The European Medicines Agency and the UK Medicines and Healthcare products Regulatory Agency recently approved the first commercial preparation of low-concentration atropine, Ryjunea, for use in children aged 3 years and older to slow the progression of myopia. Whilst optical approaches have been available for several years, the addition of a pharmacological option will increase the involvement of ophthalmologists in paediatric myopia management. However, little information is available about implementation strategies in different European countries. We conducted an electronic/telephone survey with key opinion leaders in myopia management in Germany, the Netherlands, Denmark, the UK, France, Italy, and Spain. We complemented the survey with figures on population size reported by the World Bank and UNICEF, and workforce numbers reported by the International Council of Ophthalmology, the International Orthoptic Association, and national associations, where available. We collated data in categories reflecting the current provision of eye care for children and workforce availability. Prescribing rights for medicines, spectacles, and contact lenses for children, as well as workforce numbers, including paediatric ophthalmologists, optometrists, and orthoptists, vary significantly across European countries. In general, workforce numbers appear low compared with the number of children and young people in each country. Policies and implementation pathways for myopia management in children are required to ensure equitable access. European guidelines for training in myopia management and national pathways and standards of care should be developed and endorsed by professional organisations to enable children and young people at risk of myopia progression to access appropriate interventions in a timely and economical fashion.

In this study, novel terpenyl-cinnamoyl-hydrazone analogs were synthesized and evaluated for antinociceptive potential in preclinical nociception models. The compounds were tested in chemical (formalin-induced licking) and thermal (hot plate) assays in mice. Mechanistic studies employed naloxone (opioid receptor antagonist), atropine (muscarinic receptor antagonist), AM251 (CB1 receptor antagonist), yohimbine (α2-adrenergic receptor antagonist), and ondansetron (5-HT3 receptor antagonist). Most compounds displayed antinociceptive activity, with PQM-274, PQM-291, and PQM-294 showing greater effects than cannabidiol (CBD). Naloxone and AM251 reversed the effects of these three compounds. Atropine abolished PQM-291's effect, and ondansetron inhibited PQM-290's activity, whereas yohimbine produced no change. This study reports, for the first time, the antinociceptive properties of terpenyl-cinnamyl-N-acyl-hydrazones with structural features inspired by CBD, suggesting their potential as novel multitarget analgesic candidates.

Anticholinergic pharmacological agents are commonly misused because of their euphoric effects, increased energy, improved mood, and enhanced social interactions. Some herbal products with anticholinergic properties can also be abused for their psychoactive effects. One such ornamental plant is Brugmansia suaveolens, which contains alkaloids including atropine and scopolamine and can produce toxic effects. This case report describes a male patient with Brugmansia suaveolens abuse and coexisting multiple substance use disorders. The patient reported consuming a decoction of Brugmansia suaveolens leaves and flowers as a daily tea for four years to obtain relief. He experienced anticholinergic symptoms, including drowsiness, sedation, agitation, ataxia, dry mouth, palpitations, fever, and visual and auditory hallucinations while under the influence of the plant. The patient was discharged following a four-week treatment course. Plants like Brugmansia suaveolens, which have anticholinergic but toxic properties, may be misused, especially by individuals with a history of multiple substance use disorders.

Overactive bladder (OAB) is a highly prevalent condition characterized by urinary urgency that negatively affects quality of life. Because obesity and metabolic syndrome (MetS) are known as major risk factors for OAB, we explored the mechanisms underlying obesity-/MetS-associated OAB using a high-fat-diet (HFD)-induced obesity mouse model. Four-week-old male C57BL6 mice were subjected to either a HFD (60 kcal% fat) or a normal diet (ND, 10 kcal% fat). Cystometry and bladder afferent activity recordings in anaesthetized mice, isometric tension recordings in detrusor smooth muscle (DSM) strips and intravesical pressure recordings in isolated whole bladders were performed after 12 weeks of ND or HFD feeding. Bladder morphology was examined using histochemistry. HFD mice exhibited a MetS phenotype characterized by abdominal obesity, hyperglycaemia and insulin resistance. HFD mice developed enlarged non-voiding contractions (NVCs) during bladder filling associated with enhanced afferent activity. Both were attenuated by intravenous administration of atropine (1 mg/kg) or pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), a P2X purinoceptor antagonist (10 mg/kg), or by bilateral pelvic nerve transection. In ND mice these drugs attenuated NVCs but not afferent activity. Spontaneous or nerve-evoked DSM contractions or transient pressure increases in isolated whole bladders were unaltered in HFD mice. DSM thickness, collagen deposition or parasympathetic nerve density in HFD bladders was unaltered. Thus the OAB phenotype in HFD mice appears to primarily results from the increased parasympathetic neural activity during the bladder storage phase. These results provide the basis of the clinical effectiveness of anti-muscarinic agents on OAB as well as the enhanced purinergic transmission in OAB patients known as 'atropine resistance'. KEY POINTS: High-fat-diet (HFD)-induced obese mice exhibiting metabolic syndrome phenotype display overactive bladder (OAB) phenotype characterized by enlarged non-voiding contractions (NVCs) associated with bladder afferent overactivity. Both enlarged NVCs and afferent overactivity in HFD mice are reversed by intravenous administration of atropine or the P2X receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), or by bilateral pelvic nerve transection. Detrusor muscle strip contractility, corresponding spontaneous pressure increases in isolated whole bladder and bladder morphology are unaltered in HFD mice. The OAB phenotype in HFD-induced obese mice primarily results from excessive parasympathetic activity during the bladder storage phase. These findings provide a basis for the clinical effectiveness of anti-muscarinic drugs on bladder storage symptoms as well as the relevance of enhanced purinergic transmission in OAB patients known as 'atropine resistance'.

Fipronil is a widely detected phenylpyrazole insecticide in aquatic ecosystems that acts as a GABA receptor antagonist in arthropods, but its effects on vertebrate cardiorespiratory physiology are not well understood. In this study, we investigated whether environmentally relevant concentrations of fipronil (0.5 μg l[-1], 96 h) impair the cardiovascular and ventilatory responses of rainbow trout (Oncorhynchus mykiss) during aerobic exercise. Using dorsal aortic and buccal cannulations, we continuously recorded heart rate (fH), mean arterial pressure (MAP), ventilatory rate (fV) and amplitude (VAMP) before and after pharmacological blockades (autonomic blockades using atropine and propranolol, and a GABAergic blockade to simulate the effects of fipronil with bicuculline). Exposure to fipronil induced significant tachycardia (~35%), without affecting MAP or fV. It also increased intrinsic heart rate, even after double autonomic blockade, suggesting direct effects on cardiomyocytes. During exercise, contaminated fish exhibited impaired ventilatory amplitude and autonomic imbalance characterized by vagal withdrawal and sympathetic overdrive. Interestingly, the GABA antagonist bicuculline reproduced the tachycardic pattern observed in contaminated fish, suggesting that fipronil acts through GABAergic disruption of the neural centers involved in cardiac control. These sublethal impairments in autonomic regulation likely reduce the aerobic capacity and ecological resilience of fish in contaminated habitats. ENVIRONMENTAL IMPACT STATEMENT: This study demonstrates that acute exposure to the globally prevalent insecticide fipronil, at an environmentally relevant concentration, causes significant sublethal dysfunction in the neurophysiological control of cardiorespiratory systems in rainbow trout. By disrupting GABAergic signaling, fipronil compromises the integrated cardiovascular and ventilatory responses essential for sustaining aerobic exercise. These findings reveal a critical pathway through which pesticide pollution can impair physiological performance, thereby reducing the fitness and adaptive resilience of fish populations facing concurrent anthropogenic stressors such as climate change and habitat degradation. The results underscore the need to consider subtle, neurotoxic mechanisms in environmental risk assessments for aquatic ecosystems.

Background/Objectives: Stress echocardiography (SE) had been recommended by professional societies for assessing patients with suspected angina. SE protocols are variable across hospitals and countries in the recommendation of the cessation of rate-controlling medication (RCMx) prior to SE. Some expert opinion papers recommend the cessation of beta receptor blockers (BBs) and rate-controlling calcium channel blockers 48 h prior to SE to improve the diagnostic accuracy of the test. There is no evidence that the continuation of RCMx can affect the outcome of SE and short-term major adverse cardiovascular events (MACEs). To investigate the efficacy of Dobutamine SE in a cohort of patients where the cessation of rate-controlling medication has not been mandated, we reviewed our data over a one-year period in patients investigated for suspected coronary artery disease (CAD). Methods: A retrospective data analysis was performed on 227 consecutive patients who underwent Dobutamine SE between January 2022 and January 2023 in a single centre. In addition to dobutamine, the protocol allowed the administration of intravenous atropine (maximum dose of 1.2 mg) and a "top up" handgrip exercise at the discretion of the performing cardiologist. We assessed the Dobutamine SE outcome (positive vs. negative), target heart rate (THR, 85% of maximum age predicted), and the achieved peak HR in the two groups with RCMx and without RCMx. We analysed the patients' characteristics and 12-month outcomes of a combined MACE of death, non-fatal MI, stroke, admission with angina, and unplanned revascularisation. Results: Of the 227 patients, 61% were on No-RCMx (male 40%). Ninety-three percent of the patients on RCMx were on BB and 7% on other rate-controlling medications. The THR was achieved in 74% of the patients with-RCMx and 90% in the without-RCMx groups p = 0.0018. Positive Dobutamine SE was observed in 48% (43/89) of patients on RCMx vs. 28% (39/138) on No-RCMx (p = 0.0022). Patients who did not reach THR 43% (16/37) had positive Dobutamine SE compared to 35% (66/190) who reached THR (p = 0.626). There was no difference between groups in the peak WMSI. Logistic regression analysis showed that being on RCMx was independently associated with positive Dobutamine SE (OR 2.03, 95% CI 1.06-3.91, and p = 0.034). The MACE rate was higher in patients where the THR was not achieved (9/37, 24.0%) vs. where THR was achieved (9/190, 4.7%), p < 0.001, in both the with-RCMx (7/30, 23% vs. 6/66, 9.1%, p = 0.013) and without-RCMx (2/14, 14% vs. 3/124, 2.4%; p = 0.025) groups, respectively. RCMx was independently associated with MACE (OR 3.68, 95% CI 1.227-11.046, and p = 0.020). Conclusions: The use of RCMx proved to be a predictor of both SE and MACE outcomes irrespective of the achieved THR. Our data supports the practice that patients referred for Dobutamine SE on RCMx can continue taking them without impact on the test accuracy.

Atropine is an emerging therapy for myopia, yet the optimal concentration for prescription remains uncertain. We searched PubMed, Embase, Web of Science, Cochrane Library, World Health Organization International Clinical Trials, and ClinicalTrials.gov registry platforms. We included the randomized clinical trials (RCTs) that compared any dose of atropine against a placebo in myopic children. Among 3,566 studies assessed, we identified 33 eligible RCTs involving 6,301 children aged 4 to 18 years, with 10 different concentrations and a mean follow-up time of 19.5±12.3 months. A nonlinear relationship was observed between atropine dosage and treatment efficacy (P<0.001). Compared to placebo groups, the mean differences in reducing annual spherical equivalent refraction progression for atropine concentrations of 0.01%, 0.02%, 0.03%, 0.04%, and 0.05% were 0.21 D (95% CI, 0.13 to 0.28), 0.35 D (95% CI, 0.23 to 0.46), 0.42 D (95% CI, 0.28 to 0.56), 0.45 D (95% CI, 0.30 to 0.60), and 0.46 D (95% CI, 0.32 to 0.61) respectively For higher concentrations, the estimates were 0.49 D (95% CI, 0.34 to 0.63) for 0.1% and 0.99 D (95% CI, 0.66 to 1.31) for 1%, although these were based on fewer and smaller trials. Higher doses of atropine were associated with decreased amplitude of accommodation (P=0.02), increased pupil diameters (P=0.01) and a higher frequency of photophobia (P=0.02). Our findings suggest that the increase in treatment efficacy with higher concentrations may plateau beyond a certain range, and that the current practice of increasing atropine concentrations for children who show inadequate responses to lower doses should be confined to a specific concentration range. This analysis is limited by the number, design heterogeneity, and sample sizes of available trials for higher concentrations, and by the frequent lack of pre-intervention refractive history in included studies. Therefore, estimates-particularly for doses exceeding 0.1%-should be interpreted with caution.

The purpose of this study is to compare the safety and efficacy of different ketamine-based regimens for emergence pediatric procedural sedation. We searched PubMed, Scopus, and Web of Science for RCTs enrolling pediatric patients undergoing painful procedures in the emergency department. Studies comparing ketamine alone with ketamine combined with other sedatives or alternative agents were included. A frequentist random effects NMA was conducted using R (netmeta package). Results were expressed as mean differences (MD) or risk ratios (RR) with 95% confidence intervals, and treatments were ranked according to relative efficacy and safety. A total of 24 RCTs were included in this NMA. Using IV ketamine as the reference, IM ketamine was associated with longer sedation (MD + 19.6 min, 95% CI 17.5-21.6) and longer recovery times (MD + 37.7 min, 95% CI 1.6-73.8). Recovery time was extended even further when atropine was added to IM ketamine (MD + 73.5 min, 95% CI 10.9-136.1). IM ketamine was associated with less emergence reactions (RR = 0.38, 95% CI 0.20-0.69). Regarding the adverse events, IV ketamine and midazolam significantly raised the risk of hypoxia (RR = 4.71, 95% CI 1.05-21.08), whereas the combination of IV ketamine with propofol led to less nausea (RR = 0.34, 95% CI 0.17-0.68). In conclusion, across ketamine-based sedation regimens, IM administration achieved deeper and longer sedation but was accompanied by prolonged recovery. IV combinations offered faster recovery and fewer emetic events. Among these, ketamine combined with propofol provided the most balanced profile, maintaining sedation efficacy while minimizing nausea and hypoxia.