The Multifunction of TRIM26: From Immune Regulation to Oncology.

Ubiquitination, a crucial post-translational modification, plays a role in nearly all physiological processes. Its functional execution depends on a series of catalytic reactions involving numerous proteases. TRIM26, a protein belonging to the TRIM family, exhibits E3 ubiquitin ligase activity because of its RING structural domain, and is present in diverse cell lineages. Over the last few decades, TRIM26 has been documented to engage in numerous physiological and pathological processes as a controller, demonstrating a diverse array of biological roles. Despite the growing research interest in TRIM26, there has been limited attention given to examining the protein's structure and function in existing reviews. This review begins with a concise overview of the composition and positioning of TRIM26 and then proceeds to examine its roles in immune response, viral invasion, and inflammatory processes. Simultaneously, we demonstrate the contribution of TRIM26 to the progression of various diseases, encompassing numerous malignancies and neurologic conditions. Finally, we have investigated the potential areas for future research on TRIM26.

Epidemiologic and clinical updates on viral infections in Saudi Arabia.

In the past two decades, the world has witnessed devastating pandemics affecting the global healthcare infrastructure and disrupting society and the economy worldwide. Among all pathogens, viruses play a critical role that is associated with outbreaks due to their wide range of species, involvement of animal hosts, easily transmitted to humans, and increased rates of infectivity. Viral disease outbreaks threaten public health globally due to the challenges associated with controlling and eradicating them. Implementing effective viral disease control programs starts with ongoing surveillance data collection and analyses to detect infectious disease trends and patterns, which is critical for maintaining public health. Viral disease control strategies include improved hygiene and sanitation facilities, eliminating arthropod vectors, vaccinations, and quarantine. The Saudi Ministry of Health (MOH) and the Public Health Authority (also known as Weqayah) in Saudi Arabia are responsible for public health surveillance to control and prevent infectious diseases. The notifiable viral diseases based on the Saudi MOH include hepatitis diseases, viral hemorrhagic fevers, respiratory viral diseases, exanthematous viral diseases, neurological viral diseases, and conjunctivitis. Monitoring trends and detecting changes in these viral diseases is essential to provide proper interventions, evaluate the established prevention programs, and develop better prevention strategies. Therefore, this review aims to highlight the epidemiological updates of the recently reported viral infections in Saudi Arabia and to provide insights into the recent clinical treatment and prevention strategies.

The association between infectious agents and breast cancer: a review of the epidemiologic evidence.

PURPOSE: Several viruses have been casually linked to human cancers, including cervical, nasopharyngeal, liver, sarcoma, and Merkel cell carcinomas. However, the etiologic contribution of viral infections to breast cancer, the number one incident cancer among women worldwide, is not well established. Among studies exploring associations of viruses with breast cancer, potential linkages have been identified between breast cancer and five viruses: beta retrovirus, (i.e., mouse mammary tumor virus), human papillomavirus, Epstein Barr virus. bovine leukemia virus, and human cytomegalovirus. METHODS: In this review, we provide a comprehensive evaluation of epidemiological ecologic, case-control, case-only, and cohort studies investigating these associations. We discuss results from several existing reviews and meta-analyses, evaluate epidemiological studies published in the past five years, and assess the relationship between these viruses and breast tumor clinicopathological factors. RESULTS: The strongest epidemiological evidence for a viral role in breast cancer exists for MMTV and HPV, though limitations include lack of prospective studies for MMTV and potential detection bias in HPV studies. Viral detection challenges have limited studies of EBV and HCMV. Fewer studies have evaluated BLV, and though it has been associated with higher risk of breast cancer, sample sizes are quite small.   CONCLUSION: While epidemiologic evidence exists for an association between these five viruses and breast cancer, various methodological issues and lack of prospective studies preclude robust conclusions. Future research should prioritize establishing a temporal relationship between infection and disease, minimizing misclassification of detection assays, and further exploring the influence of co-infections.

Epidemiology of Viral Infectious Diseases Reported in Saudi Arabia.

INTRODUCTION: Efficient epidemiological monitoring of virus diseases is crucial in evaluating general public health, the prevalence of specific diseases, the pattern of spread, and implementing preventative and control strategies into action. METHODS: This study analyzed data obtained from the Field Epidemiology Program (FETP) which is part of the Ministry of Health (MOH) in Saudi Arabia, which contained reported cases of infectious diseases over four years, from January 2018 to December 2021, to investigate and highlight the significant trend and incidence rate for each viral infectious disease. RESULTS: Of the reported viral infectious diseases, hepatitis B and C, dengue fever (DF), influenza, chickenpox, and measles were the highest reported viral cases over four years. For the aforementioned diseases, males were often more susceptible to viral infections than females. Except for DF, this viral infection was more common in Saudi citizens. Viral illnesses like hand, foot, and mouth disease were less prevalent, while neurological viral disorders such as acute flaccid paralysis were rarely detected. There was an overall reduction in viral cases recorded during 2020-2021, which may be attributed to the implementation of preventive measures during the Coronavirus Disease 2019 (COVID-19) pandemic or an underreporting of cases during the lockdown of that time. CONCLUSION: The prevalence of these common viral infections in the Saudi population suggests that understanding the mechanisms influencing changes in these viruses, methods of transmission, and the burden of these diseases is a priority for health policy. This understanding is necessary to develop effective intervention and preventive strategies.

Proton Pump Inhibitors and Risk of COVID-19 Infection in Children.

OBJECTIVE: To evaluate the influence of proton pump inhibitor (PPI) use on COVID-19 susceptibility and severity in children. STUDY DESIGN: This retrospective, case-control study included all children < 21 years undergoing COVID-19 PCR testing at a tertiary children's hospital between March 2020 and January 2023. The main exposure was PPI usage. The primary outcome was COVID-19 infection. The secondary outcome was COVID-19 hospitalization. Log-binomial regressions were used to examine associations between PPI use and these outcomes. RESULTS: 116,209 patients age 8.5±6.2 years underwent 234,867 COVID-19 tests. Current PPI use was associated with a decreased risk of COVID-19 test positivity compared with PPI non-use [RR 0.85 (95% CI 0.76, 0.94), P = 0.002]; however, there was a significant interaction with time of testing, and an effect of PPIs was no longer seen in the final months of the study following lessening of COVID-19 precautions [RR 1.04 (95% CI 0.0.80, 1.36), P = 0.77]. PPI use was not associated with risk of hospitalization in patients positive for COVID-19 after adjusting for other hospitalization risk factors [RR 0.85 (95% CI 0.64, 1.13), P = 0.26]. CONCLUSIONS: We did not find an association between PPI use and increased COVID-19 susceptibility or severity in this pediatric sample. These results provide reassuring evidence that PPIs may not worsen COVID-19 outcomes in children.

Impact of SARS-CoV-2 Pandemic on Emergency Hospitalizations for Acute Respiratory Infections: The Experience of a Paediatric Tertiary Care Hospital in Italy.

BACKGROUND: Acute respiratory infections (ARIs) are a major healthcare issue in children. The SARS-CoV-2 pandemic changed the epidemiology of ARIs; the aims of this study are to characterize the epidemiological trend of ARI emergency hospitalizations and virology results and to estimate the association of ARI emergency hospitalizations with respiratory viruses from January 2018 to June 2023. METHODS: This study was carried out in an Italian tertiary care children's hospital (Bambino Gesù Children's Hospital). The demographic and clinical information of children who accessed the Emergency Department (ED) with ARI and were hospitalized were retrospectively extracted from the electronic health records. Multivariate linear regression model was used to compare the number of ARI hospital admissions with the reported temporal trends in viruses diagnosed from respiratory samples throughout the same time period. RESULTS: During the study period, there were 92,140 ED visits and 10,541 hospitalizations due to ARIs, reflecting an admission rate of 11.4%. The highest proportion of hospitalizations occurred in infants ≤ 1 year of age (n = 4840, 45.9% of total admissions), with a hospitalization rate of 22.6%. Emergency hospitalizations aligned closely with the predictions made by the multivariate regression model; peaks in hospitalizations reflected Respiratory Syncytial Virus (RSV) circulation. CONCLUSIONS: ARI hospital urgent admissions are a relevant component of ARI disease burden in children. RSV prevention and control are crucial to limit the risk of urgent hospitalizations due to ARIs.

RNA-Based Vaccines and Therapeutics Against Intracellular Pathogens.

RNA-based vaccines have sparked a paradigm shift in the treatment and prevention of diseases by nucleic acid medicines. There has been a notable surge in the development of nucleic acid therapeutics and vaccines following the global approval of the two messenger RNA-based COVID-19 vaccines. This growth is fueled by the exploration of numerous RNA products in preclinical stages, offering several advantages over conventional methods, i.e., safety, efficacy, scalability, and cost-effectiveness. In this chapter, we provide an overview of various types of RNA and their mechanisms of action for stimulating immune responses and inducing therapeutic effects. Furthermore, this chapter delves into the varying delivery systems, particularly emphasizing the use of nanoparticles to deliver RNA. The choice of delivery system is an intricate process involved in developing nucleic acid medicines that significantly enhances their stability, biocompatibility, and site-specificity. Additionally, this chapter sheds light on the current landscape of clinical trials of RNA therapeutics and vaccines against intracellular pathogens.

Exploring the protective association between COVID-19 infection and laryngeal cancer: insights from a Mendelian randomization study.

Introduction: Viral infections have been implicated as a risk factor for laryngeal cancer. Given the possible effects of Corona virus disease 2019 (COVID-19) on the laryngeal tissue, we investigated the causal link between COVID-19 and laryngeal cancer using a two-sample Mendelian randomization (MR) approach. Methods: We utilized genetic data from the 5th Genome-wide association studies (GWAS) edition of the COVID-19 Host Genetics Initiative (published on January 18, 2021) and a large-scale laryngeal cancer GWAS comprising 180 cases and 218,612 controls of European ancestry. We applied inverse variance weighting, MR Egger, and weighted median methods to infer causality. We performed sensitivity analysis using the "leave-one-out" method to verify robustness. Results: We found no evidence of a causal association between gene-predicted COVID-19 and laryngeal cancer [Odds ratio (OR)=0.24 (95% Confidence intervals (CI), 0.05-1.26), P=0.09]. However, we observed significant inverse associations between gene-predicted COVID-19 hospitalization [OR=0.51 (95% CI, 0.28-0.95), P=0.03] and severe patients [OR=0.62 (95% CI, 0.43-0.90), P=0.01] and laryngeal cancer. Notably, the study detected important genetic variants, such as rs13050728, that modulate the expression of interferon alpha receptor 2 (IFNAR2), indicating possible roles for immune response pathways in both COVID-19 and cancer. Discussion: This study reveals a potential interaction between COVID-19 severity, genetic factors, and laryngeal cancer, underscoring the importance of investigating the immune response mechanisms in both conditions. These findings contribute to the understanding of the complex interactions between COVID-19 and laryngeal cancer and may guide future research on the role of immune response, particularly involving IFNAR2.

Clinical Profiles, Laboratory Biomarkers, and Mortality in Cancer Patients with Lower Respiratory Tract Infections: A Prospective Cohort Study.

Respiratory tract infections (RTIs) pose a substantial health burden worldwide, especially among immunocompromised groups like cancer patients. The aim of this prospective cohort study was to explore lower respiratory tract infections in cancer patients. We followed 107 cases with clinically or radiologically suspected lower respiratory tract infections until discharge or death, comprising 65 males and 42 females across diverse age groups. Clinical evaluations, including patient history, examination, and malignancy diagnosis, were conducted. Nasopharyngeal swabs (NPSs), sputum samples, and blood samples were collected within 24 h of symptom onset. Multiplex Real-Time PCR allowed for the simultaneous detection of viral, bacterial, and fungal infections, while conventional microbiological culture methods were used for bacterial and fungal analysis. SARS-CoV-2 infection was excluded in all of the enrolled patients using real-time RT-PCR. Hematological and biochemical analyses included hemoglobin, lymphocyte, neutrophil, and platelet counts, along with ALT, AST, creatinine, and CRP levels. Significant differences were noted in clinical presentations, management outcomes, and prognostic markers among patients with different hematological malignancies. Distinct clinical profiles were identified for leukemia, lymphoma, and solid tumors, with variations in age distribution and symptom prevalence. ICU admission rates varied significantly, with solid tumor patients exhibiting higher rates. The hematological and biochemical biomarkers differed across malignancies, with notable associations between lymphopenia, thrombocytopenia, and mortality following respiratory episodes. This study highlights the critical role of rapid pathogen detection and infection control measures in safeguarding vulnerable cancer patients from nosocomial transmission.

Exosome-mediated PROTAC delivery for treatment of RNA viral infections and zoonosis.

The increase in diseases caused by RNA viruses, such as influenza, severe acute respiratory syndrome-coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS), and Ebola, presents a growing global health challenge as well as the threat of zoonosis. Traditional antiviral treatments are often undermined by fast-mutating viruses, drug resistance, and newly emerging pathogens. Here, we explore proteolysis-targeting chimeras (PROTACs), a novel protein degradation machinery that has the potential to reshape the way in which RNA viral infections can be managed. PROTACs excel at specifically degrading pathogenic proteins, offering a targeted and efficient antiviral strategy. We also investigate the potential of exosome-based diagnostic technologies, which harness cell-derived nanovesicles for non-invasive sampling and early viral infection detection. Addressing the challenge of PROTAC delivery, we introduce a groundbreaking strategy utilizing exosomes to deliver PROTACs with improved precision and as a targeted delivery vehicle. Integrating these innovative strategies provides a novel approach to combat RNA zoonotic viral diseases, paving the way for a new era in antiviral therapy.

Changes in seasonal respiratory viral infections among pediatric population around the COVID-19 pandemic; 2019-2023.

PURPOSE: This study aims to describe the prevalence and the fluctuations of respiratory viral infections among the pediatric population in a tertiary care center during 2019-2023, parallel with the COVID-19 pandemic, and the specific preventative measures applied in the region during this time. METHODS: In this observational study, we extracted all respiratory virus PCR tests collected from pediatric patients (< 15 years old) between January 2019 and March 2023. Data on the positivity rate and prevalence of 18 respiratory viruses were presented over the study period. RESULTS: The lowest rate for the studied respiratory viruses was observed in 2020/2021 (during the COVID-19 pandemic), followed by a gradual increase in positive cases in the 2021/2022 season. Timing (seasonality) was altered during 2022/2023 with an early circulation of respiratory viruses in May-June followed by an early start of the usual respiratory viruses' season in September, leading to prolonged respiratory virus activity. Most respiratory viruses were circulating at unprecedented levels during the 2022/2023 season, with rhinovirus/enterovirus being the most commonly detected virus in all seasons. Other viruses that had atypical activity after the COVID-19 pandemic were influenza A(H3) virus, adenovirus, and parainfluenza 3 virus. CONCLUSION: Our study demonstrates the extended influence of the COVID-19 pandemic and its associated community restriction measures on the timing and distribution of other respiratory viruses. Continuous monitoring of changes in the circulation of respiratory viruses is crucial for the success of related public health measures such as vaccination distributions and epidemic preparedness.

The role of the cGAS-STING signaling pathway in viral infections, inflammatory and autoimmune diseases.

Pattern recognition receptors are an essential part of the immune system, which detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and help shape both innate and adaptive immune responses. When dsDNA is present, cyclic GMP-AMP Synthase (cGAS) produces a second messenger called cyclic GMP-AMP (cGAMP), which then triggers an adaptor protein called STING, and eventually activates the expression of type I interferon (IFN) and pro-inflammatory cytokines in immune cells. The cGAS-STING signaling pathway has been receiving a lot of attention lately as a key immune-surveillance mediator. In this review, we summarize the present circumstances of the cGAS-STING signaling pathway in viral infections and inflammatory diseases, as well as autoimmune diseases. Modulation of the cGAS-STING signaling pathway provides potential strategies for treating viral infections, inflammatory diseases, and autoimmune diseases.

Covert RNA viruses in medflies differ in their mode of transmission and tissue tropism.

Numerous studies have demonstrated the presence of covert viral infections in insects. These infections can be transmitted in insect populations via two main routes: vertical from parents to offspring, or horizontal between nonrelated individuals. Thirteen covert RNA viruses have been described in the Mediterranean fruit fly (medfly). Some of these viruses are established in different laboratory-reared and wild medfly populations, although variations in the viral repertoire and viral levels have been observed at different time points. To better understand these viral dynamics, we characterized the prevalence and levels of covert RNA viruses in two medfly strains, assessed the route of transmission of these viruses, and explored their distribution in medfly adult tissues. Altogether, our results indicated that the different RNA viruses found in medflies vary in their preferred route of transmission. Two iflaviruses and a narnavirus are predominantly transmitted through vertical transmission via the female, while a nodavirus and a nora virus exhibited a preference for horizontal transmission. Overall, our results give valuable insights into the viral tropism and transmission of RNA viruses in the medfly, contributing to the understanding of viral dynamics in insect populations. IMPORTANCE: The presence of RNA viruses in insects has been extensively covered. However, the study of host-virus interaction has focused on viruses that cause detrimental effects to the host. In this manuscript, we uncovered which tissues are infected with covert RNA viruses in the agricultural pest Ceratitis capitata, and which is the preferred transmission route of these viruses. Our results showed that vertical and horizontal transmission can occur simultaneously, although each virus is transmitted more efficiently following one of these routes. Additionally, our results indicated an association between the tropism of the RNA virus and the preferred route of transmission. Overall, these results set the basis for understanding how viruses are established and maintained in medfly populations.

Clinical impact of pulmonary arterial hypertension on SARS-CoV-2 outcomes: U.S. pre-vaccination analysis.

Our retrospective study aimed to determine how pulmonary arterial hypertension (PAH) influences the clinical outcomes of COVID-19 admissions by using data from the 2020 nationwide inpatient sample (NIS). Among the 1,018,915 adults who were hospitalized with COVID-19 in 2020, 155 also had a PAH diagnosis. After adjusting for all baseline demographics and co-morbidities through multivariate analysis, we found that in patients admitted with a principal diagnosis of COVID-19, PAH was not associated with an increased risk of mortality compared to those without PAH. (adjusted OR 0.58 [95% CI 0.2-1.6] p=0.3). In addition, patients with both COVID-19 and PAH showed no statistically significant difference in the odds of requiring mechanical ventilation (adjusted OR 1.1 [95% CI 0.5-2.6] p=0.9), vasopressor needs (adjusted OR 0.4 [95% CI 0.1-3.5] p=0.4), acute kidney injury necessitating renal replacement therapy(adjusted OR 0.7 [95% CI 0.3-1.7] p=0.5), mean length of stay (LOS) (11.1 vs. 7.5 days), adjusted difference 3.1 [95% CI -3.8- 10.1] p=0.37) or mean total hospitalization charges ($195,815 vs $79,082, adjusted difference 107,146 [95% CI -93,939 - 308,232] p=0.29). Further studies are needed to investigate this subpopulation during the post-vaccination era to observe the effects of outcomes in these patients.

Persistent Impairment in Immune Reconstitution and Worse Survival Outcomes in Allogeneic Stem Cell Transplantation Patients with Early Coronavirus Disease 2019 Infection.

Patients undergoing allogenic hematopoietic stem cell transplantation (HSCT) are at an increased risk of mortality due to transplantation-related complications in the first year post-transplantation, owing in part to the profound immune dysregulation with T cell and B cell lymphopenia and functional impairment. Although several large studies have reported higher mortality rates from Coronavirus disease 2019 (COVID-19) in HSCT recipients, to date no study has focused on the impact of early COVID-19 infection on immune reconstitution post-transplantation and the correlation with transplantation outcomes. We retrospectively analyzed 61 consecutive adult patients who underwent their first allogeneic HSCT at our institution. Thirteen patients (21.3%) experienced early COVID-19 infection, with a median time to diagnosis of 100 days post-transplantation. In multivariable analysis, patients with early COVID-19 infection had significantly worse overall survival (adjusted hazard ratio [aHR], 4.06; 95% confidence interval [CI], 1.26 to 13.05; P = .019) and progression-free survival (aHR, 6.68; 95% CI, 2.11 to 21.11; P = .001). This was attributed mainly to higher nonrelapse mortality (NRM) among early COVID-19 patients (P = .042). Allogeneic HSCT recipients with early COVID-19 infection had significant delays in absolute lymphocyte count (95% CI, -703.69 to -56.79; P = .021), CD3+CD4+ cell (95% CI, -105.35 to -11.59; P = .042), CD3+CD8+ cell (95% CI, -324.55 to -57.13; P = .038), and CD3-CD56+ cell (95% CI, -193.51 to -47.31; P = .014) recovery compared to those without early COVID-19 infection. Our findings suggest that patients with early COVID-19 infection after allogeneic HSCT have higher NRM and worse survival, at least in part due to impaired immune reconstitution post-transplantation.

Efficient detection of nitric oxide a biomarker associated with COVID19 via N, P co-doped C60 fullerene: a computational study.

CONTEXT: Coronavirus (COVID-19) is a novel respiratory viral infection, causing a relatively large number of deaths especially in people who underly lung diseases such as chronic obstructive pulmonary and asthma, and humans are still suffering from the limited testing capacity. In this article, a solution is proposed for the detection of COVID-19 viral infections through the analysis of exhaled breath gasses, i.e., nitric oxide, a prominent biomarker released by respiratory epithelial, as a non-invasive and time-saving approach. Here, we designed a novel and low-cost N and P co-doped C60 fullerene-based breathalyzer for the detection of NO gas exhaled from the respiratory epithelial cells. This breathalyzer shows a quick response to the detection of NO gas by directly converting NO to NO2 without passing any energy barrier (0 kcal/mol activation energy). The recovery time of breathalyzer is very short (0.98 × 103 s), whereas it is highly selective for NO sensing in the mixture of CO2 and H2O gasses. The study provides an idea for the synthesis of low-cost (compared to previously reported Au atom decorated nanostructure and metal-based breathalyzer), efficient, and highly selective N and P co-doped C60 fullerene-based breathalyzer for COVID-19 detection. METHODS: The geometries of N and P-doped systems and gas molecules are simulated using spin-polarized density functional theory calculations.

NK cell receptor modulation in viral infections.

Natural killer (NK) cells play a crucial role in controlling viral infections. The ability to kill infected cells without prior immunization, yet being tolerant to self, healthy cells, depends on the balance of germ-line encoded surface receptors. NK cell receptors are divided to either activating, leading to activation of NK cell and its cytotoxic and pro-inflammatory activity, or inhibitory, providing tolerance for a target cell. The signals from inhibitory receptors dominate and NK cell activation requires stimulation of activating receptors. In viral infections, NK cell interaction with infected cell can result in activation, memory-like NK cell differentiation or NK cell exhaustion, which constitutes one of the viral immune evasion mechanisms. All of these states are associated with the modulation of NK cell receptor expression. In this review, we summarize the current knowledge of NK cell receptors and their role in viral infection control, as well as the alterations of their expression observed in acute or chronic infections. We present recently discovered SARS-CoV-2-mediated modulation of NK cell receptor expression and compare them with other human viral infections. Finally, since modulation of NK cell receptor activation gives promising addition to currently used antiviral therapies, we briefly discuss the clinical significance and future perspective of application of agonists or antagonists of activating and inhibitory receptors, respectively. In sum, our review shows that although much is known about NK cell receptor biology, a deeper understanding of NK cell receptors role in viral infections is still needed.

Assessment of Medical Test Overuse and Its Impact on Pediatric Emergency Department Outcomes in Upper Respiratory Tract Infections in a University Hospital in Lithuania.

Medical overuse poses potential risks to patients and contributes to increasing healthcare costs, pediatric emergency departments (PED) in particular. Often, upper respiratory tract infection (URTI) cases are viral-induced and self-limiting, and they do not require specific investigations or treatment. We conducted a retrospective study from 1 December 2021 to 31 January 2022, thereby aiming to identify the common tests and factors influencing specific diagnostic and treatment decisions for URTI in PED. In total, 307 (74.9%) URTI cases underwent complete blood count (CBC) tests, 312 (76.1%) were subjected to C-reactive protein (CRP) tests, and 110 (26.8%) received urinalysis tests. Patients with a longer duration of fever and a physician's suspicion of bacterial infection were more likely to receive CBC, CRP, and/or urinalysis tests (p < 0.05). Moreover, 75.1% of the cases were classified as viral URTIs, 9.8% were bacterial URTIs, and 15.1% were unspecified. Notably, 86 (20.1%) children received antibiotics and antibiotic prescription correlated with age, tonsillitis diagnosis, CRP values higher than 30 mg/L, and a CBC of p < 0.05. Patients triaged in the second or third categories were three times more likely to be observed for 24 h compared to patients with URTI and the fourth triage category (p < 0.05). This study highlights the need for interventions to improve the appropriateness of emergency service utilization, thereby emphasizing the importance of judicious decision making in managing pediatric URTIs.