Identification of synthetic cathinone positional isomers using electron activated dissociation mass spectrometry.

BACKGROUND: Synthetic cathinones (SCs) are a large category of new psychoactive substances (NPS), which pose a serious threat to public health due to limited information about their toxicology and pharmacology. Many SCs are closely related in their chemical structures, with some substances being positional isomers. In this study, we propose a new workflow for the identification of SC isomers using liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS2) combined with electron activated dissociation (EAD) and chemometrics. Differentiation between isomeric SCs is essential for both legislative and public safety reasons, since minor differences in their molecular structures may change their legal status and pharmacological profiles. RESULTS: The workflow was optimized using ring-substituted isomers of methylmethcathinones, methylethcathinones, and chloromethcathinones. The kinetic energy in the EAD cell was investigated at three levels (i.e., 15, 18, and 20 eV) for each group. Two data analysis methods (i.e., t-distributed stochastic neighbor embedding [t-SNE] and a Random Forest [RF] algorithm) were applied using the obtained EAD mass spectral data. The three sets of ring-substituted SCs were clearly distinguished using t-SNE and an RF algorithm. Moreover, the RF approach resulted in a 97 % classification accuracy for isomer identification using various combinations of compounds, isomers, and electron kinetic energies. This workflow was subsequentially applied to the analysis of 26 blind street samples, resulting in a 92 % classification accuracy for isomer identification. However, the accuracy varied based on the kinetic electron energy. A subset of the original data set, focusing on 15-eV data only, was used, resulting in a classification accuracy of 100 %. SIGNIFICANCE: This study presents the first LC-HRMS2 workflow based on EAD and chemometrics, which resulted in a classification accuracy of 100 % of authentic street samples. The developed LC-HRMS2 workflow demonstrates that EAD product ions and their characteristic ion ratios can be successfully used to identify ring-substituted positional isomers of SCs.

Healthcare providers' use of a concise summary to prescribe for lactating patients.

BACKGROUND: Most breastfeeding individuals take at least one prescription drug, yet limited data from lactation studies are available to inform the safety of these drugs during breastfeeding. As a result, healthcare providers (HCPs) rely on available information about safety of drugs used during pregnancy or on personal experiences to inform prescribing/counseling decisions for breastfeeding individuals. To improve risk communication regarding drugs used during lactation, the U.S. Food and Drug Administration published the Pregnancy and Lactation Labeling Rule (PLLR) in 2015, which added a narrative summary of available risk information to the lactation section of Prescribing Information (PI). Prior studies on labeling in PLLR format revealed that although HCPs found these details valuable, they regarded the narrative as too long to support decision-making during patient encounters. OBJECTIVE: This qualitative study's objective was to assess the utility of adding a concise summary to the Lactation subsection of PI to complement the narrative and succinctly communicate to busy HCPs a drug's risks when used during lactation. The concise summary consisted of a bolded headline, bulleted descriptions of available study findings and potential adverse reactions, and recommendations for risk mitigation. METHODS: Twenty-five online focus groups were conducted with five segments of HCPs to obtain their feedback on the concise summary and discuss their prescribing/counseling decisions for four fictitious prescription drugs including one vaccine. RESULTS: HCPs utilized the concise summary to make initial prescribing/counseling decisions. Many also used the labeling narrative for a comprehensive benefit-risk assessment. CONCLUSION: The findings indicate a need to continue to improve communication about safety of drugs used during lactation, and that the concise summary may help facilitate this communication. The study also highlights the need to educate HCPs about PI limitations when clinical data are lacking and the need to encourage clinical studies to be conducted to support actionable recommendations about use of prescription drugs during lactation.

Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM.

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.