The need for alternative analgesia to opioids in the emergency department (ED) has become increasingly urgent due to the opioid epidemic. Ketamine, traditionally used for sedation, has emerged as a promising alternative for pain control in the acute care setting. This scoping review evaluates the use of intranasal (IN) ketamine compared with intravenous (IV) opioids for analgesic efficacy in treating acute pain in the ED. A search of PubMed, CINAHL and PRIMO databases was conducted for randomized controlled trials (RCTs) published between 2015 and 2025. A total of 561 records were identified, and 8 RCTs evaluating analgesic efficacy as the primary outcome were included in this review. This review was conducted in accordance with the PRISMA-ScR reporting guidelines. Eight RCTs including 846 patients were included (2016-2025), all conducted in Iran, Israel, or Thailand. IN ketamine (0.3-1.5 mg/kg) was most commonly compared with IV morphine (0.1 mg/kg). Across studies, IN ketamine demonstrated comparable reductions in pain scores to IV morphine, with several trials reporting no statistically significant differences at measured time points, although IV morphine was generally associated with faster onset of analgesia. In one study, IV fentanyl produced greater pain reduction than IN ketamine. Adverse effects were generally mild and transient with IN ketamine associated with fewer adverse events compared to IV morphine. IN ketamine may be useful for acute pain management in the ED. However, further research is needed to determine optimal dosing, compare its efficacy with more potent opioids, and evaluate long-term outcomes associated with its use.
Tarsal coalition is an abnormal union between 2 or more tarsal bones that can potentially cause pain, stiffness, and altered foot biomechanics. A 49-year-old man presented to the clinic with chronic dorsal pain in the left foot. Magnetic resonance imaging (MRI) revealed multiple unilateral nonosseous calcaneonavicular and talocalcaneal coalitions, with associated bone marrow edema. Conservative treatment of the condition, including range-of-motion and strengthening exercises, resulted in gradual improvement. This case underscores the importance of MRI in detecting nonosseous coalitions and associated edema. Notably, the presence of multiple coalitions in a nonsyndromic patient is rare, as such findings are typically associated with syndromic conditions. Awareness of this possibility aids accurate diagnosis and management.
Managing difficult airways in prehospital settings is particularly challenging, especially in rural or resource-limited environments and during patient transport. Inexperienced providers performing endotracheal intubation (ETI) during ambulance transport may have lower success rates, highlighting the potential value of real-time expert support. This study aimed to evaluate the effectiveness of real-time teleguidance from a remote airway expert in improving ETI success among inexperienced operators using videolaryngoscopy (VL) in a moving ambulance environment. This randomized controlled study included paramedic students with no prior clinical experience using VL, all of whom received standardized VL training immediately before participation. Participants were randomized to either a standard group (no external support) or a teleguidance group (remote expert assistance via the VL device's teleconsultation feature). All ETIs were performed on a high-fidelity manikin in a moving ambulance. The primary outcome was first-attempt ETI success. Secondary outcomes included intubation duration, number of attempts, successful glottic visualization, self-perceived confidence, and procedural feasibility. Ninety-eight participants were enrolled. First-attempt ETI success was significantly higher in the teleguidance group compared with the standard group (79% vs. 49%, p = 0.002). Median intubation time was shorter with teleguidance (30 vs. 61 seconds, p = 0.003), and fewer attempts were required (median 2 vs. 3, p = 0.001). No significant differences were observed in glottic visualization, confidence, or feasibility scores. In a simulated prehospital setting involving a moving ambulance, real-time teleguidance was associated with higher first-pass ETI success and shorter intubation times among inexperienced providers.
This study highlights the vital role of personalized treatment strategies in managing multiple myeloma (MM) among older patients, a population greatly affected by this disease. We conducted a retrospective analysis using data from the National Cancer Database (NCDB) collected between 2004 and 2021. Multiple myeloma patients ≥70 years were included in the analysis, as this age threshold aligns with NCDB categorization and reflects a group with higher clinical complexity. Utilizing a data analysis software, patients were categorized into three age groups: 70-74 years, 75-79 years, and 80 years and above. Patients were excluded if treatment regimen exposure could not be definitively confirmed in the database. Additionally, those lacking follow-up beyond diagnosis or with an unknown vital status were not included in the study. Analysis shows that while survival outcomes typically decline with age, tailored regimens can provide substantial benefits. The combination of chemotherapy, bisphosphonate therapy, and immunotherapy, where all treatments were given within 30 days of each other (C + H + I), yielded the highest median overall survival (64.2 months) and the lowest adjusted hazard ratio for mortality (HR = 0.575), yet this regimen remains underutilized in older patients. Findings emphasize that with proper patient selection and supportive care, intensive regimens like C + H + I can be both effective and safe. Furthermore, extended treatment duration-particularly beyond 180 days-was linked to improved survival, supporting maintenance and continuous therapy approaches. This study underscores the necessity of moving away from uniform treatment models and toward individualized care plans that account for functional status and comorbidities in older adults with MM.
Steroid hormones influence affective behavior and its underlying neural networks. However, distinguishing between organizational and activational hormonal effects, along with effects of socialization, remains challenging, limiting the understanding of the mechanisms underlying affective neurobehavioral differences. Individuals with differences in sex development (DSD), such as congenital adrenal hyperplasia (CAH) and complete androgen insensitivity syndrome (CAIS), offer a unique opportunity to examine how alterations in prenatal steroid hormone exposure have a role in shaping brain development and human behaviors. This review aims to examine how, and to what extent CAH and CAIS, can inform broader neuroendocrine mechanisms of affective behavior. It starts with an overview of experimental psychology and human imaging work on the role of steroid hormones in affective behavior, highlighting the main challenges in the field in human research, and the rationale for including CAH and CAIS. It then summarizes findings from behavioral studies, experimental psychology, and neuroimaging research in CAH and CAIS to discuss how this research contributes to the understanding of the organizational role of steroid hormones on affective outcomes. Although the current evidence is limited and heterogeneous, this review highlights the contribution of prenatal hormonal variability, particularly prenatal androgen exposure, in shaping affective behavior and underlying neural networks. It also highlights how steroid hormones, chromosomal sex, timing of hormonal exposure, developmental stage and psychosocial factors interact in influencing affective outcomes. Advancing this work through neuroimaging and standardized experimental paradigms has the potential to specify the mechanistic pathways through which steroid hormone variability influences behavior. This work can also inform targeted interventions and support emotional well-being and quality of life for individuals with CAH and CAIS.
The elimination of cervical cancer has been identified by the World Health Organisation as an achievable goal worldwide. An important component of cervical cancer prevention is the successful diagnosis and treatment of precancerous lesions with colposcopy in women with positive cervical screening tests. Colposcopy services should be of a high-quality with well trained staff delivering appropriate care using agreed clinical management protocols. Poor-quality services are associated with increased risk of both undertreatment and overtreatment for women which can significantly impair the reduction of cervical cancer in screened women. Organisational systems should be in place to ensure access to skilled colposcopy services where practice can be reviewed, measured and compared to improve performance. The current review provides guidance on how quality assurance for colposcopy services can be provided. The Quality and Standards Group of the European Federation for Colposcopy and Cervical Cancer Prevention comprised of senior colposcopists who reviewed the progress of quality assurance processes to date throughout Europe. There was considerable variation in the implementation of quality assurance programmes between countries and insight has been provided into how such variations can be rectified by implementation of best practice in colposcopy. A roadmap is described to implement the recommendations of the World Health Organisation and reduce the inequalities of colposcopy services to establish equity of access to quality diagnosis and treatment across Europe.
The recovery of ancient DNA (aDNA) from skeletal remains continues to be a critical challenge in forensic genetics and paleogenomics due to its high fragmentation, low quantity, and susceptibility to exogenous contamination. This study assessed the combined effect of four surface cleaning pretreatments (PT) and two automated extraction methods, AutoMate Express (AM) and EZ2 Connect Fx (EZ), on aDNA recovery from a pre-Hispanic individual dated to the Postclassic period (950-1521 CE). The pretreatments included chlorine (C), chlorine with ultraviolet irradiation (CUV), chlorine with bone fragment demineralization (CDB), chlorine with bone powder demineralization (CDP), and a non-treated control (NT). DNA quantity and quality were assessed using spectrophotometry, fluorometry, and quantitative PCR (qPCR), while genetic profiling was evaluated using autosomal short tandem repeat (A-STR) analysis and next-generation sequencing (NGS) of STR and SNP markers. The EZ method consistently generated higher DNA concentrations and greater amounts of amplifiable human DNA than the AM method across all pretreatments. However, differences in input mass limit direct comparisons (200 mg for EZ vs. 80 mg for AM); after normalization, EZ maintained a general performance advantage. STR analysis revealed more informative partial profiles with EZ, particularly under CDB and CUV pretreatments, while NGS results also favored EZ, showing improved locus recovery and higher read depth. Extraction methodology was the primary determinant of DNA recovery, with PT providing additional profiling. This study provides an optimized workflow for degraded human DNA, with direct relevance to forensic genetics and paleogenomics.
Human metapneumovirus (HMPV) is a leading cause of acute respiratory infection worldwide, and most people over the age of 10 have been infected. Despite its high prevalence, its pathogenesis is not yet fully elucidated. Many cell types, including stem cells, are susceptible to HMPV infection. Our previous results suggested that mesenchymal stem cells (MSCs) are susceptible and permissive to HMPV infection. This study aimed to understand the effects of HMPV on stem cell biology. Specifically, we focused on the expression and localization of cytoskeletal proteins and their role during syncytium formation. To this end, we evaluated the surface markers CD90, CD73, and CD105 in infected and non-infected cells using flow cytometry; assessed infection-induced modifications in cytoskeletal proteins using immunofluorescence, and analyzed changes in the secretion pattern of the growth factors including Ang-2, EGF, EPO, FGF-basic, G-CSF, GM-CSF, HGF, M-CSF, PDGF-AA, PDGF-BB, SCF, TGF-α, and VEGF. We observed changes in the distribution of tubulin and actin. Annexin V levels were also increased following HMPV infection, likely due to membrane modifications associated with viral fusion during entry and/or viral exit by budding. HMPV infection induced a significant decrease in EGF and VEGF secretion compared with mock-infected cultures. In contrast, Ang-2 and PDGF-AA levels were significantly elevated in infected MSCs. HMPV infection alters the structure and surface marker expression of PL-MSCs; however, these cells retain their ability to differentiate into various tissue types. Nevertheless, the virus disrupts growth factor production, creating a complex balance between cellular damage and the remaining potential for tissue repair.
Intensification of beef cattle production has encouraged the adoption of nutritional strategies to improve herd productivity. Creep-feeding has been used to promote calf growth, reduce dependence on maternal milk, and improve reproductive efficiency in cows. However, studies evaluating its effects on beef cow reproduction have reported inconsistent results. This study aimed to evaluate the effects of calf supplementation on reproductive efficiency in beef cows through a systematic review and meta-analysis. The study followed the PICO protocol, defined as population (beef cows), intervention (calf supplementation via creep-feeding), and outcome (pregnancy percentage). Four databases were searched: Scopus, MEDLINE/PubMed, Web of Science, and La Referencia. References were exported to Rayyan Web for duplicate removal and screening. Data were extracted and analyzed in R to estimate the relative risk of pregnancy according to calf supplementation status. Creep-feeding increased pregnancy rate (relative risk [RR] = 1.06; 95% CI: 1.02-1.10, p = 0.0028), with a greater effect in primiparous cows (RR = 1.13; 95% CI: 1.02-1.26). The calving interval was extended (standardized mean difference [SMD] = 0.88; 95% CI: 0.20-1.55, p = 0.0064). Average daily gain increased in cows whose calves received creep-feeding (SMD = 0.19; 95% CI: 0.05-0.32, p = 0.0025), whereas body condition score and milk production were not significantly affected. These findings suggest that creep-feeding may improve reproductive performance and weight gain, particularly in primiparous cows.
Collective motion requires coordinated movements of multiple individuals, such as people walking in the same direction and in temporal synchrony. It provides a salient social signal closely linked to coordinated group action and social cohesion. Previous research has shown that the human visual system is highly sensitive to such coordinated biological movement, efficiently representing multiple moving agents as a unified spatial entity. While coordinated biological motion also unfolds over time, it remains unclear how its temporal dynamics are processed. Here, we asked participants to complete a temporal comparison task using multiple point-light walkers, in which they indicated which of two sequentially presented displays (coordinated or uncoordinated) had a longer duration. The results revealed that coordinated biological motion sequences, defined by temporal synchrony (i.e., matched step phase) and spatial alignment (i.e., common walking direction), were perceived as shorter in duration than uncoordinated counterparts, in which both temporal synchrony and spatial alignment were disrupted. This effect persisted even when the biological motion was scrambled, but disappeared in static displays. Crucially, it was not attributable to low-level spatial perceptual organization, as it remained robust across varied stimulus configurations. Interestingly, this effect was absent in non-biological motion and object motion, suggesting that the change in perceived duration is specific to high-level bio-social signals. Moreover, the effect was stronger for temporal synchrony than for spatial alignment. These findings point to a specialized mechanism for time perception tuned to coordinated group movement, highlighting the influence of higher-order social dynamics on the subjective experience of time.
Precision fermentation is redefining microbial food manufacturing by enabling programmable biosynthesis of nutrients and functional ingredients. Despite this progress, industrial-scale deployment is limited by metabolic burden, growth-production trade-offs, biosafety concerns, and the costs of downstream processing. Conventional intracellular systems inherently generate host-derived impurities and endotoxins, challenging food-grade standards. Here, we review platform-level advances that decouple biosynthesis from cellular constraints and streamline process design, with a focus on approaches aligned to food industry requirements. We highlight cell-free systems and non-replicative minicells as intrinsically contained production chassis, detail advances in secretion and efflux engineering for efficient extracellular product recovery, and discuss division-of-labor microbial consortia to address resource allocation limits. Together, these innovations integrate biosafety and process efficiency, providing a safe-by-design framework for next-generation microbial food systems that meet both regulatory and industrial needs.
Building on our previous work on electrochemically synthesized anatase TiO2 nanoparticles (NPs), this study evaluates their environmental relevance by linking pharmaceutical photocatalytic degradation with transformation product identification and toxicity-oriented assessment. The incomplete removal of pharmaceuticals in wastewater treatment plants raises concerns about both parent compounds and transformation products formed during advanced treatments. Here, the synthesized TiO2 NPs were applied to the photocatalytic degradation of ibuprofen (IBU) and paracetamol (PCT) under ultraviolet A (UVA) irradiation. The TiO2 NPs showed higher degradation efficiency than commercial P25, with Kobs of 10.82 × 10-3 min-1 for IBU and 10.75 × 10-3 min-1 for PCT, and approximately 95% removal for both pollutants after 4 h of UVA irradiation. Liquid chromatography tandem mass spectrometry (LC-MS/MS) identified 8 transformation products for IBU and 9 for PCT, suggesting degradation pathways involving hydroxylation, decarboxylation, bond cleavage, and formation of smaller oxygenated products. In-vitro assays were performed using A549 lung cells and HepG2 liver cells. In A549 cells, TiO2 NPs caused no significant decrease in dehydrogenase activity at 1-100 µg/mL after 24 and 48 h. In HepG2 cells, TiO2 NPs showed lower cytotoxicity than P25, with viability remaining at approximately 68% after 48 h at 250 µg/mL, compared with about 60% for P25. IBU and PCT solutions before and after 4 h of photocatalytic treatment maintained HepG2 viability above 90%. The toxicity-oriented assessment, supplemented by Ecological Structure Activity Relationships (ECOSAR) software predictions, suggested that further transformation could reduce predicted ecological concern.
The benefit of intravenous thrombolysis (IVT) in patients with acute mild, non-disabling ischemic stroke remains uncertain. We evaluated the real-world effectiveness and safety of IVT and explored heterogeneity of treatment effects in prespecified subgroups. We conducted a single-center retrospective observational cohort study of consecutive adults with acute mild, non-disabling ischemic stroke treated at the Stroke Center of the Fifth Affiliated Hospital of Sun Yat-sen University (March 2019-October 2023). Eligible patients presented within 6 h, had baseline NIHSS ≤ 5 with each item ≤ 1 (and 0 on consciousness items), and had no deficits perceived as potentially disabling. Patients receiving endovascular therapy after IVT or scheduled cerebrovascular intervention within 3 months were excluded. The primary outcome was excellent functional outcome (90-day mRS 0-1). Secondary outcomes were functional independence (90-day mRS 0-2) and early neurological deterioration (END; NIHSS increase>2 within 7 days). Safety outcomes included hemorrhagic transformation (HT) and symptomatic intracranial hemorrhage (sICH). Group comparisons used standard univariable tests; prespecified subgroup analyses were performed. Among 228 patients (mean age 60.7 ± 12.5 years; 66.3% male), 185 received IVT and 43 did not. Baseline characteristics were similar, except for a slightly higher median admission NIHSS in the IVT group (2 [IQR 1-2] vs 1 [IQR 1-2]; P < 0.001). At 90 days, mRS 0-1 occurred in 84.9% with IVT versus 74.4% without IVT (P = 0.117); functional independence (mRS ≤ 2) was 94.1% vs 90.7% (P = 0.492). END occurred in 12.4% vs 25.6% (P = 0.054). Any HT occurred in 5.9% vs 4.7% (P = 0.542); sICH was rare (1.1% vs 0.0%; P = 0.658). Subgroup analyses suggested a potential benefit of IVT in patients aged ≥ 65 years for achieving mRS 0-1. In acute mild, non-disabling ischemic stroke, IVT was not associated with increased hemorrhagic complications and did not significantly improve overall 90-day excellent functional outcome. Patients aged ≥ 65 years may derive greater functional benefit from IVT, warranting confirmation in larger prospective studies.
Pneumocephalus is the presence of air in the brain parenchyma, ventricular cavities, or epidural, subdural, or subarachnoid spaces. Simple pneumocephalus is often asymptomatic; however tension pneumocephalus can present with the altered sensorium, cardiorespiratory arrest, and the Cushing's triad. The Cushing's triad (widened pulse pressure, bradycardia, and irregular respirations) is known to emergency medicine practitioners to be an ominous sign of increased intracranial pressure and indicates imminent brainstem herniation. Here we present a case of acute pneumocephalus from the patient blowing their nose. The patient was bradycardic, hypertensive, and tachypneic in triage. Her CT was notable for extensive pneumocephalus around the brainstem with a visible tract connecting the external auditory canal, through the internal auditory canal, to the infratentorial space with pressure on the brainstem. Upon further imaging, the patient had a defect in her left round window allowing for this air entry. The etiology of pneumocephalus is discussed as well as management strategies.
Hormone receptor-positive/HER2-negative advanced breast cancer (ABC) is a heterogeneous and dynamic disease. Endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitors remain the standard-of-care first-line therapy for ABC. However, the treatment landscape is rapidly evolving as our understanding of the complex biology underlying this common subtype advances. Predicting how a patient's cancer might respond to ET across lines of therapy and understanding optimal sequencing in clinical practice are key unmet needs. A range of established and emerging clinical characteristics and biomarkers, including endocrine receptor expression, presence of specific mutations (e.g., ESR1, PIK3CA), and visceral disease, are currently used to guide treatment decisions. However, international guidelines have variable definitions of ET resistance and sensitivity, making delivery of individualized care in clinical practice challenging. Considering this unmet need and leveraging the existing evidence for both prognostic and predictive markers of therapeutic response, we propose that idea of ET suitability be used as a complement to ET resistance and sensitivity. We consider ET suitability to be the clinical assessment of whether a patient could benefit from ET, where benefit is defined not solely by tumor response but by a clinically relevant constellation of characteristics and markers possibly predicting the durability of disease response and symptom control. Several unresolved questions remain regarding issues such as disease heterogeneity, optimal treatment sequencing, and biomarker precision, but further work and ongoing studies will help to support the evolution of guidelines and provide clarity around the effective application of this quickly developing field to daily clinical practice.
Generator pocket pain (GPP) may develop in spinal cord stimulation (SCS) patients, with a frequency ranging from 0.9% to 64%. While several treatments have been proposed, the only available options for SCS patients experiencing refractory pain are implantable pulse generator (IPG) relocation or removal. We treated a 62-year-old man with late-onset refractory GPP using the autologous microfragmented adipose tissue (MFAT) injection into the IPG pocket. A total of 30 mL of MFAT harvested from abdominal fat was injected. The procedure was well tolerated, with no adverse events. The patient reported a significant reduction in pain intensity immediately after the injection, with his visual analog scale (VAS) score decreasing from 80 to 20/100. At the third-month follow-up, he continued to experience the same level of pain relief. The autologous MFAT injection in refractory GPP patients is a promising salvage option. However, additional cases will be needed to better evaluate the efficacy and long-term outcomes of this treatment.
Spinal cord stimulation (SCS) is commonly used to treat chronic pain that is refractory to conservative management. SCS has demonstrated efficacy in reducing paresthesia and pain, but functional motor improvements after this type of intervention are reported less often. A 70-year-old man sustained a traumatic left forearm amputation in 2015, which was followed by surgical reattachment and persistent neuropathic pain. The patient tried several interventions, including nonsteroidal antiinflammatory drugs, muscle relaxants, gabapentin, pregabalin, opioids, duloxetine, and nerve blocks. Ultimately, in 2017, he underwent the implantation of an SCS device. The SCS provided a maximum 90% reduction in pain and eliminated the paresthesias. The pain reduction notably helped double his range of motion when compared to pre-implantation interventions. He demonstrated improved range of motion, reduced muscle atrophy, and increased strength. SCS provided both substantial pain relief and unanticipated functional recovery in this patient, whose upper limb had been amputated. This case serves to highlight a novel therapeutic benefit of SCS beyond pain relief.
Parkinson's disease (PD) is a progressive neurological condition that primarily affects the central nervous system. It causes neurons to eventually degrade, leading to muscle tremors, rigidity, bradykinesia, impaired balance, and mask-like facies, among other symptoms. A combination of levodopa and carbidopa is the most common treatment for PD, though they are also given separately. These treatments have significant side effects, including headache, dizziness, nausea, somnolence, loss of appetite, diarrhea, constipation, and dyskinesia, which further exacerbate the already present PD symptoms. No disease-modifying treatment exists. Mesenchymal stem cell (MSC) secretome refers to the molecules secreted by stem cells during expansion in culture, which can include growth factors, cytokines, and exosomes. They have shown efficacy in models of PD in numerous preclinical studies and could provide an alternative, minimally invasive, and potentially disease-modifying treatment for PD. We hypothesized that secretome treatment via intranasal instillation would decrease PD symptoms and possibly be disease modifying. Patients diagnosed with PD were enrolled in the trial and received umbilical cord-derived MSC secretome (AlloEx Exosomes®) intranasal installations over a 2-day period. All patients were treated in our treatment facility located in Antigua. Treatment was repeated if desired by the patients at a minimum of 2-month intervals. Efficacy was measured using the Parkinson's Disease Questionnaire (PDQ-39) rating, electroencephalogram (EEG) tests, and patient reports. Nineteen patients were enrolled in the trial and received a total of 40 doses throughout the treatment. There were no adverse events from treatment. Two patients reported no improvement, 2 patients had transient improvement, while the remaining patients saw a significantly maintained decrease in symptoms with follow-up of up to one year. Average combined PDQ-39 scores decreased with each treatment, indicating an increase in the patient cohort's quality of life. Improvements were seen in the patient's EEG results, tremors, sensory impairments, bladder/bowel dysfunction, and sleep quality. Limitations of the study included a short follow-up length that limited the ability to determine if the treatment was disease modifying. Intranasal MSC secretome installation is a safe method that is consistently effective in reducing Parkinson's symptoms and may represent the first-identified PD disease-modifying treatment.
Poor sleep hygiene is reported to impair subjective sleep and disrupt circadian system, yet the association between sleep hygiene and objective alterations in sleep continuity is scarcely studied. Moreover, the role of gender differences is largely neglected. In this pilot study, sixty-five adults (66% females) completed a psychometric assessment including the Sleep Hygiene Index (SHI) and wore an actigraph for one week for the assessment of sleep. No statistically significant gender differences on sleep hygiene practices were found. Bedtime and waketime were later in males than females. Males showed longer sleep onset latency (SOL), and wake after sleep onset (WASO), and lower sleep efficiency compared to females. General linear analyses showed that poorer sleep hygiene was associated with shorter SOL and longer WASO in males but not in females. Age, habitual insomnia and psychological distress did not influence the results. Current findings suggest a differential impact of sleep hygiene behaviors on objective alternations in males. While future research is needed to investigate the role of specific sleep promoting and sleep inhibiting behaviors on objective sleep, current results highlight the importance of considering gender differences in sleep hygiene research. Gender differences in homeostatic, circadian, and neuroendocrine factors related to sleep hygiene should be further investigated in mechanistic studies also considering non-binary participants.
Part 2 of the guideline addresses the updates on treatment recommendations in immunocompetent as well as immunosuppressed patients with invasive cutaneous squamous cell carcinoma (CSCC), based on current literature and expert consensus. A multidisciplinary panel of experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS)-Dermatology Venereology and the European Organization of Research and Treatment of Cancer (EORTC), was formed to update the previous guideline on CSCC (version 2023). For common primary CSCC, first-line treatment is surgical excision with post-operative margin assessment or micrographically controlled surgery. Achieving clear histological margins is key for patients with CSCC amenable to surgery. Radiotherapy should be considered for non-surgical candidates/tumors. For patients with macroscopic regional lymph node metastases, individualized treatment should be discussed in the multidisciplinary tumor board. For patients with metastatic or locally advanced CSCC who are not candidates for curative surgery or radiotherapy, anti-PD-1 agents are the first-line systemic treatment, with cemiplimab being the approved systemic agent for advanced CSCC by the EMA. Second-line systemic treatments for advanced CSCC, include clinical trials, EGFR inhibitors (cetuximab) combined with anti-PD-1 immunotherapy, or chemotherapy or radiotherapy. The decision for adjuvant cemiplimab for CSCC at high risk of recurrence after surgery and radiotherapy should be discussed in the multidisciplinary tumor board. In addition, multidisciplinary board decisions are mandatory for all patients with advanced CSCC, considering the risks of toxicity, the age and frailty of patients and co-morbidities, including immunosuppression. Patients should be engaged in informed, shared decision-making on management and be provided with best supportive care to improve symptom management and quality of life. Frequency of follow-up visits and investigations for subsequent new CSCC depend on underlying risk characteristics.