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Siew Lian Chong,1,* Asral Wirda Ahmad Asnawi,1,2,* Tengku Amatullah Madeehah Tengku Mohd,2,* Sen Mui Tan1,* 1Department of Hematology, Hospital Ampang, Ampang Jaya, Selangor, Malaysia; 2Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Nilai, Negeri Sembilan, Malaysia*These authors contributed equally to this workCorrespondence: Siew Lian Chong, Department of Hematology, Hospital Ampang, Jalan Mewah Utara, Taman Pandan Mewah, Ampang, Selangor, 68000, Malaysia, Email swian_@hotmail.com Asral Wirda Ahmad Asnawi, Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Persiaran Ilmu, Putra Nilai, Nilai, Negeri Sembilan, 71800, Malaysia, Email wirda@usim.edu.myIntroduction: The CD34+ hematopoietic cell count was used to define cell harvest goals. Successful peripheral blood stem cell transplantation depends on infusion of an appropriate number of HPCs to achieve rapid and durable hematologic recovery.Purpose: In this study, we evaluated the use of the Hematopoietic Progenitor Cell count program on the Sysmex XN-3000 hematology analyzer as an effective parameter for enumerating CD34+ cells.Patients and Methods: Whole blood samples from 144 subjects who are either healthy donors or patients scheduled to undergo peripheral blood stem cell collection were collected and hemopoietic stem cells were quantified using CD34 cell enumeration by flow cytometry and XN-HPC by hematology analyzer.Results: The correlation between the two methods was high (r = 0.766; 95% CI: 0.702– 0.818). Passing–Bablok showed an intercept at 3.45 (2.54 to 4.74) with a slope of 0.78 (95% CI 0.69 to 0.89). Residual analysis of this model indicated no significant deviation from linearity (p = 0.360). The receiver operating characteristic curve demonstrated an area under curve to be 0.88 (0.82 to 0.92), with a positive predictive value of 80.3%. The correlation between CD34+ and XN-HPC showed a strong relationship and good agreement with minimal bias.Conclusion: The XN-HPC showed good analytical performance. With the increasing requirements for stem cell transplantation, a technically simple and rapid alternative for stem cell enumeration that is sustainable is highly useful.Keywords: XN-HPC, CD34+, progenitor, leukemia, allogeneic, autologous

Objective: Pediatric early warning systems identify patients at risk for deterioration. We aimed to determine if a locally adapted pediatric early warning system [KK hospital early warning score (KEWS)] can distinguish patients who require transfer from general ward to high dependency unit (HDU) or PICU, from those who do not., Methods: We conducted a retrospective case-control single-center audit. All unplanned general ward to PICU/HDU transfer from January to December 2021 were included as cases. We collected KEWS at the time of transfer and at 2, 4 and 6 hours prior to transfer. Univariate and multivariable logistic regression with imputation analysis were performed to identify variables associated with unplanned PICU/HDU transfer., Results: There were 784 patients (196 cases and 588 controls). Median age of cases and controls were 3.3 (interquartile range: 1.0-9.7) and 3.9 (0.8-11.3) years, respectively. At the time of transfer, median (interquartile range) KEWS for cases and controls were 3 (0, 4) and 0 (0, 1), respectively (P <.001). At all timepoints, KEWS was able to distinguish between children who did and did not require transfer to HDU/PICU (At time of transfer: area under the curve = 0.80, 95% CI = 0.75-0.85, P <.001). After adjusting for age, category of admission, frequency of ordered monitoring, KEWS predicted HDU/PICU transfer with an odds ratio of 2.34 (95% CI 1.82 to 3.00, P <.001)., Conclusions: KEWS was able to distinguish patients requiring transfer from GW to HDU/PICU from those not needing a transfer., Competing Interests: CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2024 by the American Academy of Pediatrics.)

Background: Unplanned reattendances (UR) are an important quality indicator in the emergency department (ED). Understanding the risk factors associated with UR can aid clinicians in optimizing the allocation of time and resources, as well as targeted counselling for this specific group of patients. In this study, we aimed to compare patient characteristics between children who attended a pediatric emergency department (ED) with unplanned reattendances (UR) and those without UR. We also aimed to study the association between healthcare delivery factors such as timing of the attendance, patient load, changeover months for rotating junior doctors, presence of supervision, and rate of UR., Study Design: We performed a retrospective, single-center cohort study of patients < 18 years old who visited the ED between January 2018 and March 2023. UR was defined as a revisit within 72 h of the index ED visit. We collected data on demographics, attendance data and clinical characteristics. Logistic regression was performed for factors independently associated with UR, after adjusting for age, patient acuity, timing of attendance, presence of senior doctor supervision, rotation months for junior doctors, and diagnostic category., Results: Out of the 544,699 eligible children, 24,733 (4.5%) reattended the ED within 72 h, of which 10,915 (44.1%) of them were hospitalized on their reattendance visit. The independent factors associated with UR were young age (age < 3 years old: aOR 1.585 95%CI 1.481-1.698, p < 0.001), high acuity P2+ (aOR 1.398 95%CI 1.354-1.444, p < 0.001), attendance in the evening (aOR 1.086 95%CI 1.055-1.117, p < 0.001) and night (aOR 1.365 95%CI 1.314-1.417, p < 0.001), gastrointestinal diagnosis (aOR 1.528, CI 1.469-1.588; p < 0.001) and respiratory diagnosis (aOR 1.155, CI 1.121-1.189, p < 0.001)., Conclusions: We identified independent risk factors for UR that could guide resource allocation. Future studies should investigate if targeted interventions may reduce UR in these at-risk populations., (© 2024. The Author(s).)

Introduction: The last national emergency department (ED) inventory was performed in 2007, and major changes in population demographics, healthcare needs and infrastructure have since occurred. We sought to obtain an updated inventory of EDs in Singapore to identify and describe changes in their characteristics and capabilities across the years., Methods: In 2021, the National Emergency Department Inventories (NEDI) instrument was administered to the leadership of Singapore EDs. Emergency departments in Singapore are opened round the clock, have no restrictions on who can access care and are equipped to handle general medical emergencies. The questionnaire comprises 16 items across three categories: (a) general characteristics, (b) patient volume and (c) medical capabilities., Results: We achieved 100% response rate from all 17 EDs - nine EDs in public hospitals and eight in private hospitals. In 2021, the EDs saw a total of 1,140,388 visits, an increase of 27% from 2007, with the median number of visits almost doubling (from 39,450 to 77,989); 41% and 59% of the EDs reported over 20% of visits arriving by ambulance and over 20% of visits resulting in inpatient admission, respectively. A clear distinction between public and private EDs across these metrics remained. Medical capabilities grew: 59% had access to a dedicated computed tomography scanner (up from 46%) and 82% had negative pressure isolation facilities (up from 54%). Overall, 41% of EDs self-assessed to be operating above their capacity., Conclusion: Singapore EDs have progressed in capabilities and capacity. Despite this, the increasing volume, complexity and acuity of patients are imposing strains on the emergency care system, signalling potential for systems improvement., (Copyright © 2024 Copyright: © 2024 Singapore Medical Journal.)

Introduction: While the definitive diagnosis of urinary tract infection (UTI) requires a positive urine culture, the likelihood of UTI can be determined by urinalysis that includes white blood cell (WBC) count. We aimed to determine the optimal urine WBC threshold in urinalysis to predict UTIs in children presenting at the emergency department (ED)., Method: We performed a prospective observational study in the ED at KK Women's and Children's Hospital for children below 18 years old who underwent both urine microscopy and urine cultures, between 10 January and 7 November 2022. We assessed the various urine WBC thresholds associated with culture-proven UTIs using sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and area under receiver operating characteristic curve., Results: We found a culture-proven UTI rate of 460/1188 (38.7%) among all patients analysed, and 278/998 (27.9%) among those with nitrite-negative urine samples. Among all patients, a urinalysis WBC threshold of 100/μL had a sensitivity of 82.2% (95% confidence interval [CI] 78.4-85.5) and negative predictive value of 86.2% (95% CI 83.6-88.4). Among those who were nitrite-negative, a WBC threshold of ≥100/μL resulted in a potential missed rate of 48/278 (17.3%). By lowering the WBC threshold to ≥10/μL, the potential missed cases reduced to 6/278 (2.2%), with an estimated increase in 419 urine cultures annually., Conclusion: A urine microscopy WBC threshold of ≥100/μL results in a clinically significant number of missed UTIs. Implementation of various thresholds should consider both the potential missed UTI rate and the required resource utilisation.

Recognizing and prioritizing research areas in emergency care is crucial for generating evidence and advancing research programs, aiming to enhance health outcomes for both individuals and populations. The objective of this review is to document global clinical and nonclinical research priorities. The Emergency Medicine Education and Research by Global Experts network, consisting of 22 sites across six continents, conducted a mapping review of publications on emergency medicine research priorities (2000-2022) across seven databases. We included studies with replicable methodologies for determining research priorities, excluding those limited to individual diseases. Three reviewers independently screened, selected, and categorized results into clinical and nonclinical topics. Discrepancies were resolved by an independent investigator and consensus. Outcomes measures and analysis include descriptive analysis of research priorities grouped into clinical and nonclinical topics, characteristics of publications including countries represented in the author list, target audience (such as researchers or policy makers), participants (e.g. patients), and methods (e.g. Delphi) of priority setting. Among 968 screened papers, 57 publications from all WHO regions were included. Most (36, 63%) had authors from only a single country, primarily in North America and Europe. Patient representatives were included in only 10 (18%). Clinical research priorities clustered into resuscitation, cardiology, central nervous system, emergency medical services, infectious disease, mental health, respiratory disease, and trauma. Distribution was broad in North America and Europe but focused on infectious diseases and resuscitation in Africa and Asia. Eleven nonclinical topics included access to care, health policy, screening/triage, social determinants of health, staffing, technology/simulation, shared decision making, cross-sectoral collaboration, education, patient-centered care, and research networks. Nonclinical topics were broad in Europe and America, focused on access to care and health screening in Africa, and mostly absent in other WHO regions. Published research priorities in emergency medicine are heterogeneous and geographically limited, mostly containing groups of authors from the same country. The majority of publications in global research priority setting stem from Western countries, covering a broad spectrum of clinical and nonclinical topics. Research priorities from Africa and Asia tend to focus on specific issues more prevalent in those regions of the world., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Modeling patient data, particularly electronic health records (EHR), is one of the major focuses of machine learning studies in healthcare, as these records provide clinicians with valuable information that can potentially assist them in disease diagnosis and decision-making., Methods: In this study, we present a multi-level graph-based framework called MedMGF, which models both patient medical profiles extracted from EHR data and their relationship network of health profiles in a single architecture. The medical profiles consist of several layers of data embedding derived from interval records obtained during hospitalization, and the patient-patient network is created by measuring the similarities between these profiles. We also propose a modification to the Focal Loss (FL) function to improve classification performance in imbalanced datasets without the need to imputate the data. MedMGF's performance was evaluated against several Graphical Convolutional Network (GCN) baseline models implemented with Binary Cross Entropy (BCE), FL, class balancing parameter α , and Synthetic Minority Oversampling Technique (SMOTE)., Results: Our proposed framework achieved high classification performance (AUC: 0.8098, ACC: 0.7503, SEN: 0.8750, SPE: 0.7445, NPV: 0.9923, PPV: 0.1367) on an extreme imbalanced pediatric sepsis dataset (n=3,014, imbalance ratio of 0.047). It yielded a classification improvement of 3.81% for AUC, 15% for SEN compared to the baseline GCN+ α FL (AUC: 0.7717, ACC: 0.8144, SEN: 0.7250, SPE: 0.8185, PPV: 0.1559, NPV: 0.9847), and an improvement of 5.88% in AUC and 22.5% compared to GCN+FL+SMOTE (AUC: 0.7510, ACC: 0.8431, SEN: 0.6500, SPE: 0.8520, PPV: 0.1688, NPV: 0.9814). It also showed a classification improvement of 3.86% for AUC, 15% for SEN compared to the baseline GCN+ α BCE (AUC: 0.7712, ACC: 0.8133, SEN: 0.7250, SPE: 0.8173, PPV: 0.1551, NPV: 0.9847), and an improvement of 14.33% in AUC and 27.5% in comparison to GCN+BCE+SMOTE (AUC: 0.6665, ACC: 0.7271, SEN: 0.6000, SPE: 0.7329, PPV: 0.0941, NPV: 0.9754)., Conclusion: When compared to all baseline models, MedMGF achieved the highest SEN and AUC results, demonstrating the potential for several healthcare applications., (© 2024. The Author(s).)

Competing Interests: Dr. Lee’s institution received funding from the National Research Medical Council and the Thrasher Foundation. Dr. Chong has disclosed that she does not have any potential conflicts of interest.

Background and Objective: Federated learning (FL) is an emerging distributed learning framework allowing multiple clients (hospitals, institutions, smart devices, etc.) to collaboratively train a centralized machine learning model without disclosing personal data. It has the potential to address several healthcare challenges, including a lack of training data, data privacy, and security concerns. However, model learning under FL is affected by non-i.i.d. data, leading to severe model divergence and reduced performance due to the varying client's data distributions. To address this problem, we propose FedDSS, Federated Data Similarity Selection, a framework that uses a data-similarity approach to select clients, without compromising client data privacy., Methods: FedDSS comprises a statistical-based data similarity metric, a N-similar-neighbor network, and a network-based selection strategy. We assessed FedDSS' performance against FedAvg's in i.i.d. and non-i.i.d. settings with two public pediatric sepsis datasets (PICD and MIMICIII). Selection fairness was measured using entropy. Simulations were repeated five times to evaluate average loss, true positive rate (TPR), and entropy., Results: In i.i.d setting on PICD, FedDSS achieved a higher TPR starting from the 9th round and surpassing 0.6 three rounds earlier than FedAvg. On MIMICIII, FedDSS's loss decreases significantly from the 13th round, with TPR > 0.8 by the 2nd round, two rounds ahead of FedAvg (at the 4th round). In the non-i.i.d. setting, FedDSS achieved TPR > 0.7 by the 4th and > 0.8 by the 7th round, earlier than FedAvg (at the 5th and 11th rounds). In both settings, FedDSS showed reasonable fairness (entropy of 2.2 and 2.1)., Conclusion: We demonstrated that FedDSS contributes to improved learning in FL by achieving faster convergence, reaching the desired TPR with fewer communication rounds, and potentially enhancing sepsis prediction (TPR) over FedAvg., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Sepsis is associated with neurocognitive impairment among preterm neonates but less is known about term neonates with sepsis. This systematic review and meta-analysis aims to provide an update of neurocognitive outcomes including cognitive delay, visual impairment, auditory impairment, and cerebral palsy, among neonates with sepsis., Methods: We performed a systematic review of PubMed, Embase, CENTRAL and Web of Science for eligible studies published between January 2011 and March 2023. We included case-control, cohort studies and cross-sectional studies. Case reports and articles not in English language were excluded. Using the adjusted estimates, we performed random effects model meta-analysis to evaluate the risk of developing neurocognitive impairment among neonates with sepsis., Results: Of 7,909 studies, 24 studies (n = 121,645) were included. Majority of studies were conducted in the United States (n = 7, 29.2%), and all studies were performed among neonates. 17 (70.8%) studies provided follow-up till 30 months. Sepsis was associated with increased risk of cognitive delay [adjusted odds ratio, aOR 1.14 (95% CI: 1.01-1.28)], visual impairment [aOR 2.57 (95%CI: 1.14- 5.82)], hearing impairment [aOR 1.70 (95% CI: 1.02-2.81)] and cerebral palsy [aOR 2.48 (95% CI: 1.03-5.99)]., Conclusion: Neonates surviving sepsis are at a higher risk of poorer neurodevelopment. Current evidence is limited by significant heterogeneity across studies, lack of data related to long-term neurodevelopmental outcomes and term infants., (© 2024. The Author(s).)

Introduction: Prehospital trauma triage and disability assessment of pediatric patients can be challenging on the field, especially in the pre-verbal age group. It would be useful if the same triage tool and criteria can be used for both adults and children to risk-stratify the need of higher acuity of trauma care., Study Objective: We aimed to investigate if using only the motor component of Glasgow Coma Scale (mGCS), as a quick field trauma triage tool, was non-inferior to total GCS (tGCS), and if mGCS <6 was non-inferior to tGCS <14, in predicting the need for intensive care or mortality in the pediatric population., Methods: We performed a retrospective review of patients <18-years-old, who presented to our emergency department (ED) with moderate (Injury Severity Score (ISS) 9-15) to severe (ISS > 15) traumatic injuries from January 2012 to December 2021. Using ED triage data, mortality and the need for intensive care unit (ICU) admission were used as surrogate outcomes to investigate if mGCS <6 was non-inferior to tGCS <14, and the area-under-the-receiver-operating-characteristic curve (AUROC) was used as a measure of comparability., Results: Among 582 included for analysis, the median age was 7-years-old (2-12), and most were male (63.4%). 22.4% patients demised or required ICU care. mGCS <6 had an AUROC of 0.75 (95% CI 0.70 to 0.79), which was non-inferior to tGCS <14; AUROC 0.76, (95% CI 0.72 to 0.81), for identifying children requiring ICU management or demised. The results shown here were based on the AUROCs that were used to evaluate the discriminatory ability of tGCS <14 and mGCS <6 in prediction of mortality and the need for ICU care., Conclusion: Our study showed that mGCS was significantly associated with tGCS, and was non- inferior to the latter as a triage tool in pediatric trauma. It validated the use of mGCS <6 in lieu of tGCS <14 in the pre-hospital field triage of pediatric patients, in identification of children at risk of death or requiring ICU care. Larger prospective, observational studies using on-scene data would be required for more robust validation and determine optimal cut-offs., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Advancements in medical technologies have led to the development of contact-free methods of haemodynamic monitoring such as remote photoplethysmography (rPPG). rPPG uses video cameras to interpret variations in skin colour related to blood flow, which are analysed to generate vital signs readings. rPPG potentially ameliorates problems like fretfulness and fragile skin contact associated with conventional probes in children. While rPPG has been validated in adults, no prior validation has been performed in children., Methods: A two-phased prospective cross-sectional single-centre study was conducted from January to April 2023 to evaluate the feasibility, acceptability, and accuracy of obtaining heart rate (HR), respiratory rate (RR) and oxygen saturation (SpO 2 ) using rPPG in children, compared to the current standard of care. In Phase 1, we recruited patients ≤16 years from the neonatal and paediatric wards. We excluded preterm neonates with gestational age <35 weeks and newborns <24 hours old. The rPPG webcam was positioned 30 cm from the face. After 1 minute of facial scanning, readings generated were compared with pulse oximetry for HR and SpO 2 , and manual counting for RR. Correlation and Bland-Altman analyses were performed. In Phase 2, we focused on the population in whom there was potential correlation between rPPG and the actual vital signs., Results: Ten neonates and 28 children aged 5 to 16 years were recruited for Phase 1 (765 datapoints). All patients were haemodynamically stable and normothermic. Patients and caregivers showed high acceptability to rPPG. rPPG values were clinically discrepant for children <10 years. For those ≥10 years, moderate correlation was observed for HR, with Spearman's correlation coefficient (Rs) of 0.50 [95% confidence intervals (CI): 0.42, 0.57]. We performed Phase 2 on 23 patients aged 12 to 16 years (559 datapoints). Strong correlation was observed for HR with Rs=0.82 (95% CI: 0.78, 0.85). There was weak correlation for SpO 2 and RR (Rs=-0.25 and -0.02, respectively)., Conclusions: Our study showed that rPPG is acceptable and feasible for neonates and children aged 5 to 16 years, and HR values in older children aged 12 to 16 years correlated well with the current standard. The rPPG algorithms need to be further refined for younger children, and for obtaining RR and SpO 2 in all children. If successful, rPPG will provide a viable contact-free alternative for assessing paediatric vital signs, with potential use in remote monitoring and telemedicine., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1896/coif). The authors have no conflicts of interest to declare., (2024 Annals of Translational Medicine. All rights reserved.)

Phytochemical study of the fruits of Chisocheton erythrocarpus (Hiern) allowed the identification of eight undescribed limonoids, namely erythrocarpines O - V (1-6, 7a and 7b), along with seven known compounds. The structures of these compounds were elucidated based on spectroscopic and HRMS data, along with electronic circular dichroism to configure the absolute configuration. Erythrocarpines O and P are γ-hydroxybutenolide analogs of mexicanolide-type limonoids while erythrocarpine Q - V are phragmalin-type limonoids possessing a 1,29-oxymethylene bridge with either benzoyl or cinnamoyl moiety in their structures. Mosquito larvicidal activity revealed that crude DCM extract of C. erythrocarpus possessed a good larvicidal effect against Aedes aegypti larvae in 48 h (LC 50  = 153.0 ppm). Subsequent larvicidal activity of isolated compounds indicated that erythrocarpine G (10) and 14-deoxyxyloccensin K (11) were responsible for the enhanced larvicidal effect of the extract, reporting LC 50 values of 18.55 ppm and 41.16 ppm, respectively. Moreover, residual activity testing of the crude DCM extract revealed that the duration of its larvicidal effects is up to 14 days, where it maintained a 98 % larval mortality throughout the test period, under laboratory conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Febrile young infants are at risk of serious bacterial infections (SBIs), which are potentially life-threatening. This study aims to investigate the association between delayed presentation and the risk of SBIs among febrile infants., Method: We performed a prospective cohort study on febrile infants ≤90 days old presenting to a Singapore paediatric emergency department (ED) between November 2017 and July 2022. We defined delayed presentation as presentation to the ED >24 hours from fever onset. We compared the proportion of SBIs in infants who had delayed presentation compared to those without, and their clinical outcomes. We also performed a multivariable logistic regression to study if delayed presentation was independently associated with the presence of SBIs., Results: Among 1911 febrile infants analysed, 198 infants (10%) had delayed presentation. Febrile infants with delayed presentation were more likely to have SBIs (28.8% versus [vs] 16.3%, P<0.001). A higher proportion of infants with delayed presentation required intravenous antibiotics (64.1% vs 51.9%, P=0.001). After adjusting for age, sex and severity index score, delayed presentation was independently associated with the presence of SBI (adjusted odds ratio [AOR] 1.78, 95% confidence interval 1.26-2.52, P<0.001)., Conclusion: Febrile infants with delayed presentation are at higher risk of SBI. Frontline clinicians should take this into account when assessing febrile infants., Competing Interests: The authors have no conflict of interest to declare.

The Zingiber zerumbet rhizomes are traditionally used to treat fever, and the in vitro inhibitory effect of ethyl acetate extract from Zingiber zerumbet rhizomes (EAEZZR) against DENV2 NS2B/NS3 (two non-structural proteins, NS2 and NS3 of dengue virus type 2) has been reported earlier. This study was carried out to establish an acute toxicity profile and evaluate the anti-fever (anti-pyretic) activities of EAEZZR in yeast-induced fever in rats. The major compound of EAEZZR, zerumbone, was isolated using chromatographic methods including column chromatography (CC) and preparative thin-layer chromatography (PTLC). Additionally, the structure of zerumbone was elucidated using nuclear magnetic resonance (NMR), liquid chromatography mass spectrometer-ion trap-time of flight (LCMS-IT-TOF), infrared (IR), and ultraviolet (UV) spectroscopy. The toxicity of EAEZZR was evaluated using Organization for Economic Cooperation and Development Test Guideline 425 (OECD tg-425) with minor modifications at concentrations EAEZZR of 2000 mg/kg, 3000 mg/kg, and 5000 mg/kg. Anti-fever effect was determined by yeast-induced fever (pyrexia) in rats. The acute toxicity study showed that EAEZZR is safe at the highest 5000 mg/kg body weight dose in Sprague Dawley rats. Rats treated with EAEZZR at doses of 125, 250, and 500 mg/kg exhibited a significant reduction in rectal temperature (T R ) in the first 1 h. EAEZZR at the lower dose of 125 mg/kg showed substantial potency against yeast-induced fever for up to 2 h compared to 0 h in controls. A significant reduction of T R was observed in rats treated with standard drug aspirin in the third through fourth hours. Based on the present findings, ethyl acetate extract of Zingiber zerumbet rhizomes could be considered safe up to the dose of 5000 mg/kg, and the identification of active ingredients of Zingiber zerumbet rhizomes may allow their use in the treatment of fever with dengue virus infection., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: We describe the clinical course of children with IgA nephropathy (IgAN), diagnosed before and after the emergence of COVID-19. We hypothesized that COVID-19 vaccination and/or infection resulted in more children with IgAN to present clinically., Methods: We conducted a retrospective cohort study of children with IgAN diagnosed on kidney biopsy from 2014-2020 (Period 1) and 2021-2022 (Period 2). Baseline characteristics, clinical presentation, investigations and treatments were compared between patients diagnosed in Period 1 and Period 2, as well as between patients with and without chronic changes on kidney biopsy. Continuous variables were compared using the Wilcoxon rank sum test. Categorical variables were compared using χ2 or Fisher exact tests., Results: Nineteen children with IgAN were diagnosed by kidney biopsy, with 10 during Period 1 and 9 patients during Period 2 (an average of 1-2 patients/year and 4-5 patients/year in Periods 1 and 2, respectively). The most common indication for kidney biopsy is proteinuria with urine protein/creatinine ratio 1.4 (interquartile range [IQR] 1.2-9.0) vs. 0.8 (IQR 0.6-1.5) g/g (p = 0.064) at time of kidney biopsy for patients in Period 1 and 2, respectively. Clinical course was similar in both periods. No patient required acute or chronic kidney replacement therapy., Conclusions: The rate of diagnosing children with IgAN was higher since the emergence of COVID-19, suggesting that COVID-19 may trigger an immune response responsible for IgAN, similar to other mucosal infections., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Introduction: The management of fever without source in children ≤36 months old remains a diagnostic challenge as the underlying aetiologies can vary from self-limiting viral infections to serious bacterial infections (SBIs). Biomarkers such as C reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6) have varying thresholds in the prediction of SBIs due to differences in SBI definitions, SBI prevalence, patient characteristics and timing of presentation. This protocol describes a systematic review and meta-analysis that aims to determine the thresholds at which CRP, PCT and IL-6 can perform optimally in distinguishing the presence of SBIs in children ≤36 months old, as well as to determine their performances in early detection of bacterial infections within 48 hours of fever onset., Methods and Analysis: We will systematically search electronic databases including MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane CENTRAL, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Science Citation Index from 1 July 2023 to 31 July 2023. We will include studies that report the diagnostic accuracy of CRP, PCT and IL-6 in detecting SBIs in children aged ≤36 months presenting with fever without apparent source. Randomised controlled trials (RCTs) and non-randomised studies including non-RCTs and controlled before-and-after studies will be included. A meta-analysis will be performed and diagnostic performances of these biomarkers will be reported., Ethics and Dissemination: The results of this study will provide guidance on clinical decision-making in young children presenting with fever without source. Ethics approval will not be required for this study. The authors aim to publish the findings in a peer-reviewed journal as well as present at international conferences., Prospero Registration Number: CRD42023439093., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: We aimed to identify clinical characteristics, risk factors for diagnosis, and describe outcomes among children with AHT., Methods: We performed an observational cohort study in tertiary care hospitals from 14 countries across Asia and Ibero-America. We included patients <5 years old who were admitted to participating pediatric intensive care units (PICUs) with moderate to severe traumatic brain injury (TBI). We performed descriptive analysis and multivariable logistic regression for risk factors of AHT., Results: 47 (12%) out of 392 patients were diagnosed with AHT. Compared to those with accidental injuries, children with AHT were more frequently < 2 years old (42, 89.4% vs 133, 38.6%, p < 0.001), more likely to arrive by private transportation (25, 53.2%, vs 88, 25.7%, p < 0.001), but less likely to have multiple injuries (14, 29.8% vs 158, 45.8%, p = 0.038). The AHT group was more likely to suffer subdural hemorrhage (SDH) (39, 83.0% vs 89, 25.8%, p < 0.001), require antiepileptic medications (41, 87.2% vs 209, 60.6%, p < 0.001), and neurosurgical interventions (27, 57.40% vs 143, 41.40%, p = 0.038). Mortality, PICU length of stay, and functional outcomes at 3 months were similar in both groups. In the multivariable logistic regression, age <2 years old (aOR 8.44, 95%CI 3.07-23.2), presence of seizures (aOR 3.43, 95%CI 1.60-7.36), and presence of SDH (aOR 9.58, 95%CI 4.10-22.39) were independently associated with AHT., Conclusions: AHT diagnosis represented 12% of our TBI cohort. Overall, children with AHT required more neurosurgical interventions and the use of anti-epileptic medications. Children younger than 2 years and with SDH were independently associated with a diagnosis of AHT., Type of Study: Observational cohort study., Level of Evidence: III., Competing Interests: Conflicts of interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A phytochemical study on the bark of Chisocheton erythrocarpus Hiern (Meliaceae) has led to the isolation of six new phragmalin-type limonoids named erythrocarpines I - N (1-6) along with one known limonoid, erythrocarpine F (7). Their structures were fully characterized by spectroscopic methods. The pre-treatment of NG108-15 cells with 1-5, 7 (2 h) demonstrated low to good protective effects against H 2 O 2 exposure; 1 (83.77% ± 1.84 at 12.5 μM), 2 (69.07 ± 2.01 at 12.5 μM), 3 (80.38 ± 2.1 at 12.5 μM), 4 (62.33 ± 1.95 at 25 μM),5 (58.67 ± 1.85 at 50 μM) and 7 (66.07 ± 2.03 at 12.5 μM). Interestingly, 1 and 3 demonstrated comparable protective effects to positive control epigallocatechin gallate (EGCG) with similar cell viability capacity (≈ 80%), having achieved that at lower concentration (12.5 μM) than EGCG (50 μM). Collectively, the results suggested the promising use of 1 and 3 as potential neuroprotective agents against hydrogen peroxide-induced cytotoxicity in neuronal model., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: The burden of traumatic brain injury (TBI) is disproportionately high in low- and middle-income countries (LMICs). This study aimed to compare clinical outcomes and healthcare utilization for children with moderate to severe TBIs between LMICs and non-LMICs in Asia and Latin America., Methods: The authors performed an observational multicenter study from January 2014 to February 2023 among children with moderate to severe TBIs admitted to participating pediatric intensive care units (PICUs) in the Pediatric Acute and Critical Care Medicine Asian Network (PACCMAN) and Red Colaborativa Pediátrica de Latinoamérica (LARed Network). They classified sites according to their 2019 sociodemographic index (SDI). Low, low-middle, and middle SDI sites were considered LMICs, while high-middle and high SDI sites were considered non-LMICs. The authors documented patient demographics and TBI management. Accounting for death, they recorded 14-day PICU-free and 28-day hospital-free days, with fewer free days indicating poorer outcome. The authors compared children who died and those who had poor functional outcomes (defined as Pediatric Cerebral Performance Category [PCPC] level of moderate disability, severe disability, or vegetative state or coma) between LMICs and non-LMICs and performed a multivariable logistic regression analysis for predicting poor functional outcomes., Results: In total, 771 children with TBIs were analyzed. Mortality was comparable between LMICs and non-LMICs (9.6% vs 12.9%, p = 0.146). Children with TBIs from LMICs were more likely to have a poor PCPC outcome (31.0% vs 21.3%, p = 0.004) and had fewer ICU-free days (median [IQR] 6 [0-10] days vs 8 [0-11] days, p = 0.004) and hospital-free days (median [IQR] 9 [0-18] days vs 13 [0-20] days, p = 0.007). Poor functional outcomes were associated with LMIC status (adjusted OR [aOR] 1.53, 95% CI 1.04-2.26), a lower Glasgow Coma Scale score (aOR 0.83, 95% CI 0.78-0.88), and the presence of multiple trauma (aOR 1.49, 95% CI 1.01-2.19). Children with TBIs in LMICs required greater resource utilization in the form of early intubation and mechanical ventilation (81.6% vs 73.2%, p = 0.006), use of hyperosmolar therapy (77.7% vs 63.6%, p < 0.001), and use of antiepileptic drugs (73.9% vs 53.1%, p < 0.001)., Conclusions: Within Asia and Latin America, children with TBIs in LMICs were more likely to have poor functional outcomes and required greater resource utilization. Further research should focus on investigating causal factors and developing targeted interventions to mitigate these disparities.

Purpose: We aimed to investigate the association between initial dysnatremia (hyponatremia and hypernatremia) and in-hospital mortality, as well as between initial dysnatremia and functional outcomes, among children with traumatic brain injury (TBI)., Method: We performed a multicenter observational study among 26 pediatric intensive care units from January 2014 to August 2022. We recruited children with TBI under 18 years of age who presented to participating sites within 24 h of injury. We compared demographics and clinical characteristics between children with initial hyponatremia and eu-natremia and between those with initial hypernatremia and eu-natremia. We defined poor functional outcome as a discharge Pediatric Cerebral Performance Category (PCPC) score of moderate, severe disability, coma, and death, or an increase of at least 2 categories from baseline. We performed multivariable logistic regression for mortality and poor PCPC outcome., Results: Among 648 children, 84 (13.0%) and 42 (6.5%) presented with hyponatremia and hypernatremia, respectively. We observed fewer 14-day ventilation-free days between those with initial hyponatremia [7.0 (interquartile range (IQR) = 0.0-11.0)] and initial hypernatremia [0.0 (IQR = 0.0-10.0)], compared to eu-natremia [9.0 (IQR = 4.0-12.0); p = 0.006 and p < 0.001]. We observed fewer 14-day ICU-free days between those with initial hyponatremia [3.0 (IQR = 0.0-9.0)] and initial hypernatremia [0.0 (IQR = 0.0-3.0)], compared to eu-natremia [7.0 (IQR = 0.0-11.0); p = 0.006 and p < 0.001]. After adjusting for age, severity, and sex, presenting hyponatremia was associated with in-hospital mortality [adjusted odds ratio (aOR) = 2.47, 95% confidence interval (CI) = 1.31-4.66, p = 0.005] and poor outcome (aOR = 1.67, 95% CI = 1.01-2.76, p = 0.045). After adjustment, initial hypernatremia was associated with mortality (aOR = 5.91, 95% CI = 2.85-12.25, p < 0.001) and poor outcome (aOR = 3.00, 95% CI = 1.50-5.98, p = 0.002)., Conclusion: Among children with TBI, presenting dysnatremia was associated with in-hospital mortality and poor functional outcome, particularly hypernatremia. Future research should investigate longitudinal sodium measurements in pediatric TBI and their association with clinical outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Introduction: We aim to investigate the functional outcomes and long-term health-related quality of life (HRQOL) in children with major trauma associated with traumatic brain injury (TBI)., Method: We performed a retrospective review of records among patients >2 and ≤16 years old in a tertiary paediatric hospital between January 2014 and October 2019 with major trauma (Injury Severity Score of ≥16) and TBI of all severities. We recorded each child's Glasgow Outcome Scale-Extended Pediatric Version (GOS-E Peds) at 12 months post-injury and Pediatric Quality of Life Inventory (PedsQL) scores at 6 and 12 months post-injury based on the parent proxy-report scales., Results: We included 53 patients with a median age of 9.0 years old (interquartile range 2.3-15.5). Most injuries were due to falls (30, 56.6%) or road traffic collisions (15, 28.3%); 41 patients (77.3%) required intensive care while 30 patients (56.6%) underwent neurosurgical intervention. Most patients (43, 81.1%) had GOS-E Peds scores of ≤2 at 12 months post-injury. We reported a significant mean difference between the 6- and 12-month parent-reported scores for physical functioning (6.6, 95% confidence interval [CI] 0.3-12.8, P=0.041), psychosocial functioning (4.1, 95% CI 1.0-7.2, P=0.012) and overall scores (5.0, 95% CI 1.4-8.7, P=0.008). Compared with the validated PedsQL scores, our mean scores were higher across all domains at 12 months., Conclusion: With current standard of care, parents of children with major trauma and TBI reported gains in quality of life, physical, psychosocial and overall function between 6 and 12 months post-injury., Competing Interests: The authors report no conflict of interest.

Adenine phosphoribosyl transferase (APRT) deficiency is an autosomal recessive disorder and a rare cause of urolithiasis due to mutations in APRT (OMIM #102600). APRT deficiency results in increased urinary excretion of 2,8-dihydroxyadenine (DHA) which can cause urolithiasis and kidney failure. However, with prompt diagnosis, patients with APRT deficiency can be treated with xanthine oxidoreductase inhibitors which decrease urinary DHA excretion and improve outcomes. We report a pair of siblings, an 11-year-old brother and his 14-year-old sister with compound heterozygous variants c.270del (p.Lys91Serfs*46) and c.484&#95;486del (p.Leu162del) in APRT with variable clinical presentation of APRT deficiency. The brother presented at 17 months of age with urolithiasis and severe acute kidney injury. His elder sister remained well and asymptomatic with normal kidney function and did not develop renal calculi. Brownish disk or sphere-like crystals with both concentric and radial markings were reported on urine microscopy in the sister on screening. The sister's diagnosis was confirmed with further laboratory evidence of absent red cell lysate APRT activity with corresponding elevated levels of urinary DHA. In conclusion, we identified a novel mutation in the APRT gene in a pair of siblings with greater phenotypic severity in the male., (© 2023 Asian Pacific Society of Nephrology.)

Background: Recent research has demonstrated that machine learning (ML) has the potential to improve several aspects of medical application for critical illness, including sepsis. This scoping review aims to evaluate the feasibility of probabilistic graphical model (PGM) methods in pediatric sepsis application and describe the use of pediatric sepsis definition in these studies., Methods: Literature searches were conducted in PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL+), and Web of Sciences from 2000-2023. Keywords included "pediatric", "neonates", "infants", "machine learning", "probabilistic graphical model", and "sepsis"., Results: A total of 3,244 studies were screened, and 72 were included in this scoping review. Sepsis was defined using positive microbiology cultures in 19 studies (26.4%), followed by the 2005's international pediatric sepsis consensus definition in 11 studies (15.3%), and Sepsis-3 definition in seven studies (9.7%). Other sepsis definitions included: bacterial infection, the international classification of diseases, clinicians' assessment, and antibiotic administration time. Among the most common ML approaches used were logistic regression (n=27), random forest (n=24), and Neural Network (n=18). PGMs were used in 13 studies (18.1%), including Bayesian classifiers (n=10), and the Markov Model (n=3). When applied on the same dataset, PGMs show a relatively inferior performance to other ML models in most cases. Other aspects of explainability and transparency were not examined in these studies., Conclusions: Current studies suggest that the performance of probabilistic graphic models is relatively inferior to other ML methods. However, its explainability and transparency advantages make it a potentially viable method for several pediatric sepsis studies and applications., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-25/coif). All authors report this study has received payment from National Research Medical Council, Singapore. J.H.L. is serving as a Deputy Editor-in-Chief of Translational Pediatrics from July 2022 to June 2024. The authors have no other conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

Background: Introduction of the mRNA vaccination for coronavirus disease 2019 (COVID-19) has been associated with an increase in cases of peri/myocarditis. In our retrospective cross-sectional study, we aim to (I) describe paediatric chest pain attendance, and (II) study resource utilisation in the Emergency Department (ED) of KK Women's and Children's Hospital (KKH), stratified by pre-pandemic, during the pandemic pre- and post-COVID vaccination introduction in adolescents., Methods: We reviewed records of adolescents aged 12 to 18 years old who presented to our ED with the triage complaint of chest pain between 1 January 2019 to 31 January 2022, and determined the attendance rates, aetiologies and resource utilisation during the above time periods., Results: There were 2,418 ED attendances for chest pain in our study population. Among 887 inpatient admissions for chest pain, 1.8% were attributed to a cardiac cause. Comparing the pre-pandemic period to the period after the mRNA COVID-19 vaccination was introduced, ED chest pain rates increased from a median of 0.5% of ED attendances [interquartile range (IQR), 0.3-0.5%] to 0.9% (IQR, 0.7-2.0%) (P<0.001), while admission rates increased from a median of 26.2% of ED attendances (IQR, 24.1-29.1%) to 40.9% (IQR, 37.6-56.6%) (P<0.001). Cardiac enzyme orders among ED visits for chest pain increased from a pre-pandemic median of 0% (IQR, 0.0-2.6%) to a post-vaccination median of 26.1% (IQR, 17.2-56.2%) (P<0.001) and were due to concerns for vaccine-related myocarditis. Seven cases of probable vaccine-related myocarditis presented with chest pain to our ED., Conclusions: Paediatric chest pain is largely non-cardiac in origin. ED chest pain attendance rates and resource utilisation increased after the introduction of mRNA COVID-19 vaccination in adolescents., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-230/coif). The authors have no conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

Purpose: Children with moderate traumatic brain injury (modTBI) (Glasgow Coma Scale (GCS) 9-13) may benefit from better stratification. We aimed to compare neurocritical care utilization and functional outcomes between children with high GCS modTBI (hmodTBI, GCS 11-13), low GCS modTBI (lmodTBI, GCS 9-10), and severe TBI (sTBI, GCS ≤ 8). We hypothesized that patients with lmodTBI have higher neurocritical care needs and worse outcomes than patients with hmodTBI and are similar to patients with sTBI., Methods: Prospective observational study from June 2018 to October 2022 in 28 pediatric intensive care units (PICU) in Asia, South America, and Europe. We included children (age < 18 years) with modTBI and sTBI admitted to PICU and measured functional outcomes at 3 months using the Glasgow Outcome Scale-Extended Pediatric Revision (GOS-E Peds, scale 1-8, 1 = upper good recovery, 8 = death)., Results: We analyzed 409 patients: 98 (24%) and 311 (76%) with modTBI and sTBI, respectively. Patients with lmodTBI (vs. hmodTBI) were more likely to have invasive ICP monitoring (32.3% vs. 4.5%, p < 0.001), longer PICU stay (days, median [IQR]; 5.00 [4.00, 9.75] vs 4.00 [2.00, 5.00], p = 0.007), and longer hospital stay (days, median [IQR]: 13.00 [8.00, 17.00] vs. 8.00 [5.00, 12, 25], p = 0.015). Median GOS-E Peds scores were significantly different (hmodTBI (1.00 [1.00, 3.00]), lmodTBI (3.00 [IQR 2.00, 5.75]), and sTBI (5.00 [IQR 1.00, 6.00]) (p < 0.001)). After adjusting for age, sex, presence of polytrauma and cerebral edema, lmodTBI, and sTBI remained significantly associated with higher GOS-E scores (adjusted coefficient (standard error): 1.24 (0.52), p = 0.018, and 1.27 (0.33), p < 0.001, respectively) compared with hmodTBI., Conclusions: Children with lmodTBI have higher rates of neurocritical care utilization and worse functional outcomes than those with hmodTBI but better than those with sTBI. Children with lmodTBI may benefit from guideline-based management similar to what is implemented in children with sTBI. This work was performed in hospitals within the PACCMAN and LARed networks. No reprints will be ordered., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: To assist clinicians with identifying children at risk of severe outcomes, we assessed the association between laboratory findings and severe outcomes among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected children and determined if SARS-CoV-2 test result status modified the associations., Methods: We conducted a cross-sectional analysis of participants tested for SARS-CoV-2 infection in 41 pediatric emergency departments in 10 countries. Participants were hospitalized, had laboratory testing performed, and completed 14-day follow-up. The primary objective was to assess the associations between laboratory findings and severe outcomes. The secondary objective was to determine if the SARS-CoV-2 test result modified the associations., Results: We included 1817 participants; 522 (28.7%) SARS-CoV-2 test-positive and 1295 (71.3%) test-negative. Seventy-five (14.4%) test-positive and 174 (13.4%) test-negative children experienced severe outcomes. In regression analysis, we found that among SARS-CoV-2-positive children, procalcitonin ≥0.5 ng/mL (adjusted odds ratio [aOR], 9.14; 95% CI, 2.90-28.80), ferritin >500 ng/mL (aOR, 7.95; 95% CI, 1.89-33.44), D-dimer ≥1500 ng/mL (aOR, 4.57; 95% CI, 1.12-18.68), serum glucose ≥120 mg/dL (aOR, 2.01; 95% CI, 1.06-3.81), lymphocyte count <1.0 × 10 9 /L (aOR, 3.21; 95% CI, 1.34-7.69), and platelet count <150 × 10 9 /L (aOR, 2.82; 95% CI, 1.31-6.07) were associated with severe outcomes. Evaluation of the interaction term revealed that a positive SARS-CoV-2 result increased the associations with severe outcomes for elevated procalcitonin, C-reactive protein (CRP), D-dimer, and for reduced lymphocyte and platelet counts., Conclusions: Specific laboratory parameters are associated with severe outcomes in SARS-CoV-2-infected children, and elevated serum procalcitonin, CRP, and D-dimer and low absolute lymphocyte and platelet counts were more strongly associated with severe outcomes in children testing positive compared with those testing negative., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We aimed to derive the Febrile Infants Risk Score at Triage (FIRST) to quantify risk for serious bacterial infections (SBIs), defined as bacteremia, meningitis and urinary tract infections. We performed a prospective observational study on febrile infants < 3 months old at a tertiary hospital in Singapore between 2018 and 2021. We utilized machine learning and logistic regression to derive 2 models: FIRST, based on patient demographics, vital signs and history, and FIRST + , adding laboratory results to the same variables. SBIs were diagnosed in 224/1002 (22.4%) infants. Among 994 children with complete data, age (adjusted odds ratio [aOR] 1.01 95%CI 1.01-1.02, p < 0.001), high temperature (aOR 2.22 95%CI 1.69-2.91, p < 0.001), male sex (aOR 2.62 95%CI 1.86-3.70, p < 0.001) and fever of ≥ 2 days (aOR 1.79 95%CI 1.18-2.74, p = 0.007) were independently associated with SBIs. For FIRST + , abnormal urine leukocyte esterase (aOR 16.46 95%CI 10.00-27.11, p < 0.001) and procalcitonin (aOR 1.05 95%CI 1.01-1.09, p = 0.009) were further identified. A FIRST + threshold of ≥ 15% predicted risk had a sensitivity of 81.8% (95%CI 70.5-91.0%) and specificity of 65.6% (95%CI 57.8-72.7%). In the testing dataset, FIRST + had an area under receiver operating characteristic curve of 0.87 (95%CI 0.81-0.94). These scores can potentially guide triage and prioritization of febrile infants., (© 2023. Springer Nature Limited.)

Postpartum depression (PPD) is a public health problem that is associated with detrimental effects on the wellbeing of the mother, child and family. Early detection for PPD at the primary health level provides an opportunity for intervention. We aim to examine: (1) the prevalence rate of PPD in the primary care population, (2) acceptance and attendance rates of intervention for women who screened positive for PPD, (3) sociodemographic and maternal risk factors of PPD, and (4) the impact of PPD on breastfeeding. We implemented a mother-child dyadic screening program using the modified Patient Health Questionnaire-2 during routine well-child visits at 2 or 3 months postpartum between July 2019 and December 2021. We performed multivariable logistic regression to identify independent risk factors for PPD and described using adjusted odds ratio (OR) with corresponding 95 % confidence intervals. Among 5561 mothers, the prevalence rate of probable PPD was 2.4 %. About half (54.4 %) of mothers who screened positive accepted intervention and of these, about two-thirds accepted onward referrals to tertiary care and community mental health service, with higher attendance at the latter. In the final adjusted model, mothers who had probable PPD were more likely to be older than age 35 years (OR 1.88, 95 % CI 1.05-3.45; p < 0.05) and not breastfeeding (OR 1.9, 95 % CI 1.06-3.38; p < 0.05). Overall, our findings highlight the importance of early PPD screening and management in primary care. These findings can help inform maternal mental health service development and utilization, thereby optimizing maternal and infant outcomes., Competing Interests: Declaration of Competing Interest All the authors declare no conflict of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Competing Interests: None

Background: Probabilistic graphical model, a rich graphical framework in modelling associations between variables in complex domains, can be utilized to aid clinical diagnosis. However, its application in pediatric sepsis remains limited. This study aims to explore the utility of probabilistic graphical models in pediatric sepsis in the pediatric intensive care unit., Methods: We conducted a retrospective study on children using the first 24-hour clinical data of the intensive care unit admission from the Pediatric Intensive Care Dataset, 2010-2019. A probabilistic graphical model method, Tree Augmented Naive Bayes, was used to build diagnosis models using combinations of four categories: vital signs, clinical symptoms, laboratory, and microbiological tests. Variables were reviewed and selected by clinicians. Sepsis cases were identified with the discharged diagnosis of sepsis or suspected infection with the systemic inflammatory response syndrome. Performance was measured by the average sensitivity, specificity, accuracy, and area under the curve of ten-fold cross-validations., Results: We extracted 3,014 admissions [median age of 1.13 (interquartile range: 0.15-4.30) years old]. There were 134 (4.4%) and 2,880 (95.6%) sepsis and non-sepsis patients, respectively. All diagnosis models had high accuracy (0.92-0.96), specificity (0.95-0.99), and area under the curve (0.77-0.87). Sensitivity varied with different combinations of variables. The model that combined all four categories yielded the best performance [accuracy: 0.93 (95% confidence interval (CI): 0.916-0.936); sensitivity: 0.46 (95% CI: 0.376-0.550), specificity: 0.95 (95% CI: 0.940-0.956), area under the curve: 0.87 (95% CI: 0.826-0.906)]. Microbiological tests had low sensitivity (<0.10) with high incidence of negative results (67.2%)., Conclusions: We demonstrated that the probabilistic graphical model is a feasible diagnostic tool for pediatric sepsis. Future studies using different datasets should be conducted to assess its utility to aid clinicians in the diagnosis of sepsis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-510/coif). JHL serves as an unpaid Deputy Editor-in-Chief of Translational Pediatrics from July 2022 to June 2024. The other authors have no conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

Introduction: Foreign body (FB) ingestion is a common paediatric emergency. While guidelines exist for urgent intervention, less is known of the natural progress of FBs passing through the gastrointestinal tract (GIT). We reviewed these FB transit times in an outpatient cohort., Methods: A retrospective review was performed on all children (≤18 years) treated for radiopaque FB ingestion at two major tertiary paediatric centres from 2015 to 2016. Demographic data, FB types, outcomes and hospital visits (emergency department [ED] and outpatient) were recorded. All cases discharged from the ED with outpatient follow-up were included. We excluded those who were not given follow-up appointments and those admitted to inpatient wards. We categorised the outcomes into confirmed passage (ascertained via abdominal X-ray or reported direct stool visualisation by patients/caregivers) and assumed passage (if patients did not attend follow-up appointments)., Results: Of the 2,122 ED visits for FB ingestion, 350 patients who were given outpatient follow-up appointments were reviewed (median age 4.35 years [range: 0.5-14.7], 196 [56%] male). The largest proportion (16%) was aged 1-2 years. Coins were the most common ingested FB, followed by toys. High-risk FB (magnets or batteries) formed 9% of cases (n=33). The 50 th centile for FB retention was 8, 4 and 7 days for coins, batteries and other radiopaque FBs, respectively; all confirmed passages occurred at 37, 7 and 23 days, respectively. Overall, 197 (68%) patients defaulted on their last given follow-up., Conclusion: This study provides insight into the transit times of FB ingested by children, which helps medical professionals to decide on the optimal time for follow-up visits and provide appropriate counsel to caregivers., Competing Interests: None

Objective: To investigate the measurement properties of a hearing item ('bolt-on') added to the EQ-5D-5L descriptive system., Methods: Cross-sectional data on the EQ-5D-5L descriptive system with the addition of a hearing bolt-on item, namely, 'I have no/slight/moderate/severe/extreme problems hearing', was collected through face-to-face interviews with 418 participants of a community-based hearing loss screening program in Singapore. The distribution of responses to the EQ-5D and the hearing items were compared in terms of the proportion of 'no problems' and the Shannon index (H'). The measurement properties of the hearing item were assessed by testing its correlation with the hearing thresholds in dBHL; and with the standard EQ-5D items. The properties were also evaluated by comparing the proportion of 'full health' in participants with different hearing severities between standard and hearing bolt-on EQ-5D-5L; and the ability in identifying the participants between the standard EQ-5D-5L index score and the level sum score (LSS) of the hearing bolt-on system., Results: Compared to the standard EQ-5D items, the hearing item has a lower proportion of 'no problems' (80.1% vs. 80.9-97.9%); more evenly-distributed responses (H' value: 0.92 vs. 0.18-0.87); and much stronger correlation with the hearing thresholds (|r|: 0.322 and 0.325 vs. 0.008-0.139). It generally has a weak correlation with EQ-5D items (|r|: 0.055-0.160); and reduces the proportion of 'full health' for the participants with different hearing functions with the percentage reduction varying from 6.6 to 22.7%. The LSS is more discriminative than the standard EQ-5D-5L index score as well (F-statistic: 12.71 and 13.93 vs.4.06 and 4.70)., Conclusions: A hearing bolt-on to EQ-5D-5L can validly measure hearing severities and is likely to increase the sensitivity of the resultant preference-based EQ-5D index to hearing loss., (© 2022. Crown.)

Background: To study the association in moderate and severe pediatric traumatic brain injury (TBI) between hyperglycemia, hyperlactatemia, acidosis and unfavorable outcome, as assessed by Pediatric Cerebral Performance Category (PCPC) on discharge from the pediatric intensive care unit (PICU)., Methods: Children <16 years old with TBI and Glasgow Coma Scale (GCS) ≤13 in an Asian multi-center PICU TBI cohort from January 2014 to October 2017 were included in this study. We defined unfavorable outcome as PCPC ≥3-moderate disability, severe disability, vegetative state, and death. We performed logistic regression to investigate the association between metabolic changes with unfavorable outcome. We divided hyperglycemia (glucose >11.1 mmol/L) during PICU admission into early-onset (within 24 h), late-onset (beyond 48 h) and persistent (throughout first 72 h)., Results: Among the 305 children analyzed, 136 (44.6%) had unfavorable outcome. Children with unfavorable outcome were more likely to have early hyperglycemia (75/136, 55.1% vs. 33/169, 19.5%; P<0.001), high lactate levels >2.0 mmol/L (74/136, 54.4% vs. 56/169, 32.5%; P<0.001) and initial acidosis (85/136, 62.5% vs. 78/169, 56.1%; P=0.003) compared to those with favorable outcome. After adjusting for gender, GCS ≤8 and presence of polytrauma, early hyperglycemia [adjusted odds ratio (aOR) =3.68, 95% CI: 2.12-6.39, P<0.001] and late hyperglycemia (aOR =13.30, 95% CI: 1.64-107.8, P=0.015] were independently associated with unfavorable outcome. All children with persistent hyperglycemia died., Conclusions: We described unfavorable outcome in pediatric TBI especially with persistent hyperglycemia. Future trials should investigate the causal relationship between glycemic trends, early intervention and outcome in this cohort., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-443/coif). JHL serves as an unpaid Deputy Editor-in-Chief of Translational Pediatrics from July 2022 to June 2024. The other authors have no conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

BACKGROUND Plasma cell leukemia (PCL) is an aggressive form of plasma cell neoplasm. We report the first case of primary PCL successfully treated with upfront novel agents consisting of Venetoclax and daratumumab in combination with intensive chemotherapy and allogeneic transplantation. CASE REPORT A 59-year-old woman presented with epistaxis, gum bleeding, and blurred vision. On examination, she appeared pale, with multiple petechiae and hepatomegaly. Fundoscopy revealed retinal hemorrhages. Laboratory investigations revealed bicytopenia and leukocytosis, with mild coagulopathy and hypofibrinogenemia. Elevated globulin and calcium levels were also observed. Serum protein electrophoresis demonstrated IgG lambda paraproteinemia, with a serum-free light chain kappa-to-lambda ratio of 0.074. A skeletal survey revealed the presence of lytic lesions. Bone marrow investigations confirmed the presence of lambda-light-chain-restricted clonal plasma cells. FISH detected t(11;14) and 17p13.1 deletion. Therefore, a final diagnosis of primary PCL was made. The patient received 1 cycle of bortezomib, cyclophosphamide, and dexamethasone (VCD) and 5 cycles of Venetoclax-VCD, followed by an unsuccessful stem cell mobilization. One cycle of daratumumab in combination with bortezomib, lenalidomide, and dexamethasone (VRD) was then given. The patient achieved complete remission. She underwent allogeneic stem cell transplantation of an HLA-matched sibling donor. Post-transplant marrow assessment showed disease remission and absence of t(11;14) and 17p deletions. She was administered pamidronate and lenalidomide maintenance. She remained clinically well with a good performance status and no active graft-versus-host disease 18 months after transplant. CONCLUSIONS The success of our patient in achieving complete remission has highlighted the efficacy and safety of this novel therapy in the front-line management of PCL.

Objective: There is a paucity of information on pediatric traumatic brain injury (TBI) care in Asia and Latin America. In this study, the authors aimed to describe the clinical practices of emergency departments (EDs) participating in the Saline in Asia and Latin-America Neurotrauma in the Young (SALTY) study, by comparing designated trauma centers (DTCs) and nontrauma centers (NTCs) in their networks., Methods: The authors performed a site survey study on pediatric TBI management in the EDs in 14 countries. Two European centers joined other participating sites in Asia and Latin America. Questions were formulated after a critical review of current TBI guidelines and published surveys. The authors performed a descriptive analysis and stratified centers based on DTC status., Results: Of 24 responding centers (70.6%), 50.0% were DTCs, 70.8% had academic affiliations, and all centers were in urban settings. Patients were predominantly transferred to DTCs by centralized prehospital services compared to those sent to NTCs (83.3% vs 41.7%, p = 0.035). More NTCs received a majority of their patients directly from the trauma scene compared to DTCs (66.7% vs 25.0%, p = 0.041). Ten centers (41.7%) reported the use of a TBI management guideline, and 15 (62.5%) implemented CT protocols. Ten DTCs reported implementation of intervention strategies for suspected raised intracranial pressure (ICP) before conducting a CT scan, and 6 NTCs also followed this practice (83.3% vs 50.0%, p = 0.083). ED management for children with TBI was comparable between DTCs and NTCs in the following aspects: neuroimaging, airway management, ICP monitoring, fluid resuscitation, anticoagulant therapy, and serum glucose control. Hyperventilation therapy for raised ICP was used by 33.3% of sites., Conclusions: This study evaluated pediatric TBI management and infrastructure among 24 centers. Limited differences in prehospital care and ED management for pediatric patients with TBI were observed between DTCs and NTCs. Both DTCs and NTCs showed variation in the implementation of current TBI management guidelines. There is an urgent need to investigate specific barriers to guideline implementation in these regions.

Background & Aims: Lifestyle and environmental-related exposures are important risk factors for hepatocellular carcinoma (HCC), suggesting that epigenetic dysregulation significantly underpins HCC. We profiled 30 surgically resected tumours and the matched adjacent normal tissues to understand the aberrant epigenetic events associated with HCC., Methods: We identified tumour differential enhancers and the associated genes by analysing H3K27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) and Hi-C/HiChIP data from the resected tumour samples of 30 patients with early-stage HCC. This epigenome dataset was analysed with previously reported genome and transcriptome data of the overlapping group of patients from the same cohort. We performed patient-specific differential expression testing using multiregion sequencing data to identify genes that undergo both enhancer and gene expression changes. Based on the genes selected, we identified two patient groups and performed a recurrence-free survival analysis., Results: We observed large-scale changes in the enhancer distribution between HCC tumours and the adjacent normal samples. Many of the gain-in-tumour enhancers showed corresponding upregulation of the associated genes and vice versa , but much of the enhancer and gene expression changes were patient-specific. A subset of the upregulated genes was activated in a subgroup of patients' tumours. Recurrence-free survival analysis revealed that the patients with a more robust upregulation of those genes showed a worse prognosis., Conclusions: We report the genomic enhancer signature associated with differential prognosis in HCC. Findings that cohere with oncofoetal reprogramming in HCC were underpinned by genome-wide enhancer rewiring. Our results present the epigenetic changes in HCC that offer the rational selection of epigenetic-driven gene targets for therapeutic intervention or disease prognostication in HCC., Impact and Implications: Lifestyle and environmental-related exposures are the important risk factors of hepatocellular carcinoma (HCC), suggesting that tumour-associated epigenetic dysregulations may significantly underpin HCC. We profiled tumour tissues and their matched normal from 30 patients with early-stage HCC to study the dysregulated epigenetic changes associated with HCC. By also analysing the patients' RNA-seq and clinical data, we found the signature genes - with epigenetic and transcriptomic dysregulation - associated with worse prognosis. Our findings suggest that systemic approaches are needed to consider the surrounding cellular environmental and epigenetic changes in HCC tumours., Competing Interests: The authors declare no potential conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background: Conventional differential expression (DE) testing compares the grouped mean value of tumour samples to the grouped mean value of the normal samples, and may miss out dysregulated genes in small subgroup of patients. This is especially so for highly heterogeneous cancer like Hepatocellular Carcinoma (HCC)., Methods: Using multi-region sampled RNA-seq data of 90 patients, we performed patient-specific differential expression testing, together with the patients' matched adjacent normal samples., Results: Comparing the results from conventional DE analysis and patient-specific DE analyses, we show that the conventional DE analysis omits some genes due to high inter-individual variability present in both tumour and normal tissues. Dysregulated genes shared in small subgroup of patients were useful in stratifying patients, and presented differential prognosis. We also showed that the target genes of some of the current targeted agents used in HCC exhibited highly individualistic dysregulation pattern, which may explain the poor response rate., Discussion/conclusion: Our results highlight the importance of identifying patient-specific DE genes, with its potential to provide clinically valuable insights into patient subgroups for applications in precision medicine., (© 2023. The Author(s).)

Background: Acute exacerbations of asthma are common in children, however, treatment decisions for severe exacerbations are challenging due to a lack of robust evidence. In order to create more robust research, a core set of outcome measures needs to be developed. In developing these outcomes, it is important to understand the views of clinicians who care for these children in particular, views that relate to outcome measures and research priorities., Methods: To determine the views of clinicians, a total of 26 semistructured interviews based on the theoretical domains framework were conducted. These included experienced clinicians from emergency, intensive care and inpatient paediatrics across 17 countries. The interviews were recorded, and later transcribed. All data analyses were conducted in Nvivo by using thematic analysis., Results: The length of stay in hospital and patient-focused parameters, such as timing to return to school and normal activity, were the most frequently highlighted outcome measures, with clinicians identifying the need to achieve a consensus on key core outcome measure sets. Most research questions focused on understanding the best treatment options, including the role of novel therapies and respiratory support., Conclusion: Our study provides an insight into what research questions and outcome measures clinicians view as important. In addition, information on how clinicians define asthma severity and measure treatment success will assist with methodological design in future trials. The current findings will be used in parallel with a further Paediatric Emergency Research Network study focusing on the child and family perspectives and will contribute to develop a core outcome set for future research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We aim to investigate the utility of heart rate variability (HRV) and heart rate n-variability (HRnV) in addition to vital signs and blood biomarkers, among febrile young infants at risk of serious bacterial infections (SBIs)., Methods: We performed a prospective observational study between December 2017 and November 2021 in a tertiary paediatric emergency department (ED). We included febrile infants <90 days old with a temperature ≥38 ℃. We obtained HRV and HRnV parameters via a single lead electrocardiogram. HRV measures beat-to-beat (R-R) oscillation and reflects autonomic nervous system (ANS) regulation. HRnV includes overlapping and non-overlapping R-R intervals and provides additional physiological information. We defined SBIs as meningitis, bacteraemia and urinary tract infections (UTIs). We performed area under curve (AUC) analysis to assess predictive performance., Results: We recruited 330 and analysed 312 infants. The median age was 35.5 days (interquartile range 13.0-61.0); 74/312 infants (23.7%) had SBIs with the most common being UTIs (66/72, 91.7%); 2 infants had co-infections. No patients died and 32/312 (10.3%) received fluid resuscitation. Adding HRV and HRnV to demographics and vital signs at ED triage successively improved the AUC from 0.765 [95% confidence interval (CI): 0.705-0.825] to 0.776 (95% CI: 0.718-0.835) and 0.807 (95% CI: 0.752-0.861) respectively. The final model including demographics, vital signs, HRV, HRnV and blood biomarkers had an AUC of 0.874 (95% CI: 0.828-0.921)., Conclusions: Addition of HRV and HRnV to current assessment tools improved the prediction of SBIs among febrile infants at ED triage. We intend to validate our findings and translate them into tools for clinical care in the ED., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-3303/coif). SLC reports that this work was funded by the National Medical Research Council (NMRC) (NMRC/MOH-CNIG18 May 0005 to SLC) and the funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. MEHO and NL are inventors of two patents (US10299689B2 and 10202114423W) relevant to this study. ZXK, DG, MEHO and NL own stock in TIIM Healthcare that produces devices relevant to this study. The other authors have no conflicts of interest to declare., (2023 Annals of Translational Medicine. All rights reserved.)

Background: Diffusion kurtosis imaging provides in vivo measurement of microstructural tissue characteristics and could help guide management of Parkinson's disease., Objective: To investigate longitudinal diffusion kurtosis imaging changes on magnetic resonance imaging in the deep grey nuclei in people with early Parkinson's disease over two years, and whether they correlate with disease progression., Methods: We conducted a longitudinal case-control study of early Parkinson's disease. 262 people (Parkinson's disease: n = 185, aged 67.5±9.1 years; 43% female; healthy controls: n = 77, aged 66.6±8.1 years; 53% female) underwent diffusion kurtosis imaging and clinical assessment at baseline and two-year timepoints. We automatically segmented five nuclei, comparing the mean kurtosis and other diffusion kurtosis imaging indices between groups and over time using repeated-measures analysis of variance, and Pearson correlation with the two-year change in Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III., Results: At baseline, mean kurtosis was higher in Parkinson's disease than controls in the substantia nigra, putamen, thalamus and globus pallidus when adjusting for age, sex, and levodopa equivalent daily dose (p < 0.027). These differences grew over two years, with mean kurtosis increasing for the Parkinson's disease group while remaining stable for the control group; evident in significant "group ×time" interaction effects for the putamen, thalamus and globus pallidus (ηp2= 0.08-0.11, p < 0.015). However, we did not detect significant correlations between increasing mean kurtosis and declining motor function in the Parkinson's disease group., Conclusion: Diffusion kurtosis imaging of specific grey matter structures shows abnormal microstructure in PD at baseline and abnormal progression in PD over two years.