Past studies have shown that apoptosis mediated by TNF-related apoptosis-inducing ligand (TRAIL) is regulated by the expression of two death receptors [TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2] and two decoy receptors (TRAIL-R3 and TRAIL-R4) that inhibit apoptosis. In previous studies, we have shown that TRAIL but not other members of the tumor necrosis factor family induce apoptosis in approximately two-thirds of melanoma cell lines. Here, we examined whether the expression of TRAIL-R at the mRNA and protein level in a panel of 28 melanoma cell lines and melanocytes correlated with their sensitivity to TRAIL-induced apoptosis. We report that at least three factors appear to underlie the variability in TRAIL-induced apoptosis. (a) Four of nine cell lines that were insensitive to TRAIL-induced apoptosis failed to express death receptors, and in two instances, lines were devoid of all TRAIL-Rs. Southern analysis suggested this was due to loss of the genes for the death receptors. (b) Despite the presence of mRNA for the TRAIL-R, some of the lines failed to express TRAIL-R protein on their surface. This was evident for TRAIL-R1 and more so for the TRAIL decoy receptors TRAIL-R3 and -R4. Studies on permeabilized cells revealed that the receptors were located within the cytoplasm and redistribution from the cytoplasm may represent a posttranslational control mechanism. (c) Surface expression of TRAIL-R1 and -R2 (but not TRAIL-R3 and -R4) showed an overall correlation with TRAIL-induced apoptosis. However, certain melanoma cell lines and clones were relatively resistant to TRAIL-induced apoptosis despite the absence of decoy receptors and moderate levels of TRAIL-R1 and -R2 expression. This may indicate the presence of inhibitors within the cells, but resistance to apoptosis could not be correlated with expression of the caspase inhibitor FLICE-inhibitory protein. mRNA for another TRAIL receptor, osteoprotegerin, was expressed in 22 of the melanoma lines but not on melanocytes. Its role in induction of apoptosis remains to be studied. These results appear to have important implications for future clinical studies on TRAIL.
Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) has a potential role in the immune response to infections. This study investigated the association between serum TRAIL levels and illness severity in children with suspected infection. A retrospective post hoc analysis was conducted in children aged 4 months to 18 years who underwent MeMed BV testing during emergency department evaluation for suspected acute infection. Patients were categorized by serum TRAIL levels using a prespecified cutoff of ≤40 pg/mL vs. >40 pg/mL. Clinical and demographic data were compared between groups, with illness severity at presentation as the primary outcome. The analysis included 104 children, with 52 children in each TRAIL group. Children with TRAIL levels ≤40 pg/mL had longer hospitalization duration (4.06 ± 3.5 days vs. 2.50 ± 3.5 days, p = 0.026), higher pulse rates (147.9 ± 24.2 bpm vs. 135.5 ± 25.1 bpm, p = 0.012), and more abnormal white blood cell counts (67.3% vs. 36.5%, p = 0.003). They also had higher maximal C-reactive protein levels [128.6 [55.7-180.7] mg/L vs. 22.5 [4.4-56.2] mg/L, p < 0.001] and were more likely to receive antibiotics (85% vs. 42%, p < 0.001) and to require changes in antibiotic therapy (58% vs. 13.5%, p < 0.001). Illness severity differed significantly between groups, with severe illness observed in 44.2% of children with TRAIL ≤40 pg/mL compared with 9.6% in those with TRAIL >40 pg/mL (p < 0.001).A TRAIL cutoff of ≤40 pg/mL showed moderate discriminatory performance for severe illness (AUROC 0.73), with 82.1% sensitivity, 61.8% specificity, PPV 44.2%, and NPV 90.4%. Lower serum TRAIL levels in children were associated with more severe illness, as evidenced by extended hospital stays, increased antibiotic use, and more severe clinical presentations. These findings suggest an association between low TRAIL levels and illness severity, although differences in infection etiology between groups should be considered.
Expression and function of the TRAIL apoptotic pathway was investigated in normal and malignant breast epithelial cells. Glutathione-S-transferase (GST)-TRAIL extracellular domain fusion proteins were produced to analyze TRAIL-induced apoptosis. Only GST-TRAIL constructs containing regions homologous to the Fas self-association and ligand binding domains could induce apoptosis. GST-TRAIL induced significant (>90%) apoptosis in just one of eight normal and one of eight malignant breast cell lines. All other lines were relatively resistant to TRAIL-induced apoptosis. Activating TRAIL receptors DR4 and DR5 were expressed in all normal and malignant breast cell lines. The inhibitory receptor TRID was highly expressed in one of four normal and two of seven malignant breast cell lines. DR4, DR5, or TRID expression did not correlate with sensitivity to TRAIL-induced apoptosis. Incubation of cell lines with doxorubicin or 5-fluorouracil significantly augmented TRAIL-induced apoptosis in most breast cell lines. By fractional inhibition analysis, the toxicity of the combination of TRAIL and doxorubicin or 5-fluorouracil was synergistic compared with either agent alone. In contrast, melphalan and paclitaxel augmented TRAIL-induced apoptosis in few cell lines, and methotrexate did not augment it in any cell line. Augmentation of TRAIL-induced apoptosis by doxorubicin or 5-fluorouracil was mediated through caspase activation. This was evidenced by the fact that chemotherapy agents that synergized with TRAIL (e.g., doxorubicin) themselves caused cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), and their toxicity was blocked by the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH2 (ZVAD-fmk). The combination of TRAIL and doxorubicin caused significantly greater caspase-3 and PARP cleavage, and the combined toxicity also was inhibited by ZVAD-fmk. In contrast, chemotherapy agents that did not augment TRAIL-induced apoptosis (e.g., methotrexate) caused minimal caspase-3 and PARP cleavage by themselves, and their toxicity was not inhibited by ZVAD-fmk. These drugs also did not increase caspase-3 or PARP cleavage when combined with TRAIL. In summary, few breast cell lines are sensitive to TRAIL-induced apoptosis, and no difference in sensitivity is found between normal and malignant cell lines. Treatment with chemotherapy provides an approach to sensitize breast cancer cells to TRAIL-induced apoptosis.
EML4-ALK-positive lung cancer represents an important molecular subtype of non-small-cell lung cancer (NSCLC) that initially responds to ALK inhibitors but invariably develops resistance, highlighting the need for novel targeted therapeutic strategies. Death receptors DR4 and DR5 are frequently upregulated in malignancies and can selectively induce tumor cell apoptosis upon binding TRAIL. ISZ-sTRAIL, a trimer-stabilized soluble TRAIL fusion protein, exhibits potent antitumor effects via DR4/DR5 signaling activation. However, the expression status of DR4/DR5 in EML4-ALK-positive NSCLC cells and the therapeutic potential of targeting this pathway remain poorly defined. In this study, we evaluated DR4/DR5 protein expression in EML4-ALK-positive NSCLC cells and investigated the antitumor effect of ISZ-sTRAIL produced in an Escherichia coli expression system. Our results showed that DR4 and DR5 were abundantly expressed in EML4-ALK-positive NCI-H2228 and NCI-H3122 cells compared with normal human bronchial epithelial 16HBE cells. Furthermore, ISZ-sTRAIL significantly suppressed the proliferation of NCI-H2228 and NCI-H3122 cells, with IC50 values of 4.51 ± 0.22 nM and 14.98 ± 3.34 nM, respectively, while showing low cytotoxicity toward normal 16HBE cells (IC50 > 1 μM). Moreover, ISZ-sTRAIL induced caspase-dependent apoptosis in both cell lines via activation of extrinsic and intrinsic pathway, and these effects were markedly abrogated by the pan-caspase inhibitor Z-VAD. These findings identify DR4/DR5 as a potential therapeutic target and provide preclinical evidence for the development of TRAIL-based strategies in the treatment of EML4-ALK-positive NSCLC.
Renal cell carcinoma(RCC) is a therapy-resistant malignancy with rising global incidence, highlighting an urgent need for innovative treatments. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, but its clinical translation is hindered by cancer resistance. Extracellular vesicle-delivery of TRAIL (EV-T) has enhanced TRAIL activity. Recent studies reveal that programmed death-ligand 1(PD-L1), beyond its established role in immune evasion, exerts pro-survival functions and mediates TRAIL resistance. Accordingly, we propose the hypothesis that PD-L1 inhibition combined with EV-T may synergistically induce apoptosis in RCC cells. Moreover, we propose EV-based co-delivery of TRAIL and PD-L1 inhibitors could offer a highly efficient therapeutic strategy. First, TRAIL-transduced cells were cultured to prepare EV-Ts. Subsequently, the PD-L1 inhibitor ARB-272572 (ARB) was efficiently encapsulated into EV-Ts via sonication, fabricating a composite nanodrug ARB@EV-T. This formulation demonstrated improved ARB stability, cellular endocytosis, and controlled release kinetics. Importantly, ARB@EV-T overcame TRAIL resistance and showed synergistically enhanced cytotoxicity and apoptosis induction in resistant RCC lines. Mechanistically, the synergistic effect was attributed to upregulation of DR5 and concurrent suppression of anti-apoptotic factors, including cFLIP, MCL-1, BCL-2, XIAP, and Survivin, as well as inhibition of NF-kappaB pathway. In vivo, ARB@EV-T treatment resulted in significant inhibition of tumor proliferation, intense apoptosis, and robust recruitment of natural killer (NK) cells in a subcutaneous RCC xenograft mice model. These effects culminated in substantial tumor regression without any evident adverse events. Collectively, our results demonstrate ARB@EV-T represents an innovative and highly effective therapy against RCC, offering a potential breakthrough for overcoming treatment resistance in RCC.
Cell migration is a critical process in development, homeostasis, and disease. While cell migration in vitro is well investigated, much less is known about migration deep within tissues, largely due to limitations associated with deep cell imaging in tissues. In this study, we investigated cell migration history in vivo by developing a strategy based on recording cell trails formed by fusion of fluorescent protein and collagen secreted by migrating cells. By engineering different cell lines to express either fluorescent protein-fused Col1a1 or Col1a2 we identified trails formed in normal mouse tissues as well as primary tumors and metastatic organ sites. Analyses of the trail patterns revealed the paths taken by migrating cells and regions that suggest group trails, including trails along vascular adventitia. These results demonstrate that cell migration history can be traced in mouse models through postmortem analysis of normal and cancerous tissues.
Ultra-endurance running imposes extreme demands on oxygen transport, yet how red blood cells (RBCs) respond at the molecular level remains poorly defined. We integrated plasma and RBC multi-omics with hematology and hemorheology in athletes sampled before and after two trail races of distinct duration: a 40-km marathon (MCC) and a 171-km ultramarathon (UTMB). Both races elicited systemic inflammation, but UTMB was distinguished by marked IL-6 and kynurenine increases, acute-phase protein induction, and profound lipid remodeling. In RBCs, acylcarnitine accumulation, pantothenate depletion, and oxidized lipid species indicated Lands cycle activation, while purine salvage and carboxylate metabolism reflected redox-sensitive rerouting of energy pathways. Proteomics revealed non-random oxidation, particularly methionine oxidation of antioxidant enzymes, metabolic proteins, and proteasome components, correlating with impaired deformability as gleaned by testing of rheological properties. Elevated copper provided an additional correlate of reduced RBC mechanics. Despite minimal signatures of intravascular hemolysis, plasma bilirubin and hypoxanthine rose, consistent with extravascular clearance of damaged RBCs. Collectively, these results demonstrate that ultra-running accelerates RBC aging through inflammatory and oxidative pathways beyond mechanical trauma, linking systemic cytokine responses to molecular lesions, biomechanical dysfunction, and splenic sequestration. These findings not only identify actionable biomarkers of exercise-induced hemolysis but also provide translational insight into oxidative lesions that similarly limit RBC survival in transfusion and inflammatory disease settings.
Monkeypox virus (MPXV), a zoonotic viral disease first identified in 1958, has re-emerged as a major global health concern. The first human case was reported in 1970 in the Democratic Republic of Congo (DRC), and since then, MPXV has demonstrated a clinical resemblance to smallpox, with transmission occurring through both animal-to-human and human-to-human contact. In 2022, the largest recorded outbreak resulted in over 30,000 cases across the Western Pacific, Asia, Europe, and the Americas. Subsequently, between 2022 and 2024, more than 100,000 confirmed cases were documented worldwide, leading the World Health Organization to declare MPXV a Public Health Emergency of International Concern (PHEIC) in August 2024. This review provides a comprehensive, up-to-date overview of MPXV, including its viral structure, life cycle, clinical manifestations, diagnostic strategies, vaccines, and emerging therapeutics. Furthermore, it examines current challenges in disease detection and control and identifies opportunities to strengthen surveillance, prevention, and treatment strategies. Overall, this article aims to serve as a consolidated resource on MPXV, highlighting its epidemiology, clinical significance, and implications for global public health preparedness.
Post-neurosurgical bacterial meningitis (PNBM) is one of the major complications that causes high mortality in an era of antimicrobial resistance. Differentiating infective meningitis from aseptic meningitis remains challenging when we rely on culture, as it has lower sensitivity, and conventional cerebrospinal fluid biomarkers cannot differentiate between the two. This study aimed to evaluate the diagnostic utility of sequential cerebrospinal fluid lactate as a biomarker in patients with PNBM, to establish the optimal cutoff. This retrospective study included 49 PNBM and 27 non-PNBM patients from January to December 2024. In each category, a minimum of 3 and a maximum of 5 samples were considered for sequential CSF lactate analysis. In the PNBM group, ROC curve analysis revealed that CSF lactate levels had the highest diagnostic accuracy (AUC of 0.89, Youden's index, 0.78), followed by cell count (AUC of 0.86), glucose (AUC of 0.79), and protein (AUC of 0.49). Sequential CSF lactate analysis showed a significant difference between the PNBM and non-PNBM groups (p < 0.001). The optimal CSF lactate cutoff was 4.7 mmol/L, with 90% and 89% sensitivity and specificity, respectively. Among non-survivors, the average CSF lactate was 6.1 mmol/L compared to that of survivors. Our study shows that rather than relying on a single value, sequential CSF lactate monitoring helps to identify meningitis cases earlier than other CSF biomarkers and when culture results remain negative. A CSF lactate of 4.7 mmol/L serves as a diagnostic marker for PNBM, with >6.1 mmol/L being associated with higher mortality.
Human outdoor recreation is expanding across natural landscapes, yet its effects on wildlife remain poorly understood across spatial and temporal scales and across different contexts. We assessed the responses of large mammals to nonmotorized recreation near Fernie, British Columbia, Canada, using a multiscale observational approach combining data from 66 camera traps and GPS telemetry from 21 grizzly bears (Ursus arctos). We evaluated the following: (1) how wildlife detections varied by trail type, relative to the broader landscape, and with varying levels of recreational users; (2) whether animals shifted activity to avoid peak human use; and (3) how collared Grizzly Bear movement responded to recreation trails compared to other anthropogenic features. Trail type, surrounding landscape, and recreational pressure significantly influenced detection rates, but responses varied by species and scales. Elk (Cervus canadensis) showed the strongest avoidance, with reduced presence on recreation trails and a marked shift toward low-use periods. In contrast, Moose (Alces alces) and Mule Deer (Odocoileus hemionus) were more frequently detected on or near recreation trails. Grizzly bears consistently avoided areas adjacent to recreation trails in GPS movement data and camera detections but were detected on recreation trails more than nearby wildlife trails suggesting that when they do move through the trail network they do so on recreation trails. These findings highlight species- and scale-dependent behavioral responses, with effects ranging from strong (elk), to moderate (grizzly bears), to minimal (black bears, moose, mule deer, red foxes, and white-tailed deer). Our results suggest that concentrating recreation near existing developed areas and during mid-day should minimize impacts on wildlife while providing important access to recreation for people. Maintaining low-use zones elsewhere will be important for more sensitive species. While observational studies like ours are valuable for identifying patterns and informing management of rapidly changing pressures, stronger inference through experimental designs is encouraged to clarify causal relationships between recreation and wildlife behavior and further elucidate species- and context-dependent relationships.
STAR0602 is a selective bifunctional T cell agonist targeting Vβ6/Vβ10 T-cell receptors fused to interleukin-2, with emerging clinical activity in anti-PDL1-resistant tumors. Its murine surrogate, mSTAR1302, expands Vβ13 T cells and mediates antitumor activity. Docetaxel, beyond its cytotoxic effects, induces immunogenic modulation of tumor cells. We hypothesized that docetaxel-driven tumor sensitization would enhance susceptibility to immune-mediated killing, while mSTAR1302 would expand functional T cell subsets, resulting in coordinated antitumor responses. The therapeutic efficacy and mechanism of action of docetaxel and mSTAR1302 combination therapy were evaluated in 4T1 triple-negative breast cancer and TRAMP-C2 prostate cancer models. Immune profiling, functional assays, and CRISPR-mediated gene knockdown were used to define mechanisms of response. Combination therapy significantly reduced tumor burden and improved survival compared to monotherapies in both models. Docetaxel induced immunogenic modulation characterized by upregulation of MHCI, FAS, and TRAIL-R2, enhancing tumor susceptibility to immune-mediated lysis. Mechanistically, TRAIL-R2 expression contributed substantially to antitumor activity, as knockdown attenuated therapeutic efficacy. mSTAR1302 expanded Vβ13+ CD4+ and CD8+ tumor-infiltrating lymphocytes and promoted antigen-specific T cell responses. Depletion studies demonstrated that CD4+ T, CD8+ T, and NK cells collectively mediated the antitumor effects of combination therapy. These findings identify a mechanistic axis in which docetaxel-induced tumor sensitization via TRAIL-R2 cooperates with Vβ-targeted T cell expansion to drive coordinated immune-mediated tumor regression. This work supports the clinical evaluation of STAR0602 in combination with chemotherapy and highlights TRAIL-R2-mediated tumor sensitization as a mechanistically defined strategy to enhance immunotherapy efficacy in immune-excluded tumors.
Active adaptive matter has attracted considerable interest due to its rich, largely unexplained dynamics and its relevance to a wide range of synthetic and biological materials. An important subclass of such systems consists of active particles that can remodel the network in which they move. Here, we introduce a minimal yet versatile model of active particles moving on an adjustable network. In this model, particles undergo discrete run-and-tumble motion along the links of a triangular lattice and leave behind a trail of temporarily blocked links. These closed links cannot be traversed by other particles and reopen only after a characteristic healing time. The resulting trail-mediated blocking mechanism is fundamentally distinct from more familiar interactions such as excluded-volume effects. In the high-persistence limit, we find a qualitative contrast between the two mechanisms: while steric blocking leads to reduced diffusivity with increasing persistence, trail-induced blocking causes diffusivity to increase monotonically. We characterize this fundamental difference and the unexpected transport properties that arise when both blocking mechanisms are present, and discuss potential applications.
Attention deficit hyperactivity disorder (ADHD) in adolescence is associated with executive function difficulties, which compromise academic performance, daily functioning, and adaptive behaviors. Occupational therapy is aimed at improving EF and occupation and participation impairments. This study presents preliminary findings on the effectiveness of a multicomponent intervention protocol designed to enhance cognitive abilities in adolescents with ADHD. A quasi-experimental design with one-group, pretest-posttest, was used to evaluate the impact of the MOTI, which included computer-based cognitive training, academic skills training, and complementary but not mandatory a parents' psychoeducation group. Fifty-four adolescents aged 13-18 participated. Preintervention and postintervention assessments measured cognitive abilities and mental health indicators. Significant improvements were observed in working memory (digit span, CAB), mental flexibility (Trail Making B), and processing speed (Trail Making A). Omissions on the continuous attention test decreased (p = 0.046), and students self-reported better planning and organizing skills (p = 0.034). Evidence supports the effectiveness of the multicomponent intervention protocol (MOTI) in improving executive functions in adolescents aged 12-18 with ADHD. Initial analyses of the cognitive and academic skills training component reveal positive outcomes in targeted executive functions, reinforcing this multicomponent intervention as a valuable occupational therapy approach for this population.
To compare pulmonary oxygen uptake ([Formula: see text]) on-kinetics during level and uphill treadmill running performed within moderate- and severe-intensity domains in trained trail runners. Thirteen trail runners completed: (I) a traditional 3 min stage treadmill incremental test and (II) an incremental test at a fixed treadmill speed (50% of participant's peak speed from the first test) with a 2% gradient increase every 3 min to determine the first lactate threshold (LT1) and [Formula: see text]. On separate days, participants performed three 6-min square-wave transitions at 90% LT1 (moderate domain) and one 6-min transition at 70%Δ (severe domain) under both level and uphill conditions. Pulmonary [Formula: see text] was measured breath-by-breath to determine primary amplitude, time delay, time constant (τp), and slow component ([Formula: see text]), as well as blood lactate concentration ([La]) pre- and post-exercise. During moderate exercise, τp and time delay did not differ between level and uphill running, whereas the primary [Formula: see text] amplitude and post-exercise [La] were higher during uphill running (p < 0.05). In the severe domain, no differences were observed between conditions for τp, time delay, primary amplitude, or [Formula: see text] amplitude. Peak [Formula: see text] during severe exercise was higher in uphill compared with level running (p < 0.05), but values were similar to those obtained during the respective incremental tests. When exercise intensity domains are defined using slope-specific incremental testing, [Formula: see text] on-kinetics are similar between level and uphill running in trail runners. These findings support the validity of incline-based testing for physiological normalization and training prescription in uphill running contexts.
Verbal fluency tasks are ubiquitous in mild cognitive impairment (MCI) screenings. Yet, their assessment is traditionally limited to valid response counts. This subjective approach constrains analysis to univariate methods and overlooks which semantic memory dimensions are affected, introducing human bias while limiting informativeness. We tackled these gaps with a novel automated framework. Ninety-six participants (53 with MCI, 43 cognitively unimpaired individuals) performed phonemic and semantic fluency tasks alongside standard cognitive tests. Word properties (e.g., frequency, granularity, length) and timing features (e.g., number of pauses) were (i) automatically extracted to discriminate between groups via machine learning classification, (ii) benchmarked against standard cognitive measures (Trail Making Test-A, Trail Making Test-B, episodic memory subscore from the Addenbrooke's Cognitive Examination, digit span, and Mini-mental State Examination), and (iii) used to predict brain patterns and plasma phosphorylated tau 217 (pTau217) concentration. Our approach yielded moderate classification performance when using word properties and speech timing features combined (Area under the receiver operating characteristic curve [AUC] = .81, 95% confidence interval [CI] = [0.71, 0.89]), outperforming cognitive measures (AUC = .77, CI = [.68, .85]). Frequency, granularity, and semantic distance correlated with the gray matter volume of semantic-related regions commonly atrophied in MCI. No fluency feature was associated with functional connectivity patterns. Granularity was moderately associated with pTau217 levels. In sum, automated fluency analyses facilitate MCI detection, capturing fine-grained neurocognitive and biomarker patterns in the condition.
Neurocognitive impairment (NCI) is increasingly prevalent among older adults living with HIV (OALHIV). HIV clinics in low- and middle-income countries often do not routinely screen for NCI. Task-shifting screening to peer educators might be an alternative approach. We explored facilitators and barriers to implementing a peer-led NCI screening tool in an HIV clinic in Thailand. The study took place at a community hospital HIV clinic in suburban Chiang Mai. Peer educators were trained to screen OALHIV ≥50 years for NCI using the International HIV-Dementia Scale for global cognition, the Trail-Making Test for psychomotor speed and the General Practitioner Assessment of Cognition. We interviewed OALHIV who participated in the peer-led NCI screening during and after a 12-week implementation phase, peer educators and healthcare professionals to identify individual and intervention characteristics categorized according to the Consolidated Framework for Implementation Research. Transcribed and imported digital materials were used for thematic analysis in Dedoose (version 9.2.12). From March to June 2023, 162 eligible OALHIV were recruited. Among the 144 (89%) screened, the median age was 58 (IQR 54-62) years, and 93 (65%) were female. On at least one measure, 40 (28%) matched the study-defined referral criteria for NCI, of whom 20 (50%) were diagnosed with mild NCI, representing 14% of all those screened. We conducted 39 interviews with OALHIV (n = 26) and clinic-based staff (n = 12; five peer educators, eight healthcare professionals). The perceived benefits of neurocognitive screening, the empowerment of peer educators, the reliance on established links between peers and clinic clients, and OALHIV acceptance of screening were facilitators of the intervention. The main reported barriers were a lack of perceived necessity among OALHIV, clinic staff concerns about screening quality and comprehensiveness, and a lack of supportive national policies to integrate screening into routine HIV care for OALHIV. We demonstrated that a peer-led NCI screening intervention was feasible and acceptable in our setting. Raising awareness of the benefits of NCI screening among OALHIV and improved training and coordination in the healthcare setting would facilitate more effective implementation.
Emergency department (ED) nurses manage intense emotional labor that contributes to burnout while simultaneously shaping resilience. Although burnout is a recognized hazard, the dynamic interplay between burnout and resilience within the Saudi Arabian healthcare context remains poorly understood. This study explored how ED nurses experience emotional labor and the relationship between burnout and resilience. A qualitative descriptive study was conducted with 17 ED nurses purposively sampled from three healthcare facilities in Riyadh, Saudi Arabia. Semi-structured interviews, lasting 38-67 min, were conducted between December 2025 and February 2026. Data were analyzed using reflexive thematic analysis, informed by emotional labor and Conservation of Resources theories. Trustworthiness was ensured through member checking, peer debriefing, and an audit trail. Reporting followed COREQ guidelines. Five themes were generated: (1) demands of emotional labor, including high-acuity care and emotional suppression; (2) manifestations of burnout, such as exhaustion and depersonalization; (3) resilience mechanisms, comprising peer support and professional meaning-making; (4) organizational influences, involving leadership quality and resource adequacy; and (5) participant-generated recommendations for systemic reform. Burnout and resilience were experienced as concurrent, dynamic processes modulated by the organizational environment. Burnout and resilience coexist as concurrent dynamic processes in Saudi ED nurses, with organizational factors, staffing adequacy, leadership quality, and mental health support, acting as decisive determinants of occupational wellbeing. Strengthening organizational accountability, rather than individual adaptation alone, is essential for sustainable emergency nursing practice.
Rhinoplasty is among the most common facial surgeries. Evidence indicates that the rate of revision rhinoplasty remains high, particularly in Iran. While the technical causes are well documented, the lived experiences and underlying motivations for repeated revisions remain largely unexplored. This phenomenological study aimed to explain patients' experiences and the fundamental reasons for undergoing revision rhinoplasty. In this phenomenological study, using Colaizzi's method, participants were recruited from three teaching hospitals using purposive sampling. In-depth, semi-structured interviews were used for data collection and continued until data saturation. Data analysis followed Colaizzi's seven steps, utilising MAXQDA 12 software. Trustworthiness was ensured through member checking, peer debriefing, audit trail and reflexivity, in line with Lincoln and Guba's criteria. As an ethical commitment, all participants received a free clinical follow-up by an ENT specialist. To the best of our knowledge, this is the first study in Iran to explore the psychosocial and ethical dimensions of revision rhinoplasty from the patient's perspective. Analysis of 18 in-depth interviews identified three interrelated themes crystallising around the central phenomenon: 'Reconstructing the Self: The Search for a Lost Identity'. Participants described experiences related to: (1) A Fractured Sense of Lived Wholeness: The Struggle to Reclaim a Lost Self, marked by an identity crisis stemming from the unattainable 'desired self' and loss of their pre-surgical identity; (2) Disruption of Embodied Functionality: The Severed Connection to the Corporeal Self, involving a loss of the functional self, breathing difficulties and bodily alienation; and (3) The Unravelling of the Cared-for Self: Navigating Therapeutic Disenchantment and the Quest for Reconstruction, characterised by striving for self-reconstruction amidst ineffective therapeutic encounters, including unrealistic promises and inadequate post-operative support. Revision rhinoplasty in Iran extends beyond aesthetic concerns, representing an existential quest to reconstruct a self-fractured by profound identity loss, disrupted embodied functionality, and disillusionment with therapeutic processes. Centred on the phenomenon 'Reconstructing the Self: The Search for a Lost Identity', these findings underscore the critical need for ethically grounded, patient-centred approaches. These approaches should incorporate comprehensive psychosocial support and prioritise the preservation of bodily integrity within cosmetic surgical care. Participants contributed to the validation of interpreted themes through member checking. As an ethical safeguard, all participants were offered a free ENT follow-up.
The optimal anesthetic regimen for acute ischemic stroke (AIS) patients undergoing endovascular thrombectomy (EVT) remains debated. This randomized, double-blind, controlled trial compared the impact of remimazolam versus propofol on intraoperative hemodynamics in this setting. Seventy-four AIS patients were randomly assigned to receive either remimazolam-based or propofol-based general anesthesia. The incidence of intraoperative hypotension was the primary outcome. Vasopressor requirement, recovery times, and neurological outcomes were also assessed. Although the incidence of hypotension during anesthesia induction was comparable between the groups (75.68% vs. 70.27%, p = 0.601), it was significantly lower in the remimazolam group than in the propofol group during anesthesia maintenance (35.14% vs. 86.49%, p < 0.001). The remimazolam group also required significantly less vasopressor and exhibited a smaller maximum decrease in MAP (42 (35, 54) mmHg vs. 56 (47, 64) mmHg, p < 0.001). While not statistically significant, favorable trends were observed in the remimazolam group for neurological improvement at discharge. In conclusion, for AIS patients undergoing EVT, remimazolam provides superior hemodynamic stability compared to propofol, significantly reducing hypotension during anesthesia maintenance, without compromising recovery.Trial registration: This study was registered at the Chinese Clinical Trail Registry on 23/10/2023 (Registration number ChiCTR2300076880).
Clinical placements are essential for developing competence and professional identity in health professions education. In Pakistan, many undergraduate students in Allied Health Sciences, Dentistry, and Nursing complete unpaid clinical placements, which may impose financial, emotional, and educational challenges. Limited multidisciplinary qualitative research exists to understand these experiences. To explore the perspectives of undergraduate allied health sciences, dentistry and nursing students regarding the unpaid clinical placements. The qualitative study design involved semi-structured interviews with 22 undergraduate students of Dentistry, Nursing, and Allied Health Sciences programmes in various institutions in Khyber Pakhtunkhwa, Pakistan. Purposive sampling was used to recruit participants. Interviews were held in the Urdu language, taped and transcribed verbatim. Thematic analysis of data was performed in six phases as developed by Braun and Clarke. The use of reflexive note-taking, member checking, and audit trail were strategies used to increase rigor. Informed consent was received and ethical approval granted by the Ethics Review Board KMU-IHPER. The study was carried out in secrecy and anonymity. Five major themes emerged: 1. Managing Daily Costs and Practical Challenges of Clinical Rotations. 2. Emotional and Psychological Strain During Clinical Placements 3. Gaps in Supervision and Professional Support 4. Challenges Within the Clinical Learning Environment and Workload 5. Shaping Professional Identity and Motivation Through Clinical Exposure The results were subsequently explained through the Hierarchy of Needs invented by Abraham Maslow, which suggested that the physiological and safety needs that were not met, including financial strain and lack of support, inhibited the capacity of students to participate in higher-order learning, which consequently influenced their well-being and formation of professional identities.