Sarcopenia and frailty are common issues faced by individuals suffering from liver cirrhosis. These ailments greatly diminish life quality and increase the likelihood of death. Engaging in physical activity is a popular method to improve sarcopenia. Consequently, this systematic review and meta-analysis seeks to assess the effectiveness of exercise programs for addressing sarcopenia in those with liver cirrhosis. This study evaluated the efficacy of exercise interventions on sarcopenia in patients with liver cirrhosis through a meta-analysis of randomized controlled trials (RCTs). A comprehensive literature search was conducted across five databases: PubMed, Embase, CINAHL, CNKI, and the Cochrane Library, up to March 2026. Manually search for references in review articles that may meet the requirements. Two researchers independently carried out the literature search and review, data extraction and assessment of risk of bias. The analysis of results includes 6-min walk distance (6MWD), thigh circumference, knee extensor strength, gait speed, thigh muscle thickness, Chronic Liver Disease Questionnaire (CLDQ), Model for End-Stage Liver Disease (MELD) scores and handgrip strength. Statistical analyses were performed using Rev Man 5.3 and STATA 14.0. This meta-analysis included 16 studies involving a total of 942 patients. The results demonstrated that exercise significantly enhanced various physical and clinical metrics in patients suffering from liver cirrhosis and sarcopenia. Notably, significant improvements were recorded in the 6MWD (MD = 54.35, 95% CI = 34.56-74.14, P < 0.001), thigh circumference (MD = 1.83, 95% CI = 0.92-3.38, P = 0.020), knee extensor strength (MD = 8.06, 95% CI = 2.59-13.53, P = 0.004), thigh muscle thickness (MD = 0.09, 95% CI = 0.05-0.14, P < 0.001), and scores on the CLDQ (MD = 0.75, 95% CI = 0.51-0.99, P < 0.001). Additionally, gait speed exhibited a significant increase (MD = 1.17, 95% CI = 0.09-2.26, P = 0.030). However, no significant changes were observed in grip strength, or MELD scores. Subgroup analysis indicates that aerobic exercise, or Resistance exercise, appear to improve physical activity levels in patients with cirrhosis. Exercise may improve selected indicators of muscle mass and physical performance in patients with cirrhosis. Exercise improves thigh muscle thickness, thigh circumference, and knee extension strength in patients with sarcopenia and cirrhosis, while also enhancing their physical activity capacity and quality of life. In terms of exercise type, both aerobic and resistance training appear to improve physical activity levels in patients with cirrhosis. However, further research is needed to confirm this. https://www.crd.york.ac.uk/prospero/, identifier CRD420261326379.
 The wear performance of femoral head taper connections is important for the longevity of total hip replacement. Metal release may cause adverse tissue reactions. There are some clinical indications that long neck heads may show increased wear, but no laboratory tests have been published. We aimed to examine the wear performance of femoral head taper connections in long and extra-long neck heads.  Load frame and hip joint simulator wear tests were performed with the same stem designs as in the reference study. The CoCr and zirconia toughened alumina (ZTA) heads of 36 mm diameter were of the long or extra-long neck type. Optical and scanning electron microscopy were utilized to study wear marks, and mass spectrometry to estimate Ti and Co release. Head disassembly forces were measured.  Our preclinical, design-specific results showed that, compared with medium necks, long and especially extra-long necks led to increased wear while maintaining an asymmetric wear pattern more widely distributed throughout the contact area. In the hip joint simulator tests, 1 neck fracture occurred.  The long and extra-long head taper connections showed increased wear compared with that of medium heads. Although no serious damage occurred, CoCr head tapers were the most affected compared with ZTA.
To evaluate clinical and radiographic outcomes in cats with congenital pectus excavatum (PE) treated with external coaptation and to identify associations between clinical presentation, defect severity, and postoperative complications. Retrospective clinical study. A total of 25 cats. Medical records from 2010 to 2024 from a small animal referral hospital were retrospectively evaluated for cats undergoing sternal splinting for PE. A total of 25 cats met inclusion criteria. All cats were younger than 20 weeks of age. Most cats (19/25) presented with tachypnea or exercise intolerance, and 25/25 had a palpable defect on examination. The survival rate was 24/25. Significant improvement in conformation was observed postoperatively, with frontosagittal index decreasing from a mean of 5.44-2.09 (p < .001) and vertebral index increasing from 4.45-8.47 (p < .001). Clinical signs resolved in all cases by recheck. Complications included pneumothorax, suture breakage, dermatitis, persistent defect, and death. No association was found between preoperative severity and breed, pneumothorax, or suture breakage. Splint duration was for a median of 28 days (range: 21-43 days) and was significantly inversely associated with dermatitis severity (p = .036). Congenital PE in this population of cats 20 weeks of age or younger was corrected with external coaptation, resolving clinical signs and improving thoracic conformation with minimal complications. External coaptation is an effective correction method for PE in young cats, resulting in resolution of clinical signs. While the survival rate in this study was excellent, owners should be counseled on potential complications.
The convergence of resistance and hypervirulence in Klebsiella pneumoniae poses a severe global health threat, yet the genomic mechanisms underlying adaptation to different clinical source remain incompletely understood. We conducted longitudinal genomic surveillance of 282 carbapenem-resistant K. pneumoniae (CRKP) isolates (225 sputum, 57 blood) between 2021and 2024 to characterize population structure, source-associated genomic adaptations, and plasmid evolution. ST11-CG258 dominated the cohort (77.3%), with 61.3% of isolates exhibiting the CR-hvKP phenotype. Longitudinal analysis revealed significant capsular plasticity within ST11, characterized by a temporal shift from KL64/47 to KL25 and the emergence of the highly invasive ST16-KL51 lineage, whereas non-ST11 clones displayed high capsular fidelity. Although blaKPC-2 predominated, blaOXA-181 was enriched among bloodstream isolates, whereas three blaNDM variants were more frequently detected in respiratory isolates. Comparative genomics identified enrichment of genes assigned to COG categories associated with energy production and amino acid transport in bloodstream isolates, whereas sputum isolates showed enrichment of genes involved in DNA repair and insertion sequences. Plasmid clustering of carbapenem-resistant plasmid revealed six antimicrobial clusters (Aclusters 1-6), identifying hybrid plasmids within Acluster 1 co-carrying blaKPC-2 and essential virulence determinants (iucABCD-iutA, rmpA, peg-344). Hypervirulent plasmids formed two major clusters, with Vcluster 2 diverging from Vcluster 1 via a 40kb deletion encompassing the ter (tellurium resistance) operon and metabolism-associated genes. These findings provide a comprehensive genomic characterization of CRKP from respiratory tract and bloodstream infections and support genome-based surveillance integrating clonal lineages, capsular types, and plasmid architectures to strengthen infection control and facilitate early identification of emerging high-risk CRKP lineages.
Since the 1990s, marked by Health's inaugural issue and the publication of Boltanski and Thévenot's De la justification, the Sociology of Health and Medicine has been shaped by traditions rooted in Critical Sociology, particularly Foucauldian, Marxist, and Bourdieusian paradigms. These frameworks have offered incisive critiques of power, biopolitics, medicalization, and neoliberal reframing of health responsibility. Concurrently, another sociological movement emerged through the development of French Pragmatic Sociology, or the "sociology of critical capacity." By foregrounding actors' justifications, plural conceptions of worth, and regimes of engagement, it reorients the analysis from structural domination to situated critique, one that is attuned to the complexity, uncertainty, and ambivalence of health-related action. It enables a relational, context-sensitive approach to the lived experiences of patients and professionals as they engage with institutional arrangements and enact critique within situated action. Drawing on a non-exhaustive, interpretive review of empirical studies engaging with Pragmatic Sociology, particularly in healthcare controversies, clinical decision-making, patient-professional interactions, and health innovation, this article shows how this perspective fosters nuanced understandings of normativity, critique, and coordination in health practices. It traces this theoretical realignment and argues that Pragmatic Sociology offers a compelling, flexible, and still underutilized epistemological and methodological framework for health research, sustaining and extending critique through an empirically grounded analysis.
The rising prevalence of infertility has substantially increased the demand for in vitro fertilization (IVF). While various controlled ovarian stimulation (COS) protocols exist, the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol is valued for its efficacy in preventing premature luteinizing hormone (LH) surges. However, it involves high medication costs and requires frequent injections, which impose a significant burden on patients. Clomiphene citrate (CC), a classic oral ovulation induction agent, offers advantages such as low cost and convenient administration. With the widespread adoption of the "freeze-all" strategy, its potential adverse impact on the endometrium can be mitigated. Recent modifications to the CC protocol, combining it with adequate-dose gonadotropins, aim to balance efficacy and cost. However, well-designed studies directly comparing this modified CC protocol with the conventional GnRH-ant protocol in a general IVF population are lacking, particularly those incorporating comprehensive cost-effectiveness analyses. 3,157 patients undergoing IVF or intracytoplasmic sperm injection (ICSI) cycles using either the CC protocol or the GnRH-ant protocol were matched 1:1 using propensity score matching (PSM) based on female age, basal follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), antral follicle count (AFC), body mass index (BMI), fertilization method, and sperm source. A total of 1,858 patients (929 per group) were included after matching. Embryological parameters and pregnancy outcomes were compared between the two groups, along with cost-effectiveness and sensitivity analyses. Baseline characteristics were well-balanced after PSM (with almost all standardized mean differences (SMD) < 0.1). The clinical pregnancy rate was comparable between the CC group and the GnRH-ant group (46.26% vs. 41.07%, P = 0.113), and the cumulative clinical pregnancy rate was also similar (51.60% vs. 51.79%, P = 1.000). The live birth rate (35.48% vs. 31.95%, P = 0.268) and cumulative live birth rate (35.48% vs. 38.29%, P = 0.398) were also comparable between the two groups. Compared to the GnRH-ant group, the CC group exhibited a higher Day 3 embryo formation rate (66.67% vs. 62.50%, P = 0.012), despite having lower numbers of follicles on the day of hCG trigger and retrieved oocytes (9.00 vs. 10.00 and 6.00 vs. 8.00, P < 0.0001). No significant differences were observed in the oocyte retrieval rate, oocyte maturation rate, fertilization rate, and blastulation rate between two groups. The cost of COS in the CC group was significantly lower than that in the GnRH-ant group (1,414.70 [741.50-2,915.50] CNY [~198 USD] vs. 7,266.24 [5,747.64-9,011.05] CNY [~1,017 USD], P < 0.0001), representing a saving of approximately 5,851.54 CNY (~819 USD; 80.53%). Cost-effectiveness analysis indicated that the CC protocol was superior across all outcome measures, including incremental cost-effectiveness ratios (ICERs) for oocyte, embryo, and clinical pregnancy. One-way sensitivity analysis (OWSA) indicated that the clinical pregnancy rate between the two groups was the most critical factor influencing the ICER for clinical pregnancy. Probabilistic sensitivity analysis (PSA) also suggested that in 98.50% of simulations, the CC protocol was more cost-saving. The modified CC protocol was associated with ovarian stimulation effects and clinical outcomes comparable to those of the GnRH-ant protocol. Furthermore, it represented a more cost-effective ovarian stimulation strategy, significantly reducing treatment costs while maintaining a clinical pregnancy rate comparable to that of the GnRH-ant protocol.
Alzheimer's disease (AD) is a complex neurodegenerative disorder involving amyloid-β deposition, tau aggregation, neuroinflammation, synaptic dysfunction, and microvascular and epigenetic changes. Although recent therapeutic developments have energised the field, effective and widely accessible disease-modifying treatments remain limited. This reflects both the biological complexity of AD and the continuing challenge of validating drug targets in the central nervous system (CNS). Chemical probes are small molecules designed to investigate the function of specific proteins in biological systems. When selected and used carefully, they provide powerful tools for testing how particular targets and pathways contribute to AD biology. High-quality chemical probes for AD targets must have high selectivity, confirmed target engagement, and CNS exposure adequate for the specific biological question, with low efflux, and biomarker evidence that the intended target is engaged in brain-relevant tissue. CNS penetration should be interpreted alongside mechanism-appropriate pharmacodynamic biomarkers, since cerebrospinal fluid measurements and modelled Kp,uu do not always directly reflect brain exposure. Chemical probes have shaped current understanding of major AD-relevant pathways, including amyloid precursor protein processing by BACE1 and γ-secretase, tau phosphorylation and aggregation, epigenetic regulation, and neuroinflammatory signalling. Several compounds initially developed as potential therapies have provided valuable mechanistic insight, even where they did not translate into clinical benefit. New modalities, including targeted protein degradation, molecular glues, and peptides, are expanding the range of AD biology that can be studied. These developments illustrate the value and limitations of chemical probes and underline the need for rigorous probe selection, validation, and experimental design in AD research.
Artificial intelligence applied to electrocardiography (AI-ECG) has rapidly been investigated in adult cardiovascular medicine, yet translation into pediatric and congenital heart disease populations has lagged. This review summarizes contemporary AI-ECG methodologies and emerging applications in pediatric and congenital heart disease (PCHD), with emphasis on current clinical utility, technical challenges, and future opportunities for implementation. Recent studies demonstrate that deep learning models can accurately identify arrhythmias, ventricular dysfunction, and CHD from standard ECG. Convolutional neural networks remain the dominant architecture, although transformer-based foundation models and self-supervised learning approaches are increasingly being explored. AI-ECG applications in PCHD have expanded from automated interpretation toward proactive risk stratification, including prediction of ventricular dysfunction, mortality, and sudden cardiac death risk. Additional work has investigated wearable monitoring, telemetry analysis, and integration with longitudinal clinical data. Despite promising performance, most studies remain retrospective and single-center, with limited external validation and challenges related to small datasets, physiologic heterogeneity, and age-dependent ECG variation. AI-ECG has the potential to transform PCHD by improving diagnostic accuracy, enabling earlier disease detection, and enhancing longitudinal risk assessment. Broader clinical implementation will require multicenter collaboration, prospective validation, standardized datasets, and careful attention to ethical, regulatory, and equity considerations.
Cancer cachexia, affecting up to 80% of patients with advanced cancer, is characterized by metabolic and inflammatory dysregulation driven by tumour- and host-derived factors. Although cytokines are central to cachexia pathogenesis, their circulating profiles and transcriptional relevance across models and sexes remain incompletely defined. We characterized plasma cytokines and skeletal muscle inflammatory signatures in multiple cachexia models, including Lewis Lung Carcinoma (LLC), Colon-26 (C26) and ApcMin/+ mice. Animals were monitored for 4 weeks (LLC), 25 days (C26) or until ∼20 weeks of age (ApcMin/+) per model appropriate endpoints. Publicly available RNA-sequencing datasets from gastrocnemius (LLC) and tibialis anterior (C26 and ApcMin/+) muscles were integrated with plasma profiling using a Mouse Cytokine/Chemokine 32-Plex assay. To enhance accessibility and reproducibility, we developed an interactive Shiny application - thecachexiatlas/Cytokine Explorer - enabling dynamic visualization of cytokine levels, transcriptional signatures and phenotype correlations across models and sexes. Cytokine receptor encoding genes (Il6ra, Il4ra, Csf3, Osmr) and inflammatory pathways were consistently enriched in skeletal muscle of cachectic animals across models and sexes. Among circulating cytokines, granulocyte colony-stimulating factor (G-CSF) was uniquely elevated in all models and both sexes. Elevated G-CSF levels exhibited stronger negative correlations with tibialis anterior muscle mass than the commonly used cytokine interleukin (IL)-6, particularly when expressed as the ratio of G-CSF to the anti-inflammatory cytokine IL-13. The G-CSF:IL-13 ratio may represent a robust global biomarker of cachexia severity. The Cytokine Explorer Shiny app provides an open, interactive platform to facilitate hypothesis generation and advance research in cancer cachexia.
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Complete blood count (CBC) discrimination indices are widely used as low-cost triage tools for microcytosis, but their diagnostic utility in population-based samples with ferritin-defined iron status is uncertain. We evaluated whether commonly used indices distinguish ferritin-defined iron-deficient from noniron-deficient microcytosis among women aged 18-49 years. We analyzed the National Health and Nutrition Examination Survey (NHANES) 2015-2016, 2017-2018, and August 2021-August 2023 data among nonpregnant women aged 18-49 years with CBC, serum ferritin, and survey design variables. Among microcytic (MCV < 80 fL) women, iron-deficient microcytosis was defined as ferritin < 15 ng/mL and noniron-deficient microcytosis as ferritin ≥ 15 ng/mL. Mentzer, England-Fraser, Srivastava, and red cell distribution width (RDW) indices were evaluated at conventional cutoffs. Sensitivity analyses used ferritin < 30 ng/mL and C-reactive protein (CRP) restrictions of ≤ 5 and ≤ 3 mg/L. All estimates were survey-weighted. Among 3991 women, 507 had microcytosis. Ferritin-defined noniron-deficient microcytosis comprised 40.8% (95% CI, 35.5-46.2) and remained 37.0% and 33.6% after CRP restrictions of ≤ 5 and ≤ 3 mg/L. With ferritin ≥ 30 ng/mL, the corresponding proportions were 26.5%, 22.6%, and 20.2%. All four indices showed high sensitivity (92.9%-97.6%) but poor specificity (6.7%-35.3%). RDW had the highest specificity but still misclassified most noniron-deficient cases. Classic CBC indices had limited utility as standalone triage tools for ferritin-defined microcytosis. Ferritin-based assessment, interpreted in the relevant clinical and inflammatory context, should remain central. Persistent microcytosis without evidence of reduced iron stores should prompt diagnostic reconsideration and, when appropriate, hemoglobinopathy-aware evaluation.
Primary amenorrhoea is defined as the absence of menarche by the expected age, with or without delayed pubertal development in adolescents. It may result from anatomical, genetic, endocrine, and functional causes. Among the latter, we propose the term primary functional hypothalamic amenorrhoea (P-FHA) to describe primary amenorrhoea characterised by hypothalamic-pituitary-ovarian axis suppression in the absence of organic disease. P-FHA is frequently associated with low energy availability (LEA), particularly in individuals with feeding and eating disorders (FEDs) or excessive exercise, often within the spectrum of Relative Energy Deficiency in Sport (REDs). Despite its clinical relevance, P-FHA remains under-recognised, with limited dedicated research. This review aims to synthesise clinical studies addressing P-FHA in the context of FEDs or excessive exercise. A systematic literature search was conducted using PubMed, Web of Science, and Scopus. Studies focusing on P-FHA and its association with FEDs, excessive exercise, and REDs were included. Case reports and aggregated studies combining P-FHA and S-FHA were excluded to ensure specificity. Twenty-four studies addressing patients with P-FHA were identified. Available evidence suggests that the reported frequency of functional hypothalamic causes of primary amenorrhoea may have increased over time, although estimates varied substantially across populations and study designs. In patients with FEDs, the prevalence of PA ranged from 2.4% to 14.8%, while athlete cohorts reported frequencies ranging from 7.3% to 53.8%. FEDs and excessive exercise, including REDs-related conditions, emerged as major clinical settings. Data specifically addressing hormonal profiles or body composition in this context remain limited. P-FHA may represent an early clinical manifestation of chronic LEA occurring during a critical developmental window. Early recognition and multidisciplinary management are essential to minimise potential consequences on growth, skeletal health, reproductive function, body composition, and psychological well-being. Further prospective studies are needed to better define its epidemiology, neuroendocrine mechanisms, and optimal management strategies.
To prospectively compare treatment outcomes for orthograde canal obturation using Ortho MTA III (OMTA) with the continuous wave of compaction (CWC) using gutta-percha (GP) and AH Plus sealer, and to identify associated predictive factors. Informed consent was obtained (110 patients), and single- or two-rooted permanent teeth (n = 120) diagnosed with pulp necrosis (or previously treated) and asymptomatic apical periodontitis or chronic apical abscess (periapical index, PAI ≥ 3) were randomly assigned to two groups (n = 60/group). The canals were prepared to a minimal apical size #40 (ISO) based on their initial file size, disinfected and obturated by either CWC or OMTA using an enhanced disinfection protocol (GP disinfected, new gloves after each intraoperative radiograph and before starting obturation). Clinical and periapical radiographic examinations were conducted by two calibrated, independent endodontists during follow-up periods of at least 12 months. Success rates and associated predictive factors (tooth-, operator- and patient-related) were analysed statistically using binary and multiple logistic regression (p < 0.05). The median recall period was 30 months (14-48 months), and 104 teeth were finally analysed (recall rate: 86.67%). No significant differences in success rate were observed between the groups (p > 0.05) under both loose (OMTA: 88.24%, CWC: 83.02%) and strict criteria (OMTA: 64.71%, CWC: 58.49%). Multivariate analysis revealed that age (OR = 5.735, 95% CI: 1.286-25.577, p = 0.022), periapical lesion size (OR = 6.596, 95% CI: 1.397-31.138, p = 0.017) and PAI score (OR = 2.081, 95% CI: 1.047-4.136, p = 0.036) were significant predictors of treatment failure. Orthograde obturation of infected canals with Ortho MTA III demonstrated comparable success and treatment outcomes to those filled with GP and sealer by CWC, supporting its potential as a clinically viable alternative for the obturation of infected root canals. cris.nih.go.kr registration number: KCT00099939.
Case report of a young immunocompetent patient presenting with aseptic meningitis due to varicella-zoster virus (VZV) infection. Reactivation of VZV manifesting as meningitis is an uncommon clinical presentation compared to herpes zoster. While a concomitant vesicular rash is frequently observed, it may be absent in some cases. With antiviral therapy initiated promptly, the clinical outcome is generally favorable. Auf der falschen Fährte, wenn die Anamnese irreleitet. Fallbeschreibung einer jungen immunkompetenten Patientin mit einer aseptischen Meningitis aufgrund einer VZV-Infektion. Die Präsentation einer VZV-Reaktivierung mittels Meningitis ist im Vergleich zum Herpes Zoster deutlich seltener. Zudem tritt dann häufig ein begleitendes vesikuläres Exanthem auf, jedoch ist dies nicht immer vorhanden. Das zu erwartende Outcome ist bei einer rasch initiierten antiviralen Therapie gut. Schlüsselwörter: Meningitis, VZV, Varizella-Zoster-Virus, Kopfschmerzen.
Pediatric respiratory diseases such as pneumonia, asthma, bronchiolitis, tuberculosis (TB), and cystic fibrosis (CF) are among the most important global health burdens and also main causes of mortality and morbidity in the pediatric population. The traditional therapeutic interventions are associated with considerable limitations, including systemic toxicity, inadequate lung targeting, rapid mucociliary clearance, and inadequate intracellular drug delivery, which limit their effectiveness. This review aims to provide an overview on cationic lipid-based nanocarriers (CLNCs), targeted pulmonary drug delivery, pediatric respiratory diseases, formulation strategies, therapeutic potential, safety considerations, and challenges for translation. The development in nanotechnology has indicated that cationic lipid-based drug carriers are promising drug delivery systems to target respiratory diseases. Solid lipid nanoparticles (SLNPs), cationic liposomes, lipid nanoparticles (LNPs), and nanostructured lipid carriers (NLCs) are examples of CLNCs. In addition, new advances in intelligent drug carriers and inhalable nanomedicines in nanoparticle development are improving the mechanisms of precision respiratory medicine. However, there are considerable limitations and challenges in immune activation, cationic lipid toxicity, lung barriers, stability, and scalability. The multidisciplinary research, especially designed for pediatric clinical trials, is important for converting these nanocarrier systems into safe and effective clinical treatments.
Macrophages play a major role in immune responses and in the maintenance of tissue homeostasis. Most of our knowledge of macrophage biology comes from mouse studies, which have revealed the existence of distinct subpopulations differing in origin, life cycle and tissue-specific features, as well as the influence of tissue perturbations on macrophage heterogeneity. Here, we review the evidence supporting the conservation of these principles in human macrophages, along with the methodological approaches employed, including omics analyses of macrophages from clinical samples, human transplantation studies and studies of monogenic mutations. We also focus on the macrophage populations that are present in human secondary lymphoid organs-namely the spleen, lymph nodes, and tonsils. While some organ-specific features are shared with their mouse counterparts, we highlight important differences between mouse and human lymphoid tissue macrophages in their functional specialization.
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Patients with a history of extracranial cancers (EXCA) who develop new intracranial lesions are commonly presumed to harbour brain metastases, yet primary glioblastoma (GBM) can also arise de novo in cancer survivors. The clinical course, molecular features, and treatment outcomes of GBM in this population remain incompletely characterised. We retrospectively analysed adult patients with concurrent prior solid EXCA and supratentorial GBM treated at three Czech neuro-oncology centres between January 2010 and December 2022. Patients with hematologic malignancies or needle-biopsy-only diagnoses were excluded. Demographic, clinical, molecular (IDH, MGMT), surgical (RANO RESECT 2022 extent-of-resection classification), and treatment data were collected and related to progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier estimation, log-rank tests, and Cox regression. Of 1,182 patients operated for GBM, 48 (4.0%) had a documented prior solid EXCA. Median age at EXCA diagnosis was 57.5 years (range 21-82); median age at GBM diagnosis was 65 years (range 46-82). The median interval between diagnoses was 5.7 years (range 0.1-27.3). All 48 GBMs were IDH-wildtype; MGMT promoter status was assessable in 23 cases (17 unmethylated, 6 methylated), of which 22 had follow-up data available for survival analysis. Median PFS was 8.4 months (95% CI 7.6-27.3) and median OS was 10.6 months (95% CI 5.7-16.8). MGMT methylation (mOS 29.3 vs 12.0 months; p = 0.037), higher Karnofsky score, more radical surgical resection, and completion of the Stupp protocol (mOS 19.2 vs 2.5 months for no oncotherapy; p = 0.019) were each significantly associated with longer OS. A new brain lesion in a cancer survivor must not be assumed to be metastatic without histological confirmation. When patients with GBM after prior EXCA are eligible for standard radical surgery and Stupp-protocol oncotherapy, survival outcomes are comparable to those reported for sporadic GBM. Standard treatment protocols are appropriate for this population; a history of extracranial cancer is not in itself an adverse prognostic factor.
Between 2000 and 2022, annual opioid overdose fatalities in the United States rose from 10 000 per year to over 80 000 per year. It is generally agreed that a major contributing factor to the US opioid crisis was the increased and widespread availability of the prescription opioid oxycodone during the 1990s and early 2000s. While the opioid crisis and oxycodone's contribution to it have been well documented, it remains underappreciated just how early after its introduction this drug's tendency towards diversion, misuse, dependence and addiction became apparent. This paper reviews the scientific and public health literature that accumulated during the 20th century indicating oxycodone's addiction liability to be of equivalent concern to that of morphine. A narrative review drawing from original scientific, clinical and public health literature obtained from digital archives relevant to the period of interest. Attention was first drawn to oxycodone's addiction liability by concerned clinicians as early as two years after the drug became commercially available in Germany in 1917, with additional evidence accumulating both in that country and abroad over the subsequent decades. This, combined with research conducted under the supervision of the Committee on Drug Addiction and Narcotics (CDAN) within the Medical Sciences Division of the US National Research Council, led to global recognition of the fact that oxycodone should not be considered any less an addiction liability than morphine. Concerns raised by clinicians about oxycodone throughout that period, and speculation on the causal factors underlying the rapid increase in oxycodone's misuse frequency, are reminiscent of those accepted as contributory to the current global opioid crisis, including lax prescription practices, misleading marketing strategies and inconsistent government oversight. Attempts to draw on this early body of evidence to influence drug policy regarding oxycodone were undermined by a tendency to assess the addiction potential of drug formulations independently of their active ingredients.