An unexpected degradation pathway of N-hydroxy-5-methylfuran-2-sulfonamide (BMS-986231), a pH sensitive prodrug of HNO, in a prototype formulation solution.

N-hydroxy-5-methylfuran-2-sulfonamide (BMS-986231, Cimlanod) was being developed as a pH-sensitive prodrug of HNO (nitroxyl) for the treatment of acute decompensated heart failure. During a stressed study of Cimlanod in a prototype formulation solution (pH 4.5) at 40°C, a predominant unknown degradant along with three previously identified degradants were observed.

A programmatic update on COVID-19 vaccination in rural communities in the United States.

When public health experts think of rural barriers to vaccines, they often initially focus on access, which makes sense with a new vaccine during a pandemic. This commentary highlights that there can be more complexity to vaccine uptake in rural communities. What follows are some examples of CDC's efforts to better understand rural health and learnings to inform ongoing vaccination efforts in rural communities.

Teaching, Learning, and Climate Change: Anticipated Impacts and Mitigation Strategies for Educators.

The impacts of climate change present numerous risks to the present and future state of teaching and learning. Natural disasters such as hurricanes, heat waves, flooding, blizzards, wildfires, sea level rise, and droughts threaten our ability to produce the learning outcomes promised to our pupils. Taking action to adapt to imminent climate-related challenges and mitigating measures that provoke and prolong ecological challenges is critical to the survival of these cultural institutions.

Overcoming NMR line broadening of nitrogen containing compounds: A simple solution.

This study presents a straightforward solution to the challenge of elucidating the structures of nitrogen containing compounds undergoing isomerization. When spectral line broadening occurs related to isomerization, be it prototropic tautomerism or bond rotations, this poses a significant obstacle to structural elucidation. By adding acids, we demonstrate a simple approach to overcome this issue and effectively sharpen NMR signals for acid stable prototropic tautomers as well as the conformational isomers containing a morpholine or piperazine ring.

Investigation of Unusual -(Triphenyl-λ-phosphanylidene) Amide Fragmentation Observed upon MS/MS Collision-Induced Dissociation.

A mechanism of unusual tandem (MS/MS) fragmentation of protonated species of -(triphenyl-λ-phosphanylidene) derivatives, [M + H] to generate triphenylphosphine oxide (TPPO) within the mass spectrometer has been investigated and reported. Collision-induced dissociation of these molecules resulted in the generation of TPPO as a signature fragment. This fragment suggested the presence of a P-O bond in the structure which was contrary to the structure of the compound identified by nuclear magnetic resonance spectrometry (NMR) and single-crystal X-ray diffractometry (SXRD) techniques with a P═N bond rather than a P-O bond.

NMR spectroscopy as a characterization tool enabling biologics formulation development.

This review highlights recent advancements in using high resolution nuclear magnetic resonance (NMR) spectroscopy as a characterization tool to expedite biologics formulation development, meeting a current need in the biopharmaceutical industry. Conformational changes of protein therapeutics during formulation development can result in various protein-protein and protein-excipient interactions, which can lead to physical aggregation and/or chemical degradation. Innovative analytical techniques that allow studying protein integrity with high specificity during formulation development are urgently needed in order to assess protein formulation stability and mitigate product quality risks.

Addressing Racial Disparities in Pregnancy-Related Deaths: An Analysis of Maternal Mortality-Related Federal Legislation, 2017-2021.

There has been increasing national attention to the issue of racial disparities in pregnancy-related deaths. Federal legislation can support approaches at multiple levels of intervention to improve maternal health. As part of the CDC Policy Academy, a team of CDC staff completed a policy analysis to determine the approaches addressed in federal legislation to reduce racial disparities in pregnancy-related deaths.

Circumventing glass vial and diluent effects on solution stability of small molecule analytes during analytical method development and validation.

Solution stability of analytes plays an important part in qualitative analysis, especially in conducting accurate, quantitative analyses. Sample diluents and glass vials as sample containers for HPLC analyses can play a critical role and should be evaluated during chromatographic method development. We have encountered several instances during pharmaceutical development where the glass vial/diluent combination has negatively impacted method performance.

Procedures for determining and then modifying the extinction component of multiple schedules for destructive behavior.

As a component of reinforcer schedule thinning following functional communication training, multiple schedules of reinforcement produce desirable rates and patterns of communication responses as an alternative response to destructive behavior. However, reinforcement schedule thinning is a gradual process that can take many sessions to obtain therapeutic goals. The desired outcome is that manding occurs only during signaled intervals of reinforcement with a sufficiently lean terminal schedule of reinforcement availability and low rates of destructive behavior.

Hypoxemia in Young Children Undergoing One-lung Ventilation: A Retrospective Cohort Study.

Background: One-lung ventilation in children remains a specialized practice with low case numbers even at tertiary centers, preventing an assessment of best practices. The authors hypothesized that certain case factors may be associated with a higher risk of intraprocedural hypoxemia in children undergoing thoracic surgery and one-lung ventilation.

Methods: The Multicenter Perioperative Outcomes database and a local quality improvement database were queried for documentation of one-lung ventilation in children 2 months to 3 yr of age inclusive between 2010 and 2020.

Characterizing and understanding the formation of cysteine conjugates and other by-products in a random, lysine-linked antibody drug conjugate.

This study describes the characterization of conjugation sites for a random, lysine conjugated 2-iminothiolane (2-IT) based antibody-drug-conjugate synthesized from an IgG1 antibody and a duocarmycin analog-based payload-linker. Of the 80 putative lysine sites, 78 were found to be conjugated via tryptic peptide mapping and LC-HRMS. Surprisingly, seven cysteine-linked conjugated peptides were also detected resulting from the conjugation of cysteine residues derived from the four inter-chain disulfide bonds during the reaction.

Preoperative Risk and the Association between Hypotension and Postoperative Acute Kidney Injury.

Background: Despite the significant healthcare impact of acute kidney injury, little is known regarding prevention. Single-center data have implicated hypotension in developing postoperative acute kidney injury. The generalizability of this finding and the interaction between hypotension and baseline patient disease burden remain unknown.

Forced Oxidative Degradation Pathways of the Imidazole Moiety of Daclatasvir.

Daclatasvir hydrochloride (DCV) is the active pharmaceutical ingredient of Daklinza, a marketed product for the treatment of hepatitis C viral infection. The intrinsic stability of daclatasvir was evaluated via a forced degradation study. DCV was found to be stable in the solid state.

Oxidative degradation pathways of beclabuvir hydrochloride mediated by hydrogen peroxide and UV/Vis light.

Beclabuvir hydrochloride (BCV) is a marketed product for the treatment of hepatitis C viral infection. It contains functional groups such as indole, tertiary amine and amides. Forced degradation studies of BCV revealed different degradation profiles under photo and hydrogen peroxide oxidative conditions.

Deuterated active pharmaceutical ingredients: A science-based proposal for synthesis, analysis, and control. Part 1: Framing the problem.

The International Consortium for Innovation & Quality (IQ) in Pharmaceutical Development recently established a working group focused on the development of a guidance to address Deuterated Active Pharmaceutical Ingredients. Deuteration of an Active Pharmaceutical Ingredient (API) in some cases can retard and/or alter API metabolism by exploiting the primary kinetic isotope effect. Several deuterated APIs have entered into the clinic, and one has recently been approved.

Succinylcholine Use and Dantrolene Availability for Malignant Hyperthermia Treatment: Database Analyses and Systematic Review.

Background: Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality.

Improving Mass Spectral Quality of Monoclonal Antibody Middle-Up LC-MS Analysis by Shifting the Protein Charge State Distribution.

Monoclonal antibodies (mAbs) are experiencing accelerated development in the pharmaceutical industry. Utilization of middle-up LC-MS methodology can provide detailed characterization of mAbs via reduction and/or enzymatic cleavage of the mAb into smaller protein fragments. However, under typical LC-MS conditions, these fragments, especially the more heterogeneous heavy chain, can present charge state distributions (CSD) featuring a severe interference in the low mass-to-charge (m/z) region in the mass spectrum, adversely impacting spectral quality of these proteins and ultimately the deconvoluted mass spectrum.

$1.8 Million and counting: how volatile agent education has decreased our spending $1000 per day.

Study Objective: Volatile anesthetic agents comprise a substantial portion of every hospital's pharmacy budget. Challenged with an initiative to lower anesthetic drug expenditures, we developed an education-based intervention focused on reducing volatile anesthetic costs while preserving access to all available volatile anesthetics. When postintervention evaluation demonstrated a dramatic year-over-year reduction in volatile agent acquisition costs, we undertook a retrospective analysis of volatile anesthetic purchasing data using time series analysis to determine the impact of our educational initiative.

Structural characterization of low level degradants in aztreonam injection and an innovative approach to aid HPLC method validation.

Three new degradants have been identified from drug product and active pharmaceutical ingredient stability samples of aztreonam, a marketed synthetic monocyclic beta-lactam antibiotic. The degradants were detected following the implementation of a new, more selective HPLC method for the determination of impurities and degradants. The new method was developed in response to changes in the regulatory requirement for mature products.

Multiple schedules in practical application: Research trends and implications for future investigation.

Researchers began studying multiple schedules in basic laboratories, but recent advances have extended research on multiple schedules to a wide variety of socially significant applications, especially during the last decade. Applied researchers have used multiple schedules to (a) promote stimulus control over high-rate appropriate behaviors, (b) thin the schedule of reinforcement following functional communication training, and (c) obtain stimulus control over problem behaviors maintained by automatic reinforcement. In the current paper, we reviewed 31 studies with 147 applications identified through a search of the applied literature on multiple schedules.

Investigation of Air-Liquid Interface Rings in Buffer Preparation Vessels: the Role of Slip Agents.

Unlabelled: Air-liquid interface rings were observed on the side walls of stainless steel buffer vessels after certain downstream buffer preparations. Those rings were resistant to regular cleaning-in-place procedures but could be removed by manual means. To investigate the root cause of this issue, multiple analytical techniques, including liquid chromatography with tandem mass spectrometry detection (LC-MS/MS), high-resolution accurate mass liquid chromatography with mass spectrometry, nuclear magnetic resonance, Fourier transform infrared spectroscopy, and scanning electron microscopy with energy-dispersive X-ray spectroscopy have been employed to characterize the chemical composition of air-liquid interface rings.

Do mirrors facilitate acquisition of motor imitation in children diagnosed with autism?

We evaluated the efficacy of a procedure that incorporated a mirror to teach gross motor imitation with a 2-year-old boy who had been diagnosed with autistic disorder. Responses taught with a mirror were acquired more quickly than responses taught without the mirror and were maintained after the mirror was removed. These data indicate that a mirror can facilitate acquisition of motor imitation.

Trace level liquid chromatography tandem mass spectrometry quantification of the mutagenic impurity 2-hydroxypyridine N-oxide as its dansyl derivative.

A derivatization LC-MS/MS method was developed and qualified for the trace level quantification of 2-hydroxypyridine N-oxide (HOPO). HOPO is a coupling reagent used in the syntheses of active pharmaceutical ingredients (APIs) to form amide bonds. HOPO was recently confirmed to generate a positive response in a GLP Ames bacterial-reverse-mutation test, classifying it as a mutagenic impurity and as such requiring its control in APIs to the threshold of toxicological concern (TTC).

State-based Medicaid costs for pediatric asthma emergency department visits.

Introduction: The prevalence of childhood asthma in the United States increased from 8.7% in 2001 to 9.5% in 2011.