Background and Objectives Test-to-stay concepts apply serial testing of children in daycare after exposure to SARS-CoV-2 without use of quarantine. This study aims to assess safety of a test-to-stay screening in daycare facilities. Methods 714 daycare facilities and approximately 50,000 children ≤6 years in Cologne, Germany participated in a SARS-CoV-2 Pool-PCR screening from March 2021 to April 2022. The screening initially comprised post-exposure quarantine and was adapted to a test-to-stay approach during its course. To assess safety of the test-to-stay approach, we explored potential changes in frequencies of infections among children following the adaptation to the test-to-stay approach by applying regression discontinuity in time (RDiT) analyses. To this end, PCR-test data were linked with routinely collected data on reported infections in children and analyzed using ordinary least squares regressions. Results 219,885 Pool-PCRs and 352,305 Single-PCRs were performed. 6,440 (2.93%) Pool-PCRs tested positive, and 17,208 infections in children were reported. We estimated that during a period of 30 weeks, the test-to-stay concept avoided between 7 and 20 days of quarantine per eligible daycare child. RDiT revealed a 26% reduction (Exp. Coef: 0.74, CI:0.52;1.06) in infection frequency among children and indicated no significant increase attributable to the test-to-stay approach. This result was not sensitive to adjustments for 7-day incidence, season, SARS-CoV-2 variant, and socioeconomic status. Conclusion Our analyses provide evidence that suggest safety of the test-to-stay approach compared to traditional quarantine measures. This approach offers a promising option to avoid use of quarantine after exposure to respiratory pathogens in daycare settings.

Risperidone is commonly used to treat different psychiatric disorders worldwide. Knowledge on dose–concentration relationships of risperidone treatment in children and adolescents with schizophrenia or other psychotic disorders is, however, scarce and no age-specific therapeutic ranges have been established yet. Multicenter data of a therapeutic drug monitoring service were analyzed to evaluate the relationship between risperidone dose and serum concentration of the active moiety (risperidone (RIS) plus its main metabolite 9-hydroxyrisperidone (9-OH-RIS)) in children and adolescents with psychotic disorders. Patient characteristics, doses, serum concentrations and therapeutic outcomes were assessed by standardized measures. The study also aimed to evaluate whether the therapeutic reference range for adults (20–60 ng/ml) is applicable for minors. In the 64 patients (aged 11–18 years) included, a positive correlation between daily dose and the active moiety (RISam) concentration was found (rs = 0.49, p = 0.001) with variation in dose explaining 24% (rs2 = 0.240) of the variability in serum concentrations. While the RISam concentration showed no difference, RIS as well 9-OH-RIS concentrations and the parent to metabolite ratio varied significantly in patients with co-medication of a CYP2D6 inhibitor. Patients with extrapyramidal symptoms (EPS) had on average higher RISam concentrations than patients without (p = 0.05). Considering EPS, the upper threshold of the therapeutic range of RISam was determined to be 33 ng/ml. A rough estimation method also indicated a possibly decreased lower limit of the preliminary therapeutic range in minors compared to adults. These preliminary data may contribute to the definition of a therapeutic window in children and adolescents with schizophrenic disorders treated with risperidone. TDM is recommended in this vulnerable population to prevent concentration-related adverse drug reactions.

BackgroundObsessive-compulsive disorder (OCD) in children can lead to a huge burden on the concerned patients and their family members. While successful state-of-the art cognitive behavioral interventions exist, there is still a lack of available experts for treatment at home, where most symptoms manifest. Internet-based cognitive behavioral therapy (iCBT) could overcome these restrictions; however, studies about iCBT in children with OCD are rare and mostly target computerized self-help resources and only email contact with the therapist. Therefore, we intended to build up and to evaluate an iCBT approach for children with OCD, replacing successful elements of traditional in-office face-to-face CBT, with face-to-face teleconferences, online materials, and apps.MethodsWith the help of a pilot feasibility study, we developed the iCBT consisting of 14 teleconference sessions with the child and parents. The sessions are supported by an app assessing daily and weekly symptoms and treatment course completed by children and parents. Additionally, we obtain heart rate and activity scores from the child via wristbands during several days and exposure sessions. Using a waiting list randomized control trial design, we aim to treat and analyze 20 children with OCD immediately after a diagnostic session whereas the control group of another set of 20 OCD patients will be treated after waiting period of 16 weeks. We will recruit 30 patients in each group to take account for potential dropouts. Outcomes for the treatment group are evaluated before randomization (baseline, t0), 16 weeks (end of treatment, t1), 32 weeks (follow-up 1, t2), and 48 weeks after randomization (follow-up 2, t3). For the waiting list group, outcomes are measured before the first randomization (baseline), at 16 weeks (waiting list period), 32 weeks (end of treatment), 48 weeks after the first randomization (follow-up I), and 64 weeks after the first randomization (follow-up II).DiscussionBased on our experience of feasibility during the pilot study, we were able to develop the iCBT approach and the current study will investigate treatment effectiveness. Building up an iCBT approach, resembling traditional in-office face-to-face therapy, may ensure the achievement of well-known therapy effect factors, the acceptance in both patients and clinicians, and the wide distribution within the health system.Trial registrationClinicalTrials.govNCT05037344. Registered May 2019, last release August 13th, 2021.

BackgroundIn this study we tested the hypothesis that in patients with cystic fibrosis (pwCF) respiratory rate (RR) is associated with antibiotic treatment, exacerbation status, forced expiratory volume in one second (FEV1) and C-reactive protein (CRP).MethodsBetween June 2018 and May 2019, we consecutively enrolled pwCF who were referred to our hospital. We determined RR and heart rate (HR) by using the minimal-impact system VitaLog during the hospital stay. Furthermore, we performed spirometry and evaluated CRP.ResultsWe included 47 patients: 20 with pulmonary exacerbation and 27 without. RR decreased in patients with exacerbation (27.5/min (6.0/min) vs. 24.4/min (6.0/min), p = 0.004) and in patients with non-exacerbation (22.5/min (5.0/min) vs. 20.9/min (3.5/min), p = 0.024). Patients with exacerbation showed higher RR than patients with non-exacerbation both at the beginning (p = 0.004) and at the end of their hospital stay (p = 0.023). During the hospital stay, HR did not change in the total cohort (66.8/min (11.0/min) vs. 66.6/min (12.0/min), p = 0.440). Furthermore, we did not find significant differences between patients with exacerbation and patients with non-exacerbation (67.0/min (12.5/min) vs. 66.5/min (10.8/min), p = 0.658). We observed a correlation of ρ = -0.36 between RR and FEV1. Moreover, we found a correlation of ρ = 0.52 between RR and CRP.ConclusionIn pwCF requiring intravenous therapy, respiratory rate is higher at their hospital admittance and decreased by the time of discharge; it is also associated with C-reactive protein. Monitoring RR could provide important information about the overall clinical conditions of pwCF.

PurposeResidents in nursing homes for the elderly (NH) are at high risk for death from COVID-19. We investigated whether repeated non-mandatory RT-PCR SARS-CoV-2 surveillance of NH staff and visitors reduces COVID-19 incidence rates in NH residents and allows to reduce visiting restrictions.MethodsThis pilot study at the beginning of the COVID-19 pandemic compared a surveillance approach of regular, twice-weekly voluntary PCR testing of health-care workers (HCW) and visitors in interventional NH (INH) with a setting without regular testing in control NH (CNH). Residents were not tested routinely within this study. Testing was performed in a mobile testing site with same-day result reporting. SARS-CoV-2 incidence among residents in both INH and CNH was the primary endpoint; secondary endpoints being SARS-CoV-2 infection among visitors and HCW in INH.ResultsTwo INH and two CNH participated between October and December, 2020. At INH1, 787 tests of HCW and 350 tests of visitors were performed, accounting for 18.1% (n = 1930) of visits. At INH2, 78 tests of HCW and 372 tests of visitors were done, i.e., 30.5% (n = 1220) of visits. At the two INH 23 HCW and three visitors tested positive for SARS-CoV-2. COVID-19 outbreaks occurred among residents in INH1 (identified through study testing) and in CNH1. Utilization of voluntary testing was low.ConclusionIn a real-world setting without available rapid testing, voluntary RT-PCR SARS-CoV-2 testing of HCW and visitors does not prevent COVID-19 outbreaks in NH. Complete, non-selective testing for these groups should be instituted before visiting restrictions can be reduced.Trial registrationThe study has been registered at ClinicalTrials.gov with the identifier: NCT04933981.

Cognitive behavioral therapy (CBT) is the first choice of treatment of obsessive–compulsive disorder (OCD) in children and adolescents. However, there is often a lack of access to appropriate treatment close to the home of the patients. An internet-based CBT via videoconferencing could facilitate access to state-of-the-art treatment even in remote areas. The aim of this study was to investigate feasibility and acceptability of this telemedical approach. A total of nine children received 14 sessions of CBT. The first session took place face-to-face, the remaining 13 sessions via videoconference. OCD symptoms were recorded with a smartphone app and therapy materials were made accessible in a data cloud. We assessed diagnostic data before and after treatment and obtained measures to feasibility, treatment satisfaction and acceptability. Outcomes showed high acceptance and satisfaction on the part of patients with online treatment (89%) and that face-to-face therapy was not preferred over an internet-based approach (67%). The majority of patients and their parents classified the quality of treatment as high. They emphasized the usefulness of exposures with response prevention (E/RP) in triggering situations at home. The app itself was rated as easy to operate and useful. In addition to feasibility, a significant decrease in obsessive–compulsive symptoms was also achieved. Internet-based CBT for pediatric OCD is feasible and well received by the patients and their parents. Furthermore, obsessive–compulsive symptomatology decreased in all patients. The results of this study are encouraging and suggest the significance of further research regarding this technology-supported approach, with a specific focus on efficacy.Trial registration number: Clinical trials AZ53-5400.1-004/44.

A correction to this paper has been published: https://doi.org/10.1007/s00228-021-03159-0

The human genetic dissection of clinical phenotypes is complicated by genetic heterogeneity. Gene burden approaches that detect genetic signals in case-control studies are underpowered in genetically heterogeneous cohorts. We therefore developed a genome-wide computational method, network-based heterogeneity clustering (NHC), to detect physiological homogeneity in the midst of genetic heterogeneity. Simulation studies showed our method to be capable of systematically converging genes in biological proximity on the background biological interaction network, and capturing gene clusters harboring presumably deleterious variants, in an efficient and unbiased manner. We applied NHC to whole-exome sequencing data from a cohort of 122 individuals with herpes simplex encephalitis (HSE), including 13 individuals with previously published monogenic inborn errors of TLR3-dependent IFN-α/β immunity. The top gene cluster identified by our approach successfully detected and prioritized all causal variants of five TLR3 pathway genes in the 13 previously reported individuals. This approach also suggested candidate variants of three reported genes and four candidate genes from the same pathway in another ten previously unstudied individuals. TLR3 responsiveness was impaired in dermal fibroblasts from four of the five individuals tested, suggesting that the variants detected were causal for HSE. NHC is, therefore, an effective and unbiased approach for unraveling genetic heterogeneity by detecting physiological homogeneity.

Although aripiprazole is one of the most used antipsychotics, knowledge about serum concentrations in children and adolescents is scarce and age-specific therapeutic ranges have not been established yet. Data of a routine therapeutic drug monitoring service were analyzed in order to evaluate the relationship between dose and serum concentration of aripiprazole in children and adolescents. The study also aimed to evaluate whether the therapeutic reference range defined for adults with schizophrenia (100-350ng/ml) is applicable for minors. Data from 130 patients (aged 7-19years) treated with aripiprazole for different indications in doses of 2-30mg/day were evaluated. Patient characteristics, doses, serum concentrations and therapeutic outcome were assessed by standardized measures. A positive mean correlation between body weight-corrected daily dose and aripiprazole concentration was found (rp = 0.59, p < 0.001) with variation in dose explaining 35% of the variability in serum concentrations. Girls had on average 41% higher dose-corrected concentrations than boys (244.9 versus 173.4mg/l; p = 0.006). Aripiprazole concentrations did not vary with co-medication (p = 0.22). About 70% of all measured serum concentrations were within the recommended therapeutic range for adults. Using a calculation method in all responding patients with an ICD-10 F2 diagnosis for a rough estimation of a preliminary therapeutic window also demonstrated a similar therapeutic range of aripiprazole in minors (105.9-375.3ng/ml) than for adults. If confirmed in larger samples and more controlled study designs, these data may contribute to the definition of a therapeutic range of aripiprazole concentrations in children and adolescents.