Diazoxide for Severe or Recurrent Neonatal Hypoglycemia: A Randomized Clinical Trial.

Importance: Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment. Objective: To evaluate whether early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia reduces time to resolution of hypoglycemia. Design, Setting, and Participants: This 2-arm, placebo-controlled randomized clinical trial was conducted from May 2020 to February 2023 in tertiary neonatal units at 2 New Zealand hospitals. Participants were neonates born at 35 or more weeks' gestation and less than 1 week of age with severe hypoglycemia (blood glucose concentration <22 mg/dL or <36 mg/dL despite 2 doses of dextrose gel) or recurrent hypoglycemia (≥3 episodes of a blood glucose concentration <47 mg/dL within 48 hours). Interventions: Newborns were randomized 1:1 to receive diazoxide suspension (loading dose, 5 mg/kg; maintenance, 1.5 mg/kg every 12 hours) or placebo, titrated per protocol. Main Outcome and Measures: The primary outcome was time to resolution of hypoglycemia, defined as enteral bolus feeding without intravenous fluids and normoglycemia (blood glucose concentration of 47-98 mg/dL) for at least 24 hours, compared between groups using adjusted Cox proportional hazards regression. Hazard ratios adjusted for stratification variables and gestation length are reported. Prespecified secondary outcomes, including number of blood glucose tests and episodes of hypoglycemia, duration of hypoglycemia, and time to enteral bolus feeding and weaning from intravenous fluids, were compared by generalized linear models. Newborns were followed up for at least 2 weeks. Results: Of 154 newborns screened, 75 were randomized and 74 with evaluable data were included in the analysis (mean [SD] gestational age for the full cohort, 37.6 [1.6] weeks), 36 in the diazoxide group and 38 in the placebo group. Baseline characteristics were similar: in the diazoxide group, mean (SD) gestational age was 37.9 (1.6) weeks and 26 (72%) were male; in the placebo group, mean (SD) gestational age was 37.4 (1.5) weeks and 27 (71%) were male. There was no significant difference in time to resolution of hypoglycemia (adjusted hazard ratio [AHR], 1.39; 95% CI, 0.84-2.23), possibly due to increased episodes of elevated blood glucose concentration and longer time to normoglycemia in the diazoxide group. Resolution of hypoglycemia, when redefined post hoc as enteral bolus feeding without intravenous fluids for at least 24 hours with no further hypoglycemia, was reached by more newborns in the diazoxide group (AHR, 2.60; 95% CI, 1.53-4.46). Newborns in the diazoxide group had fewer blood glucose tests (adjusted count ratio [ACR], 0.63; 95% CI, 0.56-0.71) and episodes of hypoglycemia (ACR, 0.32; 95% CI, 0.17-0.63), reduced duration of hypoglycemia (adjusted ratio of geometric means [ARGM], 0.18; 95% CI, 0.06-0.53), and reduced time to enteral bolus feeding (ARGM, 0.74; 95% CI, 0.58-0.95) and weaning from intravenous fluids (ARGM, 0.72; 95% CI, 0.60-0.87). Only 2 newborns (6%) treated with diazoxide had hypoglycemia after the loading dose compared with 20 (53%) with placebo. Conclusions and Relevance: In this randomized clinical trial, early treatment of severe or recurrent neonatal hypoglycemia with low-dose oral diazoxide did not reduce time to resolution of hypoglycemia but reduced time to enteral bolus feeding and weaning from intravenous fluids, duration of hypoglycemia, and frequency of blood glucose testing compared with placebo. Trial Registration: ANZCTR.org.au Identifier: ACTRN12620000129987.

Neonatal Hypoglycemia and Neurocognitive Function at School Age: A Prospective Cohort Study.

OBJECTIVE: To determine the relationship between transient neonatal hypoglycemia in at-risk infants and neurocognitive function at 6-7 years of corrected age. STUDY DESIGN: The pre-hPOD Study involved children born with at least 1 risk factor for neonatal hypoglycemia. Hypoglycemia was defined as ≥1 consecutive blood glucose concentrations <47 mg/dl (2.6 mmol/L), severe as <36 mg/dl (2.0 mmol/L), mild as 36 to <47 mg/dL (2.0 to <2.6 mmol/L), brief as 1-2 episodes, and recurrent as ≥3 episodes. At 6-7 years children were assessed for cognitive and motor function (NIH-Toolbox), learning, visual perception and behavior. The primary outcome was neurocognitive impairment, defined as >1 SD below the normative mean in ≥1 Toolbox tests. The 8 secondary outcomes covered children's cognitive, motor, language, emotional-behavioral, and visual perceptual development. Primary and secondary outcomes were compared between children who did and did not experience neonatal hypoglycemia, adjusting for potential confounding by gestation, birthweight, sex and receipt of prophylactic dextrose gel (pre-hPOD intervention). Secondary analysis included assessment by severity and frequency of hypoglycemia. RESULTS: Of 392 eligible children, 315 (80%) were assessed at school age (primary outcome, n = 308); 47% experienced hypoglycemia. Neurocognitive impairment was similar between exposure groups (hypoglycemia 51% vs 50% no hypoglycemia; aRD -4%, 95% CI -15%, 7%). Children with severe or recurrent hypoglycemia had worse visual motion perception and increased risk of emotional-behavioral difficulty. CONCLUSION: Exposure to neonatal hypoglycemia was not associated with risk of neurocognitive impairment at school-age in at-risk infants, but severe and recurrent episodes may have adverse impacts. TRIAL REGISTRATION: Hypoglycemia Prevention in Newborns with Oral Dextrose: the Dosage Trial (pre-hPOD Study): ACTRN12613000322730.

Duration of fracture prevention after zoledronate treatment in women with osteopenia: observational follow-up of a 6-year randomised controlled trial to 10 years.

BACKGROUND: We previously identified that zoledronate administered at 18-month intervals reduced fragility fractures by a third in a 6-year trial of women older than 65 years with osteopenia. This extension aims to identify the persistence of these effects. METHODS: Of the 2000 ambulant, community dwelling, postmenopausal women older than 65 years recruited in Auckland, New Zealand, with T-scores at the total hip or femoral neck in the range -1·0 to -2·5, we invited participants who received four doses of intravenous zoledronate, completed follow-up to year 6 of the core trial, did not have metabolic bone disease (other than osteoporosis), and were not using bone-active drugs into this 4-year observational study extension, during which further treatment was at the discretion of their own doctors. Participants were asked to notify study staff of any new fractures and were telephoned at 7·5 years and 9·0 years to update their health status. Participants were then invited to an onsite visit at 10·0 years. Fractures and other health events were documented at each contact and analysed in all women who entered the extension, and bone mineral density (BMD; analysed in participants without notable use of bone-active medications who attended an onsite visit at 10 years) and turnover markers (measured from fasting morning blood in a random subset of 50 participants) were measured at year 10. FINDINGS: Of the 1000 women randomly assigned to receive zoledronate in the core trial, 796 participants were eligible for the extension, of whom 762 (96%) entered the extension between Sept 24, 2015, and Dec 13, 2017. Mean follow-up duration was 4·24 years (SD 0·57, range 0·61-6·55; final follow-up on May 25, 2022). 727 (91%) of participants were assessed at 10 years. 25 women died during the extension, six withdrew for medical reasons, and four were lost to follow-up. 92 women suffered 114 non-vertebral fractures during the extension. Non-vertebral fracture rates increased from a nadir of 15 fractures per 1000 woman-years (95% CI 10-21) in the last 2 years of the core trial to 24 fractures (17-33) in years 6-8 and 42 fractures (32-53) in years 8-10, similar to that in the placebo group in the last 2 years of the core trial. Total hip BMD (relative risk per 0·1 g/cm2 0·73, 95% CI 0·57-0·93; p=0·011) and a previous history of non-vertebral fracture (1·74, 1·12-2·69; p=0·013) at year 6 predicted incident fractures but change in total hip BMD did not. Total hip BMD decreased from 4·2% above study baseline to 0·8% above baseline (p<0·0001) during the extension. Turnover markers were not useful for predicting BMD loss in individuals. Osteonecrosis of the jaw or atypical femoral fractures did not occur in any participants. INTERPRETATION: The reduced fracture rates following zoledronate in the core trial were substantially maintained for 1·5-3·5 years after the last zoledronate infusion, but not thereafter. FUNDING: Health Research Council of New Zealand.

Dextrose gel prophylaxis for neonatal hypoglycaemia and neurocognitive function at early school age: a randomised dosage trial.

OBJECTIVE: To investigate the effect of different doses of prophylactic dextrose gel on neurocognitive function and health at 6-7 years. DESIGN: Early school-age follow-up of the pre-hPOD (hypoglycaemia Prevention with Oral Dextrose) study. SETTING: Schools and communities. PATIENTS: Children born at ≥35 weeks with ≥1 risk factor for neonatal hypoglycaemia: maternal diabetes, small or large for gestational age, or late preterm. INTERVENTIONS: Four interventions commencing at 1 hour of age: dextrose gel (40%) 200 mg/kg; 400 mg/kg; 200 mg/kg and 200 mg/kg repeated before three feeds (800 mg/kg); 400 mg/kg and 200 mg/kg before three feeds (1000 mg/kg); compared with equivolume placebo (combined for analysis). MAIN OUTCOMES MEASURES: Toolbox cognitive and motor batteries, as well as tests of motion perception, numeracy and cardiometabolic health, were used. The primary outcome was neurocognitive impairment, defined as a standard score of more than 1 SD below the age-corrected mean on one or more Toolbox tests. FINDINGS: Of 392 eligible children, 309 were assessed for the primary outcome. There were no significant differences in the rate of neurocognitive impairment between those randomised to placebo (56%) and dextrose gel (200 mg/kg 46%: adjusted risk difference (aRD)=-14%, 95% CI -35%, 7%; 400 mg/kg 48%: aRD=-7%, 95% CI -27%, 12%; 800 mg/kg 45%: aRD=-14%, 95% CI -36%, 9%; 1000 mg/kg 50%: aRD=-8%, 95% CI -29%, 13%). Children exposed to any dose of dextrose gel (combined), compared with placebo, had a lower risk of motor impairment (3% vs 14%, aRD=-11%, 95% CI -19%, -3%) and higher mean (SD) cognitive scores (106.0 (15.3) vs 101.1 (15.7), adjusted mean difference=5.4, 95% CI 1.8, 8.9). CONCLUSIONS: Prophylactic neonatal dextrose gel did not alter neurocognitive impairment at early school age but may have motor and cognitive benefits. Further school-age follow-up studies are needed.

Interaction of genetic variation at ADH1B and MLXIPL with alcohol consumption for elevated serum urate level and gout among people of European ethnicity.

BACKGROUND: Alcohol consumption is a risk factor for hyperuricaemia and gout. Multiple single-nucleotide polymorphisms (SNPs) have been identified as associated with both alcohol consumption and serum urate or gout in separate genome-wide association studies (GWAS). This study aimed to identify and characterise interactions between these shared signals of genetic association and alcohol consumption for serum urate level, hyperuricaemia, and gout. METHODS: This research was conducted using the UK Biobank resource. The association of alcohol consumption with serum urate and gout was tested among 458,405 European participants. Candidate SNPs were identified by comparing serum urate, gout, and alcohol consumption GWAS for shared signals of association. Multivariable-adjusted linear and logistic regression analyses were conducted with the inclusion of interaction terms to identify SNP-alcohol consumption interactions for association with serum urate level, hyperuricaemia, and gout. The nature of these interactions was characterised using genotype-stratified association analyses. RESULTS: Alcohol consumption was associated with elevated serum urate and gout. For serum urate level, non-additive interactions were identified between alcohol consumption and rs1229984 at the ADH1B locus (P = 3.0 × 10-44) and rs6460047 at the MLXIPL locus (P = 1.4 × 10-4). ADH1B also demonstrated interaction with alcohol consumption for hyperuricaemia (P = 7.9 × 10-13) and gout (P = 8.2 × 10-9). Beer intake had the most significant interaction with ADH1B for association with serum urate and gout among men, while wine intake had the most significant interaction among women. In the genotype-stratified association analyses, ADH1B and MLXIPL were associated with serum urate level and ADH1B was associated with hyperuricaemia and gout among consumers of alcohol but not non-consumers. CONCLUSIONS: In this large study of European participants, novel interactions with alcohol consumption were identified at ADH1B and MLXIPL for association with serum urate level and at ADH1B for association with hyperuricaemia and gout. The association of ADH1B with serum urate and gout may occur through the modulation of alcohol metabolism rate among consumers of alcohol.

Stability of executive function in children born at risk of neonatal hypoglycemia.

Executive function plays an important role in promoting learning and social-emotional development in children. Neonatal hypoglycemia associates with executive function difficulties at 4.5 years, but little is known about the development of executive function over time in children born at risk of neonatal hypoglycemia. We aimed to describe the stability of executive function from early to mid-childhood in children born at risk of neonatal hypoglycemia and its association with neonatal hypoglycemia. Participants in a prospective cohort study of infants born at risk for neonatal hypoglycemia were assessed at ages 2, 4.5, and 9-10 years. We assessed executive function with batteries of performance-based and questionnaire-based measures, and classified children into one of four stability groups (persistent typical, intermittent typical, intermittent difficulty, and persistent difficulty) based on dichotomized scores (typical versus low at each age). Multinomial logistic regression was used to determine the associations between neonatal hypoglycemia and executive function stability groups. Three hundred and nine children, of whom 197 (64%) experienced neonatal hypoglycemia were assessed. The majority of children had stable and typical performance-based (63%) and questionnaire-based (68%) executive function across all three ages. Around one-third (30-36%) of children had transient difficulties, and only a few (0.3-1.9%) showed persistent difficulties in executive function at all ages. There was no consistent evidence of an association between neonatal hypoglycemia and the stability of executive function. Neonatal hypoglycemia does not appear to predict a specific pattern of development of executive function in children born at risk.

No Effect of NSAID Use on Efficacy of Zoledronate: A Post Hoc Analysis of a Randomized Trial in Osteopenic Older Women.

Bisphosphonates are widely used for the prevention and treatment of osteoporosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are also widely used among the older population group at high risk of fractures. NSAIDs have been shown to impact on bone turnover, and a recent reanalysis of a clinical trial of clodronate found that NSAID use at baseline abrogated any effect of clodronate on either bone density (BMD) or fracture risk. To determine whether NSAIDs influence the efficacy of other bisphosphonates, we have reanalyzed our 6-year randomized controlled trial of zoledronate in 2000 osteopenic postmenopausal women. NSAID use was reported at baseline in 38% of the cohort and anytime use was reported by 65%. The evolution of the zoledronate effects on BMD were almost identical whether or not women were using NSAIDs at baseline and were significant in both subgroups at all BMD sites (p < 0.0001). The significant reduction in the risk of fracture in those allocated to zoledronate (p < 0.0001) showed no interaction with baseline use of NSAIDs (p = 0.33) nor with NSAID use at any time during the study (p = 0.28). The odds of fracture were significantly reduced in both NSAID users and nonusers. We conclude that the present analysis provides no support for the suggestion that NSAIDs interfere with the efficacy of potent bisphosphonates in terms of their effects on bone density or fracture. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Impact of Television Depictions of Gout on Perceptions of Illness: A Randomized Controlled Trial.

OBJECTIVE: Gout is a chronic disease that can be effectively managed with long-term urate-lowering therapy. However, it is frequently portrayed on screen as an acute disease caused by a poor diet that should be managed with lifestyle changes. This study was undertaken to investigate the impact of a fictional television depiction of gout on perceptions of the disease and its management. METHODS: In a randomized controlled single-blind study, 200 members of the public watched either a 19-minute commercial television comedy episode that depicted gout as an acute disease caused by poor diet and managed with lifestyle changes, or a control episode from the same television series that did not mention gout or other diseases. Participants completed a survey regarding their perceptions of gout, its likely causes, and management strategies. RESULTS: Participants randomized to watch the gout-related episode believed gout had greater consequences (mean score of 7.1 versus 6.2 on an 11-point Likert scale; P < 0.001) and were more likely to rank the most important cause as poor eating habits compared to the control group (70% versus 38%; P < 0.001). They were also less likely to believe it is caused by genetic factors or chance. Participants watching the gout-related episode believed a change in diet would be a more effective management strategy (9.0 versus 8.4; P = 0.004) and long-term medication use would be less effective (6.9 versus 7.6; P = 0.007) compared to participants in the control group. CONCLUSION: Television depictions of gout can perpetuate inaccurate beliefs regarding causes of the disease and underemphasize effective medical strategies required in chronic disease management.

Effect of a Three-Day Course of Dexamethasone on Acute Phase Response Following Treatment With Zoledronate: A Randomized Controlled Trial.

Zoledronate is a potent intravenous bisphosphonate effective in the management of osteoporosis, Paget's disease and skeletal-related events in malignancy. Its most frequent adverse effect is the acute phase response (APR), an inflammatory reaction characterized by fever, musculoskeletal pain, headache, and nausea. This randomized, placebo-controlled, double-blind study investigated the efficacy of a three-day course of dexamethasone 4 mg daily in reducing incidence of APR. Participants (n = 60) were randomized to receive either 4 mg of oral dexamethasone 1.5 hours before zoledronate and once a day for the following 2 days, or placebo. Oral temperature was measured at baseline and three times a day for the following 3 days, and questionnaires assessing symptoms of the APR were completed at baseline and for 3 days following zoledronate. Use of anti-inflammatory medication in the 3 days following zoledronate was recorded. The primary outcome was the temperature change from baseline. There was a significant difference in the primary outcome between the dexamethasone and placebo groups (p < 0.0001), with a mean decrease in temperature of 0.10°C (95% confidence interval [CI], -0.34 to 0.14) in the dexamethasone group compared with a mean increase in temperature of 0.84°C (95% CI, 0.53-1.16) in the placebo group on the evening following zoledronate. There was also a difference in APR-related symptom score over time between the two groups (p = 0.0005), with a median change in symptom score in the dexamethasone group 1 day after zoledronate of 0 (95% CI, 0-1) compared with 3 (95% CI, 0-5) in the placebo group. An increase in temperature of ≥1°C to a temperature of >37.5°C occurred in two of 30 (6.7%) participants in the dexamethasone group compared with 14 of 30 participants (46.7%) in the placebo group (p = 0.0005). This study demonstrates that a 3-day course of dexamethasone substantially reduces the APR following zoledronate infusion. © 2023 American Society for Bone and Mineral Research (ASBMR).

Changes in Tophus Composition During Urate-Lowering Therapy: A Dual-Energy Computed Tomography Study.

OBJECTIVE: The gouty tophus is an organized structure composed of monosodium urate (MSU) crystals and chronic inflammatory soft tissue. This dual-energy computed tomography (DECT) study aimed to determine whether the composition of the tophus changes during urate-lowering therapy. METHODS: Serial DECT scans from 32 people with gout were obtained over 2 years of allopurinol therapy, dose-escalated to serum urate of <0.36 mmoles/liter. Up to 5 index tophi were selected for each patient, with 103 separate tophi included in the analysis. Using manual outlining methods of conventional CT and DECT scans, the same index tophi were serially measured for total tophus volume and urate volume. For each tophus, the soft tissue volume was then calculated by subtracting the urate volume from the total tophus volume. RESULTS: The mean ± SD serum urate reduced from 0.43 ± 0.03 mmoles/liter at baseline to 0.31 ± 0.02 mmoles/liter at year 2. The mean ± SD total tophus volume reduced over the 2-year period from 5.17 ± 5.55 cm3 to 2.61 ± 2.73 cm3 (P < 0.0001). Greater reductions in tophus urate volumes than tophus soft tissue volumes were observed; the tophus urate volume decreased by 70.6%, and tophus soft tissue volume decreased by 37.8% (P < 0.0001). The mean tophus urate:soft tissue ratio reduced from 0.15 at baseline to 0.05 at year 2 (P < 0.001). CONCLUSION: The composition of the tophus is dynamic and changes during urate-lowering therapy for gout management. The soft tissue component of the tophus is slower to respond and may persist without measurable MSU crystal deposition.

Mid-Childhood Outcomes after Dextrose Gel Treatment of Neonatal Hypoglycaemia: Follow-Up of the Sugar Babies Randomized Trial.

INTRODUCTION: Dextrose gel is widely used as first-line treatment for neonatal hypoglycaemia given its cost-effectiveness and ease of use. The Sugar Babies randomized trial first showed that 40% dextrose gel was more effective in reversing hypoglycaemia than feeding alone. Follow-up of the Sugar Babies Trial cohort at 2 and 4.5 years of age reported that dextrose gel appeared safe, with similar rates of neurosensory impairment in babies randomized to dextrose or placebo gel. However, some effects of neonatal hypoglycaemia may not become apparent until school age. METHODS: Follow-up of the Sugar Babies Trial cohort at 9-10 years of age was reported. The primary outcome was low educational achievement in reading or mathematics. Secondary outcomes included other aspects of educational achievement, executive function, visual-motor function, and psychosocial adaptation. RESULTS: Of 227 eligible children, 184 (81%) were assessed at a mean (SD) age of 9.3 (0.2) years. Low educational achievement was similar in dextrose and placebo groups (36/86 [42%] vs. 42/94 [45%]; RR 1.04, 95% CI 0.76, 1.44; p = 0.79). Children allocated to dextrose gel had lower visual perception standard scores (95.2 vs. 100.6; MD -5.68, 95% CI -9.79, -1.57; p = 0.006) and a greater proportion had low (<85) visual perception scores (20/88 [23%] vs. 10/95 [11%]; RR 2.23, 95% CI 1.13, 4.37; p = 0.02). Other secondary outcomes, including other aspects of visual-motor function, were similar in both groups. CONCLUSION: Treatment dextrose gel does not appear to result in any clinically significant differences in educational achievement or other neurodevelopmental outcomes at mid-childhood.

Zoledronate Reduces Height Loss Independently of Vertebral Fracture Occurrence in a Randomized Trial in Osteopenic Older Women.

Vertebral fractures are associated with height loss, reduced quality of life, and increased mortality and are an important endpoint for osteoporosis trials. However, height loss is associated with quality of life and mortality independent of associations with fracture. We have used data from a recent 6-year trial of zoledronate in 2000 osteopenic women aged >65 years to assess the impact of the semiquantitative and quantitative components of the definition of vertebral fracture on the outcome of that trial, to determine what factors impacted on height loss and to test whether height loss can be used as a surrogate for vertebral fracture incidence. In the trial protocol, an incident vertebral fracture was defined as a change in Genant grade plus both a 20% and 4 mm decrease in a vertebral height. The addition of the quantitative criteria reduced the number of fractures detected but did not change the size of the anti-fracture effect (odds ratios of 0.49 versus 0.45) nor the width of the confidence intervals for the odds ratios. Multivariate analysis of baseline predictors of height change showed that age accelerated height loss (p < 0.0001) and zoledronate reduced it (p = 0.0001). Incident vertebral fracture increased height loss (p = 0.0005) but accounted for only 0.7% of the variance in height change, so fracture could not be reliably inferred from height loss. In women without incident vertebral fractures, height loss was still reduced by zoledronate (height change: zoledronate, -1.23; placebo -1.51 mm/yr, p < 0.0001). This likely indicates that zoledronate prevents a subtle but widespread loss of vertebral body heights not detected by vertebral morphometry. Because height loss is associated with quality of life and mortality independent of associations with fracture, it is possible that zoledronate impacts on these endpoints via its effects on vertebral body integrity. © 2022 American Society for Bone and Mineral Research (ASBMR).

Effects of elevated serum urate on cardiometabolic and kidney function markers in a randomised clinical trial of inosine supplementation.

In observational studies, serum urate positively associates with cardiometabolic and kidney diseases. We analyzed data from a randomised placebo-controlled trial to determine whether moderate hyperuricemia induced by inosine affects cardiometabolic and kidney function markers. One hundred and twenty post-menopausal women were recruited into a 6-month randomised, double-blind, placebo-controlled trial of inosine for bone health. Change from baseline in the following pre-specified endpoints was analyzed: body mass index; blood pressure; lipid profile; C-reactive protein; fasting glucose; insulin; HbA1c; serum creatinine; and estimated glomerular filtration rate (eGFR). Despite increases in serum urate levels (+ 0.17 mmol/L at week 6, P < 0.0001), no significant between-group differences were observed in cardiometabolic markers, with the exception of lower fasting glucose concentrations with inosine at week 19. In the inosine group, change in serum urate correlated with change in serum creatinine (r = 0.41, P = 0.0012). However, there was no between-group difference in serum creatinine values. Over the entire study period, there was no significant difference in eGFR (ANCOVA P = 0.13). Reduction in eGFR was greater in the inosine group at Week 13 (mean difference - 4.6 mL/min/1.73 m2, false detection rate P = 0.025), with no between-group difference in eGFR at other time points. These data indicate that increased serum urate does not negatively influence body mass index, blood pressure, lipid profile, or glycaemic control. Serum urate changes associated with inosine intake correlate with changes in serum creatinine, but this does not lead to clinically important reduction in kidney function over 6 months.Clinical trial registration number: Australia and New Zealand Clinical Trials Registry (ACTRN12617000940370), registered 30/06/2017.

Association of Neonatal Hypoglycemia With Academic Performance in Mid-Childhood.

Importance: Neonatal hypoglycemia is associated with increased risk of poor executive and visual-motor function, but implications for later learning are uncertain. Objective: To test the hypothesis that neonatal hypoglycemia is associated with educational performance at age 9 to 10 years. Design, Setting, and Participants: Prospective cohort study of moderate to late preterm and term infants born at risk of hypoglycemia. Blood and masked interstitial sensor glucose concentrations were measured for up to 7 days. Infants with hypoglycemic episodes (blood glucose concentration <47 mg/dL [2.6 mmol/L]) were treated to maintain a blood glucose concentration of at least 47 mg/dL. Six hundred fourteen infants were recruited at Waikato Hospital, Hamilton, New Zealand, in 2006-2010; 480 were assessed at age 9 to 10 years in 2016-2020. Exposures: Hypoglycemia was defined as at least 1 hypoglycemic event, representing the sum of nonconcurrent hypoglycemic and interstitial episodes (sensor glucose concentration <47 mg/dL for ≥10 minutes) more than 20 minutes apart. Main Outcomes and Measures: The primary outcome was low educational achievement, defined as performing below or well below the normative curriculum level in standardized tests of reading comprehension or mathematics. There were 47 secondary outcomes related to executive function, visual-motor function, psychosocial adaptation, and general health. Results: Of 587 eligible children (230 [48%] female), 480 (82%) were assessed at a mean age of 9.4 (SD, 0.3) years. Children who were and were not exposed to neonatal hypoglycemia did not significantly differ on rates of low educational achievement (138/304 [47%] vs 82/176 [48%], respectively; adjusted risk difference, -2% [95% CI, -11% to 8%]; adjusted relative risk, 0.95 [95% CI, 0.78-1.15]). Children who were exposed to neonatal hypoglycemia, compared with those not exposed, were significantly less likely to be rated by teachers as being below or well below the curriculum level for reading (68/281 [24%] vs 49/157 [31%], respectively; adjusted risk difference, -9% [95% CI, -17% to -1%]; adjusted relative risk, 0.72 [95% CI, 0.53-0.99; P = .04]). Groups were not significantly different for other secondary end points. Conclusions and Relevance: Among participants at risk of neonatal hypoglycemia who were screened and treated if needed, exposure to neonatal hypoglycemia compared with no such exposure was not significantly associated with lower educational achievement in mid-childhood.

Associations between neonatal hypoglycaemia and brain volumes, cortical thickness and white matter microstructure in mid-childhood: An MRI study.

Neonatal hypoglycaemia is a common metabolic disorder that may cause brain damage, most visible in parieto-occipital regions on MRI in the acute phase. However, the long term effects of neonatal hypoglycaemia on the brain are not well understood. We investigated the association between neonatal hypoglycaemia and brain volumes, cortical thickness and white matter microstructure at 9-10 years. Children born at risk of neonatal hypoglycaemia at ≥ 36 weeks' gestation who took part in a prospective cohort study underwent brain MRI at 9-10 years. Neonatal hypoglycaemia was defined as at least one hypoglycaemic episode (at least one consecutive blood glucose concentration < 2.6 mmol/L) or interstitial episode (at least 10 min of interstitial glucose concentrations < 2.6 mmol/L). Brain volumes and cortical thickness were computed using Freesurfer. White matter microstructure was assessed using tract-based spatial statistics. Children who had (n = 75) and had not (n = 26) experienced neonatal hypoglycaemia had similar combined parietal and occipital lobe volumes and no differences in white matter microstructure at nine years of age. However, those who had experienced neonatal hypoglycaemia had smaller caudate volumes (mean difference: -557 mm3, 95% confidence interval (CI), -933 to -182, p = 0.004) and smaller thalamus (-0.03%, 95%CI, -0.06 to 0.00; p = 0.05) and subcortical grey matter (-0.10%, 95%CI -0.20 to 0.00, p = 0.05) volumes as percentage of total brain volume, and thinner occipital lobe cortex (-0.05 mm, 95%CI -0.10 to 0.00, p = 0.05) than those who had not. The finding of smaller caudate volumes after neonatal hypoglycaemia was consistent across analyses of pre-specified severity groups, clinically detected hypoglycaemic episodes, and severity and frequency of hypoglycaemic events. Neonatal hypoglycaemia is associated with smaller deep grey matter brain regions and thinner occipital lobe cortex but not altered white matter microstructure in mid-childhood.

Which Attributes Are Most and Least Important to Patients When Considering Gout Flare Burden Over Time? A Best-worst Scaling Choice Study.

OBJECTIVE: Several factors contribute to the patient experience of gout flares, including pain intensity, duration, frequency, and disability. It is unknown which of these factors are most important to patients when considering flare burden over time, including those related to the cumulative experience of all flares, or the experience of a single worst flare. This study aimed to determine which flare attributes are the most and least important to the patient experience of flare burden over time. METHODS: Participants with gout completed an anonymous online survey. Questions were aimed at identifying which attributes of gout flares, representing both individual and cumulative flare burden, were the most and least important over a hypothetical 6-month period. A best-worst scaling method was used to determine the importance hierarchy of the included attributes. RESULTS: Fifty participants were included. Difficulty doing usual activities during the worst flare and pain of the worst flare were ranked as the most important, whereas average pain of all flares was considered the least important. Overall, attributes related to the single worst gout flare were considered more important than attributes related to the cumulative impact of all flares. CONCLUSION: When thinking about the burden of gout flares over time, patients rank activity limitation and pain experienced during their worst gout flare as the most important contributing factors, whereas factors related to the cumulative impact of all flares over time are relatively less important.

Effect of prophylactic dextrose gel on the neonatal gut microbiome.

OBJECTIVE: To determine the effect of prophylactic dextrose gel on the infant gut microbiome. DESIGN: Observational cohort study nested in a randomised trial. SETTING: Three maternity hospitals in New Zealand. PATIENTS: Infants at risk of neonatal hypoglycaemia whose parents consented to participation in the hypoglycaemia Prevention in newborns with Oral Dextrose trial (hPOD). Infants were randomised to receive prophylactic dextrose gel or placebo gel, or were not randomised and received no gel (controls). Stool samples were collected on days 1, 7 and 28. MAIN OUTCOME MEASURES: The primary outcome was microbiome beta-diversity at 4 weeks. Secondary outcomes were beta-diversity, alpha-diversity, bacterial DNA concentration, microbial community stability and relative abundance of individual bacterial taxa at each time point. RESULTS: We analysed 434 stool samples from 165 infants using 16S rRNA gene amplicon sequencing. There were no differences between groups in beta-diversity at 4 weeks (p=0.49). There were also no differences between groups in any other microbiome measures including beta-diversity (p=0.53 at day 7), alpha-diversity (p=0.46 for day 7 and week 4), bacterial DNA concentration (p=0.91), microbial community stability (p=0.52) and microbial relative abundance at genus level. There was no evidence that exposure to any dextrose gel (prophylaxis or treatment) had any effect on the microbiome. Mode of birth, type of milk fed, hospital of birth and ethnicity were all associated with differences in the neonatal microbiome. CONCLUSIONS: Clinicians and consumers can be reassured that dextrose gel used for prophylaxis or treatment of neonatal hypoglycaemia does not alter the neonatal gut microbiome. TRIAL REGISTRATION NUMBER: 12614001263684.

Diagnostic value of different imaging features for patients with suspected gout: A network meta-analysis.

OBJECTIVE: Microscopic identification of monosodium urate (MSU) crystals is the gold standard for gout diagnosis. However, joint aspiration is not always practical, and imaging is increasingly used in clinical practice. This study aimed to assess the diagnostic accuracy of imaging features for gout compared with microscopy, using network meta-analysis methodology. METHODS: MEDLINE, EMBASE, PubMed and Cochrane databases were searched for studies reporting on the use of imaging modalities to diagnose gout in patients with an unclear diagnosis or suspected gout, which was later confirmed by microscopy. A combination of direct and indirect comparisons were performed by network meta-analysis to evaluate the combined odds ratios for sensitivity, specificity, and accuracy. To assist interpretation, the surface under the cumulative ranking curve (SUCRA) scores were calculated to provide a ranking of the imaging features. RESULTS: Fifteen eligible studies were included. Compared to the gold standard microscopic identification of MSU crystals, dual energy computed tomography (DECT) MSU crystal deposition and ultrasound double contour had greater sensitivity than ultrasound tophus. DECT, ultrasound double contour sign and ultrasound tophus all had greater specificity than ultrasound aggregates. The SUCRA scores ranked DECT as highest for overall accuracy, followed by ultrasound double contour, aggregates, and tophus, while ultrasound snowstorm was ranked the lowest. However, there were no significant differences in the odds ratios for overall accuracy between these imaging features. CONCLUSION: DECT and ultrasound are both useful modalities for the detection of imaging features of MSU crystal deposition, and have a similar overall diagnostic accuracy for gout diagnoses.

Global patterns of treat-to-serum urate target care for gout: Systematic review and meta-analysis.

BACKGROUND: International rheumatology guidelines advocate a treat to serum urate target (T2T) approach for gout management. While individual studies have reported regional and national-level gout management, global patterns in gout care have not been synthesized. This study aimed to systematically review and meta-analyze global T2T care for patients with gout. METHODS: Electronic databases were searched for studies reporting medication and serum urate testing in patients with gout. Meta-analyses were conducted to determine the pooled proportion of patients with gout achieving pre-specified T2T indicators. RESULTS: Sixty-seven papers were included from North America (n = 31 studies), Europe (n = 22), Oceania (n = 7), Asia (n = 6), and reporting data from multiple continents (n = 1). The global pooled percentages (95% confidence interval (CI)) of patients with gout achieving T2T indicators were: 52% (45%, 59%) on urate lowering therapy (ULT), 50% (40%, 61%) on ULT receiving regular uninterrupted ULT, 53% (40%, 65%) on ULT having any serum urate testing, and 34% (28%, 41%) on ULT achieving a serum urate target. CONCLUSION: Outside North America and Europe, there are relatively few studies about T2T care for gout management. However, available data demonstrate that a minority of people with gout receive T2T care worldwide. For those prescribed ULT, there are low rates of continuous therapy, serum urate testing, and achievement of serum urate target.