Magnesium supplementation therapy to prevent cisplatin-induced acute nephrotoxicity in pediatric cancer: a randomized phase-2 trial.

BACKGROUND: The present study aimed to examine the effect of magnesium (Mg) supplementation on cisplatin-induced nephrotoxicity (CIN) in pediatric cancer patients. METHODS: The present phase-2, open-label, multicenter, randomized controlled trial enrolled patients aged less than 20 years who were scheduled to receive cisplatin-containing chemotherapy and randomly allocated them at a ratio of 1:1 to a Mg supplementation arm with even-numbered chemotherapy courses (arm AB) or another arm with odd-numbered courses (arm BA). Analysis objects were reconstructed into two groups depending on whether the chemotherapy course had Mg supplementation (group B) or not (group A). The primary outcome was the proportion of chemotherapy courses resulting in elevated serum creatinine per chemotherapy course. The secondary outcomes included efficacies evaluated using other biomarkers and the safety of the Mg supplementation. RESULTS: Twenty-eight patients were randomly allocated to either group (16 to arm AB and 12 to arm BA). The baseline characteristics of the groups were similar. There was no significant difference in the proportion of courses with increased serum creatinine between the groups (group A: 10% vs. group B: 6%; P = 0.465) nor was any significant difference observed in other biomarkers during any chemotherapy course. The Mg value during chemotherapy was significantly higher in group B than that in group A. No adverse events related to magnesium administration were observed. CONCLUSIONS: The study design, which treated a single chemotherapy course as a study object, failed to detect a statistically significant benefit of Mg supplementation for preventing CIN in pediatric cancer patients. TRIAL REGISTRATION: JRCT ( https://jrct.niph.go.jp/ ) Identifier UMIN000029215 jRCTs031180251. UMIN-CTR ( http://www.umin.ac.jp/icdr/index.html ) Identifier UMIN000029215.

Novel Approach for Detecting Respiratory Syncytial Virus in Pediatric Patients Using Machine Learning Models Based on Patient-Reported Symptoms: Model Development and Validation Study.

BACKGROUND: Respiratory syncytial virus (RSV) affects children, causing serious infections, particularly in high-risk groups. Given the seasonality of RSV and the importance of rapid isolation of infected individuals, there is an urgent need for more efficient diagnostic methods to expedite this process. OBJECTIVE: This study aimed to investigate the performance of a machine learning model that leverages the temporal diversity of symptom onset for detecting RSV infections and elucidate its discriminatory ability. METHODS: The study was conducted in pediatric and emergency outpatient settings in Japan. We developed a detection model that remotely confirms RSV infection based on patient-reported symptom information obtained using a structured electronic template incorporating the differential points of skilled pediatricians. An extreme gradient boosting-based machine learning model was developed using the data of 4174 patients aged ≤24 months who underwent RSV rapid antigen testing. These patients visited either the pediatric or emergency department of Yokohama City Municipal Hospital between January 1, 2009, and December 31, 2015. The primary outcome was the diagnostic accuracy of the machine learning model for RSV infection, as determined by rapid antigen testing, measured using the area under the receiver operating characteristic curve. The clinical efficacy was evaluated by calculating the discriminative performance based on the number of days elapsed since the onset of the first symptom and exclusion rates based on thresholds of reasonable sensitivity and specificity. RESULTS: Our model demonstrated an area under the receiver operating characteristic curve of 0.811 (95% CI 0.784-0.833) with good calibration and 0.746 (95% CI 0.694-0.794) for patients within 3 days of onset. It accurately captured the temporal evolution of symptoms; based on adjusted thresholds equivalent to those of a rapid antigen test, our model predicted that 6.9% (95% CI 5.4%-8.5%) of patients in the entire cohort would be positive and 68.7% (95% CI 65.4%-71.9%) would be negative. Our model could eliminate the need for additional testing in approximately three-quarters of all patients. CONCLUSIONS: Our model may facilitate the immediate detection of RSV infection in outpatient settings and, potentially, in home environments. This approach could streamline the diagnostic process, reduce discomfort caused by invasive tests in children, and allow rapid implementation of appropriate treatments and isolation at home. The findings underscore the potential of machine learning in augmenting clinical decision-making in the early detection of RSV infection.

Evaluation of a joint workshop on study design for hospital and community pharmacists: a retrospective cross-sectional survey.

BACKGROUND: Although pharmacists often identify numerous clinical questions, they face several barriers, including the lack of mentors for research activities in clinical settings. Therefore, a workshop for the appropriate selection of a study design, which is a fundamental first step, may be necessary. The purpose of this study was to evaluate the effectiveness of a workshop on study design for hospital and community pharmacists. Moreover, the characteristics of pharmacists with little involvement in research activities were extracted using decision-tree analysis to guide the design of future workshops. METHODS: A workshop was conducted on October 1, 2023. It comprised three parts: lectures, group work, and presentations. Questionnaire-based surveys were conducted with workshop participants regarding their basic information, their background that influenced research activities, their satisfaction, and their knowledge/awareness. For the questions on knowledge/awareness, the same responses were requested before and after the workshop using a five-scale scoring system. Multivariate logistic regression analysis was conducted to identify independent factors influencing research activities. Decision tree analysis was performed to extract low-effort characteristics of the research activities. RESULTS: Of the 40 workshop attendees, the overall satisfaction score for the workshop was 4.38 of 5, and the score for each question was 4 or higher. Significant increases were observed in the scores of knowledge/awareness after the workshop. Moreover, 95% of the pharmacists answered that it would be highly useful to conduct a joint workshop between hospitals and community pharmacists. Although independent influencing factors were not detected in the multivariate logistic regression analysis, the decision tree analysis revealed that pharmacists who were no member of an academic society (85%, 11/13) or members without any certifications or accreditations related to pharmacy practice (80%, 4/5) were the least active in clinical research. In contrast, those belonging to academic societies and holding certifications or accreditations related to pharmacy practice frequently conducted clinical research. CONCLUSION: The present study revealed that a joint workshop on study design may have the potential to change pharmacists' knowledge and awareness of research activities. Moreover, future workshops should be conducted with pharmacists who do not belong to academic societies.

Proportion of Successful Lumbar Punctures in Infants Younger Than Three Months.

It is important to perform lumbar punctures (LPs) without a single traumatic tap in infants younger than three months owing to the risk of serious complications. The proportion of LPs in which clear cerebrospinal fluid (CSF) was obtained has been previously reported, but some of the procedures involved a traumatic tap. The present study aimed to identify the proportion of LPs in which clear CSF was obtained without a single traumatic tap and the factors associated with successful LPs in infants younger than three months. This retrospective, observational study included children younger than three months who underwent an LP in the pediatric emergency department between April 2018 and March 2021. The primary outcome was the proportion of successful LPs, defined as LPs obtaining clear CSF without a single traumatic tap. Multiple logistic regression analysis was used to identify factors related to successful LPs. Of 126 eligible patients, 121 were included. Among these, 83 (69%) were in the successful group. No factors significantly associated with successful LPs were found. Larger studies based on an accurate definition of successful LPs, such as that provided by this study, are needed to investigate related factors to increase the rate of successful LPs in this age group.

Retinoid Therapy for Neuroblastoma: Historical Overview, Regulatory Challenges, and Prospects.

Retinoids are vitamin A derivatives and include trans-retinoic acid, isotretinoin, tamibarotene, and bexarotene, all of which are currently available for clinical use. The clinical development of retinoid therapy for neuroblastoma has a history spanning more than four decades. The most promising agent is isotretinoin, which can contribute to improving event-free survival in patients with high-risk neuroblastoma by approximately 10% when administered over six months as maintenance therapy. Although isotretinoin is regarded as an essential component in the standard clinical management of high-risk neuroblastoma, its use for this purpose in the US and EU is off-label. To promote isotretinoin use in Japan as a treatment for neuroblastoma, our clinical research team is planning to launch an investigator-initiated, registration-directed clinical trial. The present review article discusses the basic science behind retinoid therapy, pre-clinical/clinical evidence on neuroblastoma, the concept of the proposed clinical trial, and prospects for this therapy.

Reference values for urinary protein, albumin, beta 2-microglobulin, and the alpha 1-microglobulin-to-creatinine ratio in Japanese children.

BACKGROUND: The importance of the ratio of creatinine to urinary protein, albumin, and low-molecular weight protein as a urinary marker in chronic kidney disease patients is widely recognized. However, no reference values have hitherto been established for these markers in Japanese children. The present study aimed to establish the reference values for these urinary markers in Japanese children. METHODS: The first morning urine was randomly collected from 1712 pupils aged ≥ 3 to < 18 years during school and kindergarten mass urinary screenings. The upper limit of the reference values was set at the 97.5th percentile of the creatinine ratio per marker. RESULTS: The urinary protein-to-creatinine ratio (PCR), urinary albumin-to-creatinine ratio (ACR), urinary beta 2-microglobulin-to-creatinine ratio (BMCR), and urinary alpha 1-microglobulin-to-creatinine ratio (AMCR) showed an age-related decrease at the 50th percentile reflecting an age-related increase in urinary creatinine. The appropriate reference value for the PCR and ACR was 0.12 g/gCr and 35 mg/gCr, respectively, in the entire cohort. The appropriate reference value for the BMCR was 0.5 µg /mgCr for age ≥ 3 to < 6 years and 0.35 µg/mgCr for age 6 years or older. The appropriate reference value for the AMCR was 5.0 µg/mgCr for age ≥ 3 to < 6 years and 3.5 µg /mgCr for age 6 years or older. CONCLUSION: The present study was the first to determine appropriate reference values for the PCR, ACR, BMCR, and AMCR based on an analysis of the first morning urine samples of a large number of children.

Feasibility and Safety of Super Energy-dense Oral Nutritional Supplementation in Postoperative Gastric Cancer Patients.

BACKGROUND/AIM: Ensuring that postoperative gastric cancer patients receive sufficient oral nutritional supplementation (ONS) to prevent body weight loss (BWL) is a serious challenge. The present pilot study evaluated the feasibility and safety of small, frequent sip feeds (SIP) with super energy-dense ONS (SED ONS; 4 kcal/ml) in postoperative gastric cancer patients. PATIENTS AND METHODS: Patients received 400 kcal/day of SED ONS in four, daily, 25 ml SIP for 12 weeks after gastrectomy. The primary outcome was the percentage of postoperative weight change. The expected mean weight change was 90% (10% standard deviation). A sample population of 14 patients, sufficient for a 95% confidence interval with a 10% margin of error, was enrolled. RESULTS: The mean weight change for patients receiving SIP with SED ONS was 93.8%. The mean SED ONS intake was 348 kcal/day. Thirteen patients consumed more than 200 kcal/day of SED ONS. One patient with a mean intake of 114 kcal/day had undergone total gastrectomy followed by adjuvant chemotherapy. CONCLUSION: Small, frequent SIP with SED ONS was found to be feasible and safe in postoperative gastric cancer patients. A multicenter randomized controlled trial is warranted to determine whether SIP with SED ONS is effective in preventing BWL.

Clinical implications of gallbladder enlargement in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) presents with gallbladder enlargement (GBE) or hydrops in the acute phase. Although GBE is highly specific to KD, epidemiological data on GBE have not been updated. In this study we evaluated the occurrence rate of GBE in KD and characterized the clinical features of patients who developed GBE. METHODS: The present study was a prospective, observational study. The maximum longitudinal area of the gallbladder and the common bile duct diameter in KD patients were measured by ultrasonography at the start of initial intravenous immunoglobulin (IVIG) therapy (day 0) and on days 7, 30, and 60 of therapy. The primary outcome was the complication rate of GBE (z- score ≥2.0) on day 0. The secondary outcome was the association of GBE with cholestasis, unresponsiveness to IVIG, and coronary artery lesions (CAL). RESULTS: Gallbladder enlargement occurred in 35% (35/101) of patients on day 0. Cholestasis and severe patients (Kobayashi score [KS] ≥5) were more common in the GBE group (20.6% vs. 1.6%, p = 0.002, and 54.3% vs. 15.2%, p < 0.001, respectively). In patients with a KS of ≤4, the non-responder rate was higher in the GBE group (44% vs. 20%, p = 0.0495) but did not differ in those with a KS of ≥5 (21% vs. 20%, p = 0.95). The rate of CAL occurrence did not differ significantly between the groups (8.6% vs. 6.1%, p = 0.64). CONCLUSIONS: Gallbladder enlargement occurred in 35% of KD patients and was associated with cholestasis. Gallbladder enlargement may not only be a diagnostic finding, but also a severity marker in KD patients.

Analgesic efficacy of continuous wound infiltration compared with continuous intravenous fentanyl after gynaecological surgery: a non-inferiority, randomised controlled trial.

OBJECTIVE: The present trial aimed to prove the non-inferiority of the analgesic efficacy of continuous wound infiltration (CWI) to that of continuous intravenous fentanyl (IV) and to compare the safety of the two methods. METHODS: This trial was a prospective, single-centre, two-arm, non-inferiority, randomised controlled trial. Patients participating in the trial were randomised to a CWI group or an IV group. The VAS (visual analogue scale), additional analgesic usage and side effects were then compared between the groups. RESULTS: In total, 61 patients were enrolled; two in CWI were excluded, leaving 59 (30 in the CWI group and 29 in the IV group) for analysis. The difference in the VAS score at 24 h (CWI group - IV group) was -3.2 (95% confidence interval [CI] -14.7 to 8.2), which was less than the non-inferiority margin of 15. The mean amount of total fentanyl use at postoperative hour 48 was 1395 (95% CI 886-1903) µg in the CWI group and 3186 (95% CI 2716-3658) µg in the IV group. The amount of other analgesics and the incidence of adverse effects did not differ significantly between the groups. CONCLUSION: CWI was non-inferior to IV in terms of its analgesic effect, and has an opioid sparing effect in open gynaecological surgery.

Identifying Kawasaki Disease With a Low Coronary Artery Aneurysm Risk.

INTRODUCTION: Kawasaki disease (KD) patients with a high risk of coronary artery aneurysm (CAA) development are well characterized and targeted for intensified primary intravenous immunoglobulin (IVIG) treatment. However, the characteristics of KD patients with a low CAA risk are less well-known. METHODS: The present study was a secondary analysis of Prospective Observational study on STRAtified treatment with Immunoglobulin plus Steroid Efficacy for Kawasaki disease (Post RAISE), a multicenter, prospective cohort study of KD patients in Japan. The target of the analysis was patients with a Kobayashi score <5 who were predicted to respond to IVIG. The incidence of CAA during the acute phase, the primary outcome, was assessed based on all echocardiographic evaluations performed between week 1 (days 5-9) and month 1 (days 20-50) after the start of primary treatment. Multivariable logistic regression was used to identify the independent risk factors of CAA during the acute phase, based on which a decision tree was created to identify a subpopulation of patients with KD with a low CAA risk. RESULTS: Multivariate analysis found that a baseline maximum Z score >2.5, age <12 months at fever onset, nonresponsiveness to IVIG, low neutrophils, high platelets and high C-reactive protein were independent predictors of CAA during the acute phase. The decision tree created by using these risk factors identified 679 KD patients who had a low incidence of CAA during the acute phase (4.1%) and no medium or large CAA. CONCLUSIONS: The present study identified a KD subpopulation with a low CAA risk comprising around a quarter of the entire Post RAISE cohort.

The Impact of Cold Ambient Temperature in the Pattern of Influenza Virus Infection.

Background: Prior literature suggests that cold temperature strongly influences the immune function of animals and human behaviors, which may allow for the transmission of respiratory viral infections. However, information on the impact of cold stimuli, especially the impact of temporal change in the ambient temperature on influenza virus transmission, is limited. Methods: A susceptible-infected-recovered-susceptible model was applied to evaluate the effect of temperature change on influenza virus transmission. Results: The mean temperature of the prior week was positively associated with the number of newly diagnosed cases (0.107 [95% Bayesian credible interval {BCI}, .106-.109]), whereas the mean difference in the temperature of the prior week was negatively associated (-0.835 [95% BCI, -.840 to -.830]). The product of the mean temperature and mean difference in the temperature of the previous week were also negatively associated with the number of newly diagnosed cases (-0.192 [95% BCI, -.197 to -.187]). Conclusions: The mean temperature and the mean difference in temperature affected the number of newly diagnosed influenza cases differently. Our data suggest that high ambient temperature and a drop in the temperature and their interaction increase the risk of infection. Therefore, the highest risk of infection is attributable to a steep fall in temperature in a relatively warm environment.

Impact of glycaemic control and CYP3A5 polymorphisms on tacrolimus trough concentrations after adult kidney transplantation.

AIMS: Diabetes mellitus affects the pharmacokinetics of cytochrome P450 3A4/5 (CYP3A4/5) substrates. We evaluated the relationship between haemoglobin A1c (HbA1c) levels and the pharmacokinetics of controlled-release tacrolimus. METHODS: This retrospective observational cohort study included kidney transplant recipients (>18 years) receiving controlled-release tacrolimus orally. CYP3A5 genotypes were categorized as expressers (*1/*1 or *1/*3) and non-expressers (*3/*3). Multiple linear regression analysis determined the predictors for trough concentration/dose-normalized by body weight (C/D) ratio of tacrolimus at 7 days, 6 months and 12 months after administration. Correlations between the C/D ratio and HbA1c levels at baseline, 6 and 12 months after tacrolimus initiation were evaluated with Bonferroni correction. RESULTS: Out of 42 patients (CYP3A5 expressers, n = 17, and non-expressers, n = 25), the multiple linear regression analysis showed that the C/D ratio on Day 7 was marginally higher in CYP3A5 non-expressers than in CYP3A5 expressers (r = .43, P = .028). Factors affecting the elevation of tacrolimus C/D ratio after 6 and 12 months of treatment were male sex and CYP3A5 non-expressers (r = .59, P < .001) and increased HbA1c levels and CYP3A5 non-expressers (r = .62, P < .001), respectively. The C/D ratio and HbA1c levels after 12 months was positively correlated in CYP3A5 non-expressers (y = 54.6x - 194.6, r = .63, P = .004, Bonferroni correction). Furthermore, intra-individual changes in the C/D ratio and HbA1c levels from 6 to 12 months were nearly correlated (y = 54.5x + 20.2, r = .41, P = .036, Bonferroni correction). CONCLUSION: HbA1c and CYP3A5 genotypes might be considered to understand the inter- and intra-individual variability in blood tacrolimus concentrations after 6 months post-kidney transplantation.

Sequestration of Antimicrobial Agents in Xcoating and Heparin-Coated Extracorporeal Membrane Oxygenation Circuits: An In Vitro Study.

Limited data exist to guide antimicrobial therapy commonly prescribed to patients undergoing extracorporeal membrane oxygenation (ECMO). This study aimed to describe the kinetics of the cefazolin, doripenem, daptomycin, and levofloxacin in heparin-coated and Xcoating ECMO circuits. Circuits were primed with bovine whole blood and maintained at a physiological pH and temperature for 24 h. Each antimicrobial agent was added to the whole blood before priming. Equivalent doses of these drugs were added to glass jars containing fresh bovine whole blood as a control. Serial blood samples were collected from the ECMO circuits and controls over 24 h, and drug concentrations were quantified using validated assays. The concentrations of cefazolin, doripenem, daptomycin, and levofloxacin did not decrease significantly over 24 h. Collectively, these antimicrobial agents can be administered without the need to consider sequestration when using either heparin-coated or Xcoating circuits.

Impact of super energy-dense oral nutritional supplementation (SED ONS) on glycemic variability and food intake postoperatively in gastric cancer patients.

PURPOSE: Adherence to oral nutritional supplements (ONS) to prevent weight loss after gastrectomy is problematic. The present study evaluated the impact of super energy-dense ONS (SED ONS; 4 kcal/mL) on glycemic change and energy intake after gastrectomy. METHODS: Gastrectomy patients were placed on continuous glucose monitoring for a 3-day observation period after food intake had been stabilized postoperatively. In addition, they were given 0, 200, and 400 kcal/day of SED ONS on Days 1, 2, and 3, respectively. The primary outcome was the area under the curve < glucose 70 mg/dL (AUC < 70). The secondary outcomes were other indices of glucose fluctuation and the amount of food and SED ONS intake. RESULTS: Seventeen patients were enrolled. The AUC < 70 did not differ significantly with or without SED ONS over the observation period. SED ONS did not cause postprandial hypoglycemia and prevented nocturnal hypoglycemia. The mean dietary intake did not change significantly during the observation period, and the total energy intake increased significantly according to the amount of SED ONS provided. CONCLUSION: SED ONS after gastrectomy increased the total energy intake without dietary reduction and it did not result in hypoglycemia.

Exercise Stress Electrocardiography Using the Two-Minute Jump Test in Children.

Although the treadmill and cycle ergometer are commonly used for exercise stress electrocardiography (ECG) testing, they are often difficult to perform with children. We herein evaluated the utility and safety of the 2-minute jump test (2MJT) as a simple, alternative exercise test. One hundred patients, including 60 male patients, with an average age at study commencement of 10.7±3.5 years (mean±standard deviation) and with no exercise restriction who underwent a cardiac check-up between November 2020 and March 2022 at the study center were included. After recording their resting ECG, they jumped for 2 minutes during ECG recording, and the change in heart rate (HR), ECG findings, and occurrence of adverse events were investigated. As a result, patients jumped 185±60 times in two minutes, and their HR increased from 76±13 beats/min at rest to 172±18 beats/min at peak during the test. Ninety (90%) patients attained the ideal target HR of > 150 beats/minute. During the recovery period after loading, five patients had abnormal ECG findings (ventricular extrasystoles, second-degree atrioventricular block, and atrial extrasystoles in two, two, and one patient, respectively) but completely resolved spontaneously within three minutes. Our findings suggested that the 2MJT is a useful and safe exercise test capable of inducing sufficient increase in HR in a short time in children.

A prospective cohort study of sensorineural hearing loss associated with Kawasaki disease.

AIM: About 60 cases of sensorineural hearing loss (HL) have been reported in patients with Kawasaki disease (KD), but the current estimate of its prevalence is uncertain. The present study aimed to determine the prevalence and risk factors of sensorineural HL associated with KD. METHODS: The present, prospective cohort study, conducted from May 2019 to May 2020, evaluated patients with a diagnosis of KD who received the initial therapy and underwent two auditory brainstem response (ABR) tests. HL was defined as a threshold of 40 dB or more, and borderline hearing was defined as a threshold of 30 dB. RESULTS: In total, 107 patients were enrolled, and 75 underwent two ABR tests. Thirty-one patients (30.0%) received prednisolone with their initial intravenous immune globulin and acetylsalicylic acid therapy. HL was present in only one patient who had congenital conductive HL. Five patients had borderline hearing but had normal hearing behavior. There was no significant difference between the patients with normal hearing and those with borderline hearing in terms of the clinical variables. CONCLUSIONS: In Japan, the prevalence of sensorineural HL after KD is not high. It may therefore be unnecessary to perform routine hearing tests for all patients with KD. NAME OF TRIAL REGISTER: Association between Kawasaki Disease and Sensorineural Hearing Loss. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000037019 (the date of registration: June 11, 2019).