Type 2 diabetes is a heterogeneous, progressive chronic condition for which management has traditionally focused on glycaemic control and cardiovascular risk factors, rather than focusing on altering long-term disease trajectory. Increasing evidence indicates that progression and complications might be modifiable, but the absence of a core outcome set for disease modification limits trial design and intervention comparison. To address this gap, we developed a core outcome set for disease modification in type 2 diabetes through a modified Delphi process conducted according to COMET guidance. Candidate outcomes were identified from the literature and refined by an international multidisciplinary steering group comprising clinicians, researchers, and people living with type 2 diabetes. Across two Delphi rounds involving health-care professionals, researchers, and patients (round one n=233; round two n=79), agreement was reached for 35 outcomes spanning 11 domains. This framework aims to support outcome selection, consistency across trials, comparison of interventions, and evaluation of disease-modifying strategies in type 2 diabetes.

Dysregulation of the noradrenergic system has been implicated in the pathophysiology of schizophrenia. Although α2-adenergic receptor (α2-AR) agonists may alleviate positive symptoms, their effects on cognitive and negative symptoms remain controversial. This study aimed to characterize the dose-dependent effects of repeatedly administered α2A-AR agonist, guanfacine, on behavioral activity, cognition, and cerebral α2A-AR mRNA expression in male Long Evans rats and their schizophrenia-like substrain (Lisket). Animals received guanfacine (0.02; 0.1, and 0.5 mg/kg intraperitoneally) or vehicle for 11 days. Behavioral performance was assessed using the reward-based Ambitus test before treatment and during treatment (days 8-11). Guanfacine produced dose-dependent impairments following an inverted-U pattern in several exploration- and cognition-related parameters particularly in Lisket animals. However, guanfacine did not influence the number of collected rewards, attention-related parameters, reference memory, or overall data variability. Vehicle treated Lisket rats showed reduced α2A-AR mRNA expression in the prefrontal cortex and increased expression in the brainstem and a similar trend in the hippocampus compared with controls. Guanfacine produced region-specific effects, including decreased prefrontal and increased subcortical α2A-AR expression. These findings provide new insights into the expression of cerebral α2A-AR mRNA in a complex schizophrenia model and subsequent effects of guanfacine. They reveal that this compound has a detrimental or ineffective impact on behavioral outcomes. The results highlight the complexity of noradrenergic modulation in schizophrenia and suggest that α2A-AR agonist therapy alone is unlikely to alleviate cognitive or negative symptoms associated with the disorder. This emphasizes the need for more integrative therapeutic strategies that target multiple neuromodulator systems.

Acute heart failure (AHF) is a leading cause of hospitalisation worldwide, with the majority of cases triggered by an identifiable precipitant. Recognition of these precipitants is important for both acute management and long-term prevention, as they are frequently reversible, carry prognostic significance and directly inform targeted therapy. The epidemiology of precipitants varies across settings, and patterns are evolving as the prevalence of heart failure with preserved ejection fraction rises. In this review, we summarise the epidemiology, diagnostic evaluation and management of the most common precipitants of AHF. Globally, the leading precipitants of AHF are ischaemia/acute coronary syndrome, infection, arrhythmias, uncontrolled hypertension, nonadherence and renal dysfunction, although their relative distribution varies by geography and heart failure phenotype. Optimal medical management necessitates initial haemodynamic stabilisation, identification of the underlying precipitant and delivery of targeted therapy. Importantly, successful identification and treatment of a reversible precipitant should not preclude initiation or optimisation of guideline-directed medical therapy, which remain essential for long-term outcomes.

Several studies have supported Dr Gideon Koren’s 1993 landmark article, “Medications Which Can Kill a Toddler with One Tablet or Teaspoonful.” Although each study has its own merits, most focus solely on pediatric overdoses, and few provide an exhaustive reference list for real-time evaluation of ingestions in children and adults. The following xenobiotics warrant special attention because of their potential to cause serious outcomes, even after exposure to small volumes. This list does not imply that all pediatric exposures to these agents result in fatality, and the absence of a xenobiotic from this list does not indicate that it is necessarily safe. α1-Adrenergic agonists and imidazoline receptor agonists: Clonidine, guanfacine, naphazoline, oxymetazoline, tetrahydrozoline, xylazine (veterinary). Sulfonylureas: Chlorpropamide, glyburide, glipizide, glimepiride. Calcium channel blockers: Verapamil, diltiazem, nifedipine, amlodipine, nicardipine, nimodipine; β-Blockers: Metoprolol, labetalol, propranolol, sotalol. Tricyclic antidepressants: Imipramine, desipramine, amitriptyline, nortriptyline. Opioids: Codeine, hydrocodone, methadone, morphine, heroin. Antidiarrheals: Diphenoxylate plus atropine, loperamide. Salicylates and methyl salicylate: Oil of wintergreen, bismuth subsalicylate, mentholated balms, paramao or lawang root oil . Antipsychotics: Loxapine, thioridazine, chlorpromazine. Antimalarials: Chloroquine, hydroxychloroquine, quinine, primaquine. Antiarrhythmics: Quinidine, disopyramide, procainamide, flecainide, amiodarone. Camphor: A terpenoid used as an analgesic, antipruritic agent, and component of cooling gels, ointments, balms, mothballs, household fragrances, and essential oils. Oral camphor use occurs in some regions for religious ceremonies, traditional remedies, aphrodisiacs, or lactation suppression. Nonalkaloid toxic lignan: Podophyllin, podofilox. Unique plant toxins: Colchicine. Oral acetylcholinesterase inhibitors: Rivastigmine, donepezil, galantamine, carbamate pesticides. Methylxanthines: Theophylline, 1,3-dimethylxanthine, caffeine. Other opioids: Buprenorphine, fentanyl. Toxic alcohols: Methanol, ethylene glycol, diethylene glycol. Caustics and other household products: Acidic or alkaline household products, hydrofluoric acid, selenious acid, acetonitrile, methylene chloride. Accidental overdoses continue to occur regularly despite the implementation of various safety measures, including widespread public education, the use of childproof containers, and easy access to poison control centers. In the US, poison control centers receive more than 2.4 million calls annually, with more than 50% involving children younger than 6 years. Most pediatric accidental ingestions involve household cleaning products and analgesics, followed by cosmetics, foreign objects, and dietary supplements. Adult overdoses may be unintentional but often involve larger total doses or high-risk medications, including opioids and sedative-hypnotics. America's Poison Centers identify the 5 most common substance classes as analgesics, household cleaners, antidepressants, cosmetic or personal care items, and cardiovascular drugs. The number of ingestions involving cleaning products increased sharply during the COVID-19 pandemic but has since declined.

Tic disorders typically begin in childhood and often improve by adulthood, but some individuals continue to experience tic symptoms into adult life. Tic disorders frequently co-occur with Attention-deficit/hyperactivity disorder (ADHD), and in such cases α2-adrenergic agonists are recommended as a treatment as they can address both conditions. However, evidence in adults with ADHD and comorbid tic disorders is limited, as most studies have focused on pediatric populations. Here, we present three adult male patients with childhood-onset ADHD and chronic tic symptoms who showed a rapid and significant improvement in tics with low-dose extended-release guanfacine (GXR) monotherapy. These cases suggest that GXR can effectively treat both ADHD and tic symptoms in adults-a finding that has not been well documented in prior adult studies.

Heart failure (HF) clinical trials increasingly rely on diverse endpoints beyond mortality, including hospitalizations, imaging, hemodynamic status, biomarkers, functional capacity, and patient-reported outcomes. Although statistically significant differences between treatment groups are commonly reported, interpreting whether these changes are clinically meaningful for individual patients remains challenging. This JACC: Heart Failure position statement proposes a pragmatic framework for defining clinically meaningful within-patient change across commonly used HF outcomes by integrating measurement variability, prognostic associations, and patient-anchored evidence where available. Relative and absolute risk reductions should both inform interpretation of clinical events, while imaging, hemodynamic, biomarker, and functional measures require changes exceeding measurement variability and consideration of physiological context. Patient-reported health status measures, particularly the Kansas City Cardiomyopathy Questionnaire, currently have the strongest evidence supporting clinically meaningful thresholds. Many proposed cutpoints remain provisional, reflecting limited validation linking physiological changes to patient-perceived benefit or hard outcomes. Future work should prioritize anchor-based analyses and patient-centered validation to align trial results with shared decision-making.

Early-life stress (ELS), i.e., traumatic events during vulnerable developmental periods, adversely affects adult psychobiological outcomes, with dysregulated noradrenergic processing of trauma proposed to play a role. Guanfacine, a selective alpha-2A adrenergic receptor agonist that blunts noradrenergic signalling in mammals by activating the alpha-2A inhibitory autoreceptor, may be useful to attenuate the long-term consequences of ELS. The zebrafish (Danio rerio) is extensively used in stress research. Here, we investigated the immediate and long-term effects of a traumatic ELS procedure combined with control or guanfacine (20 µg/L) treatment in 264 juvenile zebrafish. Immediate assessments in 168 juveniles included anxiety-like and risk-taking behaviours using the light-dark test (LDT) and open field test (OFT). Long-term assessments in 96 fish raised to adulthood included anxiety-like behaviour using the novel tank test (NTT) and open field avoidance and aggressor-directed risk-taking behaviour in a novel OFT (nOFT). We found that traumatic stress exposure only modestly impacted the immediate anxiety-like behaviours of juvenile zebrafish, while guanfacine had distinct stress-dependent effects on behaviour. Guanfacine elicited anxiety-like behaviours under conditions of novelty (i.e., testing in the absence of a prior traumatic experience), but had the opposite effect and suppressed anxiety-like behaviours in trauma-exposed fish. Our results also showed that zebrafish exhibit a high degree of resilience to the long-term impact of traumatic stress, as neither traumatic stress exposure, nor guanfacine administration, affected anxiety-like or risk-taking behaviours in adulthood. These findings illustrate the presence of evolutionary conserved adaptive neurobiological mechanisms in zebrafish that may blunt the impact of traumatic events.