Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ’s ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling of target enhancers in inaccessible chromatin, whereas the PPARγ-LBD:RXR-DBD interface stabilizes the PPARγ:RXR:DNA ternary complex. Our data demonstrate how in-depth analyses of lipodystrophy mutants can unravel molecular mechanisms of PPARγ function.

The COVID-19 pandemic has been associated with a decline in mental health of adolescents. The aim of this study was to analyze the rate of deliberate self-poisonings (DSPs) among adolescents reported to the Dutch Poisons Information Center before and during the COVID-19 pandemic. A retrospective study from 2016 until 2021 was performed to characterize DSPs among adolescents, and to analyze trends in the number of DSPs. All DSPs among adolescents with the age of 13 up to and including 17 years were included. DSP characteristics included: age, gender, bodyweight, used substance, dose, and treatment advice. Trends in the number of DSPs were analyzed using time series decomposition and Seasonal Autoregressive Integrated Moving Average models. Six thousand nine hundred fifteen DSPs in adolescents were recorded from January first 2016 until December 31st 2021. Females were involved in 84% of adolescent DSPs. A strong increase in the number of DSPs was observed in 2021 (45% increase compared to 2020), which deviated from the predicted trend based on previous years. This increase was most prominent in 13-, 14-, and 15-year-old female adolescents. Commonly involved drugs were paracetamol, ibuprofen, methylphenidate, fluoxetine, and quetiapine. The contribution of paracetamol rose from 33% in 2019 to 40% in 2021. The strong increase in the number of DSPs during the second year of the COVID-19 pandemic suggests that long-term containment measures such as quarantines, lockdowns, and school closures may enhance self-harm behavior among adolescents, especially among younger females (13–15 years of age), with a preference for paracetamol as DSP substance.

In the past decade, the number of deliberate self-poisonings involving young people has increased strongly worldwide. This study aimed to gain insight into risk factors associated with deliberate self-poisonings among children and adolescents reported to the Dutch Poisons Information Center. A study was performed between 1 February 2022 and 31 January 2023 involving those aged 8-17 years of age with deliberate self-poisoning. Data were collected on patient characteristics (age, gender, body mass index and living situation) and exposure characteristics (type of toxicant, way of acquiring toxicant and day of exposure). The Dutch Poisons Information Center was consulted about 1,424 deliberate self-poisonings among children and adolescents (10-17 years old). A high percentage of patients were female (85 percent), had a body mass index classified as overweight/obese (27 percent) and lived in a mental healthcare facility (13 percent). Patients mainly exposed themselves to pharmaceuticals, especially over-the-counter medications such as paracetamol (46 percent) and ibuprofen (15 percent). Young people living with parents/caregivers had higher odds of ingesting prescription pharmaceuticals or over-the-counter medication, while those living in a mental healthcare facility were more likely to ingest household products, personal care products or foreign bodies (predominantly batteries). This study sheds light on the pervasive issue of deliberate self-poisoning among children and adolescents, advocating for poisoning prevention strategies and promoting mental health of youth. Limitations include reliance on self-reported data from patients and the absence of clinical outcome data. Female gender, a high body mass index and living in a mental healthcare facility are associated with in increased risk of deliberate self-poisonings in children and adolescents (10-17 years old). Prevention of deliberate self-poisonings among youth could focus on restricting access to medication and other potentially hazardous non-pharmaceuticals, such as household products and batteries, as well as limiting the sales of over-the-counter medication, especially paracetamol, to this young population.

The use of psychoactive drugs has been increasing worldwide, with adolescents and young adults accounting for a large share of people who use drugs. To date, there is limited information on trends of intoxications with psychoactive drugs among adolescents, particularly with regard to New Psychoactive Substances (NPS). A retrospective study was performed from 2014-2023 to characterize intoxications with psychoactive drugs among adolescents aged 13-17 years, reported to the Dutch Poisons Information Center (DPIC). Data were collected on patient (age and gender) and exposure characteristics (psychoactive drugs involved, day and month of exposure). From 2014-2023 the DPIC was consulted on 978 poisoning events among adolescents involving psychoactive drugs. A significant increase in the number of poisoning events was observed from 2014 to 2023 (RR = 1.14, 95 % CI: 1.11-1.16, p < 0.001). The largest increase was observed in the number of poisoning events with cannabis products (208 % increase, 2014: n = 13 vs. 2023: n = 40) (especially edibles), MDMA (100 % increase, 2014: n = 27 vs. 2023: n = 54) and 3-methylmethcathinone (3-MMC) (2014: n = 0, 2019: n = 2 vs. 2023: n = 24). There was also an increase in the variety of NPS the DPIC was consulted on, with 1 type of NPS reported in 2014 and 13 in 2023. In this study, a strong increase was observed in the number of intoxications with psychoactive drugs among adolescents from 2014-2023. The increase in intoxications with psychoactive drugs among adolescents, as well as the increase in the number of different types of NPS is worrying, since toxicity of especially NPS is often unknown. More education on the potential dangers along with upcoming legislative changes, might reverse this trend.

The synthesis of clandestine drugs is a widespread worldwide phenomenon, with clandestine drug laboratories occurring both in rural and urban areas. There is considerable unfamiliarity among medica...