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Design: Meta-research., Objective: To compare the prevalence of reporting p values, effect estimates and clinical relevance in physiotherapy randomised controlled trials (RCTs) published in the years 2000 and 2018., Methods: We performed a meta-research study of physiotherapy RCTs obtained from six major physiotherapy peer-reviewed journals that were published in the years 2000 and 2018. We searched the databases Embase, Medline and PubMed in May 2019, and extracted data on the study characteristics and whether articles reported on statistical significance, effect estimates and confidence intervals for baseline, between-group, and within-group differences, and clinical relevance. Data were presented using descriptive statistics and inferences were made based on proportions. A 20% difference between 2000 and 2018 was regarded as a meaningful difference., Results: We found 140 RCTs: 39 were published in 2000 and 101 in 2018. Overall, there was a high prevalence (>90%) of reporting p values for the main (between-group) analysis, with no difference between years. Statistical significance testing was frequently used for evaluating baseline differences, increasing from 28% in 2000 to 61.4% in 2018. The prevalence of reporting effect estimates, CIs and the mention of clinical relevance increased from 2000 to 2018 by 26.6%, 34% and 32.8% respectively. Despite an increase in use in 2018, over 40% of RCTs failed to report effect estimates, CIs and clinical relevance of results., Conclusion: The prevalence of using p values remains high in physiotherapy research. Although the proportion of reporting effect estimates, CIs and clinical relevance is higher in 2018 compared to 2000, many publications still fail to report and interpret study findings in this way., Competing Interests: Competing interests: AV was a member of the editorial board of the J Physiother (until 2020) and currently is an associate editor of the J Orthop Sports Phys Ther., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract Background Increasingly, researchers are involving children and young people in designing paediatric research agendas, but as far as we were able to determine, only one report exists on the academic impact of such an agenda. In our opinion, the importance of insight into the impact of research agendas designed together with children and young people cannot be overstated. The first aim of our study was therefore to develop a method to describe the academic impact of paediatric research agendas. Our second aim was to describe the academic impact of research agendas developed by involving children and young people. Methods We based our method on aspects of the Research Impact Framework developed by Kuruvilla and colleagues and the Payback Framework developed by Donovan and Hanney. We named it Descriptive Academic Impact Analysis of Paediatric Research Agendas, consisting of five steps: [1] Identification of paediatric research agendas, [2] Citation analysis, [3] Impact analysis, [4] Author assessment, and [5] Classification of the ease of determining traceability. Results We included 31 paediatric research agendas that were designed by involving children and young people. These agendas were cited 517 times, ranging from 0 to 71 citations. A total of 131 new studies (25%) were published, ranging from 0 to 23 per paediatric research agenda, based on at least one of the research priorities from the agenda. Sixty studies (46%) were developed by at least one of the first, second, or last authors of the paediatric research agenda on which the studies were based. Based on their accessibility and the ease with which we could identify the studies as being agenda-based, we categorised 44 studies (34%) as easy, 62 studies (47%) as medium, and 25 studies (19%) as difficult to identify. Conclusion This study reports on the development of a method to describe the academic impact of paediatric research agendas and it offers insight into the impact of 31 such agendas. We recommend that our results be used as a guide for designing future paediatric research agendas, especially by including ways of tracing the academic impact of new studies concerning the agendas’ research priorities.

Transcranial ultrasonic stimulation (TUS) is rapidly emerging as a promising non-invasive neuromodulation technique. TUS is already well-established in animal models, providing foundations to now optimize neuromodulatory efficacy for human applications. Across multiple studies, one promising protocol, pulsed at 1000 Hz, has consistently resulted in motor cortical inhibition in humans (Fomenko et al., 2020). At the same time, a parallel research line has highlighted the potentially confounding influence of peripheral auditory stimulation arising from TUS pulsing at audible frequencies. In this study, we disentangle direct neuromodulatory and indirect auditory contributions to motor inhibitory effects of TUS. To this end, we include tightly matched control conditions across four experiments, one preregistered, conducted independently at three institutions. We employed a combined transcranial ultrasonic and magnetic stimulation paradigm, where TMS-elicited motor-evoked potentials (MEPs) served as an index of corticospinal excitability. First, we replicated motor inhibitory effects of TUS but showed through both tight controls and manipulation of stimulation intensity, duration, and auditory masking conditions that this inhibition was driven by peripheral auditory stimulation, not direct neuromodulation. Furthermore, we consider neuromodulation beyond driving overall excitation/inhibition and show preliminary evidence of how TUS might interact with ongoing neural dynamics instead. Primarily, this study highlights the substantial shortcomings in accounting for the auditory confound in prior TUS-TMS work where only a flip-over sham and no active control was used. The field must critically reevaluate previous findings given the demonstrated impact of peripheral confounds. Furthermore, rigorous experimental design via (in)active control conditions is required to make substantiated claims in future TUS studies. Only when direct effects are disentangled from those driven by peripheral confounds can TUS fully realize its potential for research and clinical applications.

In order to survive, animals often need to navigate a complex odor landscape where odors can exist in airborne plumes. Several odor plume properties change with distance from the odor source, providing potential navigational cues to searching animals. Here, we focus on odor intermittency, a temporal odor plume property that measures the fraction of time odor is above a threshold at a given point within the plume and decreases with increasing distance from the odor source. We sought to determine if mice can use changes in intermittency to locate an odor source. To do so, we trained mice on an intermittency discrimination task. We establish that mice can discriminate odor plume samples of low and high intermittency and that the neural responses in the olfactory bulb can account for task performance and support intermittency encoding. Modulation of sniffing, a behavioral parameter that is highly dynamic during odor-guided navigation, affects both behavioral outcome on the intermittency discrimination task and neural representation of intermittency. Together, this work demonstrates that intermittency is an odor plume property that can inform olfactory search and more broadly supports the notion that mammalian odor-based navigation can be guided by temporal odor plume properties.

Abstract Intrinsic or added immune activating molecules are key for most vaccines to provide desired immunity profiles but may increase systemic reactogenicity. Regulatory agencies require rabbit pyrogen testing (RPT) for demonstration of vaccine reactogenicity. Recently, the monocyte activation test (MAT) gained popularity as in vitro alternative, yet this assay was primarily designed to test pyrogen-free products. The aim was to adjust the MAT to enable testing of pyrogen containing vaccines in an early stage of development where no reference batch is yet available. The MAT and RPT were compared for assessing unknown safety profiles of pertussis outer membrane vesicle (OMV) vaccine candidates to those of Bexsero as surrogate reference vaccine. Pertussis OMVs with wild-type LPS predominantly activated TLR2 and TLR4 and were more reactogenic than Bexsero. However, this reactogenicity profile for pertussis OMVs could be equalized or drastically reduced compared to Bexsero or a whole-cell pertussis vaccine, respectively by dose changing, modifying the LPS, intranasal administration, or a combination of these. Importantly, except for LPS modified products, reactogenicity profiles obtained with the RPT and MAT were comparable. Overall, we demonstrated that this pertussis OMV vaccine candidate has an acceptable safety profile. Furthermore, the MAT proved its applicability to assess reactogenicity levels of pyrogen containing vaccines at multiple stages of vaccine development and could eventually replace rabbit pyrogen testing.

SARS-CoV-2 infections elicit antibodies against the viral spike (S) and nucleocapsid (N) proteins; COVID-19 vaccines against the S-protein only. The BCG-Corona trial, initiated in March 2020 in SARS-CoV-2-naïve Dutch healthcare workers, captured several epidemic peaks and the introduction of COVID-19 vaccines during the one-year follow-up. We assessed determinants of systemic anti-S1 and anti-N immunoglobulin type G (IgG) responses using trial data. Participants were randomised to BCG or placebo vaccination, reported daily symptoms, SARS-CoV-2 test results, and COVID-19 vaccinations, and donated blood for SARS-CoV-2 serology at two time points. In the 970 participants, anti-S1 geometric mean antibody concentrations (GMCs) were much higher than anti-N GMCs. Anti-S1 GMCs significantly increased with increasing number of immune events (SARS-CoV-2 infection or COVID-19 vaccination): 104.7 international units (IU)/mL, 955.0 IU/mL, and 2290.9 IU/mL for one, two, and three immune events, respectively (p < 0.001). In adjusted multivariable linear regression models, anti-S1 and anti-N log10 concentrations were significantly associated with infection severity, and anti-S1 log10 concentration with COVID-19 vaccine type/dose. In univariable models, anti-N log10 concentration was also significantly associated with acute infection duration, and severity and duration of individual symptoms. Antibody concentrations were not associated with long COVID or long-term loss of smell/taste.

ObjectiveTo investigate the effect of an active choice (AC) intervention based on creating risk and choice awareness-versus a passive choice (PC) control group-on intentions and commitment to cardiovascular disease (CVD) risk-reducing behavior.MethodsAdults aged 50-70 (n = 743) without CVD history participated in this web-based randomized controlled trial. The AC intervention included presentation of a hypothetical CVD risk in a heart age format, information about CVD risk and choice options, and a values clarification exercise. The PC group received a hypothetical absolute numerical CVD risk and brief information and advice about lifestyle and medication. Key outcomes were reported degree of active choice, intention strength, and commitment to adopt risk-reducing behavior.ResultsMore AC compared to PC participants opted for lifestyle change (OR = 2.86, 95%CI:1.51;5.44), or lifestyle change and medication use (OR = 2.78, 95%CI:1.42;5.46), than 'no change'. No differences were found for intention strength. AC participants made a more active choice than PC participants (β = 0.09, 95%CI:0.01;0.16), which was sequentially mediated by cognitive risk perception and negative affect. AC participants also reported higher commitment to CVD risk-reducing behavior (β = 0.32, 95%CI:0.04;0.60), mediated by reported degree of active choice.ConclusionsFostering active choices increased intentions and commitment towards CVD risk-reducing behavior. Increased cognitive risk perception and negative affect were shown to mediate the effect of the intervention on degree of active choice, which in turn mediated the effect on commitment. Future research should determine whether fostering active choice also improves risk-reducing behaviors in individuals at increased CVD risk in real-life settings.Trial registrationClinicalTrials.gov: NCT05142280. Prospectively registered.

Summary: Background: Mycoplasma pneumoniae is a common cause of community-acquired pneumonia in school-aged children and can be preceded by asymptomatic carriage. However, its role in recurrent respiratory tract infections is unclear. We studied the prevalence of M.pneumoniae carriage in children with recurrent respiratory infections and identified associated factors. Methods: We tested M.pneumoniae carriage by qPCR in children with recurrent infections and their healthy family members in a cross-sectional study. Serum and mucosal total and M.pneumoniae-specific antibody levels were measured by ELISA and nasopharyngeal microbiota composition was characterized by 16S-rRNA sequencing. Findings: Prevalence of M.pneumoniae carriage was higher in children with recurrent infections (68%) than their family members without infections (47% in siblings and 27% in parents). M.pneumoniae carriage among family members appeared to be associated with transmission within the household, likely originating from the affected child. In logistic regression corrected for age and multiple comparisons, IgA (OR 0.16 [0.06–0.37]) and total IgG deficiency (OR 0.15 [0.02–0.74]) were less prevalent in M.pneumoniae carriers (n = 78) compared to non-carriers (n = 36). In multivariable analysis, the nasopharyngeal microbiota of M.pneumoniae carriers had lower alpha diversity (OR 0.27 [0.09–0.67]) and a higher abundance of Haemophilus influenzae (OR 45.01 [2.74–1608.11]) compared to non-carriers. Interpretation: M.pneumoniae carriage is highly prevalent in children with recurrent infections and carriers have a less diverse microbiota with an overrepresentation of disease-associated microbiota members compared to non-carriers. Given the high prevalence of M.pneumoniae carriage and the strong association with H. influenzae, we recommend appropriate antibiotic coverage of M.pneumoniae and H. influenzae in case of suspected pneumonia in children with recurrent respiratory tract infections or their family members. Funding: Wilhelmina Children’s Hospital Research Fund, ‘Christine Bader Stichting Irene KinderZiekenhuis’, Sophia Scientific Research Foundation, ESPID Fellowship funded by Seqirus, Hypatia Fellowship funded by Radboudumc and The Netherlands Organisation for Health Research and Development (ZonMW VENI grant to LM Verhagen).

ABSTRACTBackground Intrinsic values and priorities influence decision-making and are, therefore, important to consider explicitly in intervention development. Although health is generally considered an important value, individuals often make unhealthy choices, indicating a values disconnect.Study aim To investigate how becoming aware of a disconnect between the value assigned to health and the effort devoted to health is related to intentions and commitment for behavioural change and physical activity among inactive adults.Methods We performed a secondary exploratory analysis on previously collected data. The intervention included a values exercise based on the Disconnected Values Model (DVM) that made disconnected values explicit to participants in two study arms. We compared participants with a disconnect (n = 138) with participants without a disconnect (n = 101) regarding intentions and commitment for behavioural change and physical activity and sitting time 2–4 weeks follow-up. Logistic and linear regression analyses were performed to analyse the data.Results Between-group differences were found for the intention to devote more effort to health (OR = 3.75; 95%CI: 2.05; 6.86) and for the intention to become more physically active (OR = 2.21; 95%CI: 1.10; 4.46), indicating that significantly more participants with a disconnect were motivated to change, compared to participants without a disconnect. No between-group differences were found for commitment, intention strength, follow-up physical activity and sitting time.Conclusion Making explicit a disconnect regarding health in an active choice intervention was associated with intentions to become more physically active. Still, it did not translate in significant behaviour change at 2–4 weeks follow-up.Trial registration ClinicalTrials.gov: NCT04973813. Retrospectively registered.Trial registration: ClinicalTrials.gov identifier: NCT04973813..

BackgroundAlthough pre-exposure prophylaxis (PrEP) could substantially mitigate HIV risk, sexual minority men who use stimulants commonly experience difficulties with engaging in PrEP clinical services. Motivational interviewing (MI) and contingency management (CM) reduce substance use and condomless anal sex (CAS) in this population, but these motivational enhancement interventions require modifications to promote engagement along the PrEP care continuum. ObjectivePrEP Readiness Interventions for Supporting Motivation (PRISM) is a pilot sequential multiple assignment randomized trial testing the feasibility, acceptability, and preliminary effectiveness of distinct combinations of telehealth MI and CM in 70 cisgender sexual minority men who use stimulants that are not currently taking PrEP. MethodsA national sample was recruited via social networking applications to complete a baseline assessment and mail-in HIV testing. Those with nonreactive HIV results were randomized to receive either (1) a 2-session MI intervention focusing on PrEP use (session 1) and concomitant stimulant use or CAS (session 2) or (2) a CM intervention with financial incentives for documented evidence of PrEP clinical evaluation by a medical provider (US $50) and filling a PrEP prescription (US $50). At the 3-month follow-up assessment, participants who reported they had not filled a prescription for PrEP were randomized a second time to either (1) switch to a second-stage intervention (ie, MI+CM or CM+MI) or (2) continue with assessments only. Outcomes for both responders and nonresponders were reassessed at a 6-month follow-up. The primary outcome is documented evidence of filling a PrEP prescription over 6 months. Self-reported secondary outcomes include PrEP clinical evaluation by a medical provider, stimulant use, and CAS. Qualitative exit interviews were conducted with a subgroup of responders and nonresponders to characterize their experiences with the MI and CM interventions. ResultsImplementation of PRISM underscores challenges in reaching sexual minority men who use stimulants to optimize HIV prevention efforts. Approximately 1 in 10 (104/1060) eligible participants have enrolled. Of the 104 who enrolled, 87 (84%) completed mail-in HIV testing. We delivered 5 preliminary HIV-positive results, including posttest counseling with referrals to confirmatory testing. ConclusionsLessons learned from PRISM underscore the central importance of a flexible, participant-centered approach to support the engagement of sexual minority men who use stimulants. Leveraging telehealth platforms to deliver motivational enhancement interventions also expanded their reach and potential public health impact with this high-priority population. Further research is needed to determine the effectiveness of telehealth MI and CM for supporting PrEP use in sexual minority men who use stimulants. Trial RegistrationClinicalTrials.gov NCT04205487; https://clinicaltrials.gov/study/NCT04205487 International Registered Report Identifier (IRRID)DERR1-10.2196/48459

Pediatric cardiomyopathy (CM) represents a group of rare, severe disorders that affect the myocardium. To date, the etiology and mechanisms underlying pediatric CM are incompletely understood, hampering accurate diagnosis and individualized therapy development. Here, we identified biallelic variants in the highly conserved flightless-I (FLII) gene in 3 families with idiopathic, early-onset dilated CM. We demonstrated that patient-specific FLII variants, when brought into the zebrafish genome using CRISPR/Cas9 genome editing, resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in our patients. Importantly, using these genetic animal models, complemented with in-depth loss-of-function studies, we provided insights into the function of Flii during ventricular chamber morphogenesis in vivo, including myofibril organization and cardiomyocyte cell adhesion, as well as trabeculation. In addition, we identified Flii function to be important for the regulation of Notch and Hippo signaling, crucial pathways associated with cardiac morphogenesis and function. Taken together, our data provide experimental evidence for a role for FLII in the pathogenesis of pediatric CM and report biallelic variants as a genetic cause of pediatric CM.

Introduction Acute mesenteric ischaemia (AMI) is a life-threatening condition with short-term mortality of up to 80%. The diagnosis of AMI has remained troublesome due to the non-specific clinical presentation, symptoms and laboratory findings. Early unambiguous diagnosis of AMI is critical to prevent progression from reversible to irreversible transmural intestinal damage, thereby decreasing morbidity and improving survival. The present study aims to validate a panel of plasma biomarkers and investigate volatile organic compound (VOC) profiles in exhaled air as a tool to timely and accurately diagnose AMI.Methods and analysis In this international multicentre prospective observational study, 120 patients (>18 years of age) will be recruited with clinical suspicion of AMI. Clinical suspicion is based on: (1) clinical manifestation, (2) physical examination, (3) laboratory measurements and (4) the physician’s consideration to perform a CT scan. The patient’s characteristics, repetitive blood samples and exhaled air will be prospectively collected. Plasma levels of mucosal damage markers intestinal fatty acid-binding protein and villin-1, as well as transmural damage marker smooth muscle protein 22-alpha, will be assessed by ELISA. Analysis of VOCs in exhaled air will be performed by gas chromatography time-of-flight mass spectrometry. Diagnosis of AMI will be based on CT, endovascular and surgical reports, clinical findings, and (if applicable) verified by histopathological examination.Ethics and dissemination The study protocol was approved by the Medical Research Ethics Committee (METC) of Maastricht University Medical Centre+ and Maastricht University (METC azM/UM), the Netherlands (METC19-010) and the Ethics Committee Research UZ/KU Leuven, Belgium (S63500). Executive boards and local METCs of other Dutch participating centres Gelre Ziekenhuizen (Apeldoorn), Medisch Spectrum Twente (Enschede), and University Medical Centre Groningen have granted permission to carry out this study. Study results will be disseminated via open-access peer-reviewed scientific journals and national/international conferences.Trial registration number NCT05194527.

Abstract Background Core outcome sets (COSs) aim to reduce outcome heterogeneity in clinical practice and research by suggesting a minimum number of agreed-upon outcomes in clinical trials. Most COSs in the musculoskeletal field are developed for specific conditions. We propose that there are likely to be common core domains within existing musculoskeletal COSs that may be used as a starting point in the development of future COSs. We aim to identify common core domains from existing COSs and to facilitate the development of new COSs for musculoskeletal conditions. As a secondary aim, we will assess the development quality of these COSs. Methods A systematic review including musculoskeletal COSs. We will search Core Outcome Measures in Effectiveness Trials (COMET) database, MEDLINE, EMBASE, Scopus, Cochrane Methodology Register and International Consortium for Health Outcome Measurement (ICHOM). Studies will be included if related to the development of a COS in adults with musculoskeletal conditions and for any type of intervention. Quality will be assessed using the Core Outcome Set-Standards for Development (COS-STAD) recommendations. Data extracted will include scope of the COS, health condition, interventions and outcome domains. Primary outcomes will be all core domains recommended within each COS. We define a common core outcome domain as one present in at least 67% of all COSs. All findings will be summarized and presented using descriptive statistics. Discussion This systematic review of COSs will describe the core domains recommended within each musculoskeletal COS. Common domains found may be used in the initial stages of development of future musculoskeletal COSs. Systematic review registration PROSPERO CRD42021239141

Abstract A range of public health measures have been implemented to suppress local transmission of coronavirus disease 2019 (COVID-19) in Shenzhen. We examined the effect of these measures on the prevalence of respiratory pathogens in children. Clinical and respiratory pathogen data were collected for routine care from hospitalized children with acute respiratory infections in Shenzhen Children’s Hospital from July 2018 to January 2022. Nasopharyngeal swabs were collected and respiratory pathogens were detected using standardized clinical diagnostics as part of routine care. Data were analyzed to describe the effects of COVID-19 prevention procedures on other common pathogens. A total of 56,325 children under 14 years of age were hospitalized with an acute respiratory infection during the study period, 33,909 were tested from July 2018 to January 2020 (pre-lockdown), 1168 from February 2020 to May 2020 (lockdown) and 21,248 from July 2020 to January 2022 (post-lockdown). We observed a 37.3% decline of routine care in respiratory infection associated hospital admission in the 19 months’ post-lockdown vs. the 19 months’ pre-lockdown. There were 99.4%, 16.0% and 1.26% reductions measured for Mycoplasma pneumoniae, influenza virus A and adenovirus, respectively. However, a 118.7% and 75.8% rise was found for respiratory syncytial virus (RSV) and human para-influenza virus (HPIV) during the 19 months’ post-lockdown in comparison to the pre-pandemic period. The detection of RSV especially increased in toddlers after the lockdown. Lockdown measures during the COVID-19 pandemic led to a significant reduction of Mycoplasma pneumoniae, influenza virus A and adenovirus infection. In contrast, RSV and HPIV infection increased.

Background: Identification of SARS-CoV-2 infected individuals is imperative to prevent hospital transmission, but symptom-based screening may fail to identify asymptomatic/mildly symptomatic infectious children and their caregivers. Methods: A COVID-19 period prevalence study was conducted between 13 and 26 August 2020 at Tygerberg Hospital, testing all children and their accompanying asymptomatic caregivers after initial symptom screening. One nasopharyngeal swab was submitted for SARS-CoV-2 using real-time reverse-transcription polymerase chain reaction (rRT-PCR). An additional Respiratory Viral 16-multiplex rRT-PCR test was simultaneously done in children presenting with symptoms compatible with possible SARS-CoV-2 infection. Results: SARS-Co-V 2 RT-PCR tests from 196 children and 116 caregivers were included in the analysis. The SARS-CoV-2 period prevalence in children was 5.6% (11/196) versus 15.5% (18/116) in asymptomatic caregivers (p

Objectives While protection against pertussis following maternal tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccination was demonstrated in healthy term-born infants, no evidence is available on Tdap vaccination in combination with immune-modulating therapy during pregnancy. In this pilot study, we explored whether treatment with tumour necrosis factor alpha inhibitors (TNFis) in pregnant patients with rheumatic disease interferes with Tdap vaccine responses and affects maternal anti-pertussis IgG antibody levels in newborns.Methods Patients were included by a rheumatologist during pregnancy in case they received maternal Tdap vaccination in the late-second or early-third trimester of pregnancy. Blood samples were obtained from mothers during the first pregnancy trimester, 3 months after delivery and from the umbilical cord. IgG antibody levels against Tdap-included antigens were measured using a bead-based multiplex immunoassay. Findings on patients exposed to TNFis were compared with those from TNFi-unexposed patients and with data from a historical comparator study among healthy Tdap vaccinated mother–infant pairs (n=53).Results 66 patients (46 exposed and 20 unexposed to TNFIs) were enrolled. No major differences in IgG antibody levels were observed between TNFi-exposed and unexposed mothers before maternal Tdap vaccination and 3 months after delivery. In cord sera, however, antibody levels against pertussis toxin were significantly lower after TNFi-treatment (35.94 IU/mL, 95% CI 20.68 to 62.45) compared with no TNFi-treatment of mothers with rheumatic disease (94.61 IU/mL, 95% CI 48.89 to 183.07) and lower compared with a cohort of healthy mothers (125.12 IU/mL, 95% CI 90.75 to 172.50). We observed similar differences for filamentous haemagglutinin, pertactin, tetanus toxoid and diphtheria toxoid.Conclusion These preliminary data indicate no major differences in IgG antibody levels on maternal Tdap vaccination in pregnant women with or without immune-modulating treatment, although our findings suggest that TNFis during pregnancy induce lower maternal anti-pertussis-specific protective antibody levels in newborns.

Respiratory Syncytial Virus (RSV) poses a severe threat to infants, particularly preterm infants. Palivizumab, the standard preventive prophylaxis, is primarily utilized in high-risk newborns due to its cost. This study assessed palivizumab’s effectiveness in preventing RSV infections in predominantly very preterm infants during their first year of life. Serum samples from a prospective multicentre cohort study in the Netherlands were analyzed to assess RSV infection rates by measuring IgG levels against three RSV proteins: nucleoprotein, pre-fusion, and post-fusion protein. Infants were stratified based on gestational age (GA), distinguishing very preterm (≤32 weeks GA) from moderate/late preterm (>32 to ≤36 weeks GA). In very preterm infants, palivizumab prophylaxis significantly reduced infection rates (18.9% vs. 48.3% in the prophylaxis vs. non-prophylaxis group. Accounting for GA, sex, birth season, and birth weight, the prophylaxis group showed significantly lower infection odds. In infants with >32 to ≤36 weeks GA, the non-prophylaxis group (55.4%) showed infection rates similar to the non-prophylaxis ≤32-week GA group, despite higher maternal antibody levels in the moderate/late preterm infants. In conclusion, palivizumab prophylaxis significantly reduces RSV infection rates in very premature infants. Future research should explore clinical implications and reasons for non-compliance, and compare palivizumab with emerging prophylactics like nirsevimab aiming to optimize RSV prophylaxis and improve preterm infant outcomes.

Abstract Several human pathogens exhibit distinct patterns of seasonality and circulate as pairs. For instance, influenza A virus subtypes oscillate and peak during winter seasons of the world’s temperate climate zones. Alternation of dominant strains in successive influenza seasons makes epidemic forecasting a major challenge. From the start of the 2009 influenza pandemic we enrolled influenza A virus infected patients (n = 2980) in a global prospective clinical study. Complete hemagglutinin sequences were obtained from 1078 A/H1N1 and 1033 A/H3N2 viruses. We used phylodynamics to construct high resolution spatio-temporal phylogenetic hemagglutinin trees and estimated global influenza A effective reproductive numbers (R) over time (2009–2013). We demonstrate that R oscillates around R = 1 with a clear opposed alternation pattern between phases of the A/H1N1 and A/H3N2 subtypes. Moreover, we find a similar alternation pattern for the number of global viral spread between the sampled geographical locations. Both observations suggest a between-strain competition for susceptible hosts on a global level. Extrinsic factors that affect person-to-person transmission are a major driver of influenza seasonality. The data presented here indicate that cross-reactive host immunity is also a key intrinsic driver of influenza seasonality, which determines the influenza A virus strain at the onset of each epidemic season.

Background: Type I interferons (IFNs) promote the expansion of subsets of CD1c+ conventional dendritic cells (CD1c+ DCs), but the molecular basis of CD1c+ DCs involvement in conditions not associated without elevated type I IFNs remains unclear. Methods: We analyzed CD1c+ DCs from two cohorts of non-infectious uveitis patients and healthy donors using RNA-sequencing followed by high-dimensional flow cytometry to characterize the CD1c+ DC populations. Results: We report that the CD1c+ DCs pool from patients with non-infectious uveitis is skewed toward a gene module with the chemokine receptor CX3CR1 as the key hub gene. We confirmed these results in an independent case–control cohort and show that the disease-associated gene module is not mediated by type I IFNs. An analysis of peripheral blood using flow cytometry revealed that CX3CR1+ DC3s were diminished, whereas CX3CR1− DC3s were not. Stimulated CX3CR1+ DC3s secrete high levels of inflammatory cytokines, including TNF-alpha, and CX3CR1+ DC3 like cells can be detected in inflamed eyes of patients. Conclusions: These results show that CX3CR1+ DC3s are implicated in non-infectious uveitis and can secrete proinflammatory mediators implicated in its pathophysiology. Funding: The presented work is supported by UitZicht (project number #2014-4, #2019-10, and #2021-4). The funders had no role in the design, execution, interpretation, or writing of the study.

BackgroundSevere childhood infection has a dose-dependent association with adult cardiovascular events and with adverse cardiometabolic phenotypes. The relationship between cardiovascular outcomes and less severe childhood infections is unclear.AimTo investigate the relationship between common, non-hospitalised infections, antibiotic exposure, and preclinical vascular phenotypes in young children.DesignA Dutch prospective population-derived birth cohort study.MethodsParticipants were from the Wheezing-Illnesses-Study-Leidsche-Rijn (WHISTLER) birth cohort. We collected data from birth to 5 years on antibiotic prescriptions, general practitioner (GP)-diagnosed infections, and monthly parent-reported febrile illnesses (0-1 years). At 5 years, carotid intima-media thickness (CIMT), carotid artery distensibility, and blood pressure (BP) were measured. General linear regression models were adjusted for age, sex, smoke exposure, birth weight z-score, body mass index, and socioeconomic status.ResultsRecent antibiotic exposure was associated with adverse cardiovascular phenotypes; each antibiotic prescription in the 3 and 6 months prior to vascular assessment was associated with an 18.1 μm (95% confidence interval, 4.5-31.6, p = 0.01) and 10.7 μm (0.8-20.5, p = 0.03) increase in CIMT, respectively. Each additional antibiotic prescription in the preceding 6 months was associated with an 8.3 mPa-1 decrease in carotid distensibility (-15.6- -1.1, p = 0.02). Any parent-reported febrile episode (compared to none) showed weak evidence of association with diastolic BP (1.6 mmHg increase, 0.04-3.1, p = 0.04). GP-diagnosed infections were not associated with vascular phenotypes.ConclusionsRecent antibiotics are associated with adverse vascular phenotypes in early childhood. Mechanistic studies may differentiate antibiotic-related from infection-related effects and inform preventative strategies.

Phenotypic plasticity allows carcinoma cells to transiently acquire the quasi-mesenchymal features necessary to detach from the primary mass and proceed along the invasion-metastasis cascade. A broad spectrum of epigenetic mechanisms is likely to cause the epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transitions necessary to allow local dissemination and distant metastasis. Here, we report on the role played by alternative splicing (AS) in eliciting phenotypic plasticity in epithelial malignancies with focus on colon cancer. By taking advantage of the coexistence of subpopulations of fully epithelial (EpCAMhi) and quasi-mesenchymal and highly metastatic (EpCAMlo) cells in conventional human cancer cell lines, we here show that the differential expression of ESRP1 and other RNA-binding proteins (RBPs) downstream of the EMT master regulator ZEB1 alters the AS pattern of a broad spectrum of targets including CD44 and NUMB, thus resulting in the generation of specific isoforms functionally associated with increased invasion and metastasis. Additional functional and clinical validation studies indicate that both the newly identified RBPs and the CD44s and NUMB2/4 splicing isoforms promote local invasion and distant metastasis and are associated with poor survival in colon cancer. The systematic elucidation of the spectrum of EMT-related RBPs and AS targets in epithelial cancers, apart from the insights in the mechanisms underlying phenotypic plasticity, will lead to the identification of novel and tumor-specific therapeutic targets.

Purpose Doppler ultrasound (DUS) is widely used to detect vascular complications after pediatric liver transplantation (LT). This study aimed to assess the moment of first detection of vascular complications with DUS, and to determine the positive predictive value (PPV) of DUS.

Introduction Previous studies showed that the Nordic hamstring exercise (NHE) effectively prevents primary hamstring injury. However, no study investigated the secondary preventing effect of the NHE on hamstring reinjury. The primary purpose of this study is to investigate the effectiveness of the NHE for preventing hamstring reinjury after return to play (RTP) following a hamstring injury in football players. The secondary purpose is to determine the effect of the NHE on sprint and jump performance.Methods and analysis This is an international multicentre, prospective, parallel-group randomised controlled trial study. Subjects include male or female football players aged 18–40 years and within 1 week of RTP following a hamstring injury will be randomised into Nordics or a control group. Subjects in both groups continue their regular football training, but the Nordics group will perform an additional NHE programme. An online questionnaire will be sent to the subjects in both groups once per week within the first 10 weeks, then continued at months 6, 9 and 12. In a (performance) substudy, we will evaluate the effect of the NHE on sprint and vertical jump performance at three time points (at the beginning of the study, after 10 weeks and 12 months of follow-up).The primary outcomes are the incidence of hamstring reinjury within 2 and 12 months. The secondary outcomes are sprint and jump performance, adherence to the programme, duration of reinjury and reinjury burden.Ethics and dissemination This study is approved by the medical ethics committee of Amsterdam University Medical Center (UMC) in the Netherlands (METC 2021_117), Faculty of Medicine Universitas Gadjah Mada in Indonesia (KE/FK/1248/EC/2021), Norwegian School of Sport Sciences in Norway (number 216–2 70 122) and Denmark (ethical submission in process). The study’s findings will be disseminated in scientific peer-reviewed journals and presented at international conferences.Trial registration number NL9711.

Abstract Background To compare symptoms of clinical androgen deficiency between men with migraine, men with cluster headache and non-headache male controls. Methods We performed a cross-sectional study using two validated questionnaires to assess symptoms of androgen deficiency in males with migraine, cluster headache, and non-headache controls. Primary outcome was the mean difference in androgen deficiency scores. Generalized linear models were used adjusting for age, BMI, smoking and lifetime depression. As secondary outcome we assessed the percentage of patients reporting to score below average on four sexual symptoms (beard growth, morning erections, libido and sexual potency) as these items were previously shown to more specifically differentiate androgen deficiency symptoms from (comorbid) anxiety and depression. Results The questionnaires were completed by n = 534/853 (63%) men with migraine, n = 437/694 (63%) men with cluster headache and n = 152/209 (73%) controls. Responders were older compared to non-responders and more likely to suffer from lifetime depression. Patients reported more severe symptoms of clinical androgen deficiency compared with controls, with higher AMS scores (Aging Males Symptoms; mean difference ± SE: migraine 5.44 ± 0.90, p

Plain English summary A growing trend in research is to involve co-researchers. It is called Patient and Public Involvement (PPI) and includes three groups: the patients, the public, and the researchers. In child-inclusive research the patients are children with a medical condition while the public is represented by healthy children. Generally, the attitudes of patients and researchers are heard, while the public is often unheard. We aimed to give a voice to healthy children and researchers without prior experience in child-inclusive research to determine their attitudes towards the challenges encountered. We interviewed seven healthy children and five researchers without prior experience in child-inclusive research. Both groups thought that it is best to involve children in research from as early a stage as possible. The children saw no added value in training children to be involved in child-inclusive research. The attitudes of researchers varied on this point. Both groups thought that researchers did not require prior training on how to involve children provided they already worked with children on a day-to-day basis. Children thought a modest financial reward would be appropriate, while researchers were cautious about giving a reward. Our study indicated that both groups had clear attitudes about the challenges encountered during child-inclusive research. Young researchers could help adult researchers to find solutions to these challenges, even if they have no prior experience in child-inclusive research. Our results imply that children could be involved in the decision-making process concerning the challenges encountered in child-inclusive research.

BackgroundThere is growing evidence of the benefits of mobile health technology, which include symptom tracking apps for research, surveillance, and prevention. No study has yet addressed arbovirus symptom tracking in pregnancy. ObjectiveThis study aimed to evaluate the use of a smartphone app (ZIKApp) to self-report arbovirus symptoms and pregnancy complications and to assess compliance with daily symptom diaries during pregnancy in a cohort of women in an arbovirus-endemic, subtropical, middle-income country (Jamaica). MethodsPregnant women aged ≥16 years, having a smartphone, and planning on giving birth at the recruiting center were enrolled between February 2020 and July 2020. ZIKApp comprised a daily symptom diary based on algorithms to identify potential episodes of arbovirus infection and pregnancy complications. Sociodemographic, epidemiological, and obstetric information was collected at enrollment, with additional review of medical records, and users’ perception was collected through an exit survey. Descriptive analyses and logistic regression analysis of possible factors associated with diary adherence were performed. ResultsOf the 173 women enrolled, 157 (90.8%) used ZIKApp for a median duration of 155 (IQR 127-173) days until pregnancy end, 6 (3.5%) used the app for 34 years versus those aged 25 to 29 years (adjusted odds ratio 3.14, 95% CI 1.10-8.98) and 2-fold higher odds for women with tertiary versus secondary education (adjusted odds ratio 2.26, 95% CI 1.06-4.83). Of the 161 women who ever made a diary entry, 5454 individual symptom reports were made (median 17 per woman; IQR 4-42; range 0-278); 9 (5.6%) women reported symptom combinations triggering a potential arbovirus episode (none had an adverse pregnancy outcome) and 55 (34.2%) reported painful uterine contractions or vaginal bleeding, mainly in the month before delivery. Overall, 51.8% (71/137) of the women rated the app as an excellent experience and were less likely to be poor diary adherers (P=.04) and 99.3% (138/139) reported that the app was easy to understand and use. ConclusionsThis pilot found a high adherence to ZIKApp. It demonstrated the feasibility and usability of the app in an arbovirus-endemic region, supporting its future development to contribute to surveillance and diagnosis of arbovirus infections in pregnancy and to optimize maternal care.

[This corrects the article DOI: 10.1371/journal.pone.0260952.].

BackgroundAlmost 200 million children worldwide are either undernourished or overweight. Only a few studies have addressed the effect of variation in nutritional status on vaccine response. We previously demonstrated an association between stunting and an increased post-vaccination 13-valent pneumococcal conjugate vaccine (PCV13) response. In this prospective study, we assessed to what extent metabolic hormones may be a modifier in the association between nutritional status and PCV13 response.MethodsVenezuelan children aged 6 weeks to 59 months were vaccinated with a primary series of PCV13. Nutritional status and serum levels of leptin, adiponectin and ghrelin were measured upon vaccination and their combined effect on serum post-vaccination antibody concentrations was assessed by generalized estimating equations multivariable regression analysis.ResultsA total of 210 children were included, of whom 80 were stunted, 81 had a normal weight and 49 were overweight. Overweight children had lower post-vaccination antibody concentrations than normal weight children (regression coefficient -1.15, 95% CI -2.22 --0.072). Additionally, there was a significant adiponectin-nutritional status interaction. In stunted children, higher adiponectin serum concentrations were associated with lower post-PCV13 antibody concentrations (regression coefficient -0.19, 95% CI -0.24 --0.14) while the opposite was seen in overweight children (regression coefficient 0.14, 95% CI 0.049-0.22).ConclusionMetabolic hormones, in particular adiponectin, may modify the effect of nutritional status on pneumococcal vaccine response. These findings emphasize the importance of further research to better understand the immunometabolic pathways underlying vaccine response and enable a future of optimal personalized vaccination schedules.

Introduction Respiratory tract infections (RTIs) affect children all over the world and are associated with significant morbidity and mortality. In particular, recurrent RTIs cause a high burden of disease and lead to frequent doctor visits. Children with recurrent RTIs generally have no significant alterations or deficits in systemic immunity. In an attempt to treat the assumed bacterial component involved, they are often treated with prolonged courses of prophylactic antibiotics taken on a daily basis. Despite its common use, there is no evidence that this is beneficial. Studies assessing the clinical effectiveness of antibiotic prophylaxis as well as potential adverse effects and antibiotic resistance development, are therefore urgently needed.Methods and analysis We present a protocol for a randomised double-blind placebo-controlled trial comparing co-trimoxazole with placebo treatment in children with recurrent RTIs. A total of 158 children (aged 6 months–10 years) with recurrent RTIs without significant comorbidity will be enrolled from a minimum of 10 Dutch hospitals. One group receives co-trimoxazole 18 mg/kg two times per day (36 mg/kg/day) and the other group receives a placebo two times per day for a period of 3 months. The main objective is to determine whether antibiotic prophylaxis is more effective than placebo to prevent/reduce respiratory symptoms in children with recurrent RTIs. Respiratory symptoms will be scored by parents on a daily basis in both study arms by the use of a mobile phone application. Our primary outcome will be the number of days with at least two respiratory symptoms during the treatment.Ethics and dissemination Ethics approval was obtained from the Medical Ethics Research Committee Zuidwest Holland/LDD. A manuscript with the study results will be submitted to a peer-reviewed journal. All participants will be informed about the study results. The results of the study will inform clinical guidelines regarding the prophylactic treatment of children with recurrent RTIs.Trial registration number NL7044.

Digital health can drive patient-centric innovation in neuromodulation by leveraging current tools to identify response predictors and digital biomarkers. Iterative technological evolution has led us to an ideal point to integrate digital health with neuromodulation. Here, we provide an overview of the digital health building-blocks, the status of advanced neuromodulation technologies, and future applications for neuromodulation with digital health integration.

The hexanucleotide G4C2 repeat expansion in the first intron of the C9ORF72 gene accounts for the majority of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) cases. Numerous studies have indicated the toxicity of dipeptide repeats (DPRs), which are produced via repeat-associated non-AUG (RAN) translation from the repeat expansion, and accumulate in the brain of C9FTD/ALS patients. Mouse models expressing the human C9ORF72 repeat and/or DPRs show variable pathological, functional and behavioral characteristics of FTD and ALS. Here, we report a new Tet-on inducible mouse model that expresses 36× pure G4C2 repeats with 100-bp upstream and downstream human flanking regions. Brain-specific expression causes the formation of sporadic sense DPRs aggregates upon 6 months of dox induction, but no apparent neurodegeneration. Expression in the rest of the body evokes abundant sense DPRs in multiple organs, leading to weight loss, neuromuscular junction disruption, myopathy and a locomotor phenotype within the time frame of 4 weeks. We did not observe any RNA foci or pTDP-43 pathology. Accumulation of DPRs and the myopathy phenotype could be prevented when 36× G4C2 repeat expression was stopped after 1 week. After 2 weeks of expression, the phenotype could not be reversed, even though DPR levels were reduced. In conclusion, expression of 36× pure G4C2 repeats including 100-bp human flanking regions is sufficient for RAN translation of sense DPRs, and evokes a functional locomotor phenotype. Our inducible mouse model suggests that early diagnosis and treatment are important for C9FTD/ALS patients. This article has an associated First Person interview with the first author of the paper.

BackgroundHouseholds are important sites for transmission of SARS-CoV-2 and preventive measures are recommended. This study aimed to 1) investigate the impact of living with a person infected with SARS-CoV-2; 2) understand how household members implemented infection control recommendations in their home; and 3) identify the information and support needs of household members.MethodsFor this observational mixed-methods study, households with a person with confirmed SARS-CoV-2 infection were recruited via drive-through testing sites of Municipal Health Services, healthcare worker screening or hospital emergency visits in the University Medical Centre Utrecht, the Netherlands and via primary care physicians, hospital emergency visits or preoperative screening in the University Hospital of Antwerp, Belgium. We recorded household characteristics, including characteristics of all household members, together with their views on prevention measures. In a subset of households one adult household member was asked to participate in an interview investigating their views on preventive measures. Survey data were analysed using descriptive statistics and interview data by rapid framework analysis. A triangulation protocol was used to integrate findings.ResultsThirty-four households (120 household members) were included in the quantitative survey. Twenty-two households were invited to be interviewed, of which 18 completed an interview (response 81.8%). Survey data showed that almost all households implemented some preventive measures, the use of face masks being least frequently reported. Measures taken depended on what was physically possible, the perceived severity of illness of the index patient and to what extent household members were willing to limit social interaction. Respondents did not believe in the effectiveness of wearing face masks within the house, and from the interviews this was explained by media coverage of face masks, impracticality and the stigma associated with wearing masks. Interviewees reported that quarantine had a high emotional burden and wished to have more information about the exact duration of quarantine, their own COVID-19 status, symptoms and when to seek medical help.ConclusionPeople were willing to implement prevention measures, however actual adherence depended on perceived severity of illness and the perceived risk of becoming infected. Homes are social environments and recommendations for infection prevention should account for this context. Incorporating our findings into policy making could provide households with more relevant and actionable advice.

BackgroundThe prescription of physical activity (PA) in clinical care has been advocated worldwide. This “exercise is medicine” (E=M) concept can be used to prevent, manage, and cure various lifestyle-related chronic diseases. Due to several challenges, E=M is not yet routinely implemented in clinical care. ObjectiveThis paper describes the rationale and design of the Physicians Implement Exercise = Medicine (PIE=M) study, which aims to facilitate the implementation of E=M in hospital care. MethodsPIE=M consists of 3 interrelated work packages. First, levels and determinants of PA in different patient and healthy populations will be investigated using existing cohort data. The current implementation status, facilitators, and barriers of E=M will also be investigated using a mixed-methods approach among clinicians of participating departments from 2 diverse university medical centers (both located in a city, but one serving an urban population and one serving a more rural population). Implementation strategies will be connected to these barriers and facilitators using a systematic implementation mapping approach. Second, a generic E=M tool will be developed that will provide tailored PA prescription and referral. Requirements for this tool will be investigated among clinicians and department managers. The tool will be developed using an iterative design process in which all stakeholders reflect on the design of the E=M tool. Third, we will pilot-implement the set of implementation strategies, including the E=M tool, to test its feasibility in routine care of clinicians in these 2 university medical centers. An extensive learning process evaluation will be performed among clinicians, department managers, lifestyle coaches, and patients using a mixed-methods design based on the RE-AIM framework. ResultsThis project was approved and funded by the Dutch grant provider ZonMW in April 2018. The project started in September 2018 and continues until December 2020 (depending on the course of the COVID-19 crisis). All data from the first work package have been collected and analyzed and are expected to be published in 2021. Results of the second work package are described. The manuscript is expected to be published in 2021. The third work package is currently being conducted in clinical practice in 4 departments of 2 university medical hospitals among clinicians, lifestyle coaches, hospital managers, and patients. Results are expected to be published in 2021. ConclusionsThe PIE=M project addresses the potential of providing patients with PA advice to prevent and manage chronic disease, improve recovery, and enable healthy ageing by developing E=M implementation strategies, including an E=M tool, in routine clinical care. The PIE=M project will result in a blueprint of implementation strategies, including an E=M screening and referral tool, which aims to improve E=M referral by clinicians to improve patients’ health, while minimizing the burden on clinicians.

Introduction: Endovascular aneurysm repair (EVAR) became the preferred modality for infrarenal aneurysm (AAA) repair. Several available endografts have main body proximal diameters up to 36mm, allowing for treatment of proximal AAA necks up to 32 mm. However, large neck represents a predictor of proximal complications after EVAR. The purpose of this study is to evaluate mid-term outcomes of patients requiring 34-36mm main body devices. Methods: Retrospective review of a prospectively maintained database including all patients undergoing elective EVAR for degenerative AAA in a single tertiary referral hospital in The Netherlands were eligible. All measurements were performed on center-lumen line reconstructions obtained on dedicated software. Patients were classified as large diameter (LD) if the implanted device was >32mm wide. The remaining patients were classified as normal diameter (ND). Primary endpoint was neck-related events (a composite of “endoleak” (EL) 1A, neck-related secondary intervention or migration >5mm). Neck morphology changes and survival were also assessed. Differences in groups were adjusted by multivariable analysis. Results: The study included 502 patients (90 in the LD group; 412 in the ND group). Median follow-up was 3.5 years (1.5–6.2) and 4.5 years (2.1–7.3) for the LD and ND groups, respectively (P = .008). Regarding baseline characteristics, hypertension (83% vs 69.7%, P=.012) and smoking (86% vs 74.1%, P=.018) were more frequent in the LD group. Patients in the LD group had wider (Proximal neck Ø > 28 mm: 75% vs 3.3%, P45º: 21% vs 9%, P=.002), more conical (39.8% vs 20.3%, P25%: 42% vs 32.3%, P 5mm occurred similarly in both groups (7.8% vs 5.1%, P=.32). Neck-related secondary interventions were also more common among LD patients (13.3% vs 8.7%; P = .027). On multivariable regression analysis, LD group was an independent risk factor for neck-related adverse events (Hazard Ratio [HR]: 2.29; 95% confidence interval [CI], 1.37–3.83, P=0.002). Neck dilatation was greater among LD patients (median, 3 mm [IQR, 0–6] vs 2mm [IQR, 0–4]; P =.034) On multivariable analysis, LD was an independent predictor for neck dilatation > 10 % (HR: 1.61 CI 95% 1.08–2.39, P=.020). Survival at 5-years was 66.1% for LD and 71.2% for SD groups, P=.14. Conclusion: Standard EVAR in patients with large infrarenal necks requiring a 34- to 36-mm proximal endograft is independently associated to increased rate of neck related events and more neck dilatation. This subgroup of patients could be considered for more proximal seal strategies with fenestrated or branched devices, if unfit for open repair. Tighter surveillance following EVAR in these patients in the long term is also advised.

Objectives To evaluate the feasibility of a new approach to paediatric research whereby we involved children in analysing qualitative data, and to reflect on the involvement process.Setting This was a single-centre, qualitative study in the Netherlands. It consisted of research meetings with individual children at home (Phase I) or group meetings at school (Phase II). In Phase I, we identified themes from a video interview during five one-on-one meetings between a child co-researcher and the adult researcher. In Phase II, during two group meetings, we explored the themes in detail using fragments from 16 interviews.Participants We involved 14 school children (aged 10 to 14 years) as co-researchers to analyse children’s interviews about their experience while participating in medical research. Notes were taken, and children provided feedback. A thematic analysis was performed using a framework approach.Results All co-researchers identified themes. The time needed to complete the task varied, as did the extent to which the meetings needed to be structured to improve concentration. The children rated time investment as adequate and they considered acting as co-researcher interesting and fun, adding that they had learnt new skills and gained new knowledge. The experience also led them to reflect on health matters in their own lives. The adult researchers considered the process relatively time intensive, but the project did result in a more critical assessment of their own work.Conclusion The new, two-phase approach of involving children to help analyse qualitative data is a feasible research method. The novelty lies in involving children to help identify themes from original interview data, thereby limiting preselection of data by adults, before exploring these themes in detail. Videos make it easier for children to understand the data and to empathise with the interviewees, and limits time investment.

IntroductionStrict imaging surveillance protocols to detect complications following endovascular aneurysm repair (EVAR) are common practice. However, controversy exists as to whether all EVAR patients need intense surveillance. The 2019 European Society for Vascular Surgery guidelines for management of abdominal aortic aneurysm (AAA) suggest that patients may be considered for limited follow-up with imaging if classified as ‘low risk’ for complications based on their initial postoperative imaging. The current study aims to investigate the intervention-free survival and overall survival stratified for patients with and without yearly imaging surveillance.Methods and analysisThe Observing a Decade of Yearly Standardised Surveillance in EVAR patients with Ultrasound or CT Scan study comprises a national multicentre retrospective cohort study in 17 medical centres. Consecutive patients with an asymptomatic or symptomatic infrarenal AAA who underwent EVAR between January 2007 and January 2012 will be included in this study with follow-up until December 2018. Clinical variables and all follow-up information will be retrieved in extensive data collection from the patient’s medical records. In addition, an e-survey was sent to vascular surgeons at the 17 participating centres to gauge their opinions regarding the possibility of safely reducing the frequency of imaging surveillance. Primary endpoints are intervention after EVAR and aneurysm-related mortality. The initial estimated sample size is 1997 patients.Ethics and disseminationThe study has been approved by the Medical Ethics Review Committee of the Amsterdam UMC, location Academic Medical Centre, Amsterdam, the Netherlands. Study findings will be disseminated via presentations at conferences and publications in peer-reviewed journal.Trial registration numberThe Netherlands Trial Registry, NL6953 (old: NTR28773).

Sleep inertia is a potentially dangerous reduction in human alertness and occurs 0-4 hours after waking. The type of sound people set as their alarm for waking has been shown to reduce the effects of sleep inertia, however, the elemental musical factors that underpin these waking sounds and their relationships remain unclear. The goal of this research is to understand how a particular sound or music chosen to assist waking may counteract sleep inertia, and more specifically, what elements of these sounds may contribute to its reduction. Through an anonymous, self-report online questionnaire, fifty participants (N = 50) reported attributes of their preferred waking sound, their feeling towards the waking sound, and perceived sleep inertia after waking. This data enabled the analysis and comparison between these responses to identify statistically significant relationships. Our results did not return any significant association between sleep inertia and the reported waking sound type, nor the subject's feeling towards their sound. However, the analysis did reveal that a sound which is ranked as melodic by participants shows a significant relationship to reports of reductions in perceived sleep inertia, and in contrast, sound rated as neutral (neither unmelodic nor melodic) returns a significant relationship to the reports of increases in perceived sleep inertia. Additionally, our secondary analysis revealed that a sound rated as melodic is considered to be more rhythmic than a melodically neutral interpretation. Together these findings raise questions regarding the impact melody and rhythm may hold with respect to sleep inertia intensity. Considering that the implementation of auditory assisted awakening is a common occurrence, the musical elements of a chosen waking sound may be an area to further interrogate with respect to counteracting sleep inertia.

BACKGROUND:Knowledge on the molecular epidemiology of Escherichia coli causing E. coli bacteremia (ECB) in the Netherlands is mostly based on extended-spectrum beta-lactamase-producing E. coli (ESBL-Ec). We determined differences in clonality and resistance and virulence gene (VG) content between non-ESBL-producing E. coli (non-ESBL-Ec) and ESBL-Ec isolates from ECB episodes with different epidemiological characteristics. METHODS:A random selection of non-ESBL-Ec isolates as well as all available ESBL-Ec blood isolates was obtained from two Dutch hospitals between 2014 and 2016. Whole genome sequencing was performed to infer sequence types (STs), serotypes, acquired antibiotic resistance genes and VG scores, based on presence of 49 predefined putative pathogenic VG. RESULTS:ST73 was most prevalent among the 212 non-ESBL-Ec (N = 26, 12.3%) and ST131 among the 69 ESBL-Ec (N = 30, 43.5%). Prevalence of ST131 among non-ESBL-Ec was 10.4% (N = 22, P value < .001 compared to ESBL-Ec). O25:H4 was the most common serotype in both non-ESBL-Ec and ESBL-Ec. Median acquired resistance gene counts were 1 (IQR 1-6) and 7 (IQR 4-9) for non-ESBL-Ec and ESBL-Ec, respectively (P value < .001). Among non-ESBL-Ec, acquired resistance gene count was highest among blood isolates from a primary gastro-intestinal focus (median 4, IQR 1-8). Median VG scores were 13 (IQR 9-20) and 12 (IQR 8-14) for non-ESBL-Ec and ESBL-Ec, respectively (P value = .002). VG scores among non-ESBL-Ec from a primary urinary focus (median 15, IQR 11-21) were higher compared to non-ESBL-Ec from a primary gastro-intestinal (median 10, IQR 5-13) or hepatic-biliary focus (median 11, IQR 5-18) (P values = .007 and .04, respectively). VG content varied between different E. coli STs. CONCLUSIONS:Non-ESBL-Ec and ESBL-Ec blood isolates from two Dutch hospitals differed in clonal distribution, resistance gene and VG content. Also, resistance gene and VG content differed between non-ESBL-Ec from different primary foci of ECB.

Trying to meet the Sustainable Development Goals is challenging. Food supply chains may have to become more efficient to meet the increasing food requirement of 10 Billion people by 2050. At the same time, food and nutrition security are at risk from increasingly likely shocks like extreme climate events, market shocks, pandemics, changing consumer preferences, and price volatility. Here we consider some possibilities and limitations regarding the improvement of resilience (the capacity to deal with shocks) and efficiency (here interpreted as the share of produced food delivered to consumers) of food supply chains. We employ an Agent Based Model of a generic food chain network consisting of stylized individuals representing producers, traders, and consumers. We do this: 1/ to describe the dynamically changing disaggregated flows of crop items between these agents, and 2/ to be able to explicitly consider agent behaviour. The agents have implicit personal objectives for trading. We quantify resilience and efficiency by linking these to the fraction of fulfilment of the overall explicit objective to have all consumers meet their food requirement. We consider different types of network structures in combination with different agent interaction types under different types of stylized shocks. We find that generally the network structures with higher efficiency are also more sensitive to shocks, while less efficient network types display more resilience. At first glance these results seem to confirm the existence of a system-level trade-off between resilience and efficiency similar to what is reported in business management and ecology literature. However, the results are modified by the trading interactions and the type of shock. In our simulations resilience and efficiency are affected by 'soft' boundaries caused by the preference and trust of agents (i.e., social aspects) in trading. The ability of agents to switch between trading partners represents an important aspect of resilience, namely a capacity to reorganize. These insights may be relevant when considering the reorganization of real-life food chains to increase their resilience to meet future food and nutrition security goals.

Robots are used for language tutoring increasingly often, and commonly programmed to display non-verbal communicative cues such as eye gaze and pointing during robot-child interactions. With a human speaker, children rely more strongly on non-verbal cues (pointing) than on verbal cues (labeling) if these cues are in conflict. However, we do not know how children weigh the non-verbal cues of a robot. Here, we assessed whether four- to six-year-old children (i) differed in their weighing of non-verbal cues (pointing, eye gaze) and verbal cues provided by a robot versus a human; (ii) weighed non-verbal cues differently depending on whether these contrasted with a novel or familiar label; and (iii) relied differently on a robot's non-verbal cues depending on the degree to which they attributed human-like properties to the robot. The results showed that children generally followed pointing over labeling, in line with earlier research. Children did not rely more strongly on the non-verbal cues of a robot versus those of a human. Regarding pointing, children who perceived the robot as more human-like relied on pointing more strongly when it contrasted with a novel label versus a familiar label, but children who perceived the robot as less human-like did not show this difference. Regarding eye gaze, children relied more strongly on the gaze cue when it contrasted with a novel versus a familiar label, and no effect of anthropomorphism was found. Taken together, these results show no difference in the degree to which children rely on non-verbal cues of a robot versus those of a human and provide preliminary evidence that differences in anthropomorphism may interact with children's reliance on a robot's non-verbal behaviors.

INTRODUCTION:People with depression, anxiety, or psychosis often complain of confusion, problems concentrating or difficulties cognitively appraising contextual cues. The same applies to people with neurodegenerative diseases or brain damage such as dementia or stroke. Assessments of those cognitive difficulties often occurs in cross-sectional and controlled clinical settings. Information on daily moment-to-moment cognitive fluctuations and its relation to affect and context is lacking. The development and evaluation of a digital cognition task is presented. It enables the fine-grained mapping of cognition and its relation to mood, intrapersonal factors and context. METHODS:The momentary Digit Symbol Substitution Task is a modified digital version of the original paper-and-pencil task, with a duration of 30 seconds and implemented in an experience sampling protocol (8 semi-random assessments a day on 6 consecutive days). It was tested in the healthy population (N = 40). Descriptive statistics and multilevel regression analyses were used to determine initial feasibility and assess cognitive patterns in everyday life. Cognition outcome measures were the number of trials within the 30-second sessions and the percentage of correct trials. RESULTS:Subjects reported the task to be easy, pleasant and do-able. On average, participants completed 11 trials with 97% accuracy per 30-second session. Cognitive variation was related to mood, with an interaction between positive and negative affect for accuracy (% correct) (p = .001) and an association between positive affect and speed (number of trials) (p = .01). Specifically, cheerful, irritated and anxious seem to covary with cognition. Distraction and location are relevant contextual factors. The number of trials showed a learning effect (p < .001) and was sensitive to age (p < .001). CONCLUSION:Implementing a digital cognition task within an experience-sampling paradigm shows promise. Fine-tuning in further research and in clinical samples is needed. Gaining insight into cognitive functioning could help patients navigate and adjust the demands of daily life.