Urate-lowering therapy for gout and asymptomatic hyperuricemia in the pediatric population: a cross-sectional study of a Japanese health insurance database

Background Our previous research showed that uric acid lowering therapy (ULT) for gout and hyperuricemia is being prescribed for pediatric patients even though these drugs have not been approved for use in children. However, the actual clinical situation has not been clearly elucidated. In this paper, we provide an in-depth look at the details of actual clinical practice. Methods This retrospective cross-sectional study accessed health insurance data for 696,277 children from April 2016 through March 2017 to identify pediatric patients with gout or asymptomatic hyperuricemia, calculate the proportion of patients prescribed ULTs, and analyze population characteristics. Adherence and mean dose for febuxostat and allopurinol, the most commonly prescribed drugs, were also analyzed. Results Among children with gout or asymptomatic hyperuricemia, we found that 35.1% (97/276) were prescribed ULT. This proportion increased with age, especially among males. By comorbidity, ULT was prescribed to 47.9% (46/96) of patients with kidney disease, 41.3% (26/63) for cardiovascular disease, 40.0% (6/15) for Down syndrome, and 27.1% (32/118) for metabolic syndrome. In patients with kidney disease, febuxostat was prescribed more than twice as frequently as allopurinol (28 vs. 12). Median values for the medication possession ratio (MPR) of febuxostat and allopurinol were 70.1 and 76.7%, respectively, and prescriptions were continued for a relatively long period for both drugs. Both drugs were prescribed at about half the adult dose for patients 6–11 years old and about the same as the adult dose for patients 12–18 years old. Conclusions This study showed that the continuous management of serum uric acid is being explored using off-label use of ULT in pediatric patients with gout or asymptomatic hyperuricemia in Japan. Drug selection is based on patient characteristics such as sex, age, and comorbidities, and pediatric dosage is based on usage experience in adults. To develop appropriate pediatric ULT, clinical trials are needed on the efficacy and safety of ULT in the pediatric population. Trial registration UMIN000036029.

Use of Granulocyte Transfusions in Two National Cohorts and Association between Transfusion Dose and Patient Outcomes: The Best Collaborative Study

Granulocytes for transfusion (GTX) continue to be administered, mostly to treat refractory infection 1. Single center series continue to be reported, but evidence of GTX effectiveness remains uncertain. Recent attempts at randomized trials of GTX have not been completed to target although the largest trial, RING 2, identified potentially promising results in a sub-group analysis by dose. GTX can be produced by apheresis (from 'stimulated' donors), aGTX, or as a component pooled from whole blood (WB) donations. Logistic difficulties arise with aGTX, including recruitment of suitable donors willing to undergo cell mobilization and collection. In England GTX are now only supplied as pooled (10 WB donations/pool, mean volume single pooled unit 207 ml, mean granulocyte yield/unit 0.9 x10 10, typical adult dose 2 pools, available 6 days per week). In France, production moved from aGTX to pooled in 2020 (20 WB donations/pool, mean volume single pooled component 428 ml, mean granulocyte yield/unit 1.8 x10 10, typical adult dose 1 pool, available 6 days per week). There have been no recent published national data on the clinical use of pooled granulocytes, or comparisons between large datasets. The aim of this study was to 1) describe the use of GTX, including pooled granulocytes, in two national cohorts of recipients; 2) estimate the effect of dose on patient mortality using statistical methods which could be applied to a larger dataset in the future. A pre-piloted data collection form (DCF) was used to collect prospective audit data on all GTX given to patients in participating hospitals in England from March 2017 -Sept 2020 in England. The PROspective Granulocyte usage and outcomEs Survey (ProGrES) was deemed a national registry/audit with no individual patient consent required for anonymized data. Information on patient characteristics and outcomes was collected at the time of the request for GTX, following completion of GTX and at 28 days and 6 months follow up. DCFs were adapted for international use, and French data were collected from Jan 2018 to Dec 2020. Descriptive analyses were performed to summarize GTX dose, patient characteristics, and outcomes. Using the English data, we investigated the association between GTX dose and mortality within 28 days of final GTX using logistic regression models with and without adjustment for possible confounders (age, infection source, use of renal therapy) and using the target trial framework. Ethical approval was obtained from London School of Hygiene and Tropical Medicine for analysis of English data. Results are presented on 224 (England, pooled) and 139 (France) patients who received GTX. In France, 95 and 44 patients received aGTX and pooled GTX, respectively. Table 1 shows patient features and outcomes. The most frequent underlying diagnosis was acute myeloid leukemia in all groups, and the most common indication was treatment of refractory infection. Median number of transfusions was similar in all groups (5.0, 5.3, 6.0). The mean dose/kg/transfusion was highest in the aGTX group (0.55 x10 9/kg), followed by French pooled (0.40) and English pooled (0.2). Death within 28 days of last GTX varied from 20.2% (French apheresis) to 32.5% (French pooled). Additional analyses were performed on the English data; for death within 28 days, a 0.1 x10 9 increase in GTX dose was associated with a 22% reduction (95% CI -45% to +0%) in odds of death within 28 days of referral; odds ratio 0.78 (95% CI 0.57 to 1.00). After adjustment for potential confounders, the odds ratio was attenuated to 0.92 (95% CI 0.67, 1.23). In summary, GTX continue to be requested by clinicians in patients with poor outcomes, despite an uncertain evidence-base. Regression analysis found dose was associated with lower odds of 28-day mortality. This was not significant after confounder adjustment, but this proof-of-principle analysis was limited by the sample size. A potential dose effect was also seen in the RING study. Our analysis using a target trial approach provides an approach for estimating GTX effectiveness in a larger cohort, which is required given the well-recognized challenges of undertaking randomized trials. The analysis provides a range of sample size calculations for testing an association between dose and outcomes for a defined effect size in a larger international cohort, supported by the BEST Collaborative 3. References: 1. Transfusion 2019;59(1)160 2. Blood 2015;126(18)2153 3. Transfus Med Hemother 2018(45)318 Figure 1 Figure 1. Disclosures Francis-Radice: GSK: Current equity holder in publicly-traded company; Smith & Nephew: Current equity holder in publicly-traded company; Bunzl: Current equity holder in publicly-traded company; Relx: Current equity holder in publicly-traded company; Cancer Research UK: Research Funding. McCullough: Fresenius Kabi: Honoraria; Terumo BCT: Honoraria.

Natural Radiation Exposure and Carotid Intima-Media Thickness Among Women in Karunagappally, Kerala, India.

Background A cross-sectional study was conducted to examine the relationship between natural radiation exposure and intima-media thickness (IMT), an atherosclerosis indicator, among female residents in Karunagappally, Kerala, South India, which is known to have areas with high natural background radiation (HNBR) derived mainly from thorium. Methods Cumulative radiation doses received during childhood, adulthood, and entire life were estimated on the basis of annual indoor and outdoor radiation doses and hours spent indoors and outdoors. In 2013–2014, IMT of the carotid artery was measured with ultrasonography among 400 women aged 29–60 years in Karunagappally. Since there were three subjects with outlying maximum IMT values, corrected IMT values excluding those outliers were calculated. For statistical analysis, raw and corrected IMT values were used. Results The regression analysis adjusting for age and religion showed a statistically significant association of mean and maximum IMT with radiation. The most strongly related radiation dose was with the adult dose. Its association with IMT became stronger when paediatric dose was also taken into account. When adjusted for fasting blood sugar and HbA1c, adult dose was statistically significantly related to raw mean IMT (P = 0.008) and corrected mean IMT (P = 0.018). Maximum IMT values were also related to adult doses but the association was not statistically significant (raw maximum IMT, P = 0.061 and corrected maximum IMT, P = 0.138). Conclusions Among female residents in the HNBR areas in south India, mean IMT statistically significantly increased in relation to the adult dose. Further studies are necessary to evaluate the causal association of the observation.

Natural Radiation Exposure and Carotid Intima-media Thickness Among Women in Karunagappally, Kerala, India.

Background: A cross-sectional study was conducted to examine the relationship between natural radiation exposure and intima-media thickness (IMT), an atherosclerosis indicator, among female residents in Karunagappally, Kerala, South India, which is known to have areas with high natural background radiation (HNBR) derived mainly from thorium.Methods: Cumulative radiation doses received during childhood, adulthood, and entire life were estimated on the basis of annual indoor and outdoor radiation doses and hours spent indoors and outdoors. In 2013-2014, IMT of the carotid artery was measured with ultrasonography among 400 women aged 29-60 years in Karunagappally. Since there were three subjects with outlying maximum IMT values, corrected IMT values excluding those outliers were calculated. For statistical analysis, raw and corrected IMT values were used. Results: The regression analysis adjusting for age and religion showed a statistically significant association of mean and maximum IMT with radiation. The most strongly related radiation dose was with the adult dose. Its association with IMT became stronger when paediatric dose was also taken into account. When adjusted for fasting blood sugar and HbA1c, adult dose was statistically significantly related to raw mean IMT (P=0.008) and corrected mean IMT (P=0.018). Maximum IMT values were also related to adult doses but the association was not statistically significant (raw maximum IMT, P=0.061 and corrected maximum IMT, P=0.138). Conclusions: Among female residents in the HNBR areas in south India, mean IMT statistically significantly increased in relation to the adult dose. Further studies are necessary to evaluate the causal association of the observation.

A Survey of Neonatal Nurses on Mydriatic Regimens Used in Neonatal Retinopathy of Prematurity Eye Examinations

Objective This study was aimed to determine mydriatic regimen(s) used in neonatal units in Aotearoa New Zealand (NZ) and Australia and to estimate the frequency of adverse drug events following mydriatic administration in preterm neonates. Study Design A cross-sectional survey was sent to neonatal nursing staff listed in the Australian and New Zealand Neonatal Network contact list. Participants were asked to state what mydriatic regimen they use, and to estimate the frequency of adverse drug events when eye drops were administered for retinopathy of prematurity eye examinations (ROPEE). Results Thirteen different mydriatic regimens were identified; phenylephrine 2.5% and cyclopentolate 0.5% (1 standard drop of each) was the most commonly used regimen. Two of the regimens exceeded adult doses and five regimens included a mydriatic that is equivalent to an adult dose. Following mydriatic instillation, the three most common adverse effects were apnea, tachycardia, and periorbital pallor. Conclusion Low-concentration single-microdrop regimens are currently in use and resulting in successful ROPEE, yet doses exceeding adult doses are in use throughout Aotearoa NZ and Australian units. We know from this dataset that neonates are experiencing unwanted and potentially preventable, adverse effects associated with mydriatics, and every effort should be made to minimize this risk. Key Points

Phase II Clinical trial for Evaluation of BCG as potential therapy for COVID-19

Bacillus Calmette−Guérin (BCG) is widely used in national vaccination programs worldwide. It is accepted that BCG alleviates both pathogen and allergy induced respiratory diseases that could also include Covid-19. To investigate this possibility, we randomly assigned 60 Covid-19 patients, after admission to the hospital with pneumonia and requirement for oxygen therapy in a 1:1 ratio to receive either a single adult dose of intradermal BCG or normal saline with concomitant standard of care (SoC) medications. Primary endpoints were favorable prognosis of Covid-19 as deduced from resolution of pneumonia, viremia and secondary outcome were enumeration of ICU admissions, duration thereof and mortalities.ResultsBoth primary and secondary endpoints were significantly improved in the BCG+SoC group. This could be seen from reduction in oxygen requirement due to Covid-19 associated pneumonia decreasing from day 3-4, improved radiological resolution from day 7-15. There were a total of 6 (10%) adverse events in the study of which 2 deaths and 4 ICU admissions were in SoC group (1 ICU admission culminated in death of the subject) and in contrast only 1 ICU admission in the BCG+SoC group. While there was an increase in Covid-19 specific IgG levels in the BCG+SoC group, there was no evidence of BCG induced cytokine storm in this group. Four patients showed localized inflammatory response at the injection site in the BCG+SoC group.ConclusionsBCG+SoC administration resulted in a significantly higher percentage of patients with favorable outcomes than did SoC. A third of the patients were naïve for childhood BCG vaccination. This mimicked elderly patients in countries with no universal vaccination policy for BCG. No BCG related adversity was seen in this group. The study shows that BCG is a safe, cost-effective treatment that can be introduced as a standard of care in patients with moderate Covid-19 that can reduce requirement of oxygen supplemented beds and disease burden in low resource countries, with additional long-term benefits of reducing risk for tuberculosis.

DOSE ASSESSMENT FOR ATMOSPHERIC DISCHARGE OF LONG-LIVED RADIONUCLIDES IN NUCLEAR POWER PLANT DECOMMISSIONING

Decommissioning of nuclear power plants is a multistage process involving complex operations like radiological characterization, decontamination and dismantling of plant equipment, demolition of structures, and processing and disposal of waste. Radioactive effluents released into the environment may result in exposure of population through various exposure pathways. The present study estimates the public dose due to atmospheric discharge of important radionuclides during proposed decommissioning activities of Indian Pressurized Heavy Water Reactors. This study shows that major dose contributing radionuclides are 60Co followed by 94Nb, 134Cs, 154Eu, 152Eu, 133Ba, 99Tc, 93Mo and 41Ca. It is found that infant dose is higher than adult dose and major fraction of total dose (~98%) is through ground shine and ingestion; other pathways such as inhalation and plume shine contribute only a small fraction. This study will be helpful in carrying out radiological impact assessment for decommissioning operations which is an important regulatory requirement.

Determination of Appropriate Deferral Time for Repeat Apharesis Platelets Concentrate Donation in Abuja, Nigeria

Background: Plateletpheresis is the process by which a therapeutic adult dose of platelet concentrate is produced from a single donor using automated cell separator equipment. Recently, the demand for Apheresis Platelets concentrate transfusions has been increasing in our hospitals. This has been attributed to increased cases of malignancy associated bone marrow suppression and various other causes of thrombocytopaenia and thrombopathies. The Increasing use of myeloablative chemotherapy in treatment of haematological and other malignancies also results in transient severe fall in platelet count. The demand generally outstrips the supply necessitating the need to search for additional donor sources to increase the supply of platelets for transfusion. Is it therefore possible to reduce the time interval between plateletpheresis while maintaining donor safety? Aims and Objectives: The aim of the study was to determine the platelets recovery time after platelets concentrate donation with a view to determining the appropriate deferral time for repeat plateletpheresis Methods: The study was conducted at the National Hospital Abuja. Fifty seven healthy plateletpheresis donors were recruited over a period of seven months and their haematological parameters were analyzed on days 0, 2 and 7 post donation. We excluded donors whose pre-donation platelet count were less than 200 x 109/L Results and Analysis: Analysis was done in only forty eight (48) donors as nine (9) participants withdrew before the end of the study. The results show There was a significant decrease in the platelets counts (p <0.001), with subsequent good platelets recovery post donation (Pre: 259.83±44.61 x 109/L; Post - Day 0: 205.29±36.77 x 109/L, day 2: 216.88±32.71 x 109/L and day 7: 240.3±41.83 x 109/L). The apheresis donors recovered 64.29% of the lost platelets by day 2 of donation and subsequently attain 92.49% of pre-donation count within 7 days of donation. There was a statistically significant transient increase in the immediate post donation haemoglobin concentration (14.72±1.32)g/dL but this gradually reduced on day 2 (13.75±1.04)g/dL and 13.83±1.04g/dL on day 7 showing no significant different from the pre-donation Hb of 13.96±1.02g/dL Conclusion: This study has shown statistically significant platelets recovery 7 days after plateletpheresis making a 7 day deferral for repeat plateletpheresis feasible in our environment. The study also shows feasibility of a 2 days deferral as recommended by AABB. Strict monitoring and pre-donation evaluation of donors should be done to prevent any adverse events such as anaemia and thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

QOLP-34. DOSE FREQUENCY MODIFICATION OF TRAMETINIB TO MITIGATE SEVERE RASH AND IMPROVE QUALITY OF LIFE IN PEDIATRIC LOW-GRADE GLIOMA PATIENTS

Circumscribed low-grade glioma is generally driven by MAP kinase pathway activation, and this discovery motivates use of the non-competitive MEK 1/2 inhibitor trametinib for children and adults with progressive disease. However, rash is a common dose-limiting toxicity with trametinib. Accordingly, we evaluated intermittent, 3-days-on, 1-day-off dosing in an effort to reduce the incidence and severity of rash. Seven patients with MAP-kinase activated low grade glioma were treated with trametinib (6 pilocytic astrocytoma (PA), one desmoplastic infantile ganglioglioma with V600E). Patients initiated treatment at 0.025mg/kg/day up to the maximum adult dosing of 2mg. Three teenage patients with PA were treated with the maximum daily adult dose of 2mg. All three developed a painful, grade 3 acneiform rash within 3 weeks, requiring trametinib hold and treated with topical cleansers and oral antibiotics. One patient discontinued treatment, and two restarted trametinib at a reduced dose (1.5mg) administered 3-days-on and 1-day-off. With this modified dosing, patients experienced no more than grade 1 rash. Two younger patients initiated trametinib with daily dosing, and both developed grade 1 eczematous rash within 3 weeks, progressing to grade 2 in one patient. The rash resolved without recurrence after dose frequency modification to 3-days-on, 1-day-off at the same overall dose. Two younger patients initiated trametinib with 3-days-on, 1-day-off dosing and have not developed a rash. All of the younger patients are currently continuing on therapy with no progression to date. However, both teenage patients developed progressive disease by 11 months into therapy. In conclusion, acneiform rash appears to preferentially impact teenage or young adult patients but can be mitigated with modified dose frequency 3 days on, 1 day off. However, continued assessment is needed to evaluate the effect of dosing frequency modification on treatment response.