Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer.

Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.

Spatially organized multicellular immune hubs in human colorectal cancer.

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

Pinch Grafting: A Systematic Review of Modern Perspectives and Applications in Dermatologic Surgery and Wound Healing.

BACKGROUND: Pinch grafting has experienced a resurgence in interest in recent years, stemming from its simplicity, safety, and potential in restoring tissue integrity. While historically employed for chronic nonhealing wounds, pinch grafts have shown promise following surgical procedures, particularly those involving the lower extremities. OBJECTIVE: To systematically review the literature and present an updated overview of the current applications of pinch grafting. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. In collaboration with a medical reference librarian, the PubMed, Embase, Scopus, and Web of Science databases were searched for studies reporting on the use of pinch grafting from 2000 onward. The references of each included article were also screened. RESULTS: Ten articles met final inclusion criteria. In total, 300 patients underwent pinch grafting for treatment of skin ulceration, while an additional 35 cases were performed as an alternative to primary closure following skin cancer resection. Overall, pinch grafting was safe and well tolerated, with minimal adverse outcomes reported. CONCLUSION: Pinch grafting is a safe, straightforward, and effective technique to promote the healing of chronic wounds. While the procedure shows early promise in emerging applications within dermatologic surgery, only about 10% of the reported cases involved this indication, reflecting a need for further research in this area.

Permanent section margin concordance after Mohs micrographic surgery with immunohistochemistry for invasive melanoma and melanoma in situ: A retrospective dual-center analysis.

BACKGROUND: Mohs micrographic surgery (MMS) for melanoma practices vary among dermatologic surgeons. The implementation of immunohistochemical staining in MMS for melanoma mitigates challenges associated with slide interpretation; however, the reliability of melanoma antigen recognized by T cells 1 (MART-1), the preferred immunostain for melanoma, has yet to be compared with permanent section pathology. OBJECTIVE: To assess concordance rates of MART-1 frozen sections and permanent section pathologic interpretation of melanoma treated with MMS. METHODS: A dual-center retrospective analysis was conducted to collect concordance and demographic data. Chi-square tests were performed for group comparisons of categorical variables. RESULTS: Of the 379 permanent sections sent, 367 were concordant with frozen section pathology for an overall concordance rate of 96.8%. Cases were stratified into indeterminately concordant and indisputably concordant. Twenty-two (6%) of cases were indeterminately concordant, whereas 345 (94.0%) of cases were indisputably concordant. LIMITATIONS: The concordance rate is derived from a comparison of adjacent tissue margins, an inevitable consequence of utilizing 2 techniques. CONCLUSION: To the author's knowledge, this study represents the largest investigation examining concordance rates of MART-1 frozen sections in Mohs for melanoma. High concordance disputes the ongoing need for additional permanent margins when using MART-1 in routine cases.

Asthenosphere rheology inferred from observations of the 2012 Indian Ocean earthquake.

The concept of a weak asthenospheric layer underlying Earth's mobile tectonic plates is fundamental to our understanding of mantle convection and plate tectonics. However, little is known about the mechanical properties of the asthenosphere (the part of the upper mantle below the lithosphere) underlying the oceanic crust, which covers about 60 per cent of Earth's surface. Great earthquakes cause large coseismic crustal deformation in areas hundreds of kilometres away from and below the rupture area. Subsequent relaxation of the earthquake-induced stresses in the viscoelastic upper mantle leads to prolonged postseismic crustal deformation that may last several decades and can be recorded with geodetic methods. The observed postseismic deformation helps us to understand the rheological properties of the upper mantle, but so far such measurements have been limited to continental-plate boundary zones. Here we consider the postseismic deformation of the very large (moment magnitude 8.6) 2012 Indian Ocean earthquake to provide by far the most direct constraint on the structure of oceanic mantle rheology. In the first three years after the Indian Ocean earthquake, 37 continuous Global Navigation Satellite Systems stations in the region underwent horizontal northeastward displacements of up to 17 centimetres in a direction similar to that of the coseismic offsets. However, a few stations close to the rupture area that had experienced subsidence of up to about 4 centimetres during the earthquake rose by nearly 7 centimetres after the earthquake. Our three-dimensional viscoelastic finite-element models of the post-earthquake deformation show that a thin (30-200 kilometres), low-viscosity (having a steady-state Maxwell viscosity of (0.5-10) × 1018 pascal seconds) asthenospheric layer beneath the elastic oceanic lithosphere is required to produce the observed postseismic uplift.

Prevalence and predictive value of ICD-11 post-traumatic stress disorder and Complex PTSD diagnoses in children and adolescents exposed to a single-event trauma.

BACKGROUND: The 11th edition of the International Classification of Diseases (ICD-11) made a number of significant changes to the diagnostic criteria for post-traumatic stress disorder (PTSD). We sought to determine the prevalence and 3-month predictive values of the new ICD-11 PTSD criteria relative to ICD-10 PTSD, in children and adolescents following a single traumatic event. ICD-11 also introduced a diagnosis of Complex PTSD (CPTSD), proposed to typically result from prolonged, chronic exposure to traumatic experiences, although the CPTSD diagnostic criteria do not require a repeated experience of trauma. We therefore explored whether children and adolescents demonstrate ICD-11 CPTSD features following exposure to a single-incident trauma. METHOD: Data were analysed from a prospective cohort study of youth aged 8-17 years who had attended an emergency department following a single trauma. Assessments of PTSD, CPTSD, depressive and anxiety symptoms were performed at two to four weeks (n = 226) and nine weeks (n = 208) post-trauma, allowing us to calculate and compare the prevalence and predictive value of ICD-10 and ICD-11 PTSD criteria, along with CPTSD. Predictive abilities of different diagnostic thresholds were undertaken using positive/negative predictive values, sensitivity/specificity statistics and logistic regressions. RESULTS: At Week 9, 15 participants (7%) were identified as experiencing ICD-11 PTSD, compared to 23 (11%) experiencing ICD-10 PTSD. There was no significant difference in comorbidity rates between ICD-10 and ICD-11 PTSD diagnoses. Ninety per cent of participants with ICD-11 PTSD also met criteria for at least one CPTSD feature. Five participants met full CPTSD criteria. CONCLUSIONS: Reduced prevalence of PTSD associated with the use of ICD-11 criteria is likely to reduce identification of PTSD relative to using ICD-10 criteria but not relative to DSM-4 and DSM-5 criteria. Diagnosis of CPTSD is likely to be infrequent following single-incident trauma.

Innovation in a crisis: rethinking conferences and scholarship in a pandemic and climate emergency.

It is a cliché of self-help advice that there are no problems, only opportunities. The rationale and actions of the BSHS in creating its Global Digital History of Science Festival may be a rare genuine confirmation of this mantra. The global COVID-19 pandemic of 2020 meant that the society's usual annual conference - like everyone else's - had to be cancelled. Once the society decided to go digital, we had a hundred days to organize and deliver our first online festival. In the hope that this will help, inspire and warn colleagues around the world who are also trying to move online, we here detail the considerations, conversations and thinking behind the organizing team's decisions.

Impact of culture on autobiographical life structure in depression.

OBJECTIVES: Distortions in autobiographical memory have been implicated in major depressive disorder (MDD). Those with MDD demonstrate a 'depressogenic' autobiographical life structure. Research has not examined how culture influences this process. We investigated whether Malay individuals (members of an interdependent culture) with MDD demonstrated a 'depressogenic' autobiographical life structure similar to that of British individuals (members of an independent culture) with MDD. DESIGN: A 2 (Culture; Malay, British) × 2 (Mood; depressed, control) cross-sectional design using a card sort task and self-report measures was used. METHODS: Malay individuals with MDD or no history of MDD completed the life-structure card-sorting task, which provided a novel method for investigating organizational structure of the life narrative. These data were compared to previously collected data in which British individuals with MDD or without MDD had completed the same task within the same experimental protocol. RESULTS: Pan-culturally those with MDD had greater negativity (i.e., used more negative attributes), negative redundancy (i.e., used the same negative attributes repeatedly across life chapters) and negative emodiversity (i.e., had greater variety and relative abundance of negative attributes), and reduced positive redundancy (i.e., used the same positive attributes repeatedly across chapters) in their structuring relative to controls. While the British MDD group had greater compartmentalization (i.e., the negative and positive attributes were clustered separately across different chapters) than British controls, the Malay MDD group had lower levels of compartmentalization than Malay controls. CONCLUSIONS: The findings suggest culture may shape aspects of the autobiographical life structure in MDD. PRACTITIONER POINTS: The majority of the literature investigating depression pertains to individuals from European Western cultures, despite recognition that depression ranks as one of the most debilitating diseases worldwide. This raises questions as to whether current depression models and interventions can be applied universally or whether they are limited to European Western groups. The current study found that pan-culturally those with MDD had similar structuring of their life story relative to controls. However, there were some cultural differences that need to be considered (e.g., Malay individuals provided less detailed, less elaborate and less emotionally diverse life stories and while the British MDD group had greater compartmentalization than British controls, the Malay MDD group had lower levels of compartmentalization than Malay controls). Limitations of the study included group differences in gender and mood at the time of testing. Cultural differences in the number of attributes used may have influenced findings. Only the Malay group completed the individualism-collectivism measure.

Hedonic and disgust taste perception in borderline personality disorder and depression.

Depression and borderline personality disorder (BPD) are both thought to be accompanied by alterations in the subjective experience of environmental rewards. We evaluated responses in women to sweet, bitter and neutral tastes (juice, quinine and water): 29 with depression, 17 with BPD and 27 healthy controls. The BPD group gave lower pleasantness and higher disgust ratings for quinine and juice compared with the control group; the depression group did not differ significantly from the control group. Juice disgust ratings were related to self-disgust in BPD, suggesting close links between abnormal sensory processing and self-identity in BPD.

A prospective study of the acquisition of vaginal examination skills using simulation.

OBJECTIVE: To determine the number of sessions required using procedural simulation to acquire the skill of vaginal examination, which is an essential part of obstetrics, but a difficult learned skill. METHODS: Using a high-fidelity simulator, we conducted a prospective, single-center, single-blind study, at the Angers School of Midwifery. A class of students completed a theory course, and took part in three simulation sessions. During the simulation sessions, each student was asked to describe five different cervixes, under five criteria: position, length, consistency, dilation, and head station. Each participant received individual feedback as part of a debrief session, after completing their description. A pass rate of 80% was set for the entire class. RESULTS: Twenty-six students participated. The class achieved a mean score of 70.77 ± 10.23% in the first session, 81.85 ± 9.91% in the second session, and 81.23 ± 8.63% in the third session. There was a significant improvement only between the first and second sessions (P < 0.001). Of the 26 participants, 6 (23%) scored over 80% in the first session, 17 participants (65%) scored above 80% in the first two sessions, and 21 participants (80%) scored above 80% over the three sessions. CONCLUSION: Learning vaginal examination by procedural simulation with the aid of a high-fidelity simulator, and receiving individual feedback and debrief, resulted in an 80% pass rate in two practical sessions, working to describe 10 cervixes.

Prevalence of Arm Weakness, Pre-Stroke Outcomes and Other Post-Stroke Impairments Using Routinely Collected Clinical Data on an Acute Stroke Unit.

INTRODUCTION: The prevalence of upper limb motor weakness early post-stroke may be changing, which can have clinical and research implications. Our primary aim was to describe the prevalence of upper limb motor weakness early post-stroke, with a secondary aim to contextualize this prevalence by describing pre-stroke outcomes, other post-stroke impairments, functional activities, and discharge destination. METHODS: This cross-sectional observational study extracted clinical data from confirmed stroke patients admitted to a metropolitan stroke unit over 15-months. The primary upper limb weakness measure was Shoulder Abduction and Finger Extension (SAFE) score. Demographics (eg, age), clinical characteristics (eg, stroke severity), pre-stroke outcomes (eg, clinical frailty), other post-stroke impairments (eg, command following), functional activities (eg, ambulation), and discharge destination were also extracted. RESULTS: A total of 463 participants had a confirmed stroke and SAFE score. One-third of patients received ≥1 acute medical intervention(s). Nearly one-quarter of patients were classified as frail pre-stroke. Upper limb weakness (SAFE≤8) was present in 35% [95% CI: 30%-39%] at a median of 1-day post-stroke, with 22% presenting with mild-moderate weakness (SAFE5-8). The most common other impairments were upper limb coordination (46%), delayed recall (41%), and upper limb sensation (26%). After a median 3-day acute stroke stay, 52% of the sample were discharged home. CONCLUSION: Upper limb weakness was present in just over a third (35%) of the sample early post-stroke. Data on pre-stroke outcomes and the prevalence of other post-stroke impairments highlights the complexity and heterogeneity of stroke recovery. Further research is required to tease out meaningful recovery phenotypes and their implications.

Psychological aspects of vestibular disorders: a national survey of clinical practice.

OBJECTIVE: This study examines how psychological aspects of vestibular disorders are currently addressed highlighting any national variation. METHOD: An online survey was completed by 101 UK healthcare professionals treating vestibular disorders. The survey covered service configurations, attitudes towards psychological aspects and current clinical practice. RESULTS: Ninety-six per cent of respondents thought there was a psychological component to vestibular disorders. There was a discrepancy between perceived importance of addressing psychological aspects and low confidence to undertake this. Those with more experience felt more confident addressing psychological aspects. History taking and questionnaires containing one or two psychological items were the most common assessment approaches. Discussing symptoms and signposting were the most frequent management approaches. Qualitative responses highlighted the interdependence of psychological and vestibular disorders which require timely intervention. Barriers included limited referral pathways, resources and interdisciplinary expertise. CONCLUSION: Although psychological distress is frequently identified, suitable psychological treatment is not routinely offered in the UK.

Slow rupture in a fluid-rich fault zone initiated the 2024 Mw 7.5 Noto earthquake.

The 2024 moment magnitude 7.5 Noto Peninsula (Japan) earthquake caused devastation to communities and was generated by a complex rupture process. Using space geodetic and seismic observations, we have shown that the event deformed the peninsula with a peak uplift reaching 5 meters at the west coast. Shallow slip exceeded 10 meters on an offshore fault. Peak stress drop was greater than 10 megapascals. This devastating event began with a slow rupture propagation lasting 15 to 20 seconds near its hypocenter, where seismic swarms had surged since 2020 because of lower-crust fluid supply. The slow start was accompanied by intense high-frequency seismic radiation. These observations suggest a distinct coseismic slip mode reflecting high heterogeneity in fault properties within a fluid-rich fault zone.

Trauma Memory Characteristics and Neurocognitive Performance in Youth Exposed to Single-Event Trauma.

Cognitive models of posttraumatic stress disorder (PTSD) highlight characteristics of trauma memories, such as disorganisation, as key mechanisms in the aetiology of the disorder. However, studies investigating trauma memory in youth have provided inconsistent findings. Research has highlighted that PTSD in youth may be accompanied by difficulties in neurocognitive functioning, potentially impacting ability to recall the trauma memory. The present study sought to investigate both trauma memory characteristics and neurocognitive functioning in youth aged 8-17 years. Youths exposed to single-event trauma, with (N = 29, Mage = 13.6, 21 female) and without (N = 40, Mage = 13.3, 21 female) a diagnosis of PTSD, completed self-report measures of trauma memory, a narrative memory task and a set of neurocognitive tests two to six months post-trauma. A group of non trauma-exposed youths (N = 36, Mage = 13.9, 27 female) were compared on narrative and neurocognitive tasks. Results indicated that trauma memories in youth with, versus without, PTSD were more sensory-laden, temporally disrupted, difficult to verbally access, and formed a more 'central' part of their identity. Greater differences were observed for self-reported memory characteristics compared to narrative characteristics. No between group differences in neurocognitive function were observed. Self-reported trauma memory characteristics highlight an important factor in the aetiology of PTSD. The observed lack of significant differences in neurocognitive ability potentially suggests that cognitive factors represent a more relevant treatment target than neurocognitive factors in single-event PTSD. Further research to understand the cognitive factors represented by self-reported trauma memory characteristics is recommended.

The benefit of early-stage diagnosis: A registry-based survey evaluating the quality of life in patients with melanoma.

Background: The morbidity associated with advanced stage melanoma is an important consideration in the dialog surrounding early detection and overdiagnosis. Few studies have stratified melanoma patient quality of life (QoL) by stage at diagnosis. Objective: We sought to investigate if melanoma stage is independently associated with changes in QoL within a large, community-based melanoma registry. Secondarily, we investigated whether demographic factors such as age, geographic location or level of education are associated with changes in QoL in the same population. Methods: 1108 melanoma patients were surveyed over a three-month period using the QoL in Adult Cancer Survivors Survey, consisting of 47 items on a 7-point frequency scale. Data were analysed using both descriptive statistical models and adjusted multivariate logistic regression. Results: There were 677 respondents generating a 61% response rate. Overall, higher stage at diagnosis correlated with the largest decreases in QoL as it pertained to both general (p = 0.001) and Cancer-Specific stressors (p < 0.001). Education level (p = 0.020), age (p < 0.001), rural area code designation (p = 0.020) and family history of melanoma (p = 0.017) were also independently associated with changes in QoL. Conclusion: Earlier stage at melanoma diagnosis is associated with better QoL and thus represents a crucial intervention in patient care. Given our findings and the growing body of evidence surrounding morbidity in late-stage melanoma, it is essential that QoL be included in assessing the benefits of early detection.

Development of a network of carcinogenicity adverse outcome pathways and its employment as an evidence framework for safety assessment

The traditional paradigm for safety assessment of chemicals for their carcinogenic potential to humans relies heavily on a battery of well-established genotoxicity tests, usually followed up by long-term, high-dose rodent studies. There are a variety of problems with this approach, not least that the rodent may not always be the best model to predict toxicity in humans. Consequently, new approach methodologies (NAMs) are being developed to replace or enhance predictions coming from the existing assays. However, a combination of the data arising from NAMs is likely to be required to improve upon the current paradigm, and consequently a framework is needed to combine evidence in a meaningful way. Adverse outcome pathways (AOPs) represent an ideal construct on which to organize this evidence. In this work, a data structure outlined previously was used to capture AOPs and evidence relating to carcinogenicity. Knowledge held within the predictive system Derek Nexus was extracted, built upon, and arranged into a coherent network containing 37 AOPs. 60 assays and 351 in silico alerts were then associated with KEs in this network, and it was brought to life by associating data and contextualizing evidence and predictions for over 13,400 compounds. Initial investigations into using the network to view knowledge and reason between evidence in different ways were made. Organizing knowledge and evidence in this way provides a flexible framework on which to carry out more consistent and meaningful carcinogenicity safety assessments in many different contexts.

Programmatic Precision Oncology Decision Support for Patients With Gastrointestinal Cancer.

PURPOSE: With the growing number of available targeted therapeutics and molecular biomarkers, the optimal care of patients with cancer now depends on a comprehensive understanding of the rapidly evolving landscape of precision oncology, which can be challenging for oncologists to navigate alone. METHODS: We developed and implemented a precision oncology decision support system, GI TARGET, (Gastrointestinal Treatment Assistance Regarding Genomic Evaluation of Tumors) within the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute. With a multidisciplinary team, we systematically reviewed tumor molecular profiling for GI tumors and provided molecularly informed clinical recommendations, which included identifying appropriate clinical trials aided by the computational matching platform MatchMiner, suggesting targeted therapy options on or off the US Food and Drug Administration-approved label, and consideration of additional or orthogonal molecular testing. RESULTS: We reviewed genomic data and provided clinical recommendations for 506 patients with GI cancer who underwent tumor molecular profiling between January and June 2019 and determined follow-up using the electronic health record. Summary reports were provided to 19 medical oncologists for patients with colorectal (n = 198, 39%), pancreatic (n = 124, 24%), esophagogastric (n = 67, 13%), biliary (n = 40, 8%), and other GI cancers. We recommended ≥ 1 precision medicine clinical trial for 80% (406 of 506) of patients, leading to 24 enrollments. We recommended on-label and off-label targeted therapies for 6% (28 of 506) and 25% (125 of 506) of patients, respectively. Recommendations for additional or orthogonal testing were made for 42% (211 of 506) of patients. CONCLUSION: The integration of precision medicine in routine cancer care through a dedicated multidisciplinary molecular tumor board is scalable and sustainable, and implementation of precision oncology recommendations has clinical utility for patients with cancer.

Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity.

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell-cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC. SIGNIFICANCE: A high-throughput pipeline using multiplex immunofluorescence in pancreatic cancer reveals striking expression subtype intratumoral heterogeneity with implications for therapy selection and identifies co-expressor cells that may serve as intermediates during subtype switching.