A narrative review of wastewater surveillance: pathogens of concern, applications, detection methods, and challenges.

Introduction: The emergence and resurgence of pathogens have led to significant global health challenges. Wastewater surveillance has historically been used to track water-borne or fecal-orally transmitted pathogens, providing a sensitive means of monitoring pathogens within a community. This technique offers a comprehensive, real-time, and cost-effective approach to disease surveillance, especially for diseases that are difficult to monitor through individual clinical screenings. Methods: This narrative review examines the current state of knowledge on wastewater surveillance, emphasizing important findings and techniques used to detect potential pathogens from wastewater. It includes a review of literature on the detection methods, the pathogens of concern, and the challenges faced in the surveillance process. Results: Wastewater surveillance has proven to be a powerful tool for early warning and timely intervention of infectious diseases. It can detect pathogens shed by asymptomatic and pre-symptomatic individuals, providing an accurate population-level view of disease transmission. The review highlights the applications of wastewater surveillance in tracking key pathogens of concern, such as gastrointestinal pathogens, respiratory pathogens, and viruses like SARS-CoV-2. Discussion: The review discusses the benefits of wastewater surveillance in public health, particularly its role in enhancing existing systems for infectious disease surveillance. It also addresses the challenges faced, such as the need for improved detection methods and the management of antimicrobial resistance. The potential for wastewater surveillance to inform public health mitigation strategies and outbreak response protocols is emphasized. Conclusion: Wastewater surveillance is a valuable tool in the fight against infectious diseases. It offers a unique perspective on the spread and evolution of pathogens, aiding in the prevention and control of disease epidemics. This review underscores the importance of continued research and development in this field to overcome current challenges and maximize the potential of wastewater surveillance in public health.

Universal versus targeted treatment of neonatal herpes simplex virus among neonates presenting for sepsis evaluations.

PURPOSE OF REVIEW: The American Academy of Pediatrics recently published guidance for the evaluation and management of febrile infants. However, guidance on testing and empiric treatment for neonatal herpes simplex virus (HSV) remains less standardized and subject to clinical practice variation. RECENT FINDINGS: Recent reports reveal that high numbers of infants presenting for sepsis evaluations need to be treated empirically with acyclovir to capture one case of neonatal HSV. Clinical and laboratory risk factors for neonatal HSV identified in the literature can be used for a targeted approach to testing and treating infants for HSV to optimize resource utilization. SUMMARY: The literature supports a targeted approach to evaluation and empiric acyclovir treatment for neonatal HSV, but additional studies are needed to validate this approach given the rarity of disease.

Remdesivir for COVID-19 in Hospitalized Children: A Phase 2/3 Study.

OBJECTIVES: Remdesivir decreases the risk of SARS-CoV-2 infection progressing to severe disease in adults. This study evaluated remdesivir safety and pharmacokinetics in infants and children. METHODS: This was a phase 2/3, open-label trial in children aged 28 days to 17 years hospitalized for polymerase chain reaction-confirmed SARS-CoV-2 infection. Participants received for ≤10 days once-daily intravenous remdesivir doses defined using physiologically based pharmacokinetic modeling (for ≥40 kg, 200 mg day 1, then 100 mg/day; for age ≥28 days and ≥3 to <40 kg, 5 mg/kg day 1, then 2.5 mg/kg/day). Sparse pharmacokinetic samples were analyzed using population-pharmacokinetic approaches for remdesivir and metabolites GS-704277 and GS-441524. RESULTS: Among 53 participants, at enrollment the median (Q1, Q3) number of days of COVID-19 symptoms was 5 (3, 7) and hospitalization was 1 (1, 3). Underlying conditions included obesity in 19 (37%), asthma in 11 (21%), and cardiac disorders in 11 (21%). Median duration of remdesivir treatment was 5 days (range, 1-10). Remdesivir treatment had no new apparent safety trends. Two participants discontinued treatment because of adverse events including elevated transaminases; both had elevated transaminases at baseline. Three deaths occurred during treatment (and 1 after). When compared with phase 3 adult data, estimated mean pediatric parameters (area under the concentration-time curve over 1 dosing interval, AUCτ, Cmax, and Cτ) were largely overlapping but modestly increased (remdesivir, 33%-129%; GS-704277, 37%-124%; GS-441524, 0%-60%). Recovery occurred for 62% of participants on day 10 and 83% at last assessment. CONCLUSIONS: In infants and children with COVID-19, the doses of remdesivir evaluated provided drug exposure similar to adult dosing. In this study with a small sample size, no new safety concerns were observed.

Oral Valganciclovir Initiated Beyond 1 Month of Age as Treatment of Sensorineural Hearing Loss Caused by Congenital Cytomegalovirus Infection: A Randomized Clinical Trial.

OBJECTIVE: The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at US (n = 12) and UK (n = 9) sites. Patients of ages 1 month through 3 years with baseline sensorineural hearing loss were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in cytomegalovirus viral load in blood, saliva, and urine. RESULTS: Of 54 participants enrolled, 35 were documented to have congenital cytomegalovirus infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 ± 15.8 months (valganciclovir) vs 19.5 ± 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (P = .09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome. CONCLUSIONS: In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus-associated sensorineural hearing loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01649869.

Association of social vulnerability index and masking adherence among children enrolled in COVID-19 community research partnership study.

BACKGROUND: Individuals with high social vulnerability index (SVI) have poorer outcomes with COVID-19. Masking reduces transmission of COVID-19 among children, but how SVI plays a role in masking behavior is unknown. We aimed to measure the association of SVI with masking adherence among children during the COVID-19 pandemic. METHODS: We conducted a multi-site, prospective syndromic surveillance study among children aged 2 - 17 years in the Southeastern United States by daily electronic surveys which solicited symptoms of COVID-19-like illness, infection with or exposure to SARS-CoV-2, masking habits, and any receipt of COVID-19 vaccines. Parents/guardians submitted surveys for their children; adolescents 13 years and older could opt to submit their own surveys. Multivariable and univariate linear models were used to measure the associations of different predictors such as SVI with masking adherence. RESULTS: One thousand four hundred sixty-one children from 6 states and 55 counties predominately from North and South Carolina were included in the analysis. Most children in the cohort were 5 - 11 years old, non-Hispanic White, from urban counties, and with low-moderate SVI. Overall masking adherence decreased over time, and older children had higher masking adherence throughout the study period compared with younger children. Children who resided in urban counties had greater masking adherence throughout the study period than those who resided in suburban or rural counties. Masking adherence was higher among children with both low and medium SVI than those with high SVI. CONCLUSIONS: Despite being at risk for more severe outcomes with COVID-19, children with high SVI had lower levels of masking adherence compared to those with low SVI. Our findings highlight opportunities for improved and targeted messaging in these vulnerable communities.

Cost-effectiveness of two online interventions supporting self-care for eczema for parents/carers and young people.

OBJECTIVE: To estimate the cost-effectiveness of online behavioral interventions (EczemaCareOnline.org.uk) designed to support eczema self-care management for parents/carers and young people from an NHS perspective. METHODS: Two within-trial economic evaluations, using regression-based approaches, adjusting for baseline and pre-specified confounder variables, were undertaken alongside two independent, pragmatic, parallel group, unmasked randomized controlled trials, recruiting through primary care. Trial 1 recruited 340 parents/carers of children aged 0-12 years and Trial 2 337 young people aged 13-25 years with eczema scored ≥ 5 on Patient-Oriented Eczema Measure (POEM). Participants were randomized (1:1) to online intervention plus usual care or usual care alone. Resource use, collected via medical notes review, was valued using published unit costs in UK £Sterling 2021. Quality-of-life was elicited using proxy CHU-9D in Trial 1 and self-report EQ-5D-5L in Trial 2. RESULTS: The intervention was dominant (cost saving and more effective) with a high probability of cost-effectiveness (> 68%) in most analyses. The exception was the complete case cost-utility analysis for Trial 1 (omitting participants with children aged < 2), with adjusted incremental cost savings of -£34.15 (95% CI - 104.54 to 36.24) and incremental QALYs of - 0.003 (95% CI - 0.021 to 0.015) producing an incremental cost per QALY of £12,466. In the secondary combined (Trials 1 and 2) cost-effectiveness analysis, the adjusted incremental cost was -£20.35 (95% CI - 55.41 to 14.70) with incremental success (≥ 2-point change on POEM) of 10.3% (95% CI 2.3-18.1%). CONCLUSION: The free at point of use online eczema self-management intervention was low cost to run and cost-effective. TRIAL REGISTRATION: This trial was registered prospectively with the ISRCTN registry (ISRCTN79282252). URL www.EczemaCareOnline.org.uk .

Retraction: Colonic Angiolipoma: An Extremely Rare Tumor Clinically Masquerading as Acute Appendicitis.

[This retracts the article DOI: 10.7759/cureus.20659.].

Persistence of antibody responses to COVID-19 vaccines among participants in the COVID-19 Community Research Partnership.

Introduction: High levels of immunity to SARS-CoV-2 in the community correlate with protection from COVID-19 illness. Measuring COVID-19 antibody seroprevalence and persistence may elucidate the level and length of protection afforded by vaccination and infection within a population. Methods: We measured the duration of detectable anti-spike antibodies following COVID-19 vaccination in a multistate, longitudinal cohort study of almost 13,000 adults who completed daily surveys and submitted monthly dried blood spots collected at home. Results: Overall, anti-spike antibodies persisted up to 284 days of follow-up with seroreversion occurring in only 2.4% of the study population. In adjusted analyses, risk of seroreversion increased with age (adults aged 55-64: adjusted hazard ratio [aHR] 2.19 [95% confidence interval (CI): 1.22, 3.92] and adults aged > 65: aHR 3.59 [95% CI: 2.07, 6.20] compared to adults aged 18-39). Adults with diabetes had a higher risk of seroreversion versus nondiabetics (aHR 1.77 [95% CI: 1.29, 2.44]). Decreased risk of seroreversion was shown for non-Hispanic Black versus non-Hispanic White (aHR 0.32 [95% CI: 0.13, 0.79]); college degree earners versus no college degree (aHR 0.61 [95% CI: 0.46, 0.81]); and those who received Moderna mRNA-1273 vaccine versus Pfizer-BioNTech BNT162b2 (aHR 0.35 [95% CI: 0.26, 0.47]). An interaction between healthcare worker occupation and sex was detected, with seroreversion increased among male, non-healthcare workers. Conclusion: We established that a remote, longitudinal, multi-site study can reliably detect antibody durability following COVID-19 vaccination. The survey platform and measurement of antibody response using at-home collection at convenient intervals allowed us to explore sociodemographic factors and comorbidities and identify predictors of antibody persistence, which has been demonstrated to correlate with protection against disease. Our findings may help inform public health interventions and policies to protect those at highest risk for severe illness and assist in determining the optimal timing of booster doses.Clinical trials registry: NCT04342884.

Use of Interferon-Gamma Release Assays in Children <2 Years Old.

While interferon-gamma release assays (IGRAs) are widely used for detecting tuberculosis (TB) infection, tuberculin skin tests (TSTs) remain preferred for children under the age of 2 years. The preference for TST stems from concern over IGRA sensitivity in young children. However, TSTs are susceptible to false-positive results following Bacille Calmette-Guérin (BCG) vaccination, which is common in infancy, and exposure to nontuberculous mycobacteria. We reviewed available data for IGRA performance in children under age 2 years. Across four cohorts of high-risk children under age 2 (mostly case contacts or those born in tuberculosis endemic regions), 0 of 575 untreated children with negative IGRA test results progressed to tuberculosis disease-including 0 of 70 who were TST positive but IGRA negative. While neither TSTs nor IGRAs are perfectly sensitive for the diagnosis of tuberculosis infection, IGRAs are an acceptable alternative to TST in children <2 years of age.

Examining Test Cutoffs to Optimize Diagnosis of Latent Tuberculosis Infection in People Born Outside the United States.

Rationale: Detection of latent tuberculosis infection (LTBI) in persons born in high tuberculosis (TB) incidence countries living in low TB incidence countries is key to TB elimination in low-incidence countries. Optimizing LTBI tests is critical to targeting treatment. Objectives: To compare the sensitivity and specificity of tuberculin skin test (TST) and two interferon-γ release assays at different cutoffs and of a single test versus dual testing. Methods: We examined a subset (N = 14,167) of a prospective cohort of people in the United States tested for LTBI. We included non-U.S.-born, human immunodeficiency virus-seronegative people ages 5 years and older with valid TST, QuantiFERON-TB Gold-in-Tube (QFT), and T-SPOT.TB (TSPOT) results. The sensitivity/specificity of different test cutoffs and test combinations, obtained from a Bayesian latent class model, were used to construct receiver operating characteristic (ROC) curves and assess the area under the curve (AUC) for each test. The sensitivity/specificity of dual testing was calculated. Results: The AUC of the TST ROC curve was 0.81 (95% credible interval (CrI), 0.78-0.86), with sensitivity/specificity at cutoffs of 5, 10, and 15 mm of 86.5%/61.6%, 81.7%/71.3%, and 55.6%/88.0%, respectively. The AUC of the QFT ROC curve was 0.89 (95% CrI, 0.86-0.93), with sensitivity/specificity at cutoffs of 0.35, 0.7, and 1.0 IU/mL of 77.7%/98.3%, 66.9%/99.1%, and 61.5%/99.4%. The AUC of the TSPOT ROC curve was 0.92 (95% CrI, 0.88-0.96) with sensitivity/specificity for five, six, seven, and eight spots of 79.2%/96.7%, 76.8%/97.7%, 74.0%/98.6%, and 71.8%/99.5%. Sensitivity/specificity of TST-QFT, TST-TSPOT, and QFT-TSPOT at standard cutoffs were 73.1%/99.4%, 64.8%/99.8%, and 65.3%/100%. Conclusion: Interferon-γ release assays have a better predictive ability than TST in people at high risk of LTBI.

Characterisation of infection-induced SARS-CoV-2 seroprevalence amongst children and adolescents in North Carolina.

Few prospective studies have documented the seropositivity among those children infected with severe acute respiratory syndrome coronavirus 2. From 2 April 2021 to 24 June 2021, we prospectively enrolled children between the ages of 2 and 17 years at three North Carolina healthcare systems. Participants received at least four at-home serological tests detecting the presence of antibodies against, but not differentiating between, the nucleocapsid or spike antigen. A total of 1,058 participants were enrolled in the study, completing 2,709 tests between 1 May 2021 and 31 October 2021. Using multilevel regression with poststratification techniques and considering our assay sensitivity and sensitivity, we estimated that the seroprevalence of infection-induced antibodies among unvaccinated children and adolescents aged 2-17 years in North Carolina increased from 15.2% (95% credible interval, CrI 9.0-22.0) in May 2021 to 54.1% (95% CrI 46.7-61.1) by October 2021, indicating an average infection-to-reported-case ratio of 5. A rapid rise in seropositivity was most pronounced in those unvaccinated children aged 12-17 years, based on our estimates. This study underlines the utility of serial, serological testing to inform a broader understanding of the regional immune landscape and spread of infection.

Estimated COVID-19 vaccine effectiveness against seroconversion from SARS-CoV-2 Infection, March-October, 2021.

BACKGROUND: Monitoring the effectiveness of COVID-19 vaccines against SARS-CoV-2 infections remains important to inform public health responses. Estimation of vaccine effectiveness (VE) against serological evidence of SARS-CoV-2 infection might provide an alternative measure of the benefit of vaccination against infection. METHODS: We estimated mRNA COVID-19 vaccine effectiveness (VE) against development of SARS-CoV-2 anti-nucleocapsid antibodies in March-October 2021, during which the Delta variant became predominant. Participants were enrolled from four participating healthcare systems in the United States, and completed electronic surveys that included vaccination history. Dried blood spot specimens collected on a monthly basis were analyzed for anti-spike antibodies, and, if positive, anti-nucleocapsid antibodies. We used detection of new anti-nucleocapsid antibodies to indicate SARS-CoV-2 infection, and estimated VE by comparing 154 case-participants with new detection of anti-nucleocapsid antibodies to 1,540 seronegative control-participants matched by calendar period. Using conditional logistic regression, we estimated VE ≥ 14 days after the 2nd dose of an mRNA vaccine compared with no receipt of a COVID-19 vaccine dose, adjusting for age group, healthcare worker occupation, urban/suburban/rural residence, healthcare system region, and reported contact with a person testing positive for SARS-CoV-2. RESULTS: Among individuals who completed a primary series, estimated VE against seroconversion from SARS-CoV-2 infection was 88.8% (95% confidence interval [CI], 79.6%-93.9%) after any mRNA vaccine, 87.8% (95% CI, 75.9%-93.8%) after BioNTech vaccine and 91.7% (95% CI, 75.7%-97.2%) after Moderna vaccine. VE was estimated to be lower ≥ 3 months after dose 2 compared with < 3 months after dose 2, and among participants who were older or had underlying health conditions, although confidence intervals overlapped between subgroups. CONCLUSIONS: VE estimates generated using infection-induced antibodies were consistent with published estimates from clinical trials and observational studies that used virologic tests to confirm infection during the same period. Our findings support recommendations for eligible adults to remain up to date with COVID-19 vaccination.

'Eczema shouldn't control you; you should control eczema': qualitative process evaluation of online behavioural interventions to support young people and parents/carers of children with eczema.

BACKGROUND: There is a lack of well-conducted randomized controlled trials evaluating the effectiveness of theory-based online interventions for eczema. To address these deficiencies, we previously developed and demonstrated the effectiveness of two online behavioural interventions: Eczema Care Online for parents/carers of children with eczema, and Eczema Care Online for young people with eczema. OBJECTIVES: To explore the views and experiences of people who have used the Eczema Care Online interventions to provide insights into how the interventions worked and identify contextual factors that may impede users' engagement with the interventions. METHODS: Qualitative semistructured interviews were conducted with 17 parents/carers of children with eczema and 17 young people with eczema. Participants were purposively sampled from two randomized controlled trials of the interventions and recruited from GP surgeries in England. Transcripts were analysed using inductive thematic analysis, and intervention modifications were identified using the person-based approach table of changes method. RESULTS: Both young people and parents/carers found the interventions easy to use, relatable and trustworthy, and perceived that they helped them to manage their eczema, thus suggesting that Eczema Care Online may be acceptable to its target groups. Our analysis suggested that the interventions may reduce eczema severity by facilitating empowerment among its users, specifically through improved understanding of, and confidence in, eczema management, reduced treatment concerns, and improved treatment adherence and management of irritants/triggers. Reading about the experiences of others with eczema helped people to feel 'normal' and less alone. Some (mainly young people) expressed firmly held negative beliefs about topical corticosteroids, views that were not influenced by the intervention. Minor improvements to the design and navigation of the Eczema Care Online interventions and content changes were identified and made, ready for wider implementation. CONCLUSIONS: People with eczema and their families can benefit from reliable information, specifically information on the best and safest ways to use their eczema treatments early in their eczema journey. Together, our findings from this study and the corresponding trials suggest wider implementation of Eczema Care Online (EczemaCareOnline.org.uk) is justified.

Intracranial hemorrhage with concurrent aortic dissection.

Aortic dissection is a rare yet lethal condition that is often missed. Presenting symptoms often include chest pain, abdominal pain, or loss of consciousness. Rarely is it asymptomatic, and the concurring symptoms may draw attention away from the dissection. We present a case of a 51-year-old male who presented to the emergency department with sudden onset of slurred speech and right-sided weakness. The CT scan showed a basal ganglia hemorrhage. However, during the scan, the radiologist incidentally found some aortic changes and recommended an ECG-gated CT scan of the thorax, which revealed a Stanford type B aortic dissection. We aim to shed light on patients presenting with neurological findings and conclude to have aortic dissection to increase awareness and facilitate rapid diagnosis and treatment.

Infrastructure to Support Accrual of Older Adults to National Cancer Institute Clinical Trials.

As part of ongoing efforts to meaningfully improve recruitment, enrollment, and accrual of older adults into cancer clinical trials, the National Cancer Institute (NCI) sponsored a workshop with experts across the country entitled Engaging Older Adults in the NCI Clinical Trials Network: Challenges and Opportunities. Three working groups, including Study Design, Infrastructure, and Stakeholders, were formed, who worked together to offer synergistic improvements in the system. Here, we summarize the workshop discussions of the Infrastructure Working Group, whose goal was to address infrastructural challenges, identify underlying resources, and offer solutions to facilitate accrual of older adults into cancer clinical trials. Based on preconference work and workshop discussions, four key recommendations to strengthen NCI infrastructure were proposed: 1) further centralize resources and expertise; 2) provide training for clinical research staff; (3) develop common data elements; and 4) evaluate what works and does not work. These recommendations provide a strategy to improve the infrastructure to enroll more older adults in cancer clinical trials.

Breakthrough SARS-CoV-2 Infections after Vaccination in North Carolina.

We characterize the overall incidence and risk factors for breakthrough infection among fully vaccinated participants in the North Carolina COVID-19 Community Research Partnership cohort. Among 15,808 eligible participants, 638 reported a positive SARS-CoV-2 test after vaccination. Factors associated with a lower risk of breakthrough in the time-to-event analysis included older age, prior SARS-CovV-2 infection, higher rates of face mask use, and receipt of a booster vaccination. Higher rates of breakthrough were reported by participants vaccinated with BNT162b2 or Ad26.COV2.S compared to mRNA-1273, in suburban or rural counties compared to urban counties, and during circulation of the Delta and Omicron variants.

Feasibility of At-Home Virological and Serological Testing for SARS-CoV-2 in Children.

Longitudinal virological and serological surveillance is essential for understanding severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) transmission among children but requires increased test capacity. We assessed the uptake of serial at-home testing in children (2-17 years) via mailed SARS-CoV-2 antibody and molecular tests. Completion rates demonstrated the feasibility and sustainability of at-home testing across age groups.

Evaluation of the Latent Tuberculosis Care Cascade Among Public Health Clinics in the United States.

BACKGROUND: Tuberculosis (TB) elimination within the United States will require scaling up TB preventive services. Many public health departments offer care for latent tuberculosis infection (LTBI), although gaps in the LTBI care cascade are not well quantified. An understanding of these gaps will be required to design targeted public health interventions. METHODS: We conducted a cohort study through the Tuberculosis Epidemiologic Studies Consortium (TBESC) within 15 local health department (LHD) TB clinics across the United States. Data were abstracted on individuals receiving LTBI care during 2016-2017 through chart review. Our primary objective was to quantify the LTBI care cascade, beginning with LTBI testing and extending through treatment completion. RESULTS: Among 23 885 participants tested by LHDs, 46% (11 009) were male with a median age of 31 (interquartile range [IQR] 20-46). A median of 35% of participants were US-born at each site (IQR 11-78). Overall, 16 689 (70%) received a tuberculin skin test (TST), 6993 (29%) received a Quantiferon (QFT), and 1934 (8%) received a T-SPOT.TB; 5% (1190) had more than one test. Among those tested, 2877 (12%) had at least one positive test result (3% among US-born, and 23% among non-US-born, P < .01). Of 2515 (11%) of the total participants diagnosed with LTBI, 1073 (42%) initiated therapy, of whom 817 (76%) completed treatment (32% of those with LTBI diagnosis). CONCLUSIONS: Significant gaps were identified along the LTBI care cascade, with less than half of individuals diagnosed with LTBI initiating therapy. Further research is needed to better characterize the factors impeding LTBI diagnosis, treatment initiation, and treatment completion.