10 years) were enrolled. All patients completed induction therapy; five patients did not complete maintenance therapy either because of recurrent disease (n = 2) or toxicity (n = 3). The most common grade 3 and 4 toxicities of pegylated IFN α-2b were neutropenia (35%) and elevated liver transaminases (17%). The median nonpegylated IFN α-2b AUC0-∞ (5,026 pcg⋅hr/ml) was similar to adults. The median pegylated IFN α-2b exposure (48,480 pcg⋅hr/ml) was greater than the cumulative weekly exposure for nonpegylated IFN α-2b administered SQ three times per week (TIW). Validated measures demonstrated an improvement in QOL scores and no decline in psychological functioning over the course of therapy. CONCLUSIONS: Pegylated IFN α-2b 1 µg/kg/dose SQ weekly as maintenance therapy in children and adolescents with high-risk melanoma is feasible with tolerable toxicity and appears to yield higher exposures than nonpegylated IFN α-2b administered SQ TIW.

Safety and diagnostic accuracy of tumor biopsies in children with cancer.

BACKGROUND: Tumor biopsies are central to the diagnosis and management of cancer and are critical to efforts in personalized medicine and targeted therapeutics. In the current study, the authors sought to evaluate the safety and accuracy of biopsies in children with cancer. METHODS: All biopsies performed in children at the study institution with a suspected or established diagnosis of cancer from 2003 through 2012 were reviewed retrospectively. Patient characteristics and disease-related and procedure-related factors were correlated with procedure-related complications and diagnostic accuracy using logistic regression analysis. RESULTS: A total of 1073 biopsies were performed in 808 patients. Of 1025 biopsies with adequate follow-up, 79 (7.7%) were associated with an adverse event, 35 (3.4%) of which were minor (grade 1-2) and 32 (3.1%) of which were major (grade 3-4) (grading was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The most common major adverse events were blood transfusion (>10 mL/kg; 24 cases) and infection requiring intravenous antibiotics (6 cases). Eleven deaths (1.4%) occurred within 30 days after the procedure, but the procedure may have contributed to the outcome in only 2 cases. A total of 926 biopsies (90.3%) provided definitive histologic diagnoses. Using multivariable analysis, biopsy site, preprocedure hematocrit level, and body mass index were found to be associated with the risk of postprocedural complications (P<.0001, P<.0001, and P =.0029, respectively). Excisional biopsy and biopsy site were found to be independently associated with obtaining a diagnostic result (P =.0002 and P =.0008, respectively). CONCLUSIONS: Tumor biopsies in children with cancer are associated with a low incidence of complications and a high rate of diagnostic accuracy. The predictive factors identified for adverse outcomes may aid in risk assessment and preprocedural counseling.

Comparison of pain outcomes between two anti-GD2 antibodies in patients with neuroblastoma.

BACKGROUND: Addition of anti-GD2 antibody ch14.18 to the treatment of neuroblastoma has improved outcomes. The most common side effect of ch14.18 is neuropathic pain, which may in part be complement-mediated. Hu14.18K322A is a humanized anti-GD2 antibody designed to diminish complement activation and induce less pain. We compare the pain outcomes in patients treated with ch14.18 and those treated with hu14.18K322A, and explore dose-dependent relationships between pain scores, opioid requirements, and complement levels in patients treated with hu14.18K322A. PROCEDURE: Opioid (morphine equivalent mg/kg) and anxiolytic requirements during course 1 (4 days) in patients treated with hu14.18K322A and ch14.18 were reviewed. Correlations between antibody dose and pain scores, opioid requirements, and complement levels were examined for patients receiving hu14.18K322A. RESULTS: Patients treated with hu14.18K322A (n = 19) had lower opioid requirements than those who received ch14.18 (n = 9). The differences in median opioid requirements (mg/kg) were statistically significant for the overall course (1.57 vs. 2.41, P = 0.019) as well as for Days 3 (0.34 vs. 0.65, P = 0.005), and 4 (0.32 vs. 0.64, P = 0.010). No difference in anxiolytic use was observed between the two groups. In the group treated with hu14.18K322A, we found a positive correlation between antibody dose administered and pain scores, but no correlation between antibody dose and opioid requirements or changes in complement levels. CONCLUSIONS: In this retrospective analysis, hu14.18K322A induced less pain than ch14.18 based on opioid requirements. Pediatr Blood Cancer 2015;62:224-228. © 2014 Wiley Periodicals, Inc.

The role of chest computed tomography (CT) as a surveillance tool in children with high-risk neuroblastoma.

BACKGROUND: Standardization of imaging obtained in children with neuroblastoma is not well established. This study examines chest CT in pediatric patients with high-risk neuroblastoma. PROCEDURE: Medical records and imaging from 88 patients with high-risk neuroblastoma, diagnosed at St. Jude Children's Research Hospital between January, 2002 and December, 2009, were reviewed. Surveillance imaging was conducted through 2013. Ten patients with thoracic disease at diagnosis were excluded. Event free survival (EFS) and overall survival (OS) were estimated. Size specific dose estimates for CT scans of the chest, abdomen, and pelvis were used to estimate absolute organ doses to 23 organs. Organ dosimetry was used to calculate cohort effective dose. RESULTS: The 5 year OS and EFS were 51.9% ± 6.5% and 42.6% ± 6.5%, respectively. Forty-six (58.9%) patients progressed/recurred and 41 (52.6%) died of disease. Eleven patients (14%) developed thoracic disease progression/recurrence identified by chest CT (1 paraspinal mass, 1 pulmonary nodules, and 9 nodal). MIBG (metaiodobenzylguanidine) scans identified thoracic disease in six patients. Five of the 11 had normal chest MIBG scans; three were symptomatic and two were asymptomatic with normal chest MIBG scans but avid bone disease. The estimated radiation dose savings from surveillance without CT chest imaging was 42%, 34% when accounting for modern CT acquisition (2011-2013). CONCLUSIONS: Neuroblastoma progression/recurrence in the chest is rare and often presents with symptoms or is identified using standard non-CT imaging modalities. For patients with non-thoracic high-risk neuroblastoma at diagnosis, omission of surveillance chest CT imaging can save 35-42% of the radiation burden without compromising disease detection.

A case report of avian influenza H7N9 killing a young doctor in Shanghai, China.

BACKGROUND: The novel avian influenza H7N9 virus has caused severe diseases in humans in eastern China since the spring of 2013. On January 18(th) 2014, a doctor working in the emergency department of a hospital in Shanghai died of H7N9 virus infection. To understand possible reasons to explain this world's first fatal H7N9 case of a health care worker (HCW), we summarize the clinical presentation, epidemiological investigations, laboratory results, and prevention and control policies and make important recommendations to hospital-related workers. CASE PRESENTATION: The patient was a 31-year-old male Chinese surgeon who was obese and had a five-year history of hypertension and suspected diabetes. On January 11(th) 2014, he showed symptoms of an influenza-like illness. Four days later, his illness rapidly progressed with bilateral pulmonary infiltration, hypoxia and lymphopenia. On January 17th, the case had a high fever, productive cough, chest tightness and shortness of breath, so that he was administered with oseltamivir, glucocorticoid, immunoglobulin, and broad-spectrum antibiotic therapy. The case died in the early morning of next day after invasive ventilation. He had no contact with poultry nor had he visited live-poultry markets (LPMs), where positive rates of H7N9 were 14.6 % and 18.5 %. Before his illness, he cared for three febrile patients and had indirect contact with one severe pneumonia patient. Follow-up with 35 close contacts identified two HCWs who had worked also in emergency department but had not worn masks were anti-H7N9-positive. Viral sequence identity percentages between the patient and two LPM-H7N9 isolates were fewer than between the patient and another human case in shanghai in January of 2014. CONCLUSIONS: Important reasons for the patient's death might include late treatment with oseltamivir, and the infected H7N9 virus carrying both mammalian-adapted signature (HA-Q226L) and aerosol transmissibility (PB2-D701N). The LPM he passed every day was an unlikely source of his infection, but a contaminated environment, or an unidentified mild/asymptomatic H7N9 carrier were more probable. We advocate rigorous standard operating procedures for infection control practices in hospital settings and evaluations thereafter.

VIR-2218 (elebsiran) plus pegylated interferon-alfa-2a in participants with chronic hepatitis B virus infection: a phase 2 study.

BACKGROUND: Chronic hepatitis B virus (HBV) remains a global concern, with current treatments achieving low rates of HBsAg seroclearance. VIR-2218 (elebsiran), a small interfering RNA agent against HBV transcripts, reduces HBsAg concentrations. We aimed to evaluate the safety and antiviral activity of VIR-2218 with and without pegylated interferon-alpha-2a treatment in participants with chronic HBV. METHODS: This open-label, phase 2 study was conducted at 23 sites in six countries (New Zealand, Australia, Hong Kong, Thailand, South Korea, and Malaysia). Adults (aged 18-65 years) with chronic HBV infection without cirrhosis and with HBsAg more than 50 IU/mL and HBV DNA less than 90 IU/mL who were on continued nucleoside or nucleotide reverse transcriptase inhibitor (NRTI) therapy for 2 months or longer were eligible. Participants were enrolled into one of six cohorts to receive VIR-2218 200 mg subcutaneously every 4 weeks, with or without 180 µg subcutaneous pegylated interferon-alfa-2a once per week. Cohort 1 received six doses of VIR-2218 (total 20 weeks); cohort 2 received six doses of VIR-2218 starting at day 1, plus 12 doses of pegylated interferon-alfa-2a starting at week 12 (total 24 weeks); cohort 3 received six doses of VIR-2218 and 24 doses of pegylated interferon-alfa-2a (total 24 weeks); cohort 4 received six doses of VIR-2218 and up to 48 doses of pegylated interferon-alfa-2a (total 48 weeks); cohort 5 received up to 13 doses of VIR-2218 and up to 44 doses of pegylated interferon-alfa-2a (total 48 weeks); and cohort 6 received three doses of VIR-2218 and 12 doses of pegylated interferon-alfa-2a (total 12 weeks). The primary endpoints were the incidence of adverse events and clinical assessments (including results of laboratory tests). Secondary endpoints were the mean maximum reduction of serum HBsAg at any timepoint; the proportion of participants with serum HBsAg seroclearance at any timepoint and for more than 6 months after the end of treatment; and the proportion of participants with anti-HBs seroconversion at any timepoint. For patients who were HBeAg-positive, we also assessed the proportion with HBeAg seroclearance or anti-HBe seroconversion at any timepoint. This study is registered with ClinicalTrials.gov, NCT03672188, and is ongoing. FINDINGS: Between July 2, 2020, and Nov 2, 2021, 124 individuals were screened for eligibility, 84 of whom were enrolled (15 in cohort 1, 15 in cohort 2, 18 in cohort 3, 18 in cohort 4, 13 in cohort 5, and five in cohort 6). Participants were predominantly HBeAg-negative, Asian, and male (66 [79%] participants were male and 18 [21%] were female). Most treatment emergent adverse events were grades 1-2. Three (20%) participants in cohort 1, four (27%) in cohort 2, eight (44%) in cohort 3, seven (39%) in cohort 4, six (46%) in cohort 5, and two (40%) in cohort 6 reported treatment-emergent adverse events related to VIR-2218. 12 (80%) participants in cohort 2, 12 (67%) in cohort 3, 14 (78%) in cohort 4, 13 (100%) in cohort 5, and three (60%) in cohort 6 reported treatment-emergent adverse events related to pegylated interferon-alfa-2a. Two (13%) participants in cohort 1 had elevations in alanine aminotransferase, compared with 13 (87%) participants in cohort 2, 15 (83%) in cohort 3, 17 (94%) in cohort 4, 11 (85%) in cohort 5, and three (60%) in cohort 6. The mean maximum change from baseline at any timepoint in HBsAg concentration was -2·0 log10 IU/mL (95% CI -2·1 to -1·8) in cohort 1, -2·2 log10 IU/mL (-2·5 to -1·8) in cohort 2, -2·5 log10 IU/mL (-2·8 to -2·1) in cohort 3, -2·4 log10 IU/mL (-3·1 to -1·8) in cohort 4, -3·0 log10 IU/mL (-3·7 to -2·3) in cohort 5, and -1·7 log10 IU/mL (-2·1 to -1·4) in cohort 6. 11 participants (one in cohort 2, one in cohort 3, five in cohort 4, and four in cohort 5) receiving VIR-2218 plus pegylated interferon-alfa-2a had HBsAg seroclearance at any timepoint. Of these, ten (91%; one in cohort 2, five in cohort 4, and four in cohort 5) had anti-HBs seropositivity. Six participants (one in cohort 2, three in cohort 4, and two in cohort 5) had sustained HBsAg seroclearance through to 24 weeks after the end of treatment. No participants receiving VIR-2218 monotherapy (cohort 1) or VIR-2218 plus pegylated interferon-alfa-2a 12-week regimen (cohort 6) had HBsAg seroclearance. 12 (42%) of 26 participants (one of four in cohort 1, two of six in cohort 2, four of seven in cohort 3, four of six in cohort 4, and one of three in cohort 5) who were HBeAg positive at baseline had HBeAg seroclearance or anti-HBe seroconversion. INTERPRETATION: The results of this phase 2 study support further development of VIR-2218 as a potential therapy for patients with chronic HBV infection. Additional clinical trials of VIR-2218 with and without pegylated interferon-alfa-2a in combination with an HBsAg-targeting monoclonal antibody are ongoing. FUNDING: Vir Biotechnology.

Relationship of close contact settings with transmission and infection during the SARS-CoV-2 Omicron BA.2 epidemic in Shanghai.

INTRODUCTION: We analysed case-contact clusters during the Omicron BA.2 epidemic in Shanghai to assess the risk of infection of contacts in different settings and to evaluate the effect of demographic factors on the association of infectivity and susceptibility to the Omicron variant. METHODS: Data on the settings and frequency of contact, demographic characteristics and comorbidities of index cases, contacts and secondary cases were analysed. Independent effect of multiple variables on the risk for transmission and infection was evaluated using generalised estimating equations. RESULTS: From 1 March to 1 June 2022, we identified 450 770 close contacts of 90 885 index cases. The risk for infection was greater for contacts in farmers' markets (fixed locations where farmers gather to sell products, adjusted OR (aOR): 3.62; 95% CI 2.87 to 4.55) and households (aOR: 2.68; 95% CI 2.15 to 3.35). Children (0-4 years) and elderly adults (60 years and above) had higher risk for infection and transmission. During the course of the epidemic, the risk for infection and transmission in different age groups initially increased, and then decreased on about 21 April (17th day of citywide home quarantine). Compared with medical workers (reference, aOR: 1.00), unemployed contacts (aOR: 1.77; 95% CI 1.53 to 2.04) and preschoolers (aOR: 1.61; 95% CI 1.26 to 2.05) had the highest risk for infection; delivery workers (aOR: 1.90, 95% CI 1.51 to 2.40) and public service workers (aOR: 1.85; 95% CI 1.64 to 2.10) had the highest risk for transmission. Contacts who had comorbidities (aOR: 1.10; 95% CI 1.09 to 1.12) had a higher risk for infection, particularly those with lung diseases or immune deficiency. CONCLUSION: Farmers' markets and households were the main setting for transmission of Omicron. Children, the elderly, delivery workers and public service workers had the highest risk for transmission and infection. These findings should be considered when implementing targeted interventions.

Clusters of 2019 coronavirus disease (COVID-19) cases in Chinese tour groups.

International travel may facilitate the spread of the novel coronavirus disease (COVID-19). The study describes clusters of COVID-19 cases within Chinese tour groups travelling in Europe January 16-28. We compared characteristics of cases and non-cases to determine transmission dynamics. The index case travelled from Wuhan, China, to Europe on 16 January 2020, and to Shanghai, China, on 27 January 2020, within a tour group (group A). Tour groups with the same outbound flight (group B) or the same tourism venue (group D) and all Chinese passengers on the inbound flight (group C) were investigated. The outbreak involved 11 confirmed cases, 10 suspected cases and six tourists who remained healthy. Group A, involving seven confirmed cases and six suspected cases, consisted of familial transmission followed by propagative transmission. There was less pathogenicity with propagative transmission than with familial transmission. Disease was transmitted in shared outbound flights, shopping venues within Europe and inbound flight back to China. The novel coronavirus caused clustered cases of COVID-19 in tour groups. When tourism and travel opens up, governments will need to improve screening at airports and consider increased surveillance of tour groups-particularly those with older tour members.

Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours.

BACKGROUND: Angiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours. METHODS: An expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m2 po twice daily, days 1-21) and low-dose cyclophosphamide (50 mg/m2 po daily, days 1-21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1. RESULTS: Twenty-four patients (15 males; median age 14.5 yrs; range 1-22 yr) received a median of 6 courses (range 1-18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6-95.6%) and 54% (95% CI 30.2-78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results. CONCLUSIONS: Intravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours.

Epidemiological and clinical characteristics of 333 confirmed cases with coronavirus disease 2019 in Shanghai, China.

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease first identified in Wuhan City, Hubei Province, China. As of 19 February 2020, there had been 333 confirmed cases reported in Shanghai, China. This study elaborates on the epidemiological and clinical characteristics of COVID-19 based on a descriptive study of the 333 patients infected with COVID-19 in Shanghai for the purpose of probing into this new disease and providing reference. Among the 333 confirmed cases in Shanghai, 172 (51.7%) were males and 161 (48.3%) were females, with a median age of 50 years. 299 (89.8%) cases presented mild symptoms. 139 (41.7%) and 111 (33.3%) cases were infected in Wuhan and Shanghai, respectively. 148 (44.4%) cases once had contact with confirmed cases before onset, while 103 (30.9%) cases had never contacted confirmed cases but they had a sojourn history in Wuhan. The onset date of the first case in Shanghai was 28 December, with the peak appearing on 27 January. The median incubation period of COVID-19 was estimated to be 7.2 days. 207 (62.2%) cases had fever symptoms at the onset, whereas 273 (82.0%) cases experienced fever before hospitalization. 56 (18.6%) adults experienced a decrease in white blood cell and 84 (42.9%) had increased C-reactive protein after onset. Elderly, male and heart disease history were risk factors for severe or critical pneumonia. These findings suggest that most cases experienced fever symptoms and had mild pneumonia. Strengthening the health management of elderly men, especially those with underlying diseases, may help reduce the incidence of severe and critical pneumonia. Time intervals from onset to visit, hospitalization and diagnosis confirmed were all shortened after Shanghai's first-level public health emergency response. Shanghai's experience proves that COVID-19 can be controlled well in megacities.