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The current monkeypox disease (MPX) outbreak constitutes a new threat and challenge for our society. With more than 55,000 confirmed cases in 103 countries, World Health Organization declared the ongoing MPX outbreak a Public Health Emergency of International Concern (PHEIC) on July 23, 2022. The current MPX outbreak is the largest, most widespread, and most serious since the diagnosis of the first case of MPX in 1970 in the Democratic Republic of the Congo (DRC), a country where MPX is an endemic disease. Throughout history, there have only been sporadic and self‐limiting outbreaks of MPX outside Africa, with a total of 58 cases described from 2003 to 2021. This figure contrasts with the current outbreak of 2022, in which more than 55,000 cases have been confirmed in just 4 months. MPX is, in most cases, self‐limiting; however, severe clinical manifestations and complications have been reported. Complications are usually related to the extent of virus exposure and patient health status, generally affecting children, pregnant women, and immunocompromised patients. The expansive nature of the current outbreak leaves many questions that the scientific community should investigate and answer in order to understand this phenomenon better and prevent new threats in the future. In this review, 50 questions regarding monkeypox virus (MPXV) and the current MPX outbreak were answered in order to provide the most updated scientific information and to explore the potential causes and consequences of this new health threat.

An increase in pediatric cases of invasive group A streptococcus (iGAS) disease was noted in the Netherlands starting in early 2022. GAS disease can range from mild to life-threatening invasive infections. Clinical and public health decisions rely on timely and detailed reporting of clinical data. To determine risk factors associated with severe pediatric iGAS, defined as requiring admission to an intensive care unit and/or death, and to analyze pediatric iGAS incidence, presentations, and outcome between pre-COVID-19 pandemic (January 2015 to March 2020), COVID-19 pandemic (April 2020 to December 2021), and post-COVID-19 pandemic (January 2022 to June 2024) periods. This observational, retrospective and prospective cohort study in 20 hospitals (tertiary and nontertiary) in the Netherlands was conducted from January 2015 to June 2024, with real-time reporting of data on the study website since January 2022. Children aged 0 to 17 years with iGAS (positive culture or polymerase chain reaction test and/or clinical presentation) were included. iGAS infection. The primary outcome was risk factors for severe iGAS; secondary outcomes included iGAS incidence rate and clinical phenotypes prior, during, and after the COVID-19 pandemic. Risk factors for severity and mortality were analyzed using univariable and multivariable logistic regression analyses, and incidence rate ratios (IRRs) between pre-COVID-19 and postCOVID-19 pandemic periods were calculated using Poisson regression. Of 617 children included, 351 (56.9%) were aged 0 to 4 years. For the 192 participants with detailed data collection, median (IQR) age was 4.2 (1.7-7.1) years and 91 (47.4%) were male. iGAS cases decreased during the COVID-19 pandemic and increased significantly in the post-COVID-19 period (IRR, 2.93; 95%, 2.46-3.49), as compared with the pre-COVID-19 pandemic period. By late 2023, the incidence of iGAS returned to pre-COVID-19 pandemic levels. Factors associated with increased risk of severe disease included a post-COVID-19 pandemic diagnosis (odds ratio [OR], 3.49; 95% CI, 2.31-6.26), pulmonary involvement (OR, 8.64; 95% CI, 5.50-13.55), streptococcal toxic shock syndrome (STSS; OR, 11.71; 95% CI, 4.39-31.18), and meningitis or encephalitis (OR, 4.38; 95% CI, 4.39-31.18). Clinical factors associated with increased risk of severe disease were reduced consciousness (OR, 7.61; 95% CI, 1.84-34.41), dyspnea (OR, 9.89; 95% CI, 3.04-32.14), abnormal auscultation (OR, 6.32; 95% CI, 2.18-18.32), and elevated C-reactive protein (OR, 6.32; 95% CI, 2.18-18.32), while estimated glomerular filtration rate was associated with a decreased risk (OR, 0.64; 95% CI, 0.49-0.84). Disease severity increased in post-COVID-19-pandemic cases, with higher mortality (13 of 294 cases [4.4%] vs 3 of 218 cases [1.4%]) and intensive care admission rates (113 of 294 cases [38.4%] vs 34 of 218 cases [15.6%]), as compared with pre-COVID-19 pandemic cases. Severity of pulmonary iGAS was similar in both periods. In the post-COVID-19 pandemic period, there was a significant increase in the incidence of pulmonary infections (IRR, 5.04; 95% CI, 3.27-7.97) , STSS (IRR, 10.30; 95% CI, 3.88-35.60), meningitis or encephalitis (IRR, 12.30; 95% CI, 4.14-52.70), and necrotizing fasciitis (IRR, 26.10; 95% CI, 5.14-475.00). In this cohort study, risk factors for a complicated course of iGAS in children included pulmonary or central nervous system involvement, STSS, reduced consciousness or pulmonary clinical signs, elevated CRP, and decreased eGFR. Awareness of these risk factors is important to improve timely recognition of at-risk cases and improve clinical outcomes.

Lower respiratory tract infections (LRTIs) in children are common and, although often mild, a major cause of mortality and hospitalization. Recently, the respiratory microbiome has been associated with both susceptibility and severity of LRTI. In this current study, we combined respiratory microbiome, viral, and clinical data to find associations with the severity of LRTI. Nasopharyngeal aspirates of children aged one month to five years included in the STRAP study (Study to Reduce Antibiotic prescription in childhood Pneumonia), who presented at the emergency department (ED) with fever and cough or dyspnea, were sequenced with nanopore 16S-rRNA gene sequencing and subsequently analyzed with hierarchical clustering to identify respiratory microbiome profiles. Samples were also tested using a panel of 15 respiratory viruses and Mycoplasma pneumoniae, which were analyzed in two groups, according to their reported virulence. The primary outcome was hospitalization, as measure of disease severity. Nasopharyngeal samples were isolated from a total of 167 children. After quality filtering, microbiome results were available for 54 children and virology panels for 158 children. Six distinct genus-dominant microbiome profiles were identified, with Haemophilus-, Moraxella-, and Streptococcus-dominant profiles being the most prevalent. However, these profiles were not found to be significantly associated with hospitalization. At least one virus was detected in 139 (88%) children, of whom 32.4% had co-infections with multiple viruses. Viral co-infections were common for adenovirus, bocavirus, and enterovirus, and uncommon for human metapneumovirus (hMPV) and influenza A virus. The detection of enteroviruses was negatively associated with hospitalization. Virulence groups were not significantly associated with hospitalization. Our data underlines high detection rates and co-infection of viruses in children with respiratory symptoms and confirms the predominant presence of Haemophilus-, Streptococcus-, and Moraxella-dominant profiles in a symptomatic pediatric population at the ED. However, we could not assess significant associations between microbiome profiles and disease severity measures.

BackgroundSeveral antibiotic stewardship interventions have been proven effective and safe for reducing the high number of antibiotic prescriptions in late preterm and term neonates at risk of early-onset sepsis (EOS). For successful translation of EOS interventions to clinical practice, implementation strategies should be employed targeting stakeholders. The primary aim of this study is to assess the impact of implementing an antibiotic stewardship bundle, including the EOS calculator, procalcitonin-guided therapy and intravenous-to-oral switch therapy on antibiotic exposure for EOS in Dutch secondary hospitals. Secondary aims are to examine additional clinical outcomes and implementation outcomes.Methods and analysisWe will conduct a multicentre, prospective implementation study with interrupted time series and before-after analyses at the paediatric or specialised neonatal departments of 11 Dutch secondary hospitals and their surrounding neonatal care networks. A multimodal implementation strategy, designed using Implementation Mapping, is employed to facilitate implementation. The study population is twofold: (1) neonates born at 34 weeks of gestation or later with suspected EOS that will receive intervention-related care and (2) paediatricians, paediatric residents, neonatal nurses, maternity nurses and parents who are the focus of the implementation strategies. The primary outcome is days of antibiotic therapy per 1000 live-born neonates, which will be evaluated using interrupted time series analysis as well as before-after comparison. Secondary clinical outcomes will be assessed by comparing clinical data from the 12 months pre-implementation and post implementation. Implementation outcomes are adoption, fidelity, feasibility and acceptability of the interventions and fidelity and appropriateness of the implementation strategies. Implementation outcomes will be assessed using both qualitative and quantitative methods, including surveys, individual interviews and focus group interviews. A mixed-methods approach will be used to integrate clinical and implementation outcomes.Ethics and disseminationThe Medical Ethics Committee United (MEC-U) declared (reference: W24.132) that this study does not fall under the Dutch Medical Research Involving Human Subjects Act (WMO). Subsequently, ethical approval was granted by the Scientific Committee of the Franciscus Hospital (T110). The scientific committees of all participating sites adopted this decision and granted permission for local conduct of the study. As electronic health record data are sampled retrospectively and anonymously, a waiver of consent was given to collect these data. Informed consent will be obtained from participants completing surveys or taking part in interviews and focus group discussions. The findings will be disseminated through journal publications and conference presentations. Furthermore, practice and policy recommendations will be collaboratively developed with partner organisations.Trial registration numberNCT06845332.

IntroductionHigh morbidity and mortality rates of proven bacterial infection are the main reason for substantial use of intravenous antibiotics in neonates during the first week of life. In older children, intravenous-to-oral switch after 48 hours of intravenous therapy has been shown to have many advantages and is nowadays commonly practised. We, therefore, aim to evaluate the effectiveness, safety and cost-effectiveness of an early intravenous-to-oral switch in neonates with a probable bacterial infection.Methods and analysisWe present a protocol for a multicentre randomised controlled trial assessing the non-inferiority of an early intravenous-to-oral antibiotic switch compared with a full course of intravenous antibiotics in neonates (0–28 days of age) with a probable bacterial infection. Five hundred and fifty patients will be recruited in 17 hospitals in the Netherlands. After 48 hours of intravenous treatment, they will be assigned to either continue with intravenous therapy for another 5 days (control) or switch to amoxicillin/clavulanic acid suspension (intervention). Both groups will be treated for a total of 7 days. The primary outcome will be bacterial (re)infection within 28 days after treatment completion. Secondary outcomes are the pharmacokinetic profile of oral amoxicillin/clavulanic acid, the impact on quality of life, cost-effectiveness, impact on microbiome development and additional yield of molecular techniques in diagnosis of probable bacterial infection.Ethics and disseminationThis study has been approved by the Medical Ethics Committee of the Erasmus Medical Centre. Results will be presented in peer-reviewed journals and at international conferences.Trial registration number NCT03247920

Cystic fibrosis (CF) is characterized by early structural lung disease caused by pulmonary infections. The nasopharynx of infants is a major ecological reservoir of potential respiratory pathogens. To investigate the development of nasopharyngeal microbiota profiles in infants with CF compared with those of healthy control subjects during the first 6 months of life. We conducted a prospective cohort study, from the time of diagnosis onward, in which we collected questionnaires and 324 nasopharynx samples from 20 infants with CF and 45 age-matched healthy control subjects. Microbiota profiles were characterized by 16S ribosomal RNA-based sequencing. We observed significant differences in microbial community composition (P < 0.0002 by permutational multivariate analysis of variance) and development between groups. In infants with CF, early Staphylococcus aureus and, to a lesser extent, Corynebacterium spp. and Moraxella spp. dominance were followed by a switch to Streptococcus mitis predominance after 3 months of age. In control subjects, Moraxella spp. enrichment occurred throughout the first 6 months of life. In a multivariate analysis, S. aureus, S. mitis, Corynebacterium accolens, and bacilli were significantly more abundant in infants with CF, whereas Moraxella spp., Corynebacterium pseudodiphtericum and Corynebacterium propinquum and Haemophilus influenzae were significantly more abundant in control subjects, after correction for age, antibiotic use, and respiratory symptoms. Antibiotic use was independently associated with increased colonization of gram-negative bacteria such as Burkholderia spp. and members of the Enterobacteriaceae bacteria family and reduced colonization of potential beneficial commensals. From diagnosis onward, we observed distinct patterns of nasopharyngeal microbiota development in infants with CF under 6 months of age compared with control subjects and a marked effect of antibiotic therapy leading toward a gram-negative microbial composition.

Background and Objective Clavulanic acid is a commonly used β-lactam inhibitor in pediatrics for a variety of infections. Clear insight into its mode of action is lacking, however, and a target has not been identified. The dosing of clavulanic acid is currently based on that of the partner drug (amoxicillin or ticarcillin). Still, proper dosing of the compound is needed because clavulanic acid has been associated with adverse effects. In this systematic review, we aim to describe the current literature on the pharmacokinetics of clavulanic acid in the pediatric population Methods We performed a systematic search in MEDLINE, Embase.com, Cochrane Central, Google Scholar, and Web of Science . We included all published studies reporting pharmacokinetic data on clavulanic acid in neonates and children 0–18 years of age. Results The search resulted in 18 original studies that met the inclusion criteria. In general, the variation in drug exposure was large, which can be partly explained by differences in disease state, route of administration, or age. Unfortunately, the studies’ limited background information hampered in-depth assessment of the observed variability. Conclusion The pharmacokinetics of clavulanic acid in pediatric patients is highly variable, similar to reports in adults, but more pronounced. Significant knowledge gaps remain with regard to the population-specific explanation for this variability. Model-based pharmacokinetic studies that address both maturational and disease-specific changes in the pediatric population are therefore needed. Furthermore, additional pharmacodynamic studies are needed to define a clear target. The combined outcomes will eventually lead to pharmacokinetic-pharmacodynamic modeling of clavulanic acid and targeted exposure. Clinical Trial Registration PROSPERO CRD42020137253.

During the COVID-19 pandemic, countries imposed (partial) lockdowns that reduced viral transmission. However, these interventions may have unfavorable effects on emotional and psychological well-being. The aim of this study was to quantify possible adverse effects of the COVID-19 pandemic on psychological wellbeing in children and adolescents. Hospital admission data between January 2017 and September 2021 from eight general hospitals in the Netherlands was collected, comparing the incidences of sub-categorized psychological diagnoses, more specifically eating disorders, intentional intoxications, accidental intoxications, and excessive crying, before (2017–2019) and during the pandemic (2020–2021). Data was summarized per month and per year, and the years 2020 and 2021 were compared to 2017–2019. The relative increase or decrease in diagnoses since the start of the pandemic was calculated. Overall pediatric hospital admissions decreased with 28% since the start of the pandemic. Non-infectious diagnoses showed a decrease of 8%. Of these non-infectious diagnoses, overall psychosocial admissions were increased (+ 9%), mostly caused by an increase in admissions for eating disorders (+ 64%) and intoxications in adolescents (+ 24%). In addition, the proportion of admissions due to psychosocial diagnoses increased post-pandemic (6% vs 4%, p  < 0.001). Overall admissions for intoxications in children (− 3%) and excessive crying (− 1%) did not increase, although peaks in incidence were found at the start of the second lockdown. Conclusion : During the COVID-19 pandemic, admission rates for eating disorders and intentional intoxications showed a substantial increase, indicating a high burden of pediatric psychiatric diseases. What is Known: • The COVID-19 pandemic has had an impact on psychosocial wellbeing in children and adolescents. What is New: • There was an increase in admissions due to psychosocial problems in the Netherlands in the period after the pandemic. • This was mainly caused by an increase in crisis admissions due to eating disorders and intoxications in adolescents.

Population studies showed a decrease in psychological wellbeing during the COVID-19 pandemic. Asthma is associated with a negative effect on anxiety and depression, which might worsen during the COVID-19 lockdown. The aim of the study was to compare fear, anxiety and depression between asthma patients and patients wit hout asthma pre-COVID-19 and during COVID-19 pandemic. This study compares fear, anxiety and depression in asthma patients and controls between pre-COVID-19 and during COVID-19 lockdown with a cross-sectional online survey. Participants were invited to fill out several questionnaires pertaining to fear, anxiety, depression, asthma control and quality of life. Asthma patients (N = 37) displayed, during the course of the pandemic, a clinically relevant increase in anxiety (3.32 ± 2.95 vs. 6.68 ± 3.78; p < 0.001) and depression (1.30 ± 1.15 vs. 3.65 ± 3.31; p < 0.001), according to the hospital anxiety and depression levels (HADS) compared to pre-COVID-19 assessment. This was not seen in controls. Also, asthma patients displayed more anxiety about acquiring COVID-19 disease compared to controls ((5.11 ± 1.99 vs. 3.50 ± 2.79), p = 0.006). Patients with asthma experienced an increase in anxiety and depression levels and were more afraid of acquiring COVID-19 disease compared to controls. Also, patients with asthma were more likely to avoid healthcare facilities due to fear of acquiring COVID-19 disease compared to controls. Therefore, we advise health care workers to address these possible negative effects on mental health by phone or e-consults.

Abstract Background Discriminating noninfected from infected neonatal cases remains challenging, and subsequently many neonates are treated with antibiotics in the first week of life. We aimed to study the additional value of a targeted polymerase chain reaction (PCR) for group B streptococcus (GBS) and Escherichia coli on leftover blood culture media from term and near-term neonates with probable early-onset sepsis (EOS). Methods Leftover blood culture material from neonates participating in the RAIN study was stored after 5 days of incubation. The RAIN study evaluated intravenous-oral antibiotic switch in probable bacterial infection, defined as risk factors and/or clinical signs and elevated inflammatory parameters but negative blood culture results. We applied 2 targeted PCRs for GBS and E coli, the main pathogens in EOS, and analyzed the samples batchwise in triplicate for each PCR. Results PCR was performed in triplicate on blood culture media from 284 neonates. In 23 neonates, the PCR result was positive (3 cycle threshold values <37) for GBS (n = 1) or E coli (n = 22). Inflammatory parameters did not discriminate for positive PCR result, nor did risk factors for sepsis, such as maternal GBS status and prolonged rupture of membranes. However, 96% of neonates with a positive PCR result were born vaginally vs 74% in the PCR-negative group (P = .05); furthermore, 96% vs 81% (P = .21) of neonates had clinical symptoms. Conclusions Blood culture–negative “probable” EOS in neonates is accompanied by an 8% rate of PCR positivity, suggesting low-grade bacteriemia after birth with yet unclear clinical consequences. Further research should focus on how PCR can contribute to more targeted antibiotic use of neonates, specifically in those highly suspected of infection but in the absence of a positive blood culture result. Targeted Escherichia coli and group B streptococcus polymerase chain reactions show bacteria in 8% of negative blood culture results in neonates with suspected early-onset sepsis. Those findings are mainly observed in neonates with vaginal delivery.