OBJECTIVE: To test whether an individualized opioid-prescription protocol (IOPP) with a shared decision-making component can be used without compromising postcesarean pain management. METHODS: In ...this multicenter randomized controlled noninferiority trial, we compared IOPP with shared decision making with a fixed quantity of opioid tablets at hospital discharge. We recruited at 31 centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Study participants had uncomplicated cesarean births. Follow-up occurred through 12 weeks postdischarge. Individuals with complicated cesarean births or history of opioid use in the pregnancy were excluded. Participants were randomized 1:1 to IOPP with shared decision making or fixed quantity (20 tablets of 5 mg oxycodone). In the IOPP group, we calculated recommended tablet quantity based on opioid use in the 24 hours before discharge. After an educational module and shared decision making, participants selected a quantity of discharge tablets (up to 20). The primary outcome was moderate to severe pain (score 4 or higher possible range 0–10) on the BPI (Brief Pain Inventory) at 1 week after discharge. A total sample size of 5,500 participants was planned to assess whether IOPP with shared decision making was not inferior to the fixed quantity of 20 tablets. RESULTS: From September 2020 to March 2022, 18,990 individuals were screened and 5,521 were enrolled (n=2,748 IOPP group, n=2,773 fixed-quantity group). For the primary outcome, IOPP with shared decision making was not inferior to fixed quantity (59.5% vs 60.1%, risk difference 0.67%; 95% CI, −2.03% to 3.37%, noninferiority margin −5.0) and resulted in significantly fewer tablets received (median 14 interquartile range 4–20 vs 20, P <.001) through 90 days postpartum. CONCLUSION: Compared with fixed quantity, IOPP with shared decision making was noninferior for outpatient postcesarean analgesia at 1 week postdischarge and resulted in fewer prescribed opioid tablets at discharge. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04296396.
Conservation of mitochondrial adenosine triphosphate (ATP) synthase proteins during ischemia is critical to preserve ATP supply and ventricular function. Following myocardial ischemia in adults, ...higher order ATP synthase tetramer proteins disassemble into simpler monomer units, reducing the efficiency of ATP production. However, it is unknown if myocardial ischemia following the use of cardioplegia results in tetramer disassembly in neonates, and whether it can be mitigated by cardioplegia if it does occur. We investigated myocardial ATP synthase tetramer disassembly in both a neonatal lamb cardiac surgery model and in neonatal children requiring cardiac surgery for the repair of congenital heart disease. Neonatal lambs (
) were placed on cardiopulmonary bypass (CPB) and underwent cardioplegic arrest using a single dose of 30 mL/kg antegrade blood-based potassium cardioplegia (
= 4) or a single dose of 30 mL/kg antegrade del Nido cardioplegia (
= 6). Right ventricular biopsies were taken at baseline on CPB (
= 10) and after approximately 60 minutes of cardioplegic arrest before the cross clamp was released (
= 10). Human right ventricular biopsies (
= 3) were taken following 40.0 ± 23.1 minutes of ischemia after a single dose of antegrade blood-based cardioplegia. Protein complexes were separated on clear native gels and the tetramer to monomer ratio quantified. From the neonatal lamb model regardless of the cardioplegia strategy, the tetramer:monomer ratio decreased significantly during ischemia from baseline measurements (.6 ± .2 vs. .5 ± .1;
= .03). The del Nido solution better preserved the tetramer:monomer ratio when compared to the blood-based cardioplegia (Blood .4 ± .1 vs. del Nido .5 ± .1;
= .05). The tetramer:monomer ratio following the use of blood-based cardioplegia in humans aligned with the lamb data (tetramer:monomer .5 ± .2). These initial results suggest that despite cardioprotection, ischemia during neonatal cardiac surgery results in tetramer disassembly which may be limited when using the del Nido solution.
Conservation of mitochondrial adenosine triphosphate (ATP) synthase proteins during ischemia is critical to preserve ATP supply and ventricular function. Following myocardial ischemia in adults, ...higher order ATP synthase tetramer proteins disassemble into simpler monomer units, reducing the efficiency of ATP production. However, it is unknown if myocardial ischemia following the use of cardioplegia results in tetramer disassembly in neonates, and whether it can be mitigated by cardioplegia if it does occur. We investigated myocardial ATP synthase tetramer disassembly in both a neonatal lamb cardiac surgery model and in neonatal children requiring cardiac surgery for the repair of congenital heart disease. Neonatal lambs (
Ovis aries
) were placed on cardiopulmonary bypass (CPB) and underwent cardioplegic arrest using a single dose of 30 mL/kg antegrade blood-based potassium cardioplegia (
n
= 4) or a single dose of 30 mL/kg antegrade del Nido cardioplegia (
n
= 6). Right ventricular biopsies were taken at baseline on CPB (
n
= 10) and after approximately 60 minutes of cardioplegic arrest before the cross clamp was released (
n
= 10). Human right ventricular biopsies (
n
= 3) were taken following 40.0 ± 23.1 minutes of ischemia after a single dose of antegrade blood-based cardioplegia. Protein complexes were separated on clear native gels and the tetramer to monomer ratio quantified. From the neonatal lamb model regardless of the cardioplegia strategy, the tetramer:monomer ratio decreased significantly during ischemia from baseline measurements (.6 ± .2 vs. .5 ± .1;
p
= .03). The del Nido solution better preserved the tetramer:monomer ratio when compared to the blood-based cardioplegia (Blood .4 ± .1 vs. del Nido .5 ± .1;
p
= .05). The tetramer:monomer ratio following the use of blood-based cardioplegia in humans aligned with the lamb data (tetramer:monomer .5 ± .2). These initial results suggest that despite cardioprotection, ischemia during neonatal cardiac surgery results in tetramer disassembly which may be limited when using the del Nido solution.
To estimate the rate of perinatal transmission of hepatitis C virus (HCV) infection, to identify risk factors for perinatal transmission of HCV infection, and to determine the viremic threshold for ...perinatal transmission.
This was a prospective, multicenter, observational study of pregnant individuals at less than 24 weeks of gestation screened for HCV infection from 2012 to 2018 in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Individuals found to be HCV antibody-positive were followed throughout pregnancy. Children were followed for evidence of perinatal transmission at 2-6 months (HCV RNA testing) and at 18-24 months (HCV RNA and antibody testing) of life. The primary outcome was perinatal transmission, defined as positive test results at either follow-up time point.
A total of 109,379 individuals were screened for HCV infection. Of the 1,224 participants who screened positive, 772 (63.1%) enrolled and 432 of those 772 (56.0%) had data available to assess primary outcome. The overall rate of perinatal transmission was 6.0% (26/432, 95% CI 4.0-8.7%). All children with HCV infection were born to individuals with demonstrable viremia. In viremic participants (n=314), the perinatal transmission rate was 8.0% (95% CI 5.2-11.5%). Risk factors for perinatal transmission included HCV RNA greater than 106 international units/mL (adjusted odds ratio aOR 8.22, 95% CI 3.16-21.4) and vaginal bleeding reported at any time before delivery (aOR 3.26, 95% CI 1.32-8.03). A viremic threshold for perinatal transmission could not be established.
Perinatal transmission of HCV infection was limited to viremic individuals. High viral loads and antepartum bleeding were associated with perinatal transmission.
Background: Achieving optimal iron status in children in malaria-endemic areas may increase the risk of malaria. Malaria itself may contribute to iron deficiency, but the impact of an interruption in ...malaria transmission on the prevalence of iron deficiency is unknown.Objectives: We aimed to determine whether 1) iron status improved in children living in 2 Kenyan villages with a documented cessation in malaria transmission and 2) changes in iron status correlated with changes in hemoglobin.Design: We measured iron hemoglobin, ferritin, soluble transferrin receptor (sTfR) and inflammatory C-reactive protein (CRP) markers in paired plasma samples from 190 children aged 4–59 mo at the beginning (May 2007) and end (July 2008) of a documented 12-mo period of interruption in malaria transmission in 2 highland areas in Kenya with unstable malaria transmission and ongoing malaria surveillance.Results: Between May 2007 and July 2008, mean (±SD) hemoglobin increased from 10.8 ± 1.6 to 11.6 ± 1.6 g/dL. Median (25th, 75th percentile) ferritin increased from 17.0 (9.7, 25.6) to 22.6 (13.4, 34.7) μg/L (P < 0.001), whereas median sTfR decreased from 32.4 (26.3, 43.2) to 27.7 (22.1, 36.0) nmol/L (P < 0.001). Median CRP was low (<1 mg/L in both years) and did not change significantly. Iron deficiency prevalence (ferritin <12 μg/L, or <30 μg/L if CRP ≥10 mg/L) decreased from 35.9% (95% CI: 28.9%, 43.0%) to 24.9% (18.5%, 31.2%) (P = 0.005). The prevalence of iron deficiency with anemia (hemoglobin <11.0 g/dL) declined from 27.2% (20.7%, 33.8%) to 12.2% (7.4%, 17.1%) (P < 0.001). Improvement in iron status correlated with an increase in hemoglobin and was greater than explained by physiologic changes expected with age.Conclusions: In this area of unstable malaria transmission, the prevalence of iron deficiency in children decreased significantly after the interruption of malaria transmission and was correlated with an increase in hemoglobin. These findings suggest that malaria elimination strategies themselves may be an effective way to address iron deficiency in malaria-endemic areas.
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Glycerol phenylbutyrate is under development for treatment of urea cycle disorders (UCDs), rare inherited metabolic disorders manifested by hyperammonemia and neurological impairment. We report the ...results of a pivotal Phase 3, randomized, double‐blind, crossover trial comparing ammonia control, assessed as 24‐hour area under the curve (NH3‐AUC0‐24hr), and pharmacokinetics during treatment with glycerol phenylbutyrate versus sodium phenylbutyrate (NaPBA) in adult UCD patients and the combined results of four studies involving short‐ and long‐term glycerol phenylbutyrate treatment of UCD patients ages 6 and above. Glycerol phenylbutyrate was noninferior to NaPBA with respect to ammonia control in the pivotal study, with mean (standard deviation, SD) NH3‐AUC0‐24hr of 866 (661) versus 977 (865) μmol·h/L for glycerol phenylbutyrate and NaPBA, respectively. Among 65 adult and pediatric patients completing three similarly designed short‐term comparisons of glycerol phenylbutyrate versus NaPBA, NH3‐AUC0‐24hr was directionally lower on glycerol phenylbutyrate in each study, similar among all subgroups, and significantly lower (P < 0.05) in the pooled analysis, as was plasma glutamine. The 24‐hour ammonia profiles were consistent with the slow‐release behavior of glycerol phenylbutyrate and better overnight ammonia control. During 12 months of open‐label glycerol phenylbutyrate treatment, average ammonia was normal in adult and pediatric patients and executive function among pediatric patients, including behavioral regulation, goal setting, planning, and self‐monitoring, was significantly improved. Conclusion: Glycerol phenylbutyrate exhibits favorable pharmacokinetics and ammonia control relative to NaPBA in UCD patients, and long‐term glycerol phenylbutyrate treatment in pediatric UCD patients was associated with improved executive function (ClinicalTrials.gov NCT00551200, NCT00947544, NCT00992459, NCT00947297). (HEPATOLOGY 2012)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Glycerol phenylbutyrate (GPB) is currently approved for use in the US and Europe for patients of all ages with urea cycle disorders (UCD) who cannot be managed with protein restriction and/or amino ...acid supplementation alone. Currently available data on GPB is limited to 12 months exposure. Here, we present long-term experience with GPB.
This was an open-label, long-term safety study of GPB conducted in the US (17 sites) and Canada (1 site) monitoring the use of GPB in UCD patients who had previously completed 12 months of treatment in the previous safety extension studies. Ninety patients completed the previous studies with 88 of these continuing into the long-term evaluation. The duration of therapy was open ended until GPB was commercially available. The primary endpoint was the rate of adverse events (AEs). Secondary endpoints were venous ammonia levels, number and causes of hyperammonemic crises (HACs) and neuropsychological testing.
A total of 45 pediatric patients between the ages of 1 to 17 years (median 7 years) and 43 adult patients between the ages of 19 and 61 years (median 30 years) were enrolled. The treatment emergent adverse events (TEAE) reported in ≥10% of adult or pediatric patients were consistent with the TEAEs reported in the previous safety extension studies with no increase in the overall incidence of TEAEs and no new TEAEs that indicated a new safety signal. Mean ammonia levels remained stable and below the adult upper limit of normal (<35 µmol/L) through 24 months of treatment in both the pediatric and adult population. Over time, glutamine levels decreased in the overall population. The mean annualized rate of HACs (0.29) established in the previously reported 12-month follow-up study was maintained with continued GPB exposure.
Following the completion of 12-month follow-up studies with GPB treatment, UCD patients were followed for an additional median of 1.85 (range 0 to 5.86) years in the present study with continued maintenance of ammonia control, similar rates of adverse events, and no new adverse events identified.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders.
The relationships between fasting ammonia, daily ammonia exposure, ...and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders.
Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations <0.5 upper limit of normal (ULN), 0.5 to <1.0 ULN, and ≥1.0 ULN, the probability of a normal average daily ammonia value was 87, 60, and 39%, respectively, and 10.3, 14.1, and 37.0% of these patients, respectively, experienced ≥1 hyperammonemic crisis over 12 months. Time to first hyperammonemic crisis was shorter (P = 0.008) and relative risk (4.5×; P = 0.011) and rate (~5×, P = 0.006) of hyperammonemic crises were higher in patients with fasting ammonia ≥1.0 ULN vs. <0.5ULN; relative risk was even greater (20×; P = 0.009) in patients ≥6 years old. A 10- or 25-µmol/l increase in ammonia exposure increased the relative risk of a hyperammonemic crisis by 50 and >200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, urea cycle disorder subtype, dietary protein intake, or blood urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24-hour area under the curve and was not a significant predictor of hyperammonemic crisis.
Fasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with urea cycle disorder may benefit from tight ammonia control.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in ...patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes.
Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate NaPBA) and during treatment with glycerol phenylbutyrate (GPB).
After 3 months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p<0.0001), the number of symptoms per patient (2.5 vs. 1.1; p<0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p<0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose.
The reduction in symptoms following 3 months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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