Researchers from Ann & Robert H. Lurie Children’s Hospital of Chicago and colleagues analyzed data using Emergency Medical Services (EMS) encounters from January 2018 to December 2022. They found that opioid overdoses in youth increased at pandemic onset and remained elevated compared to pre-pandemic levels. The majority (86 percent) occurred in young adults in the 18-24 age group. Adolescents aged 12-17, however, also emerged as high-risk, with significantly increasing trends both before and during the pandemic. Most of the opioid overdoses in youth (58 percent) happened at home.

“Since so many overdoses occur at home, a critical message for parents of youth, especially adolescents, is to keep naloxone, an over-the-counter medication that can reverse opioid overdoses, at home,” said lead author Jamie Lim, MD, a third-year fellow in Pediatric Emergency Medicine at Lurie Children’s. “Providers also need to screen youth for substance use and risk of opioid overdose, since it is clearly a growing concern among young people. Parents and patients need to be advised that fentanyl is now in a lot of street drugs too and can lead to accidental overdoses.”

Senior author and attending physician from Boston Children’s Hospital’s Division of Emergency Medicine, Michael Toce, MD, expands on the broader impact of the findings: “Evaluating prehospital data for opioid overdose among U.S. youth may provide crucial insights into the opioid epidemic outside of emergency department surveillance data. Although overdose rates have stabilized post-pandemic, it’s important to understand at-risk youth populations to develop better-targeted prevention strategies and inform future public health measures.”

Co-authors from Lurie Children’s include Sriram Ramgopal, MD, and Jennifer Hoffmann, MD, MS.

Several approaches have been studied to reduce the amount of Sm reagents to catalytic amounts. However, most of the currently available methods require harsh conditions and highly reactive reducing agents and still require significant amounts of Sm, typically 10-20% of the raw materials. Considering the high cost of Sm, there is a significant demand for an efficient catalyst system that uses minimal Sm under mild conditions.

In a recent breakthrough, a research team from Chiba University in Japan, led by Assistant Professor Takahito Kuribara from the Institute for Advanced Academic Research and the Graduate School of Pharmaceutical Sciences, developed an innovative method that significantly reduces the amount of Sm. The team developed a 9,10-diphenyl anthracene (DPA)-substituted bidentate phosphine oxide ligand for coordination to trivalent samarium, enabling the use of visible light to facilitate Sm-catalyzed reductive transformations. They call this ligand a visible-light antenna. Assistant Professor Kuribara explains, “Antenna ligands are known to help in the excitation of lanthanoid metals like Sm. Previously, we reported a DPA-substituted secondary phosphine oxide ligand capable of reduction-oxidation reactions under visible light. Inspired by this, we designed a new DPA-substituted bidentate phosphine oxide ligand that uses visible light to reduce the amount of Sm to a catalytic level.”

The team included Ayahito Kaneki, Yu Matsuda, and Tetsuhiro Nemoto from the Graduate School of Pharmaceutical Sciences at Chiba University. Their study was made available online on July 20, 2024, and published in Volume 146, Issue 30 of the Journal of the American Chemical Society on July 31, 2024.

Through a series of experiments, the research team showed that using the Sm catalyst in combination with DPA-1 under blue-light irradiation produced high yields of up to 98% for pinacol coupling reactions of aldehydes and ketones, which are commonly used in pharmaceuticals. Remarkably, these reactions could proceed with only 1-2 mol% of the Sm catalyst, a significant reduction compared to the stoichiometric amounts typically required. Furthermore, the reactions could proceed even with mild organic reducing agents like amines, in contrast to the highly reducing agents previously used.

The results showed that the addition of a small amount of water improved yields, while excess water inhibited the reaction. In comparison, DPA-2 and DPA, which have similar structures to DPA-1, yielded poor results.

To understand why DPA-1 was so effective, the researchers studied the emission characteristics of the Sm catalyst and DPA-1 combination. They found that DPA-1, with its visible-light antenna, functions as a multifunctional ligand that coordinates with Sm, selectively absorbs blue light, and efficiently transfers electrons from the antenna to Sm.

The researchers successfully applied the Sm catalyst and DPA-1 combination to various molecular transformation reactions, including carbon-carbon bond formation and carbon-oxygen and carbon-carbon bond cleavage, which are crucial for drug development. Moreover, by utilizing visible light as an energy source, they also achieved molecular transformations that combined Sm-based reduction with photo-oxidation.

“Our new visible-light antenna ligand reduced the amount of Sm to 1-2 mol%, a significant decrease compared to the stoichiometric amounts typically required, by utilizing low-energy visible light,” remarks Assistant Professor Kuribara. Adding further, he says, “Importantly, we were able to use trivalent Sm as the starting material, which is more stable and easier to handle as compared to divalent Sm.”

Overall, this study provides valuable insights for further development and design of Sm-based catalysts, marking a significant step forward in organic chemistry by enabling efficient Sm-catalyzed reductive transformations under mild conditions with minimal Sm loading.

The study, published in the journal Cell, reveals that respiratory complex I, the first enzyme of the mitochondrial electron transport chain, possesses a hitherto unknown sodium transport activity that is crucial for efficient cellular energy production.

The discovery of this activity provides a molecular explanation for the origin of the neurodegenerative disease Leber’s hereditary optic neuropathy (LHON). First described in 1988, LHON is linked to defects in mitochondrial DNA and is the most frequent mitochondrially inherited disease in the world. The new study shows that the hereditary optic neuropathy in LHON is caused by a specific defect in the transport of sodium and protons by complex I.

According to the chemiosmotic hypothesis, mitochondrial synthesis of ATP — the main source of cellular energy — is driven by an electrochemical gradient of protons across the inner mitochondrial membrane. The hypothesis was first proposed by Peter Mitchell in 1961 and won him a Nobel Prize in 1978. But since then, the model has remained substantially unchanged. Now, the results of the new study show that this process also involves the transport of sodium ions, a possibility not considered before.

Led by CNIC scientists José Antonio Enríquez and Pablo Hernansanz, the research team used an array of mutants and diverse genetic models to demonstrate that mitochondrial complex I exchanges sodium ions for protons, thus generating a gradient of sodium ions that parallels the proton gradient. This sodium gradient accounts for as much as half of the mitochondrial membrane potential and is essential for ATP production.

Dr. Enríquez explained that, “Sodium-proton transport activity was lost when we eliminated complex I in mice, but was maintained when we eliminated complex III or complex IV, confirming that sodium-proton transport is directly affected by the lack of complex I function.” Through these experiments, the researchers were able to demonstrate that while the two complex I functions (hydrogenase activity and sodium-proton transport) are independent of each other, both are essential for cell function.

Pablo Hernansanz commented that, “Our results demonstrate that mitochondria have a sodium-ion reservoir that is essential for their function and for resisting cellular stress,” while José Antonio Enríquez emphasized that the regulation of this mechanism is an essential feature of mammalian biology.

Discussing possible treatments for LHON, José Antonio Enríquez commented that while drugs are available that successfully replicate sodium transport across the inner membrane of isolated mitochondria, clinical use of these drugs is hindered by their toxic secondary effects on sodium transport in the cell membrane. “The challenge now is to design drugs that act specifically in mitochondria without effecting other parts of the cell,” said Dr. Enríquez.

The researchers also believe that defects in sodium-proton transport may play a role in other, more frequent neurodegenerative diseases such as Parkinson’s, in which an involvement of complex I has been detected.