The organic cation/carnitine transporters OCTN1 and OCTN2 are related to other organic cation transporters (OCT1, OCT2, and OCT3) known for transporting oxaliplatin, an anticancer drug with dose-limiting neurotoxicity. In this study, we sought to determine whether OCTN1 and OCTN2 also transported oxaliplatin and to characterize their functional expression and contributions to its neuronal accumulation and neurotoxicity in dorsal root ganglion (DRG) neurons relative to those of OCTs. [ 14 C]Oxaliplatin uptake, platinum accumulation, and cytotoxicity were determined in OCTN-overexpressing human embryonic kidney (HEK) 293 cells and primary cultures of rat DRG neurons. Levels of mRNA and functional activities of rat (r)Octns and rOcts in rat DRG tissue and primary cultures were characterized using reverse transcription-polymerase chain reaction and uptake of model OCT/OCTN substrates, including [ showed increased uptake and cytotoxicity of oxaliplatin compared with mock-transfected HEK293 controls; in addition, both uptake and cytotoxicity were inhibited by ergothioneine and L-carnitine. The uptake of ergothioneine mediated by OCTN1 and of L-carnitine mediated by OCTN2 was decreased during oxaliplatin exposure. rOctn1 and rOctn2 mRNA was readily detected in rat DRG tissue, and they were functionally active in cultured rat DRG neurons, more so than rOct1, rOct2, or rOct3. DRG neuronal accumulation of [ 14 C]oxaliplatin and platinum during oxaliplatin exposure depended on time, concentration, temperature, and sodium and was inhibited by ergothioneine and to a lesser extent by L-carnitine but not by MPP ϩ . Loss of DRG neuronal viability during oxaliplatin exposure was inhibited by ergothioneine but not by L-carnitine or MPP ϩ . OCTN1 and OCTN2 both transport oxaliplatin and are functionally expressed by DRG neurons. OCTN1-mediated transport of oxaliplatin appears to contribute to its neuronal accumulation and treatmentlimiting neurotoxicity more so than OCTN2 or OCTs.

Introduction: Self-harm presentations in children and young people have increased internationally over the last decade. The COVID-19 pandemic has the potential to worsen these trends. Objective: To describe trends in emergency department self-harm or suicidal ideation presentations for children and young people in New South Wales before and since the COVID-19 pandemic. Methods: We studied presentations for self-harm or suicidal ideation by 10- to 24-year-olds to New South Wales emergency departments, using interrupted time series analysis to compare annualised growth before COVID (2015 to February 2020) and since COVID (March 2020 to June 2021). Subgroup analyses compared age group, gender, triage category, rurality and disadvantage. Time series decomposition via generalised additive models identified long-term, seasonal and short-term trends. Results: Self-harm or suicidal ideation presentations by young people in New South Wales increased by 8.4% per annum pre-COVID. Growth accelerated since COVID, to 19.2% per annum, primarily due to increased presentations by females aged 13–17 years (47.1% per annum since COVID, from 290 per 10,000 in 2019 to 466 per 10,000 in 2021). Presentations in males aged 10–24 years did not increase since COVID (105.4 per 10,000 in 2019, 109.8 per 10,000 in 2021) despite growing 9.9% per annum before COVID. Presentation rates accelerated significantly in socio-economically advantaged areas. Presentations in children and adolescents were strongly linked to school semesters. Conclusion: Emergency department self-harm or suicidal ideation presentations by New South Wales young people grew steadily before COVID. Understanding the sustained increase remains a priority. Growth has increased since COVID particularly for adolescent females, but not among adolescent males. Surprisingly, the largest post-COVID increases in annual growth occurred in socio-economically advantaged and urban regions. The COVID-19 pandemic appears to have added new challenges, particularly in females in the developmentally critical early adolescent and teenage years.

CTR1 is preferentially expressed by a subset of DRG neurons that are particularly vulnerable to the toxicity of platinum drugs. These findings, together with its neuronal membrane localization, are suggestive of CTR1-related mechanisms of platinum drug neuronal uptake and neurotoxicity.

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