Effective pandemic plans must be applicable to all members of our communities. However, people from multicultural communities with diverse language needs often engage with a wide range of organisations and individuals when seeking information during a pandemic or health emergency. Despite this, there is limited evidence on levels of trust and the influence of these sources on promoting community engagement with pandemic preparedness activities in high-income settings. A cross-sectional survey was conducted among members of ethnic minority communities in Australia who self-identified with one or more of six selected language or cultural groups. The survey, available in translated online and paper formats, incorporated several validated instruments and included both closed and open-ended items. Cross-tabulation analyses were used to examine associations between participant characteristics and levels of trust in community organisations and community leaders during the COVID-19 pandemic. 590 completed responses were included in the study. Participants were aged between 18 and ≥95 years old and identified as: Arabic (28.7%), Chinese (24.7%), Bangladeshi (22.3%), Pasifika (10%), Nepalese (8.2%) or Ezidi (6.1%). Predictors of moderate-to-very high trust in community-based organisations (CBOs) included participants who had arrived in Australia ≥20 years ago and had previously sought information from community groups, local councils and community workers. Likewise, moderate-to-very high trust in community leaders was more common among those who were more willing to seek assistance, arrived in Australia ≥20 years ago, were aged between 35 and 44 and had higher trust in community groups. Results indicated that trust in CBOs and community leaders was associated with willingness to seek assistance, satisfaction with communication efforts, trusted local councils and longer settlement in Australia; however, these associations may not reflect the reach or influence of community organisations and leaders across all ethnic minority groups.
Human apical sodium-dependent bile acid transporter (ASBT) and Na+-dependent co-transporting polypeptide (NTCP) are secondary transporters from the SLC10 family. These 9- transmembrane-helix proteins play critical roles in enterohepatic recycling of bile acids. Here we solve the crystal structure of a bacterial homolog, also with nine transmembrane helices and high sequence homology to human ASBT. We report two different structures of the bacterial homolog in the inward-facing state and a humanized version in the outward-facing state, with and without bile acid bound. Structures of NTCP show a pore through the protein in violation of the classical alternating access mechanism. In our structures, the flexible TM6 seals this pore, showing that an outward-closed structure is not necessarily precluded in this 9-transmembrane-helix protein family. Molecular dynamics simulations of bacterial and human proteins highlight that while the bile acid substrate is anchored to residues at the center of the transporter, lipids from the surrounding membrane interact with the hydrophobic sterol group.
Family caring roles create significant impacts on individual family members' physical, mental and social wellbeing, and can disrupt family financial stability, relationships and functioning. The perspectives of family members other than mothers are often omitted from research, reducing understanding of the broader impacts of supportive interventions such as care coordination. This study aimed to understand how multiple family members experience the impacts of caring for children with medical complexity (CMC) in a rural setting in Australia, and how paediatric care coordination influences their experiences. This qualitative study involved thematic narrative analysis and multimember comparison to identify themes within and across families, which were then mapped against the socioecological model. Members of 13 families of CMC receiving a nurse-delivered care coordination intervention, the Rural Kids Guided Personalised Service, participated in semi-structured interviews, including mothers (n = 12), fathers (n = 7), siblings (n = 3), CMC (n = 2) and an aunt (n = 1). Five themes were generated, including: Caring for CMC in varied family contexts, Coordinating care to support family strengths, Accessing appropriate care when living in a rural area, Impact on the whole family (including two subthemes: Family relationships and Enabling support within and for families) and Quality care closer to home. These findings are relevant for future implementation of integrated care models, and can inform the development of expanded models of care that address broader family health and social needs. Future service evaluations would benefit from inclusion of multiple family members, rather than only mothers, to allow a more comprehensive understanding of how best to support whole families. Parents with lived experience of caring for CMC in rural areas sat on the steering committee guiding the implementation and evaluation of RuralKidsGPS, alongside clinicians, Aboriginal health workers and advisors, health managers, researchers and policy officers.
To construct a substantive theory regarding the meanings attributed to and the factors influencing the decision regarding the place of death in the context of advanced cancer. Symbolic Interactionism and Grounded Theory were used as theoretical frameworks. Audio-recorded interviews, conducted in person or remotely between 2023 and 2024, were carried out with 96 participants from nine states located in four Brazilian regions, who were organized into five sample groups. The hospital is perceived as a space offering protection, relief from pain and suffering, and relief from family burden, while the home is seen as an environment that promotes the patient's dignity and autonomy and fosters emotional connection with family members, accompanied by uncertainty regarding the management of pain and suffering. Professional mediation and active listening facilitate the negotiation of meanings, while structural and communicational barriers limit the feasibility of choices. The decision regarding the place of death constitutes a symbolic, relational, and dynamic process, shaped by family conflicts, limitations in the physical structure, and interactions among patients, family members, and the multidisciplinary team. It is important to implement public policies that enable choices consistent with the values of the person with a terminal illness.
Six new species of Inocybaceae from North America are described as new. Most are common and widespread throughout eastern North America. Phylogenetic analyses of nuc rDNA ITS1-5.8S-ITS2 (ITS), harnessing numerous community science records, together with nuc 28S rDNA support the phylogenetic distinctiveness of each species with strong support values. Sequences of additional genetic loci, including RNA polymerase II largest subunit (rpb1) and second largest subunit (rpb2), were also produced to supplement the descriptions and strengthen future phylogenetic studies. Of these new taxa, three are described in Inocybe: I. albofusca, a smooth-spored species in the Flocculosa clade; I. communis, a nodulose-spored species in the Xanthomelas clade; and I. lincoffii, a nodulose-spored species in I. subsect. Napipedinae. Inosperma aureiavis is a member of the Maculatum clade, whereas Pseudosperma aurivetum is a member of the Umbrinellum clade. Mallocybe diabolica is a narrow-range endemic known only from southeastern Arizona and Mexico and is allied with the Heimii clade. Complete descriptions and illustrations are presented for each species.
The toxic mechanisms of norgestrel (NGT), an emerging marine pollutant, on the sperm from externally fertilized invertebrates remain elusive. This study employed an integrated physiological and multi-omics framework to elucidate how NGT (10 and 1000 ng/L) disrupts acrosome reaction (AR) signaling machinery, thereby impairing the functional integrity of Pacific oyster (Crassostrea gigas, also known as Magallana gigas) sperm. Exposure to NGT triggered a significant, dose-dependent premature AR, characterized by elevated acrosin activity and a loss of acrosomal integrity. Multi-omics integration supports a model in which this premature exocytosis is linked to signaling disturbances, including disruption of calcium signaling and reduced transcript abundance of calmodulin (CaM) and the primary recognition protein zonadhesin (Zan). This signaling interference induced an premature AR, subsequently driving a cascade of bioenergetic and structural failures. At the mitochondrial level, NGT induced abnormal mitochondrial permeability transition pore (mPTP) opening and elevated the transcript levels of antioxidant defense genes (e.g., peroxiredoxin-5, PRDX5). These alterations indicate the occurrence of mitochondrial collapse. Concurrently, scanning electron microscopy verified localized plasma membrane wrinkling and pore formation in sperm. In addition, NGT exposure decreased the transcript abundance of cytoskeleton-related genes, including solute carrier family 26 member 6 (SLC26A6), actin (ACT), and tubulin polymerization promoting protein family member 3 (TPPP3). These molecular changes further disrupted membrane phospholipid homeostasis, as represented by altered glycerophospholipid metabolism. At the same time, cumulative cellular stress was associated with decreased transcript abundance of cytoprotective factors (e.g., baculoviral IAP repeat-containing proteins, birc2) and changes in apoptosis-related genes consistent with activation of a caspase-8-mediated apoptotic programme. In conclusion, NGT, as a representative synthetic progestin, exerts reproductive toxicity by interfering with signaling mediators to induce premature AR, which subsequently exhausts metabolic energy and triggers plasma membrane impairment. These findings provide a critical mechanistic basis for the aquatic ecological risk assessment of synthetic progestins.
The bradykinin 2 receptor (B2R) is one of two members of the kinin receptor family and is a G protein-coupled receptor (GPCR) that regulates important physiological processes including pain, inflammation, and cardiovascular homeostasis. Functionally, B2R is activated by the kinin peptides, bradykinin and kallidin. Carboxypeptidase cleavage of bradykinin and kallidin results in the formation of des-Arg9-bradykinin (DABK) and des-Arg10-kallidin (DAKD) respectively, which are classically described as agonists of the bradykinin 1 receptor (B1R), the other member of the kinin family. Affinity binding studies have reported that DABK and DAKD can also bind to B2R. Upon activation, B2R signals through the recruitment of heterotrimeric G proteins, and earlier work has highlighted the promiscuous G protein coupling to B2R in response to bradykinin. However, a comprehensive G protein activation profile of the B2R receptor when activated by the other endogenous agonists has not yet been established. In this study, we used Bioluminescence Resonance Energy Transfer (BRET)-based in vitro assays to monitor the coupling of 14 different Gα proteins upon B2R activation. Our results show that there is a shift in G protein activation profiles and kinetics among the different peptides. By analyzing responses across a range of agonist concentrations, we further identified biased signaling among these peptides, with differential activation of specific Gα subtypes. These results improve understanding of intracellular mechanisms through which the kinin system regulates different aspects of its physiological role and provide valuable information for the design of drugs targeting the kinin receptors.
In this paper, I consider a group of patients that is often taken to be incapable of providing legitimate informed consent - populations with psychiatric disorders. I suggest this view is misguided using the philosophical tools of standpoint theory and epistemic injustice. Given that psychiatric patients are members of socially marginalized groups, standpoint theory would suggest that they are socially situated in ways that give them privileged epistemic access to relevant features of their worlds relative to the non-marginalized. Standpoint theory explains why patients like these have a particular perspective that enables them to see important elements of their experience that others do not. Epistemic injustice, on the other hand, enables us to see not only how and why these patients have special epistemic standing, but the ways in which this standing is systematically ignored. This disregard can then ultimately lead to injustice in the treatment of psychiatric service users.
American healthcare is in turmoil despite major advances in science, technology, and medical education. Although the United States spends more on healthcare than other industrialized nation, it continues to underperform in health outcomes and equity. We performed a review of the literature on professionalism, health equity, medical education, and medical history to explore why physicians and healthcare systems often fail to translate ethical principles into meaningful systemic reform. Our review identified a persistent "action gap", defined as the disparity between recognition of healthcare inequities and implementation of corrective action, and a failure of professionalism. The modern Physician Charter established professionalism as a social contract requiring physicians to promote patient welfare, social justice, and equitable access to care. Yet physicians and institutions have struggled to operationalize those obligations. The recent transition to the 2025-2026 Competency-Based Medical Education (CBME) with professionalism as a core competency offers an opportunity to reconnect medical training to the ethical foundations of medicine. Role models like internist Jean Cowsert, MD (1925-1967) and a 7-member Black "Medical Intelligence Group", illustrate how professionalism can transcend rhetoric and become action.
Drought and salt stress are significant environmental limitations that severely constrain plant growth and productivity, therefore, enhancing stress tolerance is a key goal in crop improvement. The plant-specific FCS-like zinc finger (FLZ) proteins have been identified as important regulators of stress adaptation. In this study, we conducted a genome-wide characterization of the FLZ gene family in apple and functionally characterized MdFLZ2. qRT-PCR analysis revealed that MdFLZ2 was differentially expressed across various tissues and transcriptionally induced by both drought and salt stress. Subcellular localization assays demonstrated that the MdFLZ2 protein is localized to both the nucleus and the cytoplasm. The overexpression of MdFLZ2 in apple calli, Arabidopsis and tomato conferred increased resistance to drought and salt stress. In addition, yeast two-hybrid (Y2H) assays confirmed that MdFLZ2 interacted with MdSnRK1.1, and similar interactions were also detected between other MdFLZ family members and MdSnRK1.1. Collectively, our findings suggest MdFLZ2 as a positive regulator of drought and salt tolerance and highlight its potential to serve as a genetic resource for abiotic stress improvement.
The global move toward open education has led to greater receptivity to the concept of Open Educational Resources (OER) in terms of being able to foster inclusivity and innovation. However, it remains challenging to implement OER in the institutional context. This study examined teachers' perceptions on the adoption, challenges and future of OER at a Hong Kong higher education institution. A qualitative interpretivist approach was taken, and eight faculty members across different disciplines participated in semi-structured interviews. The major findings of this study are as follow: First, there is a distinct conceptual gap where faculty equate "free" commercial tools with "open" licensed resources; adoption is driven by "pedagogical pragmatism" rather than an ideological commitment to openness. Second, significant barriers persist, including the time burden of curation, quality concerns, and a lack of institutional incentives. Third, the study highlights the disruptive potential of Artificial Intelligence (AI) on open education. Participants view AI not merely as a tool but as a future "co-creator" that could automate content generation. These findings mean the shift for faculty is becoming a facilitator and course designer not just a content disseminator. The study also suggests that institutional policy must move beyond basic technical support to provide holistic professional development focused on copyright literacy, open licensing, and the integration of AI within open educational ecosystems.
Advances in medical research, early diagnosis, and therapeutic strategies have significantly improved survival among children with chronic pulmonary diseases (CPDs), leading to a growing population of adolescents and young adults transitioning to adult care. Despite this demographic shift, healthcare systems, including Italy's, remain inadequately equipped to manage the evolving needs of these patients. This study aims to identify key barriers and unmet needs within the Italian healthcare system regarding the transition from pediatric to adult care for individuals with CPDs. A nationwide survey was conducted among members of SIMRI (Italian Society for Childhood Respiratory Diseases) through a questionnaire consisting of thirteen questions. The survey was sent between June and August 2023, with responses collected until July 2024. A total of Fifty-one responses were collected from pulmonologists, hospital-based pediatricians, primary care pediatricians, and adult pulmonologists from 14 Italian regions. Of these, 64.7% reported the absence of a structured transition program within their institutions. Where programs existed, they primarily targeted severe asthma (60.6%) and PCD or non-CF bronchiectasis (24.2%). Only 15.7% of respondents consistently addressed transition with patients and families, and 13.8% of centers had dedicated transition clinics. Proposed improvements included the establishment of specialized clinics (76.5%) and targeted professional training (72.5%). The transition of CPDs patients in Italy is currently fragmented and underdeveloped. Standardized protocols, dedicated transition services, interdisciplinary collaboration, continuous education, and involvement of patient associations are essential to ensure continuity of care and optimize long-term health outcomes.
Delirium is a frequent neuropsychiatric disorder, particularly in older hospitalized and critically ill patients, which is associated with negative consequences such as increased mortality and morbidity. Due to the ageing population, an increase in delirium cases is to be expected, further increasing the need for standardized inpatient delirium care; however, the implementation of structured delirium management in an inpatient setting has not been sufficiently examined. As part of the Delirium Awareness Campaign launched by the Initiative on Quality in Medicine (Initiative Qualitätsmedizin, IQM) a retrospective, descriptive, multicenter analysis was carried out based on peer reviews. Case files from German and Swiss IQM member hospitals were retrospectively evaluated by medical and nursing professionals using a standardized questionnaire. In this study 115 questionnaires from 8 peer reviews could be descriptively evaluated. In 90% of cases risk factors for delirium were present, in particular advanced age, surgical procedures and pre-existing cognitive disorders. In 26% of cases structured delirium screening was used, mostly once. Guideline-compliant diagnostics and treatment were determined by IQM peers in 13.9% of cases. Delirium was documented in the discharge letter in 19.1% of cases. In almost half of the cases (46.1%) a clear potential for improvement was identified during the course of inpatient treatment. The IQM peer review revealed a relevant gap in the routine clinical inpatient treatment and underscored the need to structurally embed delirium management as an interprofessional and standardized care process. HINTERGRUND: Delir ist ein häufiges neuropsychiatrisches Störungsbild, insbesondere bei älteren hospitalisierten und schwer kranken Patient:innen, mit negativen Folgen wie erhöhter Sterblichkeit und Morbidität. Bei steigendem Altersdurchschnitt der Bevölkerung ist mit einer Zunahme der Delirfälle zu rechnen, was die Notwendigkeit einer standardisierten stationären Delirversorgung weiter erhöht. Bislang ist die Umsetzung eines strukturierten Delirmanagements im stationären Setting jedoch unzureichend untersucht. Im Rahmen der Delir Awareness-Kampagne der Initiative Qualitätsmedizin (IQM) wurde eine retrospektive, deskriptive, multizentrische Analyse auf Basis strukturierter Peer Reviews durchgeführt. Akten von Fällen mit dokumentiertem Delir und Delirrisiko aus deutschen und Schweizer IQM-Mitgliedskrankenhäusern wurden durch ärztliche und pflegerische Fachpersonen anhand eines standardisierten Bewertungsbogen bewertet. Es konnten 115 Bewertungsbogen aus 8 Peer Reviews deskriptiv ausgewertet werden. In 90 % der Fälle lagen Delirrisikofaktoren vor, insbesondere höheres Lebensalter, operative Eingriffe und kognitive Vorerkrankungen. In 26,1 % der Fälle wurde ein strukturiertes Delirscreening eingesetzt, meist einmalig. Eine leitliniengerechte Diagnostik und Therapie wurden in 13,9 % der Fälle durch IQM Peers festgestellt. Die Dokumentation des Delirs im Entlassbrief erfolgte in 19,1 % der Fälle. In nahezu der Hälfte der Fälle (46,1 %) wurde ein deutliches Verbesserungspotenzial im klinischen Verlauf identifiziert. Die IQM Peer Reviews zeigen eine relevante Versorgungslücke in der klinischen Routine und unterstreichen die Notwendigkeit, Delirmanagement als interprofessionellen, verbindlich standardisierten Versorgungsprozess strukturell zu verankern.
The purpose of this study is to explore the experiences of socio-ecological stressors impacting 2S/LGBTQ+ individuals in the Waterloo Region in Ontario, Canada in the new wave of anti-queer rhetoric. Data was collected from semi-structured interviews with 2S/LGBTQ+ community members (N = 30) in the Waterloo Region. Braun & Clarke's six-step process of thematic analysis was employed. Minority stress theory was used to assess how socio-ecological factors (e.g., structural discrimination) contribute to manifestations of minority stress and how this health shapes health and well-being. Participants reported experiences of distal stressors (e.g., institutional exclusion, violence, social marginalization) and proximal stressors (e.g., fear, identity concealment, and isolation) across different social and ecological contexts. Individuals with multiple marginalized identities described excess minority stress. The findings highlight an urgent need for trauma-informed, intersectional approaches in service provision, community support, and policy development. This research contributes to a growing body of literature on the mental health and social challenges faced by 2S/LGBTQ+ communities. Given the current socio-political climate in Canada, further inquiry is essential to not only document ongoing harms but also to identify persistent gaps and failures in program implementation and make recommendations facilitating the delivery of services to alleviate these shortcomings.
Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders and is associated with various age-related neurodegenerative diseases. Here, we investigated the question of underlying mechanisms using a mouse model of mucopolysaccharidosis type IIIA caused by deficiency of the lysosomal hydrolase SGSH. Systematic imaging and transcriptomic and epigenetic studies revealed microglia to be the most profoundly impacted cell type in brains of Sgsh-deficient mice. Further investigation identified dominant and context-dependent roles of members of the MITF/TFE family as major drivers of microglia-specific epigenetic and transcriptional changes resulting from lysosomal stress that are dependent on collaborative interactions with AP-1/ATF, C/EBP, and PU.1/ETS transcription factors. Features of the transcriptomic and epigenetic alterations observed in murine Sgsh deficiency were also observed in microglia derived from mouse models of age-related neurodegeneration and in human Alzheimer's disease patients. These findings reveal common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.
Protein-based biosurfactants remain underexplored compared to glycolipids and lipopeptides, despite their unique interfacial properties and self-assembly behavior. PAC3, a surface-active protein produced by the marine fungus Acremonium sclerotigenum, exhibits dual behavior as both a biosurfactant and bioemulsifier. For this reason, it can be seen as a high molecular weight proteinaceous compound, able to efficiently reduce surface tension. Here, we identify PAC3 as the first member of a previously unrecognized family of fungal protein biosurfactants. The complete amino acid sequence of PAC3 was determined through a combined de novo transcriptomic and mass spectrometry approach, revealing an 83-residue protein that lacks the canonical eight-cysteine motif typical of hydrophobins, the most surface-active proteins known. Sequence, phylogenetic, and structural analyses revealed a distinct fold and amphipathic architecture, with a negatively charged surface and a hydrophobic planar region, providing a molecular basis for its strong interfacial activity. The identification of homologous sequences across fungi supports the existence of a novel protein family. Notably, we show through spectroscopy and confocal microscopy that PAC3 fibrils exhibit deep-blue intrinsic fluorescence, a property recently associated with amyloid architecture. To support industrial application, we developed a simplified downstream process based on methanol/chloroform extraction, reducing costs while preserving functionality. In parallel, the use of waste frying oil enhanced fungal biomass production and supported efficient PAC3 synthesis, demonstrating a sustainable production strategy. Overall, this study introduces a new class of fungal biosurfactant proteins and provides a foundation for their biotechnological exploitation.
A woman in her mid-50s presented with an uncomfortable pulling sensation in the right neck that worsened with movement. This was diagnosed as cervical dystonia and treated symptomatically for several years through trials of botulinum toxin. As the years progressed, her symptoms worsened and evolved with the patient eventually experiencing debilitating ataxia requiring use of a wheelchair for mobility, severe dysphagia requiring the use of a feeding tube for nutrition and dysarthria requiring the need of a family member for translation. Through genetic testing, the patient was diagnosed with spinocerebellar ataxia-CACNA1A (SCA-CACNA1A, previously SCA6). The patient had an unusual presentation of the syndrome with dystonia having been the initial symptom, resulting in the patient failing to receive diagnostic clarification of her symptoms until 10 years after the onset of symptoms. Clinicians should consider SCA-CACNA1A in their differential diagnoses if a patient presents with dystonia of unknown aetiology.
Objective: To explore the causal relationships between human inflammatory proteins and hypertrophic scars (HS) and keloids. Methods: This study was conducted based on bidirectional two-sample Mendelian randomization (MR) analysis. Data of human inflammatory proteins, HS, and keloids were acquired from genome-wide association study database. The inverse variance weighted (IVW) method was adopted to evaluate the causal relationships between 91 kinds of human inflammatory proteins and HS and keloids, i.e., a forward MR analysis. For the above associations, Cochran's Q test was used to assess heterogeneity, MR-Egger regression and MR-PRESSO outlier tests were performed to evaluate horizontal pleiotropy, and the leave-one-out method was applied to analyze the robustness of the results. The IVW method was also used to evaluate whether there was a reverse causal relationship between HS, keloids and inflammatory proteins screened out by aforementioned forward MR analysis. Results: CD6, leukemia inhibitory factor (LIF), tumor necrosis factor ligand superfamily member 12 (TNFSF12), programmed death-ligand 1 (PD-L1), interleukin-17C (IL-17C), LIF receptor (LIFR), osteoprotegerin (OPG), and fibroblast growth factor 23 (FGF23) had significant causal relationships with HS (with ORs of 1.365, 0.506, 1.567, 1.683, 0.621, 1.375, 0.623, and 0.553, respectively, 95% CIs of 1.100-1.693, 0.289-0.887, 1.081-2.273, 1.090-2.599, 0.408-0.947, 1.025-1.845, 0.402-0.966, and 0.315-0.971, respectively, P<0.05). Among them, CD6, TNFSF12, PD-L1, and LIFR were risk factors for HS, while LIF, IL-17C, OPG, and FGF23 were protective factors for HS. CD5, IL-10 receptor subunit alpha (IL-10RA), IL-5, LIF, and OPG had significant causal relationships with keloids (with ORs of 0.744, 1.303, 0.686, 0.603, and 0.715, respectively, 95% CIs of 0.573-0.965, 1.024-1.660, 0.472-0.996, 0.431-0.842, and 0.553-0.924, respectively, P<0.05). Among them, IL-10RA was a risk factor for keloids, whereas CD5, IL-5, LIF, and OPG were protective factors for keloids. No significant heterogeneity or horizontal pleiotropy was observed in the above associations (P>0.05), and the robustness of the results was not driven by any single nucleotide polymorphism. Significant reverse causal relationships existed between HS and TNFSF12 and LIFR of the 8 inflammatory proteins which had significant causal relationships with HS screened out by aforementioned forward MR analysis (with ORs of 0.972 and 0.968, respectively, 95% CIs of 0.949-0.997 and 0.942-0.994, respectively, P<0.05). No reverse causal relationship was found between keloids and the 5 inflammatory proteins which had significant causal relationships with keloids screened out by aforementioned forward MR analysis (P>0.05). Conclusions: CD6, TNFSF12, PD-L1, and LIFR may increase the risk of HS, while LIF, IL-17C, OPG, and FGF23 may decrease the risk of HS. IL-10RA may increase the risk of keloids, while CD5, IL-5, LIF, and OPG may decrease the risk of keloids. 目的： 探讨人炎症蛋白与增生性瘢痕（HS）、瘢痕疙瘩之间的因果关系。 方法： 该研究为基于双向双样本孟德尔随机化（MR）分析的研究。从全基因组关联分析数据库中获取人炎症蛋白、HS和瘢痕疙瘩的数据，采用逆方差加权（IVW）法评估91种炎症蛋白与HS、瘢痕疙瘩之间的因果关系，即正向MR分析。针对前述关联，采用Cochran Q检验评估异质性，采用MR-Egger回归检验和MR-PRESSO离群值检验评估水平多效性，采用留一法分析结果的稳健性。采用IVW法评估增生性瘢痕、瘢痕疙瘩与前述正向MR分析筛选出的炎症蛋白之间是否存在反向因果关系。 结果： CD6、白血病抑制因子（LIF）、肿瘤坏死因子配体超家族成员12（TNFSF12）、程序性死亡配体1（PD-L1）、白细胞介素-17C（IL-17C）、LIF受体（LIFR）、骨保护素、成纤维细胞生长因子23（FGF23）与HS之间均存在显著因果关系（OR分别为1.365、0.506、1.567、1.683、0.621、1.375、0.623、0.553，95%CI分别为1.100~1.693、0.289~0.887、1.081~2.273、1.090~2.599、0.408~0.947、1.025~1.845、0.402~0.966、0.315~0.971，P<0.05），其中CD6、TNFSF12、PD-L1、LIFR为HS的风险性因素，LIF、IL-17C、骨保护素、FGF23为HS的保护性因素；CD5、IL-10受体α亚基（IL-10RA）、IL-5、LIF、骨保护素与瘢痕疙瘩之间均存在显著因果关系（OR分别为0.744、1.303、0.686、0.603、0.715，95%CI分别为0.573~0.965、1.024~1.660、0.472~0.996、0.431~0.842、0.553~0.924，P<0.05），其中IL-10RA为瘢痕疙瘩的风险性因素，CD5、IL-5、LIF、骨保护素为瘢痕疙瘩的保护性因素。上述关联均不存在显著异质性或显著水平多效性（P>0.05），结果的稳健性未受单个单核苷酸多态性驱动。HS与前述正向MR分析筛选出的与HS之间存在显著因果关系的8种炎症蛋白中的TNFSF12、LIFR之间均存在显著反向因果关系（OR分别为0.972、0.968，95%CI分别为0.949~0.997、0.942~0.994，P<0.05），瘢痕疙瘩与前述正向MR分析筛选出的与瘢痕疙瘩之间存在显著因果关系的5种炎症蛋白之间均不存在反向因果关系（P>0.05）。 结论： CD6、TNFSF12、PD-L1、LIFR可能增加HS患病风险，LIF、IL-17C、骨保护素、FGF23可能降低HS患病风险；IL-10RA可能增加瘢痕疙瘩患病风险，CD5、IL-5、LIF、骨保护素可能降低瘢痕疙瘩患病风险。.
p21-activated kinase 4 (PAK4), a Group II PAK family member, is a therapeutically relevant candidate target in cancer, metabolic disease, and tissue injury. However, translation of PAK4 biology into drug candidates has been constrained by the conserved ATP-binding architecture of PAK isoforms, unfavorable pharmacokinetic profiles, and suboptimal clinical efficacy. We summarize the evolution of ATP-competitive Type I inhibitors, Type I½ back-pocket inhibitors, allosteric modulators, and PROTAC degraders, and compare representative compounds using potency, isoform selectivity, cellular activity, oral bioavailability, and development status. Particular emphasis is placed on structural determinants of selectivity, including the αC-helix-dependent hydrophobic back pocket, the inward Asp444/Asp458 floor pocket arrangement, and peripheral microenvironment differences that distinguish PAK4 from Group I PAKs. We also summarize the potential ADMET liabilities-such as pronounced efflux, metabolic instability, and poor oral bioavailability-that may arise from structural modifications aimed at enhancing PAK4 selectivity, and discuss rational optimization strategies to navigate these inherent barriers. Finally, we discuss clinical lessons from PF-3758309 and KPT-9274/padnarsertib and highlight how allosteric inhibitors and PROTAC degraders may help address limitations of conventional ATP-site inhibitors.
To evaluate post-traumatic stress symptoms, anxiety, depression, and health-related quality of life six months after intensive care unit (ICU) discharge, and to explore potential dyadic associations of psychological outcomes within ICU survivor-caregiver dyads. Prospective single-center pilot observational study. Adult intensive care unit of a tertiary-care hospital. Adult ICU survivors with length of stay ≥72 h and their identified primary caregivers enrolled as dyads. No therapeutic interventions were performed. ICU-related stressors (ICUESS) and caregiver satisfaction (FS-ICU) were assessed at ICU discharge. At 6 months, post-traumatic stress symptoms (IES-R), anxiety and depression (HADS), and patient-reported quality of life (EQ-5D-5L and EQ-VAS) were evaluated. Prevalence of probable PTSD (IES-R ≥33), dyadic concordance of PTSD symptoms, and associations between PTSD and health-related quality of life deterioration. Thirty-nine dyads were enrolled; 31 patients and 36 caregivers completed follow-up. Probable PTSD occurred in 15.4% of patients and 23.1% of caregivers. Within-dyad concordance was high (82% overall agreement: φ = 0.44), suggesting non-random clustering of PTSD symptoms within dyads. Nearly half of survivors (≈48%) experienced clinically meaningful deterioration in EQ-VAS, which was associated with probable PTSD in both dyad members. Perceived ICU-related stressors showed high concordance across dyads. Post-ICU psychological distress may show relational patterns within ICU survivor-caregiver dyads. Functional decline and shared psychological vulnerability may contribute to post-traumatic stress symptom burden after ICU discharge. These preliminary findings should be considered exploratory and hypothesis-generating and require confirmation in larger, adequately powered dyadic studies.