Twenty years' experience of midgut malrotation and volvulus in a tertiary center in northern Taiwan: A retrospective study.

BACKGROUND: Early diagnosis and surgical intervention for midgut malrotation with bowel obstruction are crucial. We aimed to identify risk factors for adverse outcomes in infants with midgut malrotation and to develop a prediction model. METHODS: We reviewed the operation records of infants surgically diagnosed with midgut malrotation at Chang Gung Children's Medical Center between January 2000 and December 2020. Patients were classified into the poor-outcome group (PO) if they underwent bowel resection or experienced mortality; all others were categorized as the favorable-outcome group (FO). Data on demographics, initial presentations, laboratory results, radiographic or sonographic findings, maternal conditions, and outcomes were collected and analyzed. Fisher's exact test, the independent sample t-test, and the Mann-Whitney test were utilized for comparative analysis when suitable. RESULTS: The study included 103 infants. Eleven were in the PO group, and 92 were in the FO group. Initial presentations such as respiratory distress, poor activity, and shock status were notably more prevalent in the PO group. The INR, hemoglobin, HCO3, base excess, and aspartate transaminase values showed significant variation between the two groups. Multivariate analysis identified that lower hemoglobin (OR 0.677, p = 0.043) and higher AST (OR 1.036, p = 0.044) were independent predictors of adverse outcomes. An AST/Hb ratio of <3.78 demonstrated a high negative predictive value (98.6%) for an adverse outcome in midgut malrotation. CONCLUSIONS: Prompt diagnosis and surgical treatment of midgut malrotation are vital to prevent bowel resection or mortality. The independent predicting factors for poor outcomes include low hemoglobin and elevated AST levels.

Corrigendum: Unraveling the interplay between norovirus infection, gut microbiota, and novel antiviral approaches: a comprehensive review.

[This corrects the article DOI: 10.3389/fmicb.2023.1212582.].

Assessment of the detection accuracy of SARS-CoV-2 rapid antigen test in children and adolescents: An updated meta-analysis.

BACKGROUND: Real-time and appropriate antigen tests play a pivotal role in preventing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, a previous meta-analysis reported that the antigen test had lower sensitivity for the detection of SARS-CoV-2 in children. To provide a comprehensive evaluation of diagnostic efficiency, we performed an updated meta-analysis to assess the detection accuracy of SARS-CoV-2 antigen tests stratified by days after symptom onset and specimen type in children and adolescents. METHODS: We comprehensively searched for appropriate studies in the PubMed, Embase, and Cochrane Library databases. Studies on the diagnostic accuracy of antigen tests for SARS-CoV-2 in children and adolescents were included. The relevant data of the included studies were extracted to construct a 2 × 2 table on a per-patient basis. The overall sensitivity and specificity of the SARS-CoV-2 antigen tests were estimated using a bivariate random-effects model. RESULTS: Seventeen studies enrolling 10 912 patients were included in the present meta-analysis. For the detection accuracy of SARS-CoV-2 antigen tests, the meta-analysis generated a pooled sensitivity of 77.9% (95% confidence interval [CI]: 67.3%-85.8%) and a pooled specificity of 99.6% (95% CI: 98.9%-99.8%). The subgroup analysis of studies that examined antigen tests in symptomatic participants ≦7 days after symptom onset generated a pooled sensitivity of 79.4% (95% CI: 47.6%-94.2%) and a pooled specificity of 99.4% (95% CI: 98.2%-99.8%). Another subgroup analysis of studies that evaluated nasal swab specimens demonstrated a pooled sensitivity of 80.1% (95% CI: 65.0%-89.7%) and a pooled specificity of 98.5% (95% CI: 97.3%-9.2%). CONCLUSION: Our findings demonstrated that the antigen test performed using nasal swab specimens exhibited high sensitivity for the detection of SARS-CoV-2 within 7 days after symptom onset. Therefore, antigen testing using nasal swabs may be effective in blocking SARS-CoV-2 transmission in children.

Unraveling the interplay between norovirus infection, gut microbiota, and novel antiviral approaches: a comprehensive review.

Norovirus infection is a leading cause of acute gastroenteritis worldwide and can also cause harmful chronic infections in individuals with weakened immune systems. The role of the gut microbiota in the interactions between the host and noroviruses has been extensively studied. While most past studies were conducted in vitro or focused on murine noroviruses, recent research has expanded to human noroviruses using in vivo or ex vivo human intestinal enteroids culture studies. The gut microbiota has been observed to have both promoting and inhibiting effects on human noroviruses. Understanding the interaction between noroviruses and the gut microbiota or probiotics is crucial for studying the pathogenesis of norovirus infection and its potential implications, including probiotics and vaccines for infection control. Recently, several clinical trials of probiotics and norovirus vaccines have also been published. Therefore, in this review, we discuss the current understanding and recent updates on the interactions between noroviruses and gut microbiota, including the impact of norovirus on the microbiota profile, pro-viral and antiviral effects of microbiota on norovirus infection, the use of probiotics for treating norovirus infections, and human norovirus vaccine development.

Molecular and Genetics-Based Systems for Tracing the Evolution and Exploring the Mechanisms of Human Norovirus Infections.

Human noroviruses (HuNoV) are major causes of acute gastroenteritis around the world. The high mutation rate and recombination potential of noroviruses are significant challenges in studying the genetic diversity and evolution pattern of novel strains. In this review, we describe recent advances in the development of technologies for not only the detection but also the analysis of complete genome sequences of noroviruses and the future prospects of detection methods for tracing the evolution and genetic diversity of human noroviruses. The mechanisms of HuNoV infection and the development of antiviral drugs have been hampered by failure to develop the infectious virus in a cell model. However, recent studies have demonstrated the potential of reverse genetics for the recovery and generation of infectious viral particles, suggesting the utility of this genetics-based system as an alternative for studying the mechanisms of viral infection, such as cell entry and replication.

Viral Pneumonia during the COVID-19 Pandemic, 2019-2021 Evoking Needs for SARS-CoV-2 and Additional Vaccinations.

Coronaviruses can cause pneumonia, with clinical symptoms that may be similar to the symptoms of other viral pneumonias. To our knowledge, there have been no reports regarding cases of pneumonia caused by coronaviruses and other viruses among hospitalized patients in the past 3 years before and during coronavirus disease 2019 (COVID-19). Here, we analysed the causes of viral pneumonia among hospitalized patients during the coronavirus disease 2019 (COVID-19) pandemic (2019-2021). Between September 2019 and April 2021, patients hospitalized at Shuang Ho Hospital in north Taiwan with a diagnosis of pneumonia were enrolled in this study. Age, sex, onset date, and season of occurrence were recorded. Respiratory tract pathogens were identified with molecular detection using the FilmArray® platform from nasopharyngeal swabs. In total, 1147 patients (128 patients aged <18 years and 1019 patients aged ≥18 years) with pneumonia and identified respiratory tract pathogens were assessed. Among the 128 children with pneumonia, the dominant viral respiratory pathogen was rhinovirus (24.2%), followed by respiratory syncytial virus (RSV; 22.7%), parainfluenza virus (1 + 2 + 3 + 4) (17.2%), adenovirus (12.5%), metapneumovirus (9.4%), coronavirus (1.6%), and influenza virus (A + B) (1.6%). Among the 1019 adults with pneumonia, the dominant viral respiratory pathogen was rhinovirus (5.0%), followed by RSV (2.0%), coronavirus (2.0%), metapneumovirus (1.5%), parainfluenza virus (1 + 2 + 3 + 4) (1.1%), adenovirus (0.7%), and influenza virus (A + B) (0%). From 2019-2021, older patients (aged >65 years) with pneumonia tested positive for coronavirus most commonly in autumn. Coronavirus was not detected during summer in children or adults. Among children aged 0-6 years, RSV was the most common viral pathogen, and RSV infection occurred most often in autumn. Metapneumovirus infection occurred most often in spring in both children and adults. In contrast, influenza virus was not detected in patients with pneumonia in any season among children or adults from January 2020 to April 2021. Among all patients with pneumonia, the most common viral pathogens were rhinovirus in spring, adenovirus and rhinovirus in summer, RSV and rhinovirus in autumn, and parainfluenza virus in winter. Among children aged 0-6 years, RSV, rhinovirus, and adenovirus were detected in all seasons during the study period. In conclusion, the proportion of pneumonia cases caused by a viral pathogen was higher in children than the proportion in adults. The COVID-19 pandemic period evoked a need for SARS-CoV-2 (severe acute respiratory disease coronavirus 2) vaccination to prevent the severe complications of COVID-19. However, other viruses were also found. Vaccines for influenza were clinically applied. Active vaccines for other viral pathogens such as RSV, rhinovirus, metapneuomoccus, parainfluenza, and adenovirus may need to be developed for special groups in the future.

The Health Care Utilization and Medical Costs in Long-Term Follow-Up of Children Diagnosed With Leukemia, Solid Tumor, or Brain Tumor: Population-Based Study Using the National Health Insurance Claims Data.

BACKGROUND: Childhood cancer survivors are at a high risk of medical consequences of their disease and treatment. There is growing information about the long-term health issues of childhood cancer survivors; however, there are very few studies describing the health care utilization and costs for this unique population. Understanding their utilization of health care services and costs will provide the basis for developing strategies to better serve these individuals and potentially reduce the cost. OBJECTIVE: This study aims to determine the utilization of health services and costs for long-term survivors of childhood cancer in Taiwan. METHODS: This is a nationwide, population-based, retrospective case-control study. We analyzed the claims data of the National Health Insurance that covers 99% of the Taiwanese population of 25.68 million. A total of 33,105 children had survived for at least 5 years after the first appearance of a diagnostic code of cancer or a benign brain tumor before the age of 18 years from 2000 to 2010 with follow-up to 2015. An age- and gender-matched control group of 64,754 individuals with no cancer was randomly selected for comparison. Utilization was compared between the cancer and no cancer groups by χ2 test. The annual medical expense was compared by the Mann-Whitney U test and Kruskal-Wallis rank-sum test. RESULTS: At a median follow-up of 7 years, childhood cancer survivors utilized a significantly higher proportion of medical center, regional hospital, inpatient, and emergency services in contrast to no cancer individuals: 57.92% (19,174/33,105) versus 44.51% (28,825/64,754), 90.66% (30,014/33,105) versus 85.70% (55,493/64,754), 27.19% (9000/33,105) versus 20.31% (13,152/64,754), and 65.26% (21,604/33,105) versus 59.36% (38,441/64,754), respectively (all P<.001). The annual total expense (median, interquartile range) of childhood cancer survivors was significantly higher than that of the comparison group (US $285.56, US $161.78-US $535.80 per year vs US $203.90, US $118.98-US $347.55 per year; P<.001). Survivors with female gender, diagnosis before the age of 3 years, and diagnosis of brain cancer or a benign brain tumor had significantly higher annual outpatient expenses (all P<.001). Moreover, the analysis of outpatient medication costs showed that hormonal and neurological medications comprised the 2 largest costs in brain cancer and benign brain tumor survivors. CONCLUSIONS: Survivors of childhood cancer and a benign brain tumor had higher utilization of advanced health resources and higher costs of care. The design of the initial treatment plan minimizing long-term consequences, early intervention strategies, and survivorship programs have the potential to mitigate costs of late effects due to childhood cancer and its treatment.

A Systematic Review and Meta-Analysis of Randomized Controlled Trials of the Effects of Vitamin D Supplementation on Children and Young Adults with HIV Infection.

BACKGROUND: Children and young adults with HIV infection may exhibit vitamin D deficiency, which is harmful to bone health as well as the endocrine and immune systems. OBJECTIVES: This study sought to investigate the effect of vitamin D supplementation on children and young adults with HIV infection. METHODS: The PubMed, Embase, and Cochrane databases were searched. Randomized controlled trials that have evaluated the effects of vitamin D supplementation (ergocalciferol or cholecalciferol) at any dose or for any duration in children and young adults with HIV infection, aged 0-25 y, were included. A random-effects model was used, and the standardized mean difference (SMD) and 95% CI were calculated. RESULTS: Ten trials, with 21 publications and 966 participants (mean age: 17.9 y), were included in the meta-analysis. The supplementation dose and the duration of the studies included ranged from 400 to 7000 IU/d and from 6 to 24 mo, respectively. Vitamin D supplementation was associated with a significantly higher serum 25(OH)D concentration at 12 mo (SMD: 1.14; 95% CI: 0.64, 1.65; P < 0.00001) compared with a placebo. No significant difference was observed in spine BMD (SMD: -0.09; 95% CI: -0.47, 0.3; P = 0.65) at 12 mo between these 2 groups. However, participants who received higher doses (1600-4000 IU/d) had significantly higher total BMD (SMD: 0.23; 95% CI: 0.02, 0.44; P = 0.03) and nonsignificantly higher spine BMD (SMD: 0.3; 95% CI: -0.02, 0.61; P = 0.07) at 12 mo compared with those who received standard doses (400-800 IU/d). CONCLUSIONS: Vitamin D supplementation in children and young adults with HIV infection increases the serum 25(OH)D concentration. A relatively high daily dose of vitamin D (1600-4000 IU) improves total BMD at 12 mo and results in sufficient 25(OH)D concentrations.

Diagnostic accuracy of SARS-CoV-2 antigen test in the pediatric population: A systematic review and meta-analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused the global coronavirus disease 2019 (COVID-19) pandemic. Rapid identification and isolation of patients infected with SARS-CoV-2 are critical methods for blocking COVID-19 transmission. The advantages of antigen tests, such as their relatively low cost and short turnaround time, can contribute to the prompt identification of infectious individuals. However, the diagnostic accuracy of antigen tests for COVID-19 in children remains inconclusive. This meta-analysis aimed to evaluate the diagnostic performance of antigen tests for SARS-CoV-2 in the pediatric population. METHODS: We conducted a literature search for relevant studies in the PubMed, Embase, Google Scholar, and Biomed Central databases. Studies evaluating the diagnostic accuracy of antigen tests for SARS-CoV-2 in pediatric patients were included. In addition, we included studies that provided sufficient data to construct a 2 × 2 table on a per-patient basis. The final literature search was performed on October 10, 2021. Days after symptom onset, asymptomatic and symptomatic individuals may have been potential sources of heterogeneity. The overall sensitivity and specificity of the antigen tests were generated using a bivariate random-effects model. RESULTS: Five studies with 4400 participants were included. The meta-analysis of antigen tests generated a pooled sensitivity of 65.9% (95% CI: 52.8%-77.0%) and pooled specificity of 99.9% (95% CI: 98.9%-100.0%). A subgroup analysis of studies reporting antigen test data for symptomatic patients showed a pooled sensitivity of 64.5% and a pooled specificity of 99.7%. The subgroup analysis of studies that included 881 asymptomatic participants generated a pooled sensitivity of 48.4% and a pooled specificity of 99.5%. CONCLUSION: Antigen tests exhibit moderate sensitivity and high specificity for detecting SARS-CoV-2 in children. Antigen tests might have moderate sensitivity for detecting SARS-CoV-2 in symptomatic children, and serial testing might effectively prevent further SARS-CoV-2 transmission.

Clinical features and characteristics of pediatric patients with COVID-19 infection: Experiences in a Tertiary Taiwan Hospital.

Coronavirus disease 2019 (COVID-19) patients have distinct clinical features in the pediatric groups. However, there is a paucity of research focused on clinical manifestation within pediatric group in Taiwan. This study is to conduct a retrospective study of the clinical features of COVID-19 in Taiwan pediatric patients. A retrospective study was conducted on pediatric patients (Aged ≤ 18 years) in a Northern Taiwan hospital from May 1st, 2021 to June 30th, 2021. Thirty-eight patients were included from emergency room. They were laboratory confirmed COVID-19 through specimens from nasopharyngeal swab by real-time reverse-transcription polymerase chain reaction (RT-PCR). Data including RT-PCR cycle threshold (Ct) values, clinical and epidemiological features were collected and analyzed. Thirty-eight patients aged from 7-month to 18-year-old were included. The median age of patients was 15-year-old. The patients had sex ratio of 23 males to 15 females. More than half patients were infected from family members. Asymptomatic patients were 47.37%. In the symptomatic patients, fever (34.21%) was the most predominant symptom. Cough, nasal obstruction and sore throat were also common. Asymptomatic children had significantly higher Ct-values than symptomatic children, and diagnosed patients with Ct-values more than 19 were associated with asymptomatic infection (P = .0084). Ct-values higher than 19 were associated with asymptomatic infection, which may be a predictor of pediatric disease severity. Our results highlight the distinct clinical manifestations and outcomes in pediatric COVID-19 patients. Compared to the adults, pediatric patients aged ≤ 18 years with COVID-19 in Taiwan mainly had mild disease.

Validation of a point-of-need diagnostic tool for rapid diagnosis of norovirus gastroenteritis.

BACKGROUND: The genogroups GI and GII of norovirus (NoV) ribonucleic acid (RNA) genetic variants are the most prevalent cause of acute gastroenteritis outbreaks, especially in children, worldwide. A fast, accurate and convenient tool for diagnosis of NoV may be preferable to the more complicated performance of real-time reverse transcription-polymerase chain reaction (RT-PCR). METHODS: In this study, we developed and evaluated a tool using insulated isothermal PCR (iiPCR)-mediated POCKIT Central NoV GI and NoV GII assay systems for diagnosis of NoV infection in pediatric patients suspected with gastroenteritis. RESULTS: Performance of POCKIT Central Norovirus GI and GII assays using RT-iiPCR, compared to regular real-time RT-PCR showed the same diagnosis rate to NoV GI (100% of total percent agreement and 1.0 of Cohen's kappa value) and a similar detection rate to norovirus GII (96.3% of total percent agreement and 0.92 of Cohen's kappa value). In exclusivity tests, the POCKIT Central NoV GI and GII assays showed negative results to other viruses, indicating that the assays may be a NoV-specific detection tool. CONCLUSION: POCKIT Central NoV GI and GII Assay systems can provide a simple, rapid, sensitive, and specific point-of-need diagnostic tool for the detection of NoV GI and GII RNAs in clinical specimens from children with acute gastroenteritis.

Clinical significance and intestinal microbiota composition in immunocompromised children with norovirus gastroenteritis.

BACKGROUND: Norovirus (NoV) infection is common in pediatric patients with immunodeficiency and is more likely to cause severe disease. Objective Our study aims to figure out the clinical differences and distribution of intestinal microbiota in immunocompromised children with NoV gastroenteritis. METHODS: Pediatric patients admitted to Shang-Ho Hospital with diagnosis of acute gastroenteritis including different immune status were enrolled and their medical records were reviewed. NoV gastroenteritis was validated using RT-PCR molecular methods. Viral shedding period was determined by real-time RT-PCR assays. Intestinal microbiota enrichment analysis was carried out by next generation sequencing after fecal DNA extraction and subsequent Linear Discriminant Analysis (LDA) Effect Size (LEfSe) method. RESULTS: Significantly higher frequency of diarrhea [mean, (IQR), 3.8 (3-5) /day] and longer viral shedding time [mean, IQR, 8.5 (5-13) days] was found in immunocompromised NoV infections than in immunocompetent patients without NoV infections (p = 0.013*) and immunocompetent patients with NoV infections (p = 0.030**). The fever prevalence was significantly lower in immunocompromised NoV infections than in different immune or infection status. Intestinal microbiota metagenomics analysis showed no significant community richness difference while the LEfSe analysis showed a significant difference in commensal richness at the phylum level, the family level, and the genus level in patients under different immune status. CONCLUSION: We evaluated the clinical significances and microbiota composition in immunocompromised children with norovirus gastroenteritis. This will further facilitate studies of the interaction between the intestinal microbiota in such patients with precise determination of their bacterial infection control and probiotic supplements strategy.

Epidemiology, Clinical Features, and Unusual Complications of Norovirus Infection in Taiwan: What We Know after Rotavirus Vaccines.

Noroviruses (NoVs) are one of the emerging and rapidly spreading groups of pathogens threatening human health. A reduction in sporadic NoV infections was noted following the start of the COVID-19 pandemic, but the return of NoV gastroenteritis during the COVID-19 pandemic has been noted recently. Research in recent years has shown that different virus strains are associated with different clinical characteristics; moreover, there is a paucity of research into extraintestinal or unusual complications that may be associated with NoV. The genomic diversity of circulating NoVs is also complex and may vary significantly. Therefore, this short narrative review focuses on sharing the Taiwan experience of NoV infection including epidemiology, clinical features, and complications following suboptimal rotavirus immunization in Taiwan (after October 2006). We also highlight the unusual complications associated with NoV infections and the impacts of NoV infection during the COVID-19 pandemic in the literature for possible future research directions. To conclude, further research is needed to quantify the burden of NoV across the spectrum of disease severity in Taiwan. The evidence of the connection between NoV and the unusual complications is still lacking.

The Human Virome: Viral Metagenomics, Relations with Human Diseases, and Therapeutic Applications.

The human body is colonized by a wide range of microorganisms. The field of viromics has expanded since the first reports on the detection of viruses via metagenomic sequencing in 2002. With the continued development of reference materials and databases, viral metagenomic approaches have been used to explore known components of the virome and discover new viruses from various types of samples. The virome has attracted substantial interest since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic. Increasing numbers of studies and review articles have documented the diverse virome in various sites in the human body, as well as interactions between the human host and the virome with regard to health and disease. However, there have been few studies of direct causal relationships. Viral metagenomic analyses often lack standard references and are potentially subject to bias. Moreover, most virome-related review articles have focused on the gut virome and did not investigate the roles of the virome in other sites of the body in human disease. This review presents an overview of viral metagenomics, with updates regarding the relations between alterations in the human virome and the pathogenesis of human diseases, recent findings related to COVID-19, and therapeutic applications related to the human virome.

The optimal strategy for pertussis vaccination: a systematic review and meta-analysis of randomized control trials and real-world data.

OBJECTIVE: Severe pertussis infection has been reported in infants before receiving routine immunization series. This problem could be solved by vaccinating mothers during pregnancy or children at birth. This study aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) and real-world evidence to evaluate the optimal strategy for pertussis vaccination. DATA SOURCES: PubMed, Embase, and the Cochrane Library databases were searched until December 2020. STUDY ELIGIBILITY CRITERIA: RCTs, cohort studies, case-control studies, and case series were included if they investigated the efficacy, immunogenicity, and safety of acellular pertussis vaccine during pregnancy and at birth. METHODS: Number of pertussis cases, severe adverse events (SAEs), and pertussis antibody concentration in infants before and after they receive routine vaccination series were extracted and random-effect model was used to pool the analyses. RESULTS: Overall, 29 studies were included. Our meta-analysis revealed that pertussis immunization during pregnancy significantly increased the concentrations of 3 pertussis antibodies and reduced the incidence rates of infected infants below 3 months of age (odds ratio, 0.22; 95% confidence interval, 0.14-0.33). Similarly, infants vaccinated at birth had higher levels of pertussis antibody than those who were not. No significant difference in rates of severe adverse events was seen in all vaccination groups (during pregnancy [risk ratio, 1.18; 95% confidence interval, 0.76-1.82] and at birth [risk ratio, 0.72; 95% confidence interval, 0.34-1.54]). CONCLUSION: Pertussis vaccination during pregnancy could protect infants against pertussis disease before the routine vaccination. Pertussis immunization at birth would be an alternative for infants whose mothers did not receive pertussis vaccines during pregnancy.

Clinical and virological characteristics of viral shedding in children with norovirus gastroenteritis.

BACKGROUND: The correlation between the clinical manifestations and fecal viral load of norovirus (NoV) infection remains unknown. METHODS: We established a SYBR® Green-based real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) method to quantify NoV and then sequenced its genomes from the feces of patients admitted at the Chang Gung Memorial Hospital from 2017 to 2018. RESULTS: NoV GII.4 Sydney (n = 21, 36.2%) and GII.P16-GII.2 (n = 19, 32.8%), the two predominant genotypes found among 58 isolates, were closely related to the Taiwan variant 2012a cluster in the VP1 region and genotypes of China strain. An increase in viral load could be observed on Day 3 following the onset of NoV infection. The viral load then declined rapidly from days 10-15 but remained high for >1 month in a severe combined immunodeficiency patient. Significantly longer shedding was found in patients with fever (p = 0.03) or infected by the GII.4 Sydney strain (p < 0.01). CONCLUSION: The qRT-PCR-mediated method proposed in this work could quantify the viral load in patients with NoV infection. Significant viral shedding over a period of 2 weeks in children with acute gastroenteritis and >1 month in an immunodeficient patient was observed. Significantly longer shedding could be correlated with infection by the GII.4 Sydney strain and febrile patients.