Health information technology (HIT) is now integral to healthcare delivery, supporting clinical documentation, prescribing, diagnostics, and care coordination. Although these technologies offer substantial benefits, they have also introduced new patient safety risks that are often difficult to anticipate, detect, or manage. Many HIT-related safety problems arise not from isolated technical failures or individual mistakes, but from complex interactions between digital systems, clinical work practices, organisational structures, and governance arrangements. Traditional patient safety models that focus on discrete errors or linear causality are therefore insufficient for explaining how digital risks emerge and persist in practice. This article develops a sociotechnical theory of HIT-related risk grounded in patient safety science and sociotechnical systems theory. The theory is informed by empirical insights from incident-based research on HIT-related safety problems and synthesises evidence from real-world incident narratives. It adopts a conceptual, theory-building approach informed by purposive, iterative engagement with the relevant literature on health IT safety, sociotechnical systems, and resilience-oriented patient safety frameworks. Rather than analysing a single dataset, the paper identifies recurring mechanisms through which digital risks arise, remain hidden, propagate across contexts, and become recoverable or not. The proposed theory conceptualises HIT-related risk as a dynamic process involving four interrelated mechanisms: risk emergence, risk concealment, risk propagation, and recoverability. Risks emerge through misalignments between system design, configuration, and clinical workflows; they are concealed by automation, information fragmentation, and adaptive workarounds; they propagate through tightly coupled digital infrastructures and shared dependencies; and their recoverability depends on organisational capacity for detection, escalation, and learning. Together, these mechanisms explain why HIT-related incidents may affect multiple patients or services, why attribution to individual error is misleading, and why safety problems may persist despite corrective efforts. By reframing HIT-related incidents as manifestations of system-level vulnerabilities rather than isolated failures, this sociotechnical theory provides a coherent explanatory framework for understanding digital patient safety. It highlights how risks can evolve silently within routine practice, vary in visibility and scale, and emphasises the importance of organisational learning, governance, and resilience in managing digital safety risks.
While perpetrators of anti-Jewish harassment and violence are a small minority in democratic societies, they rely on a larger number of people who justify such aggression or silently condone it. Using data from nationally representative surveys of the Norwegian population, I report two studies investigating whether endorsement of Holocaust inversion-the belief that Israel treats Palestinians as badly as Jews were treated during World War II-is associated with (a) justification of harassment and violence against Jews and (b) refusal to take a stance against such aggression. Study 1 (N = 1,575) found support for both hypotheses. In a preregistered replication, Study 2 (N = 1,653) confirmed these results. Follow-up analyses found that endorsement of Holocaust inversion was also associated with refusal to answer questions measuring blatant antisemitic prejudice. The findings support theorizing that sees Holocaust inversion as a socially more acceptable vehicle for expressing and legitimizing antisemitic hostility. (PsycInfo Database Record (c) 2026 APA, all rights reserved).
Biomedical knowledge graphs (KGs) such as PrimeKG, Hetionet, UMLS, and PharmGKB are increasingly used as the substrate for downstream machine-learning, retrieval-augmented generation, drug-repurposing, and electronic health record (EHR) augmentation pipelines. The dominant assumption in published work is that integrating two or more such KGs is a tractable engineering step solved by identifier (ID) matching. This paper interrogates that assumption empirically. We quantify how much concept overlap survives realistic alignment, and we characterize the new failure modes introduced by the methods that practitioners reach for when ID matching is insufficient. We compared four widely used biomedical KGs (PrimeKG, Hetionet v1.0, the full UMLS Metathesaurus, and PharmGKB) across eleven node types using a tiered alignment pipeline: (1) direct ID matching for nodes sharing a primary vocabulary; (2) cross-ontology bridging using standard mappings (e.g., MONDO↔DOID, HPO↔UMLS, HPO↔UMLS↔MeSH for side effects, NCBI Gene↔HGNC↔UMLS, UBERON↔FMA/SNOMEDCT_US/NCI/MeSH for anatomy); (3) ClinicalBERT cosine-similarity grouping at threshold ≥ 0.98 for over-segmented disease nodes, with a deterministic suffix-stripping canonicalizer; (4) exact name matching for ontology-poor types (anatomy, REACTOME pathways); and (5) embedding-based fuzzy matching with UMLS lookup (SapBERT and ClinicalBERT) for free-text microbiome concepts. We applied the pipeline to a 698-concept gut-microbiome benchmark spanning taxa, pathways, and disease labels, validated grouping decisions against the curated SSSOM mappings released by the MONDO project, and audited the ClinicalBERT consolidation against five clinical-genetics case studies drawn from the literature. Per-type pairwise coverage was strikingly asymmetric. Genes/proteins and the three Gene Ontology categories aligned cleanly across PrimeKG and Hetionet (mutual coverage 94-99%), but disease overlap was sparse: only 0.7% of PrimeKG individual disease nodes mapped to Hetionet, rising to 2.0% after MONDO grouping (versus 78.7% and 18.4% from the Hetionet side). PrimeKG-to-UMLS coverage spanned 100% (effect/phenotype via HPO) down to 20.8% (REACTOME pathways), with drugs at 73.7% and anatomy at 58.8%. PrimeKG-to-PharmGKB drug coverage required up to two bridging hops (DrugBank → UMLS → RxNorm/ATC/MeSH). Bigger was not uniformly more complete: on a 698-concept microbiome drug benchmark, Hetionet missed 0 concepts while PrimeKG missed 16. ClinicalBERT-based grouping consolidated 22,205 raw MONDO disease nodes into 17,080 groups but introduced three reproducible failure modes documented in case studies: (i) peer over-merging: for example, all 22 osteogenesis imperfecta subtypes collapsed into a single node despite distinct severity classes; (ii) parent-child collapse: e.g. acute myeloid leukemia merged with myeloid leukemia, erasing the acute/chronic distinction that drives clinical management; and (iii) lexical false positives: neurofibromatosis and schwannomatosis grouped together despite cellular-pathology differences. Identifier matching alone is a weak baseline for biomedical KG integration. Cross-ontology bridges and embedding-based consolidation expand coverage but do so at the cost of clinically meaningful resolution, and the resulting failures are systematic rather than random. Reporting only aggregate coverage statistics obscures these losses, which propagate silently into downstream tasks. We provide reusable per-type coverage tables, a taxonomy of three integration failure modes, and concrete recommendations for downstream studies that depend on a unified biomedical KG. We argue that future KG integration work should report per-type coverage and per-cluster confidence rather than aggregate match rates.
Aphasiacs with impaired vocal organs suffer profound communication barriers, making silent speech decoding essential. Although audible speech is absent, subtle multi-muscle activities are retained. This provides a physiological basis for the sensing modality that reliably decodes silent speech. Yet conventional microphone and piezoelectric films remain susceptible to dispersion-fidelity conflict, external disturbance in the complex environments, and are further constrained by sensing-communication separation. Here, we report an in-sensor communication scarf interface that imperceptibly captures multi-muscle activities and ultrarobustly decodes silent speech. By fusing spoof surface plasmon-driven in-sensor electromagnetic physiological communication with metamaterial topological embroidery, the system establishes exquisite reconciliation between dispersion-regulated spatial selectivity and ultrahigh fidelity (7 fs²), enabling phase-resolved differentiation and precise capture of multi-muscle activities. This minimalist yet informative rich component design radically transcends limitations of sensing-communication separation, microphone, and piezoelectric films, and greatly delivers anti-motion artifact by 24,300%, anti-electromagnetic interference by 46.4 dB, and anti-noise by 33.44 dB in the complex environments. Combining with machine learning, the interface achieves 98.7% recognition and supports assistive interaction and sleep apnea monitoring. The interface bridges metamaterial electromagnetics and human electrophysiology, establishing a transformative in-sensor physiological decoding paradigm for electromagnetic physiological communication and adaptive myogenic interfacing.
Red blood cells (RBCs) are transcriptionally silent yet dynamically remodel metabolism in response to oxygen tension. Using ultra-pure human RBCs, we generated the deepest contamination-free proteome to date (3,775 proteins) and mapped the oxygen-dependent interactome. These datasets reveal an oxygen-responsive metabolon centered on the Band 3 (SLC4A1) N-terminus. We identify biliverdin reductase B (BLVRB) as a previously unrecognized Band 3 interactor that dissociates under hypoxia, coincident with increased Band 3-deoxyhemoglobin contacts. This reversible assembly functions as an oxygen-sensitive switch coordinating redox and glycolytic remodeling. Humanized mice lacking Band 3 N-terminal segments exhibit impaired oxygen-dependent regulation of BLVRB binding to band 3, impaired hypoxic activation of glycolysis, reduced 2,3-bisphosphoglycerate synthesis, and diminished exercise tolerance, demonstrating physiological relevance. Population-scale cis-pQTLs for SLC4A1 and BLVRB suggest functions beyond canonical heme catabolism. Mechanistically, biochemical analyses in vitro suggest that hemoglobin β (HBB), Band 3, and BLVRB can undergo S-nitrosation and may participate in trans-nitrosation reactions with the glycolytic enzyme GAPDH, whose modification at C152 inhibits enzymatic activity in vitro. Collectively, these findings define a Band 3-BLVRB axis that integrates oxygen-dependent protein interactions with thiol-based redox chemistry, providing a framework for understanding how an anucleate cell achieves metabolic adaptability through reversible protein-protein interactions and post-translational modification. These findings suggest that perturbation of the Band 3-BLVRB axis may influence oxygen delivery and metabolic flexibility during hypoxic stress, with potential relevance to high-altitude adaptation, exercise physiology, and cardiopulmonary disease.
The increased prevalence of stroke around the globe is a notable challenge as there are few treatments and the long‑term effects include neurological impairment. Oxidative stress, mitochondrial dysfunction and neuroinflammation are key mechanisms underlying the complex pathophysiology of stroke, yet their precise interactions remain poorly understood. Notably, the silent information regulator 2 homolog 1 (SIRT1)/AMP‑activated protein kinase (AMPK)/peroxisome proliferator‑activated receptor γ coactivator 1‑α (PGC1α) pathway contributes to the neuronal protection against stroke damage. The possible beneficial effects through modulations of this pathway are explored in the present review, in particular, how flavonoids may provide a promising solution to reducing the consequences of stroke. Over the years, there has been a focus on treatments using alternative methods, leaving behind the traditional drugs‑based approaches. These involve researching the impacts of physical activity and caloric intake and assessing the possible advantages of naturally available products. This versatile approach provides new prospects of therapeutic development. The present comprehensive review aimed to understand the complexity of SIRT1/AMPK/PGC1α pathway with the aim to identify potential multi‑target therapeutic approaches to reduce the notable effects of stroke on global health and wellbeing and offer new promise in the current management of ischemic stroke. The present review demonstrates that SIRT1/AMPK/PGC1α is a key neuroprotective target in stroke. Moreover, it reveals that flavonoids combined with exercise and caloric restriction enhance treatment, and that flavonoid nanoparticles crossing the blood‑brain barrier offer neuroprotection. Finally, the review focuses on brain PGC1α, improved delivery and trials performed to advance stroke therapy.
Irreversible damage to auditory hair cells is a primary etiology of sensorineural hearing loss. Across the vertebrate phylogenetic lineage, the regenerative capacity of these cells exhibits a marked decline: from robust regeneration in fish and amphibians, to functionally limited regeneration in birds, culminating in the permanent loss of this ability upon hair cell maturation in mammals. To elucidate the molecular logic underlying this evolutionary divergence and explore viable pathways for regeneration, this article employs a systematic cross-species comparative analysis. We propose that regenerating species share a highly conserved regenerative framework, whose most representative core components include: supporting cells as the key progenitor source, transcriptional reprogramming centered on genes such as Atonal homolog 1 (Atoh1), and a switch to a permissive microenvironmental state. The variation in regenerative capacity primarily stems from species-specific regulatory networks superimposed upon this core framework (e.g., the Forkhead box G1a (Foxg1a)/SRY-related HMG-box (SOX)/Sine oculis homeobox (Six) network in fish, the Fibroblast growth factor (FGF)-Extracellular signal-regulated kinase (ERK)-SOX2 cascade in birds), which fine-tune the efficiency and mode of regeneration. Based on this, we advance a "Multiple Checkpoints" hypothesis, positing that the acquisition of a regeneration-silent state in mammals is not due to the loss of the core framework. Instead, evolutionary processes have erected physiological barriers requiring coordinated overcoming at these key junctures, including: deep quiescence of progenitor cells, failure to initiate core reprogramming programs, and degeneration of the permissive microenvironment. This framework suggests that future therapeutic strategies aimed at achieving functional hearing restoration will likely require the concerted targeting of these multiple barriers. Through temporally precise interventions, microenvironmental remodeling, and combinatorial therapies, it may be possible to reactivate this evolutionarily dormant regenerative potential into a clinically viable new pathway.
Levamisole, once a common anthelmintic and now a frequent adulterant in street cocaine, has emerged as a silent marker of illicit drug use and exposure. Detecting it in biological samples remains difficult due to its rapid metabolism and low concentrations. Here, we introduce a rapid electrochemical biosensor that turns this challenge into an opportunity by exploiting the inhibitory power of levamisole on alkaline phosphatase (ALP). Using flexible screen-printed electrodes and a simple enzyme drop-casting step, the device converts enzyme inhibition into a measurable current drop, providing a direct electrochemical signature of levamisole. The biosensor displayed a limit of detection of 3.4 nM (≈0.8 ng mL-1), limit of quantification of 11.5 nM (≈2.8 ng mL-1), and RSD of 7 %, ensuring reproducible performance. To assess its applicability in biological matrices, the sensor was tested in artificial urine, chosen as a model fluid for potential for potential forensic and toxicological screening. The system maintained high sensitivity and selectivity, consistent with concentrations and interferents reported in urine. The method was further validated through the analysis of urine samples spiked with cocaine samples different percentages of levamisole, yielding recoveries between 89 and 95 %. This work presents the first ALP-based electrochemical biosensor for levamisole, offering a fast, low-cost, and portable platform that could support on-site forensic screening of cocaine adulteration and levamisole exposure, bridging the gap between laboratory toxicology and field-deployable diagnostics.
We aimed to determine the frequency of subclinical optic nerve (ON) lesions using MRI, optical coherence tomography (OCT), and visual evoked potentials (VEP) in radiologically isolated syndrome (RIS), and to assess their diagnostic and prognostic significance. We conducted a retrospective, multicenter study of 179 RIS individuals followed in clinical practice who met the 2023 RISC criteria. The diagnostic performance of the 2024 McDonald criteria, with and without optic nerve assessment, was evaluated and compared with that of the 2017 criteria. Associations with clinical conversion, comorbidities, and MRI disease activity were analyzed using multivariate models. Silent ON lesions appeared in 107/179 (59.8%) individuals, mainly detected by VEP (100/164; 61.0%) and OCT (69/118; 58.5%), with routine MRI identifying 31/166 (18.7%). During follow-up, 71 (39.7%) had a first clinical event. The presence, laterality, or number of silent ON lesions did not correlate with clinical conversion, event type, or MRI activity. Younger age and the absence of comorbidities associated with other MRI lesions, rather than with ON lesions, were associated with clinical conversion. Including ON in the 2024 McDonald criteria increased sensitivity but decreased specificity, with 17/179 (9.5%) meeting dissemination-in-space criteria solely due to ON lesions. Subclinical ON lesions are common in RIS and are mainly found by OCT and VEP, not routine MRI. Including ON increases sensitivity but does not predict clinical conversion and may lower specificity. These findings suggest cautious interpretation of ON and support a multimodal assessment approach in RIS.
Silent treatment represents a subtle yet harmful form of ostracism, often accompanied by emotional distress and ambiguity regarding the reasons for exclusion. This research investigated the emotional responses of individuals exposed to silent treatment, with a particular focus on the role of guilt. Study 1 involved participants recalling episodes of silent treatment and neglect, allowing for a comparison of the emotions elicited in these relational contexts. Results indicated that guilt, sadness, and fear were more pronounced during silent treatment, while the source was perceived as expressing greater anger and disgust. Study 2 employed an experimental design to explore the specific nature of guilt, distinguishing between altruistic and deontological guilt. Findings revealed that silent treatment is associated with heightened deontological guilt, which is linked to violations of moral norms and uncertainty. These studies provide a contribution to the understanding of silent treatment and its implications for relational and emotional well-being.
Measles is one of the most highly contagious and inflictive human viral infections, and approximately 90% of exposed individuals become infected following the exposure. The infection is communicable from one day before the prodromal symptom onset until four days after rash onset. Up to 40% of people who attract measles will have other health problems arising during the course of infection. There is no specific treatment for measles. Recent reports highlight that measles infection erases the already existing immune memory of various pathogens. The latest measles outbreaks in sub-Saharan Africa and Europe show the ease with which measles virus can re-enter communities. However, measles outbreaks in recent years have been reported in all regions of the world, including countries that had previously declared the disease eliminated such as United Kingdom and the United States. The present review article provides an outlook of the current epidemiology and challenges to support the global efforts in controlling the disease through discussion on the recent resurgence and enumerating the factors hindering the eradication of measles. This constellation of factors contributing to measles resurgence and outbreak propagation is multifactorial. Key drivers include suboptimal vaccine coverage, stemming from either outright vaccine refusal or barriers to healthcare access leading to incomplete vaccination schedules. This results in a diminution of herd immunity, compromising community-wide protection. Furthermore, primary or secondary vaccine failure, while rare, contributes to a residual pool of susceptible individuals. Diagnostic challenges, including the misdiagnosis of measles as other exanthematous illnesses, can delay outbreak containment and facilitate silent transmission. An epidemiological consequence of prolonged low transmission is an upward shift in the age-specific susceptibility profile, exposing older children and adults who lack natural immunity. Finally, sociopolitical instability, conflict, and resultant internal displacement create conditions conducive to outbreaks by disrupting healthcare infrastructure, hampering vaccination campaigns, and fostering high-density living conditions among vulnerable populations. This review addresses a major gap in measles eradication by integrating scattered evidence on measles resurgence into an integrated comprehensive framework, encompassing health system, epidemiological, immunological, and sociopolitical factors.
Accurate cerebral arteriovenous malformation (CAVM) nidus volume measurement is important for evaluating treatment strategy and neurologic prognosis. This study aimed to compare the accuracy of silent MRA for measuring CAVM nidus volume with TOF-MRA and to analyze the clinical factors that may affect the nidus volume measurement. A total of 45 patients diagnosed with CAVM who received silent MRA, TOF-MRA, and DSA examinations were retrospectively enrolled. A standardized protocol was used for nidus volume measurement using thresholding by these three imaging tools. The mean nidus volume measured by 3D-DSA, silent MRA, and TOF-MRA was 9.073 (SD, 7.667) mL, 9.55 (SD, 7.814) mL, and 7.773(SD, 7.11) mL, respectively. The linear correlation coefficient of the nidus volume was 0.976 (P < .001) and .966 (P < .001), respectively. Silent MRA was significantly higher than TOF MRA in nidus overlap volume (0.775 [SD. 0.109] versus 0.538 [SD. 0.206] P = .00), while TOF MRA was significantly higher than silent MRA in absolute volume difference (0.196 [SD. 0.192] versus 0.114 [SD. 0.147], P = .005). For both silent MRA and TOF-MRA, the nidus overlap volume and absolute volume difference were significantly associated with previous embolization status. Nidus volume measurement by silent MRA is comparable with DSA and is practical. Silent MRA can be used for nidus volume measurement and as a follow-up tool for evaluating nidus volume change after therapy.
Hospital-at-home (HaH) is becoming more widely available to children with cancer, providing care in a familiar environment while upholding medical safety and quality. Little is known, however, about how these children experience their parents' caregiving in the context of HaH, how they perceive and interpret parental roles, what they require in daily care, and how they communicate these needs. Seven children aged 7 to 12 years undergoing home-based cancer treatment were interviewed using interpretative phenomenological analysis (IPA). These interviews, conducted via telephone, were open-ended and exploratory, allowing the children to express their experiences freely. One major theme-'the child's voice'-emerged, encompassing two interrelated sub-themes: (1) parental presence as a condition of care; and (2) the strategies children use to express their voice. Parental presence was described as essential for emotional security, predictability and meaning, serving as both a psychological anchor and a temporal organiser in the child's daily life. The children expressed their voice through multiple forms-verbal, gestural, symptom-focused or silent-revealing their active participation in care and their capacity to preserve relational and emotional continuity within the family setting. Children with cancer perceive HaH as more than a transfer of hospital treatment; they experience it as a shared relational experience built on parental presence and mutual understanding. Recognising and supporting the child's voice in its various forms is vital for ensuring that HaH becomes not only a site for medical care but also a meaningful space for living. Our findings highlight the need for healthcare teams to take into account the variety of children's voices and grant them a real place in HaH. They are not simply recipients of care, but also active participants in the care relationship, capable of expressing their needs, emotions, and expectations in their own way. No patient or public contribution.
Cytochrome P450 (P450)-mediated metabolism may contribute to diclofenac (DCF)-induced hepatotoxicity via reactive metabolites that damage cellular biomolecules. Several drugs inhibit or induce the P450 enzymes and affect DCF hepatotoxicity signaling pathways. Building on our recent Hepatocyte Pharmacology Lab elucidation of the mechanisms underlying the direct protective effects of a drug against DCF-induced hepatocytotoxicity, the current study aimed further to explore the drug's indirect, metabolic-mediated effects. To achieve this aim, in vitro inhibition was performed in isolated rat hepatocyte suspensions to investigate the impact of amiodarone (AMIO). In vivo induction in rats was also undertaken to investigate the effects of dexamethasone. Parameters assessed included oxidative stress, inflammation, and apoptosis markers, as well as P450 signaling and the silent mating type information regulation 2 homolog /nuclear erythroid 2-related factor 2/nuclear factor kappa light-chain-enhancer of activated B cells (SIRT1/Nrf2/NF-κb) pathways in DCF-induced hepatotoxicity. AMIO significantly decreased markers of oxidative stress, inflammation, and apoptosis. Furthermore, AMIO exerted its protective effects by reducing pregnane X receptor expression and decreasing the protein level of CYP3A4 and CYP2C9. Alternatively, DEXA pretreatment exacerbated DCF-induced hepatotoxicity by elevating liver enzyme indices and potentiating oxidative stress, inflammation, and markers of apoptosis. Additionally, DEXA pretreatment upregulated pregnane X receptor expression and increased CYP3A4 and CYP2C9 protein content. The P450 enzymes were induced by DEXA-mediated metabolic activation of DCF, which aggravated its hepatotoxicity indices and signaling pathways. At the same time, P450 inhibition by AMIO attenuated its hepatocytotoxicity by targeting SIRT1/Nrf2/NF-kB and counteracting oxidative, inflammatory, and apoptotic damage. SIGNIFICANT STATEMENT: This study shows that dexamethasone and amiodarone have distinct effects on diclofenac-induced hepatotoxicity, mediated by pregnane X receptor-regulated P450 enzymes. This study demonstrates that these interactions modify the SIRT1/Nrf2 and NF-κB pathways, thereby influencing oxidative damage and caspase-3-mediated apoptosis. The findings elucidate the mechanistic basis for drug-drug interactions involving diclofenac, dexamethasone, and amiodarone.
Whilst perioperative complications of implant-based breast surgery are well described in literature, late complications are comparatively uncommon, including anaplastic large cell lymphoma, late seroma, and late haematoma. The latter is rarely reported, and its aetiology remains a subject of ongoing debate with proposed mechanisms including direct trauma and capsular microfracture. We present a case in which low velocity blunt chest wall trauma precipitated concurrent implant rupture and late peri-implant haematoma 17 years following cosmetic breast augmentation (outside the perioperative period), in a patient with severe capsular contracture, requiring complex single-stage revisional surgery. This case contributes to the limited body of evidence on late postoperative complications of cosmetic breast augmentation in particular and implant-based breast surgery in general and highlights the diagnostic challenges inherent to the 'silent rupture' phenomenon. Clinicians should maintain a low threshold for implant assessment following blunt chest trauma, regardless of the velocity of the inciting injury.
Intracranial dermoid cysts are rare congenital inclusion cysts derived from ectodermal elements and account for a very small proportion of intracranial lesions. Although they are usually slow-growing and may remain clinically silent for years, they can become symptomatic once they exert mass effect or obstruct cerebrospinal fluid pathways. Posterior fossa involvement is uncommon, and delayed clinical presentation may occur despite long-standing lesion growth. This report describes a posterior fossa dermoid cyst causing obstructive hydrocephalus in an adolescent patient and highlights the radiological, histopathological, and surgical considerations relevant to its management. The patient, a 16-year-old female, presented with a 3-year history of progressive visual impairment, daily vomiting, fatigue, and loss of appetite. Radiological studies, including computerized tomography and magnetic resonance imaging scans, revealed a midline cystic lesion within the fourth ventricle, leading to active obstructive hydrocephalus. Clinical manifestations included signs of increased intracranial pressure and fourth ventricle narrowing. Histopathological examination of tissue fragments from the cyst wall demonstrated a lining of squamous epithelium with evidence of parakeratosis. Furthermore, the necessity for careful consideration of surgical techniques is underscored, as dermoid cysts could exhibit adherence to arachnoid tissue. Intraoperatively, the lesion was approached through a posterior fossa craniotomy, and cyst decompression/ excision was performed with careful microsurgical dissection because the capsule was adherent to surrounding arachnoid and neural structures. This report emphasizes the significance of early diagnosis and surgical intervention in managing the intricate challenges posed by posterior fossa dermoid cysts.
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Mechanical hypersensitivity following peripheral nerve injury is common and difficult to treat. It has been suggested that this results from activation of a normally silent spinal cord circuit that links low-threshold mechanoreceptive primary afferents to nociceptive projection neurons in lamina I and that this pathway involves a class of excitatory interneurons known as vertical cells. We have recently identified 2 neurochemical types of vertical cells, based on expression of the gastrin-releasing peptide receptor (GRPR) and neuropeptide FF (NPFF). Although little is known about the role of NPFF cells, those that express GRPR are strongly implicated in itch; for example, it has been reported that ablation of GRPR cells suppresses itch but has no effect on pain. In this study, we have used chemogenetics to inhibit each population separately (in GRPRCreERT2 and NPFFCre mice) and both together (in GRPRCreERT2; NPFFCre mice). We found that the itch evoked by intradermal injection of chloroquine in the calf was suppressed in each case, but there was no effect on baseline mechanical sensitivity. In addition, we saw no effect of the chemogenetic inhibition on either mechanical hypersensitivity or on a measure of spontaneous pain in the spared nerve injury model of neuropathic pain. These results indicate that both of these populations of vertical cells are involved in the itch evoked by chloroquine but do not support a role for these cells in neuropathic mechanical hypersensitivity.
Class C GPCRs function as obligate dimers in which only one G protein can engage the complex at a time, but how each protomer contributes to heterodimer coupling has remained unresolved. Using CODA-RET, a BRET-based assay reporting direct Gα q recruitment to defined, full-length receptor pairs, we show that signaling at the mGlu₁/₅ heterodimer flows predominantly through the mGlu₁ protomer; domain-swapped chimeras localize this dominance to the transmembrane domain. The dominance generates emergent signaling: cis-acting mGlu₁ PAMs and NAMs undergo allosteric inversion when coupling is restricted to mGlu₅. By contrast, the mGlu₅-selective NAM MTEP is silent at the heterodimer, mirroring mGlu₅'s minimal role in driving Gα q . Because the mGlu₁ PAM tested acts only in cis, a trans-acting mGlu₁ PAM would theoretically be selective for mGlu₁/₁ homomers. These findings open a pharmacological design space in which protomer target and cis-versus-trans mode of action tune selectivity across mGlu₁/₁, mGlu₅/₅, and mGlu₁/₅ dimers.