Global untargeted metabolomics (GUM) has entered clinical diagnostics for genetic disorders. We compared the clinical utility of GUM with traditional targeted metabolomics (TM) as a screening tool in ...patients with established genetic disorders and determined the scope of GUM as a discovery tool in patients with no diagnosis under investigation. We compared TM and GUM data in 226 patients. The first cohort (n = 87) included patients with confirmed inborn errors of metabolism (IEM) and genetic syndromes; the second cohort (n = 139) included patients without diagnosis who were undergoing evaluation for a genetic disorder. In patients with known disorders (n = 87), GUM performed with a sensitivity of 86% (95% CI: 78-91) compared with TM for the detection of 51 diagnostic metabolites. The diagnostic yield of GUM in patients under evaluation with no established diagnosis (n = 139) was 0.7%. GUM successfully detected the majority of diagnostic compounds associated with known IEMs. The diagnostic yield of both targeted and untargeted metabolomics studies is low when assessing patients with non-specific, neurological phenotypes. GUM shows promise as a validation tool for variants of unknown significance in candidate genes in patients with non-specific phenotypes.
We present the first observations of electron cyclotron harmonic waves at the Earth's bow shock from STEREO and Wind burst waveform captures. These waves are observed at magnetic field gradients at a ...variety of shock geometries ranging from quasi‐parallel to nearly perpendicular along with whistler mode waves, ion acoustic waves, and electrostatic solitary waves. Large amplitude cyclotron harmonic waveforms are also observed in the magnetosheath in association with magnetic field gradients convected past the bow shock. Amplitudes of the cyclotron harmonic waves range from a few tens to more than 500 mV/m peak‐peak. A comparison between the short (15 m) and long (100 m) Wind spin plane antennas shows a similar response at low harmonics and a stronger response on the short antenna at higher harmonics. This indicates that wavelengths are not significantly larger than 100 m, consistent with the electron cyclotron radius. Waveforms are broadband and polarizations are distinctively comma‐shaped with significant power both perpendicular and parallel to the magnetic field. Harmonics tend to be more prominent in the perpendicular directions. These observations indicate that the waves consist of a combination of perpendicular Bernstein waves and field‐aligned waves without harmonics. A likely source is the electron cyclotron drift instability which is a coupling between Bernstein and ion acoustic waves. These waves are the most common type of high‐frequency wave seen by STEREO during bow shock crossings and magnetosheath traversals and our observations suggest that they are an important component of the high‐frequency turbulent spectrum in these regions.
Key Points
Large amplitude waves with cyclotron harmonics observed at bowshock crossings
Waves a combination of perpendicular Bernstein and parallel ion acoustic waves
May be important component of bowshock efield spectrum at a few hundred Hz
To explore the relationship between tobacco smoke exposure (reported versus biomarker) and rates of readmission for children hospitalized for asthma.
We enrolled a prospective cohort of 774 children ...aged 1 to 16 years admitted for asthma or bronchodilator-responsive wheezing. The primary outcome was at least 1 asthma- or wheeze-related readmission within 1 year. Caregivers reported any tobacco exposure at home, in a secondary residence, or in the car. We measured serum and saliva cotinine levels with mass spectrometry. We used logistic regression to evaluate associations between tobacco exposure and readmissions.
A total of 619 children had complete tobacco exposure data; 57% were African American and 76% had Medicaid. Seventeen percent of children were readmitted within 1 year. Tobacco exposure rates were 35.1%, 56.1%, and 79.6% by report, serum, and saliva measures, respectively. Caregiver report of any tobacco exposure was not associated with readmission (adjusted odds ratio: 1.18; 95% confidence interval: 0.79-1.89), but having detectable serum or salivary cotinine was associated with increased odds of readmission (adjusted odds ratio 95% confidence interval: 1.59 1.02-2.48 and 2.35 1.22-4.55, respectively). Among children whose caregivers reported no tobacco exposure, 39.1% had detectable serum cotinine and 69.9% had detectable salivary cotinine. Of the children with reported exposure, 87.6% had detectable serum cotinine and 97.7% had detectable salivary cotinine.
Detectable serum and salivary cotinine levels were common among children admitted for asthma and were associated with readmission, whereas caregiver report of tobacco exposure was not.
•Most clinical labs measure vitamins A & E using liquid-liquid extraction and HPLC.•This approach is laborious, often requiring dedicated staff and instrumentation.•We describe a simple, rapid ...protocol for measurement of vitamins A and E.•Use of multiplexing SPLC-MS/MS consolidates tests and reduces analysis times.
Vitamin A and E are routinely monitored to assess nutritional status. The most commonly used approach for their measurement involves laborious liquid-liquid extraction followed by high-performance liquid chromatography (HPLC) analysis on dedicated instrumentation. We describe a simple, rapid protocol for measurement of vitamin A and E and their integration into an existing online sample preparation liquid chromatography tandem mass spectrometry (SPLC-MS/MS) workflow.
We performed a method comparison between the SPLC-MS/MS and HPLC methods for vitamin A and E by measuring patient specimens across the concentration range 11–81 µg/dL for vitamin A and 1–18 mg/L for vitamin E. The analysis times on each platform were also compared.
SPLC-MS/MS and HPLC methods were comparable with regards to analytical performance; mean bias across the measured range was 2.54% (95% CL: −11.56–16.64%) for vitamin A and −2.04% (95% CL: −18.20–14.12%) for vitamin E. Total analysis times were 7 min and 15 min for SPLC-MS/MS and HPLC respectively.
The development of a simplified sample preparation protocol and the use of multiplexing SPLC-MS/MS have reduced sample analysis times for vitamin A and E. This method has also optimized clinical workflow through consolidation of previously independent benches.
Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker that produces prolonged local anesthesia in animals and humans. Under a Food and Drug Administration-approved phase 1 Investigational New Drug ...trial, the authors evaluated safety and efficacy of NeoSTX alone and combined with 0.2% bupivacaine (Bup) with and without epinephrine.
The authors conducted a double-blind, randomized, controlled trial involving healthy male volunteers aged 18 to 35 yr receiving two 10-ml subcutaneous injections. Control sites received Bup. In part 1, active sites received (1) 5 to 40 μg NeoSTX+Saline (NeoSTX-Saline), (2) 5 to 40 μg NeoSTX+Bup (NeoSTX-Bup), or (3) placebo (Saline). In part 2, active sites received 10 or 30 μg NeoSTX+Bup+Epinephrine (NeoSTX-Bup-Epi) or placebo. Primary outcome measures were safety and adverse events associated with NeoSTX. Secondary outcomes included clinical biochemistry, NeoSTX pharmacokinetics, and cutaneous hypoesthesia.
A total of 84 subjects were randomized and completed the two-part trial with no serious adverse events or clinically significant physiologic impairments. Perioral numbness and tingling increased with NeoSTX dose for NeoSTX-Saline and NeoSTX-Bup. All symptoms resolved without intervention. NeoSTX-Bup-Epi dramatically reduced symptoms compared with other NeoSTX combinations (tingling: 0 vs. 70%, P = 0.004; numbness: 0 vs. 60%, P = 0.013) at the same dose. Mean peak plasma NeoSTX concentration for NeoSTX-Bup-Epi was reduced at least two-fold compared with NeoSTX-Saline and NeoSTX-Bup (67 ± 14, 134 ± 63, and 164 ± 81 pg/ml, respectively; P = 0.016). NeoSTX-Bup showed prolonged cutaneous block duration compared with Bup, NeoSTX-Saline, or placebo, at all doses. Median time to near-complete recovery for 10 μg NeoSTX-Bup-Epi was almost five-fold longer compared with Bup (50 vs. 10 h, P = 0.007).
NeoSTX combinations have a tolerable side effect profile and appear promising for prolonged local anesthesia.
A better understanding of how poverty-related hardships affect child health could highlight remediable intervention targets. Tobacco smoke exposure may be 1 such consequence of family hardship. Our ...objective was to explore the relationship between family hardships and tobacco exposure, as measured by serum cotinine, a tobacco metabolite, among children hospitalized for asthma.
We prospectively enrolled a cohort of 774 children, aged 1 to 16 years, admitted for asthma or bronchodilator-responsive wheezing. The primary outcome was detectable serum cotinine. We assessed family hardships, including 11 financial and social variables, through a survey of the child's caregiver. We used logistic regression to evaluate associations between family hardship and detectable cotinine.
We had complete study data for 675 children; 57% were African American, and 74% were enrolled in Medicaid. In total, 56% of children had detectable cotinine. More than 80% of families reported ≥ 1 hardship, and 41% reported ≥ 4 hardships. Greater numbers of hardships were associated with greater odds of having detectable cotinine. Compared with children in families with no hardships, those in families with ≥ 4 hardships had 3.7-fold (95% confidence interval, 2.0-7.0) greater odds of having detectable serum cotinine in adjusted analyses. Lower parental income and educational attainment were also independently associated with detectable serum cotinine.
Family hardships are prevalent and associated with detectable serum cotinine level among children with asthma. Family hardships and tobacco smoke exposure may be possible targets for interventions to reduce health disparities.
•Neosaxitoxin has shown potential as an effective, long-acting, anesthetic.•We have developed a sensitive method for measurement of neosaxitoxin in plasma LC–MS/MS.•We have demonstrated the ...application of our method to a pharmacokinetic study.
Neosaxitoxin, a member of the saxitoxin family of paralytic shellfish poisoning toxins, has shown potential as an effective, long-acting, anesthetic. We describe the development and validation of a highly sensitive method for measurement of neosaxitoxin in human plasma using liquid chromatography tandem mass spectrometry (LC–MS/MS) and provide evidence for its use in a human pharmacokinetic study. Samples were prepared using cation exchange solid phase extraction followed by hydrophilic interaction liquid chromatography and MS/MS detection in positive electrospray ionization mode. Multiple reaction monitoring was used to monitor neosaxitoxin (m/z 316.17>220.07) and the internal standard analogue decarbamoylneosaxitoxin (m/z 273.12>180.00). The method was validated for lower limit of quantification, precision, accuracy, linearity and matrix effect. The stability of neosaxitoxin in plasma matrix at various storage conditions was also investigated. Standard curves for calibration were linear (r>0.995) across the assay calibration range, 10 to 1000pg/mL. The analytical measurable range of the assay was 10–10,000pg/mL in plasma matrix. This method has demonstrated excellent sensitivity demonstrating a lower limit of quantification in human plasma of 10pg/mL. The mean, inter-batch variation was <5.2% across the concentration range 30 to 800pg/mL. This method was successfully used in a phase 1 trial to investigate the pharmacokinetic profile of neosaxitoxin in humans following the intravenous administration of the drug at a range of doses up to 40μg. We conclude that our high-sensitivity method for measurement of neosaxitoxin in human plasma is capable of supporting future clinical trials.
PDF
