Aims: To examine the level of vendor compliance with age-verification legislation governing alcohol sales in Cyprus across two repeated cross-sectional mystery shopping studies conducted in 2015 and 2024, and to identify factors influencing the likelihood of selling alcoholic beverages to underage-appearing individuals. Methods: In 2015, 200 purchase attempts were conducted across six venue types using paired student mystery shoppers. In 2024, 200 visits were conducted by individual mystery shoppers in comparable venue types, excluding nightclubs. In both studies, vendor responses were coded as: no age verification, verbal confirmation, or ID request. Descriptive statistics were computed, and logistic regression assessed venue and seller characteristics associated with vendor compliance. Results: In 2015, 94.5% of vendors sold alcohol without any verification, verbal confirmation was requested in 4.0%, and only 1.5% requested ID. Logistic regression showed that age verification was more likely with male buyers. In 2024, non-compliance remained high (85.5%), with verbal confirmation requested in 13.5% of visits, and ID requests at just 1%. Regression analyses showed higher compliance in bars than in kiosks, and female mystery shoppers were more often asked for age confirmation. Few vendors reported receiving training or legislative updates, with 22% recalling any regulatory updates and just 15% stating they had ever been formally informed about alcohol sales regulations. Compliance rates remain well below those reported in Northern and Western Europe, where structured inspection and vendor training are routine. Conclusions; Vendor compliance with age-verification laws in Cyprus remains persistently low. The findings highlight the need for systematic compliance monitoring, vendor education, and stronger enforcement policies, contributing to the broader European discussion on effective alcohol-control implementation.
This study used mystery shoppers to assess cannabis retail practices in 5 US states regulating legal nonmedical cannabis retail. This mystery shopper study assessed 130 cannabis retailers in 5 cities (Los Angeles [LA], California; Las Vegas [LV], Nevada; Denver, Colorado; Portland, Oregon; Seattle, Washington) in summer 2025. Researchers recorded: 1) age verification; and 2) retail staff responses to inquiries about: a) use for anxiety, sleep, pregnancy-related nausea, etc.; b) use-related risks/cautions; c) interstate cannabis transport; and d) availability of derived intoxicating cannabis products (DICPs) and 'mushrooms' (psilocybin). Mystery shoppers were asked for ID at 87.7% of retailers. When asked, most (>88%) retail staff responded that cannabis helps with anxiety and insomnia. While 40.8% warned against use for pregnancy-related nausea, 36.2% suggested it helps and 24.6% said it depends on the person/situation. Over half (58.5%) warned against driving post-use, but 50.0% said it depends (on person/situation). When asked about interstate transport, several indicated not to (42.3%) and/or it was illegal (39.2%); however, 44.6% indicated ways to pack cannabis to be undetectable, and 27.7% said not to worry about getting caught. Retail staff generally indicated DICPs are not as safe as delta-9 THC (27.7%) or are illegal (20.0%). The majority said mushrooms were illegal (67.7%), but 53.8% indicated they were easy to obtain, and 29.2% suggested their mental health benefits. Cannabis retailer frequently made prohibited health claims and minimized risks, reinforcing public health concerns and the need for ongoing cannabis retail surveillance and stronger regulatory oversight and enforcement.
Patients presented with jaundice and splenomegaly are easily diagnosed as having liver diseases. Actually, some atypical cases belong to hemolytic diseases leading to secondary hemochromatosis, which is easily misdiagnosed or never diagnosed. Here, we describe an atypical case in a 27 years old man presenting with unconjugated hyperbilirubinemia and splenomegaly since early childhood, who was hospitalized to check for any possible causes related to liver diseases. However, the probable etiology related to hemolytic diseases and liver disease was ruled out by negative traditional tests, which left a mystery to us. Fortunately, next-generation sequencing is becoming a suitable choice to determine the candidate genes responsible for rare or inherited disorders. A novel de novo mutation (c.5032delA) was firstly identified through whole exome sequencing which could induce an arginine to glycine substitution at residue 1678 (p.R1678Gfs*12), causing a premature termination codon in exon 38 of ANK1. ANK1 is involved in erythrocyte cytoskeleton formation, and contributes to one of the most common causes of hereditary spherocytosis (HS). Besides, homology-modeling analysis confirmed the loss-of-function of frameshift variant of ANK1 with bioinformatics methods. This work adds new knowledge in the etiology of hereditary spherocytosis. In addition, genetic testing can open up new perspectives for atypical and unknown diseases when traditional tests cannot be met.
A 73-year-old man with severe aortic stenosis and preexisting right bundle branch block (RBBB) underwent transcatheter aortic valve replacement. Postprocedural day 4 mobile cardiac outpatient telemetry revealed intermittent atrioventricular block. A 12-lead electrocardiogram obtained in the emergency department revealed PR interval alternans with RBBB, with longer PR following longer preceding RP intervals, and shorter PR following shorter RP intervals. He suddenly experienced cardiac arrest due to proximal atrioventricular block, requiring cardiopulmonary resuscitation. Inverse decremental conduction, known as Yan conduction, demonstrates an inverse relationship between conduction time and frequency of upstream stimulation. Inverse decremental conduction within the left bundle branch in the setting of RBBB may manifest as PR alternans, heralding proximal atrioventricular block.
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Clozapine remains an unparalleled antipsychotic nearly seven decades after its synthesis, distinguished by superior efficacy in treatment-resistant schizophrenia and a unique anti-suicidal effect, alongside a complex profile of adverse events and persistent underutilization. Traditional explanations based on receptor-binding broad variety and active metabolites fail to fully account for its singular clinical impact, particularly given that other compounds share similarly broad pharmacodynamics profiles without comparable efficacy. This editorial proposes that clozapine's three-dimensional molecular geometry represents a critical, yet underexplored, determinant of its biological activity. Beyond receptor affinity tables, clozapine's tricyclic dibenzazepine scaffold, subtle non-planarity, flexible substituents, and electronic distribution appear to enable qualitatively distinct interactions with neurotransmitter receptors, immune pathways, and intracellular signaling systems. Structural analyses seem to suggest that clozapine preferentially exploits less polar binding pockets and stabilizes unique receptor conformations, potentially facilitating biased signaling and modulation of receptor heteromers. These geometric properties may also underpin idiosyncratic immune-mediated adverse reactions, such as drug reaction with eosinophilia and systemic symptoms syndrome, linking therapeutic efficacy and toxicity through shared structural determinants. The overlap of clozapine's chemical scaffold with antiseizure medications and tricyclic antidepressants further supports the relevance of molecular architecture in shaping both pharmacological and immunological outcomes. Reframing clozapine as a structurally complex, biologically polyvalent molecule, rather than a collection of receptor targets, may resolve longstanding uncertainties surrounding its mechanism of action. Emphasizing molecular geometry may inform a new paradigm in psychiatric drug development, prioritizing structural complexity and multidimensional biological engagement over narrow target selectivity.
The pathophysiology of neurodegenerative illnesses is increasingly understood to be influenced by vascular aging, with blood-brain barrier (BBB) disruption emerging as a crucial mechanistic connection. Comprising endothelial cells, pericytes, astrocytes, and microglia, the BBB is a complex neurovascular unit (NVU) that strictly regulates molecular trafficking and shields neural tissue from circulating toxins and immune cells, therefore maintaining central nervous system homeostasis. The integrity of the BBB is compromised as people age due to structural and functional changes in the cerebrovasculature, such as endothelial senescence, pericyte loss, mitochondrial dysfunction, and persistent low-grade inflammation. These alterations speed up neuronal damage and encourage the development of classical proteinopathies like tau aggregation and amyloid-β by making it easier for neurotoxic proteins, immunological mediators, and metabolic waste to enter the brain parenchyma. BBB disruption is both an early occurrence and a factor in the development of neurodegenerative diseases including Alzheimer's disease, cerebral amyloid angiopathy, and vascular dementia. It exacerbates neuroinflammation, hinders clearance processes, and contributes to cognitive decline. Recent developments in single-cell omics, fluid biomarkers, and molecular imaging have made it possible to identify and characterize BBB failure in preclinical and clinical contexts, creating new opportunities for early diagnosis and treatment. Restoring BBB function and addressing vascular aging are two viable approaches to alter the course of neurodegenerative illnesses and enhance their prognoses. The processes, effects, and translational potential of vascular aging and BBB degradation in neurodegeneration are summarized in this review, which also identifies new treatment targets and research objectives for the future.
[This corrects the article DOI: 10.1002/hsr2.72263.].
Sugarcane serves as one of the world's most crucial economic crops, with fundamental importance to global sugar production and the sustainable biofuel industry. To meet the rising global demands and tackle various biotic and abiotic stresses, there is an urgent necessity to enhance the sugarcane breeding programme. Deciphering the intricate sugarcane genomes and integrating valuable agronomic traits into elite cultivars are vital to sustainable crop improvement. We review the major challenges in genomics-enabled sugarcane improvement, including genome complexity, polyploidy, and the limitation of traditional breeding methods. We discuss recent advancements in sugarcane genomic research, with a particular focus on cutting-edge strategies and algorithms for polyploid genome assembly, the key features and characteristics of newly assembled sugarcane genomes, and the development of graph-based pangenomes to capture genomic diversity. Our review highlights genomics-based sugarcane breeding from three perspectives: the history of conventional breeding, advanced breeding strategies empowered by genomic resources, and the emerging era of big data-driven crop improvement. These advancements provide powerful tools to accelerate sugarcane breeding and genetic improvement. Over the past decades, sugarcane genomics has made significant progress, including the assembly of high-quality reference genomes, the generation of comprehensive multi-omics datasets, and the development of precision genetic engineering tools. These advancements enable targeted manipulation of key alleles to improve yield, stress tolerance, and other important agronomic traits. Finally, this review summarises key breakthroughs in sugarcane gene-editing technologies and offers future perspectives on how these innovations are reshaping crop enhancement strategies.
Meniere's disease remains a poorly understood inner ear disorder since its first description by Prosper Meniere in the early 1800s. Characterized by episodic vertigo, fluctuating hearing loss, and tinnitus, it continues to challenge clinicians due to its unpredictable course and variable treatment response. Lifestyle modification alone often fails to adequately control vertigo episodes. To assess the effectiveness of oral pharmacotherapy in controlling vertigo and stabilizing hearing in patients with Meniere's disease, and to develop a practical, non-invasive treatment protocol suitable for routine clinical use. Patients diagnosed with Meniere's disease as per 1995 AAO-HNS criteria were managed with standard lifestyle advice followed by oral pharmacotherapy, including an antihistaminic agent (betahistine) and a combination of diuretics (furosemide and spironolactone). Treatment response was evaluated based on vertigo control, reduction in episode frequency, and stabilization of audiometric thresholds. Surgical options were considered only for patients with persistent, disabling vertigo despite maximal medical therapy. Lifestyle measures alone did not provide adequate vertigo control. In contrast, combined oral pharmacotherapy resulted in marked improvement, with significant reduction in vertigo frequency and satisfactory stabilization of hearing levels. Only a small proportion of patients required evaluation for surgical intervention. A regimen combining betahistine with diuretics offers a reliable, non-invasive, and effective approach to managing Meniere's disease. This protocol provides substantial vertigo control and hearing stabilization, and may be adopted as a first-line strategy before considering surgical options. Résumé Contexte:La maladie de Ménière demeure un trouble de l’oreille interne mal compris depuis sa première description par Prosper Ménière au début des années 1800. Caractérisée par des épisodes vertigineux, une surdité fluctuante et des acouphènes, elle représente toujours un défi clinique en raison de son évolution imprévisible et de la variabilité de la réponse au traitement. Les seules mesures hygiéno-diététiques sont souvent insuffisantes pour contrôler les épisodes vertigineux.Objectif(s):Évaluer l’efficacité d’une pharmacothérapie orale pour contrôler les vertiges et stabiliser l’audition chez les patients atteints de la maladie de Ménière, et proposer un protocole thérapeutique pratique et non invasif.Matériels et Méthodes:Les patients diagnostiqués avec la maladie de Ménière ont reçu des conseils hygiéno-diététiques standards, suivis d’une pharmacothérapie orale comprenant un antihistaminique (bétahistine) associé à des diurétiques (furosémide et spironolactone). La réponse au traitement a été évaluée en fonction du contrôle des vertiges, de la réduction de la fréquence des épisodes et de la stabilisation des seuils audiométriques. Une prise en charge chirurgicale n’a été envisagée que chez les patients présentant des vertiges persistants et invalidants malgré un traitement médical optimal.Résultats:Les mesures hygiéno-diététiques seules n’ont pas permis d’obtenir un contrôle satisfaisant des vertiges. En revanche, la pharmacothérapie combinée a entraîné une amélioration nette, avec une réduction significative de la fréquence des vertiges et une stabilisation satisfaisante des niveaux auditifs. Seule une minorité de patients a nécessité une évaluation en vue d’un traitement chirurgical.Conclusion:L’association de la bétahistine et de diurétiques constitue une approche non invasive, fiable et efficace pour la prise en charge de la maladie de Ménière. Ce protocole assure un bon contrôle des vertiges et une stabilisation de l’audition, et peut être adopté comme stratégie de première intention avant d’envisager une intervention chirurgicale.
Breast cancer (BC) is estimated to be around 2.3 million new cases and 670 000 deaths in 2020 resulting it into the most frequent cancer globally and ranks fifth among mortalities. Numerous studies have established the link between BC and microRNAs (miRNAs), which are endogenous non-protein-coding master regulators that modulate genetic expressions and influences many physiological and pathological cellular processes. In addition, hypoxia, which also consequently leads to cancer, is a pivotal driver of biological behaviour and malignant traits of cancer cells and eventually tumour cell survival. Hypoxia and hypoxia-inducible factors (HIFs) further regulates the miRNAs expression and promotes invasion and metastasis via increased invasive, migratory, and intravasation properties of the cancer cell, which initiates the metastatic process. In subsequent stages of metastasis, cancer cells navigate immune escape, vascular extravasation, metabolic reprogramming, and tumour-stromal crosstalk at the distant tissue site. Hypoxia dysregulates cancer metabolism post-transcriptionally through miRNAs, promoting glycolysis and fatty acid metabolism by inducing the expression of genes such as GLUT1, SCD, lipidome, and glycolytic enzyme biosynthesis. Hypoxia, on the other hand, also regulates immunogenic reprogramming by circumventing immunosurveillance, perpetuating cell survival and progression via hampering CD-47, PD-L1 markers and T-cell activation. Another process of cancer known as programmed cell death types I and II also involves a complex intricate protein mediated by HIF-1α. Hypoxia-mediated drug resistance influence drug therapeutic effect via altering transporter flux, drug targets, and inactivate of apoptotic pathways. In this review, we are focusing on understanding the clinical implications of hypoxia-driven miRNAs in BC diagnosis and prognosis. Therapeutic landscape for these molecules remains largely untapped, resulting into conducting more research in this field for harbouring potential translational discoveries in the diagnosis, prognosis and therapeutics for BC.
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In honor of the new section on Forensic Dermatology that appears in Clinics in Dermatology, we present a modern-day detective story that we created based upon Sherlock Holmes, the famous fictional character of Sir Arthur Conan Doyle (1859-1930). In our tale, a victim suspects that he is being slowly poisoned. An alteration of the victim's tongue (atrophic glossitis) and jaundice, provide diagnostic forensic dermatologic clues. The serum toxicology is negative, and the police can find no evidence for the presence of common poisons in the household. Sherlock Holmes, however, suspects foul play and must solve the crime to save the victim's life.
Due to legal restrictions, many patients pay out of pocket for later abortion care in the US. Knowledge of facility availability, self-pay prices, and state Medicaid acceptance may enable timely access to care. To estimate quoted self-pay prices and assess state Medicaid acceptance for later abortion care from 23 to 33 weeks of pregnancy duration. This cross-sectional study used a mystery caller design from November 2024 through April 2025. Contacted US health care facilities (clinics and hospitals) advertised offering abortion care at or after 23 weeks in August 2024. Mystery calls at 2-week pregnancy duration periods advertised for providing care (23, 25, 27, 29, 31, and 33 weeks) to request self-pay prices. Facilities in states permitting Medicaid coverage received additional calls regarding acceptance. Facility availability by pregnancy duration, quoted self-pay prices, and reported state Medicaid acceptance. A total of 130 facilities in 20 states and the District of Columbia advertised providing abortion care at or after 23 weeks of pregnancy (52 clinics, 78 hospitals). The overall response rate for obtaining at least 1 usable quoted self-pay price or range was 60.2% (112 of 186 facilities). Median self-pay prices increased from $3000 at 23 weeks to $17 250 at 33 weeks, with a statistically significant increase of $2541 from 23 to 25 weeks. The number of facilities providing care declined from 130 at 23 weeks to 31 at 25 weeks and 3 at 33 weeks. Among facilities in states with Medicaid coverage, 73 of 105 (69.5%) consistently reported accepting Medicaid; acceptance declined at later pregnancy durations and varied by state. In this cross-sectional mystery call study of 130 facilities advertising later abortion care in August 2024, self-pay prices increased with pregnancy duration, while service availability and Medicaid acceptance declined. Improving self-pay price transparency and expanding the availability of later abortion care, especially in states with Medicaid coverage, may facilitate more timely access to care.
Parallel importation (PI) is a TRIPS-recognized flexibility intended to improve access to medicines through price competition. In low- and middle-income countries, however, concerns persist regarding regulatory oversight, product quality, and patient safety. Empirical evidence on the real-world implementation of PI in Kenya remains limited. This study aimed to assess the regulatory compliance of selected parallel imported medicines marketed in Nairobi County, identify predictors of compliance, evaluate their market prevalence, and examine whether PI delivers the intended economic benefits for patients. Twenty-two medicines identified as parallel imports were evaluated against Kenyan regulatory requirements, including Pharmacy and Poisons Board (PPB) guidelines on labeling, packaging, patient information leaflets, storage conditions, and the Parallel Imported Medicinal Substances Rules (2019). A mystery-shopper survey covering 2,348 retail pharmaceutical outlets across all 85 Nairobi wards estimated the prevalence of non-compliant PI products. Logistic regression was used to identify predictors of compliance, and independent t-tests compared retail prices of PI products with those supplied through authorized channels. Regulatory non-compliance was widespread. Ninety percent of PI products failed to meet labeling and package insert requirements, primarily due to foreign-language packaging that precluded verification of critical safety information. Forty-five percent displayed storage instructions inconsistent with Kenya's ICH climatic Zone IV requirements, indicating supply chains not adapted to tropical conditions. Overall, 90% of products violated key provisions of the PPB PI Rules. Nearly all PI medicines were off-patent and already had multiple generic alternatives registered in Kenya, undermining the TRIPS-based public health rationale for PI. Unauthorized PI products were identified in approximately 90% of surveyed outlets. Price analysis showed significant differences in 53% of comparisons, but nearly half of PI products offered no economic advantage over authorized equivalents. Parallel importation of medicines in Nairobi is characterized by extensive regulatory non-compliance, limited or absent price benefits, and significant risks to medicine quality and patient safety. In its current implementation, PI in Kenya operates largely outside its intended TRIPS scope and fails to deliver meaningful public health value. Strengthened regulatory enforcement, climate-appropriate packaging, mandatory language compliance, and a reassessment of PI policy are urgently required to protect patients and preserve trust in the pharmaceutical system.
Sudden, global reversals in shell coiling direction are a striking and recurrent feature in the fossil record of planktonic foraminifera (marine zooplankton), yet their evolutionary significance has been a mystery. Because coiling direction is a simple, binary character, such shifts have often been interpreted as environmentally induced phenotypic responses rather than indicators of evolutionary change, although it is increasingly evident that genetic variants can have different coiling preferences. Here, we synthesize recent evidence from multiple case studies spanning the Eocene to the Recent (the last 56 Mya). Coiling flips occur on timescales of thousands of years or less, across diverse taxa and ocean basins, far too abruptly to be explained by gradual trait evolution. Instead, these rapid, synchronous coiling reversals may signal cryptic speciation and episodic population sweeps, associated with distinct habitat preferences and water mass distributions. In most cases such replacements would leave little trace in the fossil record, but when competing groups differ in coiling preference, a dramatic and geologically abrupt coiling reversal becomes visible. These findings challenge the assumption that reproductive isolation alone delimits species in planktonic foraminifera and instead supports a model of ecological speciation mediated by habitat partitioning in the open ocean. Shell coiling direction thus serves not as an adaptive trait, but as a fortuitous marker of hidden evolutionary dynamics shaping marine microplankton diversity.
Necrotizing pneumonia (NP) is a severe and life-threatening complication of lung infection in children. While rare, it can lead to catastrophic complications such as hemothorax, where blood fills the pleural cavity. We present the case of a previously healthy 5-year-old girl who initially appeared to have a gastrointestinal illness. Her condition rapidly evolved into a complex medical emergency involving influenza-associated NP, which was then complicated by a sudden, massive hemothorax. Her hospital course was further challenged by drug-induced acute kidney injury (AKI) requiring temporary hemodialysis and the persistent mystery of negative bacterial cultures. This case highlights the aggressive potential of NP, the critical need for vigilance when clinical signs worsen abruptly, and the essential role of timely surgical intervention. Following an urgent thoracotomy and lung resection, the child made a full recovery, underscoring how a multidisciplinary approach can be life-saving in these extreme scenarios.