Long-chain fatty acid oxidation disorders (LC-FAOD) can cause cardiac hypertrophy and cardiomyopathy, often presenting in infancy, typically leading to death or heart transplant despite ongoing treatment. Previous data on triheptanoin treatment of cardiomyopathy in LC-FAOD suggested a clinical benefit on heart function during acute failure. An additional series of LC-FAOD patients with critical emergencies associated with cardiomyopathy was treated with triheptanoin under emergency treatment or compassionate use protocols. Case reports from 10 patients (8 infants) with moderate or severe cardiomyopathy associated with LC-FAOD are summarized. The majority of these patients were detected by newborn screening, with follow up confirmatory testing, including mutation analysis; all patients were managed with standard treatment, including medium chain triglyceride (MCT) oil. While on this regimen, they presented with acute heart failure requiring hospitalization and cardiac support (ventilation, ECMO, vasopressors) and, in some cases, resuscitation. The patients discontinued MCT oil and began treatment with triheptanoin, an investigational drug. Triheptanoin is expected to provide anaplerotic metabolites, to replace deficient TCA cycle intermediates and improve effective energy metabolism. Cardiac function was measured by echocardiography and ejection fraction (EF) was assessed. EF was moderately to severely impaired prior to triheptanoin treatment, ranging from 12-45%. Improvements in EF began between 2 and 21days following initiation of triheptanoin, and peaked at 33-71%, with 9 of 10 patients achieving EF in the normal range. Continued treatment was associated with longer-term stabilization of clinical signs of cardiomyopathy. The most common adverse event observed was gastrointestinal distress. Of the 10 patients, 7 have continued on treatment, 1 elected to discontinue due to tolerability issues, and 2 patients died from other causes. Two of the case histories illustrate that cardiomyopathy may also develop later in childhood and/or persist into adulthood. Overall, the presented cases suggest a therapeutic effect of triheptanoin in the management of acute cardiomyopathy associated with LC-FAOD.

Unlabelled

We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD).

Study design

These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine.

Results

Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control.

Conclusion

The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.

Faced with unresolved tensions between neutrino interaction measurements at few-GeV neutrino energies, current experiments are forced to accept large systematic uncertainties to cover discrepancies between their data and model predictions. In this paper, the widely used pion production model in GENIE is compared to four MINERvA charged current pion production measurements using NUISANCE. Tunings, ie, adjustments of model parameters, to help match GENIE to MINERvA and older bubble chamber data are presented here. We find that scattering off nuclear targets as measured in MINERvA is not in good agreement with scattering off nucleon (hydrogen or deuterium) targets in the bubble chamber data. An additional ad hoc correction for the low-$Q^2$ region, where collective effects are expected to be large, is also presented. While these tunings and corrections improve the agreement of GENIE with the data, the modeling is imperfect. The development of these tunings within the NUISANCE frameworkallows for straightforward extensions to other neutrino event generators and models, and allows omitting and including new data sets as they become available.

We present double-differential measurements of antineutrino charged-current quasielastic scattering in the MINERvA detector. This study improves on a previous single-differential measurement by using updated reconstruction algorithms and interaction models and provides a complete description of observed muon kinematics in the form of a double-differential cross section with respect to muon transverse and longitudinal momentum. We include in our signal definition zero-meson final states arising from multinucleon interactions and from resonant pion production followed by pion absorption in the primary nucleus. We find that model agreement is considerably improved by a model tuned to MINERvA inclusive neutrino scattering data that incorporates nuclear effects such as weak nuclear screening and two-particle, two-hole enhancements.

Single neutral pion production via muon antineutrino charged-current interactions in plastic scintillator (CH) is studied using the MINERvA detector exposed to the NuMI low-energy, wideband antineutrino beam at Fermilab. Measurement of this process constrains models of neutral pion production in nuclei, which is important because the neutral-current analog is a background for ν-e appearance oscillation experiments. The differential cross sections for π0 momentum and production angle, for events with a single observed π0 and no charged pions, are presented and compared to model predictions. These results comprise the first measurement of the π0 kinematics for this process.

Neutrino induced coherent charged pion production on nuclei, $\overline{ u}_\mu A\to\mu^\pm\pi^\mp A$, is a rare inelastic interaction in which the four-momentum squared transfered to the nucleus is nearly zero, leaving it intact. We identify such events in the scintillator of MINERvA by reconstructing |t| from the final state pion and muon momenta and by removing events with evidence of energetic nuclear recoil or production of other final state particles. We measure the total neutrino and antineutrino cross sections as a function of neutrino energy between 2 and 20 GeV and measure flux integrated differential cross sections as a function of $Q^2$, $E_\pi$ and $\theta_\pi$. The $Q^2$ dependence and equality of the neutrino and anti-neutrino cross-sections at finite $Q^2$ provide a confirmation of Adler's PCAC hypothesis.

Final-state kinematic imbalances are measured in mesonless production of ν_{μ}+A→μ^{-}+p+X in the MINERvA tracker. Initial- and final-state nuclear effects are probed using the direction of the μ^{-}-p transverse momentum imbalance and the initial-state momentum of the struck neutron. Differential cross sections are compared to predictions based on current approaches to medium modeling. These models underpredict the cross section at intermediate intranuclear momentum transfers that generally exceed the Fermi momenta. As neutrino interaction models need to correctly incorporate the effect of the nucleus in order to predict neutrino energy resolution in oscillation experiments, this result points to a region of phase space where additional cross section strength is needed in current models, and demonstrates a new technique that would be suitable for use in fine-grained liquid argon detectors where the effect of the nucleus may be even larger.