Revisiting the effectiveness of cognitive-behavioural therapy for reducing reoffending in the criminal justice system: A systematic review.

This is the protocol for a Campbell systematic review. The objectives are as follows. The proposed systematic review is an update to, and extension of, Lipsey et al. (2007). As such we build on their previous aims to: (i) Assess and synthesise the overall impact of cognitive behavioural therapy (CBT) on offender recidivism; (ii) Examine possible sources of variability in the effectiveness of CBT. Data permitting, we will examine if the effectiveness of CBT varies by: (a) Characteristics of the CBT intervention (e.g., cognitive restructuring vs. cognitive skills training, group v. individual implementation; and/or custodial v. community setting, and/or), (b) Characteristics of the population (e.g., juveniles vs. adult offenders), (c) Implementation factors (e.g., implementing practitioner, use of structured/manualised approaches, delivery mode, and/or programme duration or intensity), (d) Evaluation methods (e.g., randomised vs. non-randomised research designs); (iv) Determine whether there is a decline in the effect of CBT on recidivism over time; and (v) Investigate whether there is an interaction between implementation factors and time in terms of the effect on recidivism.

Lack of prion transmission barrier in human PrP transgenic Drosophila.

While animal prion diseases are a threat to human health, their zoonotic potential is generally inefficient because of interspecies prion transmission barriers. New animal models are required to provide an understanding of these prion transmission barriers and to assess the zoonotic potential of animal prion diseases. To address this goal, we generated Drosophila transgenic for human or non-human primate PrP and determined their susceptibility to known pathogenic prion diseases, namely vCJD and classical BSE, and that with unknown pathogenic potential, namely CWD. Adult Drosophila transgenic for M129 or V129 human PrP, or non-human primate PrP developed a neurotoxic phenotype and showed an accelerated loss of survival after exposure to vCJD, classical BSE, or CWD prions at the larval stage. vCJD prion strain identity was retained after passage in both M129 and V129 human PrP Drosophila. All of the primate PrP fly lines accumulated prion seeding activity and concomitantly developed a neurotoxic phenotype, generally including accelerated loss of survival, after exposure to CWD prions derived from different cervid species, including North American white-tailed deer and muntjac, and European reindeer and moose. These novel studies show that primate PrP transgenic Drosophila lack known prion transmission barriers since, in mammalian hosts, V129 human PrP is associated with severe resistance to classical BSE prions, while both human and cynomolgus macaque PrP are associated with resistance to CWD prions. Significantly, our data suggest that interspecies differences in the amino acid sequence of PrP may not be a principal determinant of the prion transmission barrier.

What Are We Transfusing? Evaluating the Quality and Clinical Utility of Intraoperatively Salvaged Red Blood Cells in Spinal Deformity Surgery: A Nonrandomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Intraoperative red blood cell (RBC) salvage is frequently used in contemporary spine surgery, despite clinical concern in its efficacy as a surrogate for blood-banked allogeneic packed RBCs (pRBCs). During spine surgery, salvaged RBCs (sRBCs) are exposed to injurious high-heat electrocautery, prolonged stasis, and abrasive pharmaceuticals, potentially making sRBCs a poor blood substitute. We therefore sought to scientifically and objectively define the quality of sRBCs in the context of complex spine surgery. METHODS: This is a single-center, prospective, nonrandomized controlled trial of patients undergoing posterior-based multilevel thoracolumbar instrumented fusion for spinal deformity with planned use of intraoperative RBC salvage between June 2022 and July 2023. Surgeries were performed by fellowship-trained spinal neurosurgeons and orthopedic surgeons. The participants were split based on transfusion of sRBCs (given sufficient yield) vs no sRBC transfusion. Primary outcomes were RBC electrolyte composition, indices, deformability, and integrity, which were evaluated in comparison blood samples: Baseline, pRBC, and sRBC. Secondary outcomes were related to clinical effects of sRBC transfusion. Morphological assessment used Stimulated Raman Histology and machine learning. Deformability was assessed using ektacytometry. RESULTS: A total of 174 patients were included. The mean age was 50.2years ±25.4, 58.6% was female, the mean level fused was 10.0 ± 3.9, and 58.0% received sRBCs (median 207.0 mL). sRBCs differed significantly on standard laboratory measures, had a high proportion (30.7%) of shrunken and irregularly spiculated morphologies, and demonstrated abnormal deformability and relaxation kinetics. The hemolysis index was significantly elevated in sRBCs (2.9 ± 1.8) compared with Baseline samples and pRBCs (P < .01). Transfusion of sRBCs was associated with suboptimal resuscitation and provided no practical clinical benefit. CONCLUSION: RBCs salvaged during posterior thoracolumbar spine surgery are irreversibly injured, with hemolysis index exceeding Food and Drug Administration and Council of Europe transfusion standards in all samples, questioning their efficacy and safety as a blood substitute.

Does Physiological Arousal Increase Social Transmission of Information? Two Replications of Berger (2011).

People share information for many reasons. For example, Berger (2011, N = 40) found that undergraduate participants manipulated to have higher physiological arousal were more likely to share a news article with others via email than people who had low arousal. Berger's research is widely cited as evidence of the causal role of arousal in sharing information and has been used to explain why information that induces high-arousal emotions is shared more than information that induces low-arousal emotions. We conducted two replications (N = 111, N = 160) of Berger's study, using the same arousal manipulation but updating the sharing measure to reflect the rise of information sharing through social media. Both studies failed to find an impact of incidental physiological arousal on undergraduate participants' willingness to share news articles on social media. Our studies cast doubt on the idea that incidental physiological arousal-in the absence of other factors-impacts people's decisions to share information on social networking sites.

Life-course influences of poverty on violence and homicide: 30-year Brazilian birth cohort study.

BACKGROUND: Homicide is the leading cause of death among young people in Latin America, one of the world's most violent regions. Poverty is widely considered a key cause of violence, but theories suggest different effects of poverty, depending on when it is experienced in the life-course. Longitudinal studies of violence are scarce in Latin America, and very few prospective data are available worldwide to test different life-course influences on homicide. METHODS: In a prospective birth cohort study following 5914 children born in southern Brazil, we examined the role of poverty at birth, in early childhood, and in early adulthood on violence and homicide perpetration, in criminal records up to age 30 years. A novel Structured Life Course Modelling Approach was used to test competing life-course hypotheses about 'sensitive periods', 'accumulation of risk', and 'downward mobility' regarding the influence of poverty on violence and homicide. RESULTS: Cumulative poverty and poverty in early adulthood were the most important influences on violence and homicide perpetration. This supports the hypothesis that early adulthood is a sensitive period for the influence of poverty on lethal and non-lethal violence. Results were replicable using different definitions of poverty and an alternative outcome of self-reported fights. CONCLUSION: Cumulative poverty from childhood to adulthood was an important driver of violence and homicide in this population. However, poverty experienced in early adulthood was especially influential, suggesting the importance of proximal mechanisms for violence in this context, such as unemployment, organized crime, drug trafficking, and ineffective policing and justice systems.

Resuscitation on the field of play: a best-practice guideline from Resuscitation Council UK.

Sudden cardiac arrest (SCA) is the leading cause of sudden death in athletes during high-level, organised sport. Patient-related and event-related factors provide an opportunity for rapid intervention and the potential for high survival rates. The aim of this consensus was to develop a best-practice guideline for dedicated field-of-play medical teams responding to SCA during an organised sporting event. A task-and-finish group from Resuscitation Council UK identified a stakeholder group of relevant experts and cardiac arrest survivors in March and April 2022. Together, they developed a best-practice guideline using the best available evidence. A public consultation period further refined the guideline before it was finalised in December 2023. Any sudden collapse, without rapid recovery during sporting activity, should be considered an SCA until proven otherwise. Field-of-play medical teams should be empowered to access the collapsed athlete as soon as possible and perform initial essential interventions in situ. This includes a suggested minimum of three cycles of cardiopulmonary resuscitation and defibrillation in persistent shockable rhythms while other aspects of advanced life support are initiated. There should be careful organisation and practice of the medical response, including plans to transport athletes to dedicated facilities for definitive medical care. This best-practice guideline complements, rather than supersedes, existing resuscitation guidelines. It provides a clear approach to how to best treat an athlete with SCA and how to organise the medical response so treatments are delivered effectively and optimise outcomes.

One-Pot Access to Functionalised Malamides via Organocatalytic Enantioselective Formation of Spirocyclic ß-Lactone-Oxindoles and Double Ring-Opening.

Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein, an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic ß-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the ß-lactone and oxindole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereo-selectivity (up to >95:5 dr and >99:1 er).

The effect of host size on binding in host-guest complexes of cyclodextrins and polyoxometalates.

Harnessing flexible host cavities opens opportunities for the design of novel supramolecular architectures that accommodate nanosized guests. This research examines unprecedented gas-phase structures of Keggin-type polyoxometalate PW12O40 3- (WPOM) and cyclodextrins (X-CD, X = α, ß, γ, δ, ε, ζ) including previously unexplored large, flexible CDs. Using ion mobility spectrometry coupled to mass spectrometry (IM-MS) in conjunction with molecular dynamics (MD) simulations, we provide first insights into the binding modes between WPOM and larger CD hosts as isolated structures. Notably, γ-CD forms two distinct structures with WPOM through binding to its primary and secondary faces. We also demonstrate that ε-CD forms a deep inclusion complex, which encapsulates WPOM within its annular inner cavity. In contrast, ζ-CD adopts a saddle-like conformation in its complex with WPOM, which resembles its free form in solution. More intriguingly, the gas-phase CD-WPOM structures are highly correlated with their counterparts in solution as characterized by nuclear magnetic resonance (NMR) spectroscopy. The strong correlation between the gas- and solution phase structures of CD-WPOM complexes highlight the power of gas-phase IM-MS for the structural characterization of supramolecular complexes with nanosized guests, which may be difficult to examine using conventional approaches.

Association Between Right Ventricular Systolic Parameters Measured by Echocardiography and Stroke Volume Derived From Pulmonary Artery Catheter in Ischemic Cardiogenic Shock.

OBJECTIVE: To determine the right ventricular (RV) systolic function echocardiographic parameter best associated with native stroke volume (SV) by thermodilution via a pulmonary artery catheter (PAC) in patients admitted to intensive care with ST elevation myocardial infarction (STEMI) complicated by cardiogenic shock (CS). DESIGN, SETTING, AND PARTICIPANTS: An observational cohort study of 43 prospectively identified patients admitted to a tertiary cardiac intensive care unit in London, United Kingdom. INTERVENTIONS: Simultaneous collection of comprehensive transthoracic echocardiographic, clinical, and PAC-derived hemodynamic data. Seven RV systolic function parameters were correlated with the PAC-derived SV. MEASUREMENTS AND MAIN RESULTS: The median patient age was 61 years (interquartile range [IQR], 52-67 years), and 36 of the 43 patients (84%) were male. The median PAC-derived SV and left ventricular ejection fraction were 57 mL (IQR, 39-70 mL) and 31% (IQR, 22%-35%), respectively. The RV outflow tract velocity time integral (RVOT VTI) and tricuspid plane systolic excursion (TAPSE) correlated significantly with the PAC-derived SV (r = 0.42 [p = 0.007] and r = 0.37 [p = 0.02], respectively). The RVOT VTI was independently associated with and predicted low PAC-derived SV (odds ratio, 1.3; p = 0.03) with a good area under the curve (AUC = 0.71; p = 0.02). An RVOT VTI <12.7 cm predicted low PAC-derived SV with a sensitivity of 66% and specificity of 72%. CONCLUSIONS: RVOT VTI is the echocardiographic RV systolic function parameter that best correlates with PAC-derived native SV in patients with STEMI complicated by CS. This parameter can help guide the hemodynamic management of this cohort.

Assessing the Efficacy of an AI-Powered Chatbot (ChatGPT) in Providing Information on Orthopedic Surgeries: A Comparative Study With Expert Opinion.

Background The use of artificial intelligence (AI) as a tool for patient care has continued to rapidly expand. The technology has proven its utility in various applications across several specialties in a variety of applications. However, its practicality in orthopedics remains widely unknown. This study seeks to determine if the open-access software Chat Generative Pre-Trained Transformer (ChatGPT) can be a reliable source of data for patients. Questions/purposes This study aims to determine: (1) Is the open-access AI software ChatGPT capable of accurately answering commonly posed patient questions? (2) Will there be a significant difference in agreement among the study experts in the answers generated by ChatGPT? Methods A standard list of questions for six different procedures across six subspecialties is posed to ChatGPT. The procedures chosen were anterior cruciate ligament (ACL) reconstruction, microdiscectomy, total hip arthroplasty (THA), rotator cuff repair, carpal tunnel release, and ankle fracture open reduction and internal fixation. The generated answers are then compared to expert opinion using a Likert scale based on the agreement of the aforementioned experts. Results On a three-point Likert scale with 1 being disagree and 3 being agree, the mean score across all subspecialties is 2.43, indicating at least partial agreement with expert opinion. There was no significant difference in the Likert scale mean across the six subspecialties surveyed (p = 0.177). Conclusions This study shows promise in using ChatGPT as an aid in answering patient questions regarding their surgical procedures. This opens doors for the use of the software by patients for understanding and increased shared decision-making with their surgeons. However, studies with larger participation groups are necessary to ensure accuracy on a larger and broader scale as well as studies involving specific application of AI within surgeon's practice.

Toward Concurrent Identification of Human Activities with a Single Unifying Neural Network Classification: First Step.

The characterization of human behavior in real-world contexts is critical for developing a comprehensive model of human health. Recent technological advancements have enabled wearables and sensors to passively and unobtrusively record and presumably quantify human behavior. Better understanding human activities in unobtrusive and passive ways is an indispensable tool in understanding the relationship between behavioral determinants of health and diseases. Adult individuals (N = 60) emulated the behaviors of smoking, exercising, eating, and medication (pill) taking in a laboratory setting while equipped with smartwatches that captured accelerometer data. The collected data underwent expert annotation and was used to train a deep neural network integrating convolutional and long short-term memory architectures to effectively segment time series into discrete activities. An average macro-F1 score of at least 85.1 resulted from a rigorous leave-one-subject-out cross-validation procedure conducted across participants. The score indicates the method's high performance and potential for real-world applications, such as identifying health behaviors and informing strategies to influence health. Collectively, we demonstrated the potential of AI and its contributing role to healthcare during the early phases of diagnosis, prognosis, and/or intervention. From predictive analytics to personalized treatment plans, AI has the potential to assist healthcare professionals in making informed decisions, leading to more efficient and tailored patient care.

Effects of Enclosure Complexity and Design on Behaviour and Physiology in Captive Animals.

Individual animals in managed populations are subject to controlled social and physical environmental conditions that impact their behaviour patterns, choice of social associates, ability to experience positive welfare states, and ultimately their overall health status and quality of life [...].

Cervical spine proprioception and vestibular/oculomotor function: An observational study comparing young adults with and without a concussion history.

OBJECTIVE: To investigate dizziness, vestibular/oculomotor symptoms, and cervical spine proprioception among adults with/without a concussion history. METHODS: Adults ages 18-40 years with/without a concussion history completed: dizziness handicap inventory (DHI), visio-vestibular exam (VVE), and head repositioning accuracy (HRA, assesses cervical spine proprioception). Linear regression models were used to assess relationships between (1) concussion/no concussion history group and VVE, HRA, and DHI, and (2) DHI with HRA and VVE for the concussion history group. RESULTS: We enrolled 42 participants with concussion history (age = 26.5 ± 4.5 years, 79% female, mean = 1.4± 0.8 years post-concussion) and 46 without (age = 27.0± 3.8 years, 74% female). Concussion history was associated with worse HRA (ß = 1.23, 95% confidence interval [CI]: 0.77, 1.68; p < 0.001), more positive VVE subtests (ß = 3.01, 95%CI: 2.32, 3.70; p < 0.001), and higher DHI scores (ß = 9.79, 95%CI: 6.27, 13.32; p < 0.001) after covariate adjustment. For the concussion history group, number of positive VVE subtests was significantly associated with DHI score (ß = 3.78, 95%CI: 2.30, 5.26; p < 0.001) after covariate adjustment, while HRA error was not (ß = 1.10, 95%CI: -2.32, 4.51; p = 0.52). CONCLUSIONS: Vestibular/oculomotor symptom provocation and cervical spine proprioception impairments may persist chronically (i.e., 3 years) after concussion. Assessing dizziness, vestibular/oculomotor and cervical spine function after concussion may inform patient-specific treatments to address ongoing dysfunction.

Absolute-judgment models better predict eyewitness decision-making than do relative-judgment models.

When presented with a lineup, the witness is tasked with identifying the culprit or indicating that the culprit is not present. The witness then qualifies the decision with a confidence judgment. But how do witnesses go about making these decisions and judgments? According to absolute-judgment models, witnesses determine which lineup member provides the strongest match to memory and base their identification decision and confidence judgment on the absolute strength of this MAX lineup member. Conversely, relative-judgment models propose that witnesses determine which lineup member provides the strongest match to memory and then base their identification decision and confidence judgment on the relative strength of the MAX lineup member compared to the remaining lineup members. We took a critical test approach to test the predictions of both models. As predicted by the absolute-judgment model, but contrary to the predictions of the relative-judgment model, witnesses were more likely to correctly reject low-similarity lineups than high-similarity lineups (Experiment 1), and more likely to reject biased lineups than fair lineups (Experiment 2). Likewise, witnesses rejected low-similarity lineups with greater confidence than high-similarity lineups (Experiment 1) and rejected biased lineups with greater confidence than fair lineups (Experiment 2). Only a single pattern was consistent with the relative model and inconsistent with the absolute model: suspect identifications from biased lineups were made with greater confidence than suspect identifications from fair lineups (Experiment 2). The results suggest that absolute-judgment models better predict witness decision-making than do relative-judgment models and that pure relative-judgment models are unviable.

Xenogeneic Collagen Matrix Versus Free Gingival Graft for Augmenting Peri-Implant Keratinized Mucosa Around Dental Implants: A Systematic Review and Meta-Analysis.

OBJECTIVES: There is a growing evidence to suggest augmenting peri-implant keratinized mucosa in the presence of ≤ 2 mm of keratinized mucosa. However, the most appropriate surgical technique and augmentation materials have yet to be defined. The aim of this systematic review and meta-analyses was to evaluate the clinical and patient-reported outcomes of augmenting keratinized mucosa around implants using free gingival graft (FGG) versus xenogeneic collagen matrix (XCM) before commencing prosthetic implant treatment. MATERIAL AND METHODS: Electronic databases were searched to identify observational studies comparing implant sites augmented with FGG to those augmented with XCM. The risk of bias was assessed using the Cochrane Collaboration's Risk of Bias tool. RESULTS: Six studies with 174 participants were included in the present review. Of these, 87 participants had FGG, whereas the remaining participants had XCM. At 6 months, sites augmented with FGG were associated with less changes in the gained width of peri-implant keratinized mucosa compared to those augmented with XCM (mean difference 1.06; 95% confidence interval -0.01 to 2.13; p = 0.05). The difference, however, was marginally significant. The difference between the two groups in changes in thickness of peri-implant keratinized mucosa at 6 months was statistically significantly in favor of FGG. On the other hand, XCM had significantly shorter surgical time, lower postoperative pain score, and higher color match compared to FGG. CONCLUSIONS: Within the limitation of this review, the augmentation of keratinized mucosa using FGG before the placement of the final prosthesis may have short-term positive effects on soft tissue thickness. XCM might be considered in aesthetically demanding implant sites and where patient comfort or shorter surgical time is a priority. The evidence support, however, is of low to moderate certainty; therefore, further studies are needed to support the findings of the present review.

Work-related musculoskeletal disorders, fatigue and stress among gas station workers in China: a cross-sectional study.

INTRODUCTION: Work-related musculoskeletal disorders (WMSDs) are disorders of the musculoskeletal system that have the highest prevalence among workers worldwide. Workers in gas stations usually work in poor ergonomic working conditions, including prolonged standing and repetitive posturing. OBJECTIVE: The study aimed to investigate the prevalence of WMSDs and fatigue and to identify the predictors of WMSDs among gas station workers. DESIGN: The present study was a cross-sectional study. SETTING AND PARTICIPANTS: 2962 gas station workers from an oil and gas company in China, with ages ranging from 17 to 75 years old, 55.47% female. RESULTS: The prevalence of WMSDs within the 12 months prior to the study was 73.23%, with the highest prevalence in the neck, shoulders, ankles and feet. Furthermore, a correlation was observed between fatigue, stress and WMSDs. Fatigue and job role were the strongest predictors of WMSDs, with an OR range of 2.211-3.413. CONCLUSIONS: This research identified the detrimental impact of WMSDs and fatigue on gas station workers, indicating the critical need for interventions to reduce WMSDs and relieve fatigue.

Mechanical release of homogenous proteins from supramolecular gels.

A long-standing challenge is how to formulate proteins and vaccines to retain function during storage and transport and to remove the burdens of cold-chain management. Any solution must be practical to use, with the protein being released or applied using clinically relevant triggers. Advanced biologic therapies are distributed cold, using substantial energy, limiting equitable distribution in low-resource countries and placing responsibility on the user for correct storage and handling. Cold-chain management is the best solution at present for protein transport but requires substantial infrastructure and energy. For example, in research laboratories, a single freezer at -80 °C consumes as much energy per day as a small household1. Of biological (protein or cell) therapies and all vaccines, 75% require cold-chain management; the cost of cold-chain management in clinical trials has increased by about 20% since 2015, reflecting this complexity. Bespoke formulations and excipients are now required, with trehalose2, sucrose or polymers3 widely used, which stabilize proteins by replacing surface water molecules and thereby make denaturation thermodynamically less likely; this has enabled both freeze-dried proteins and frozen proteins. For example, the human papilloma virus vaccine requires aluminium salt adjuvants to function, but these render it unstable against freeze-thaw4, leading to a very complex and expensive supply chain. Other ideas involve ensilication5 and chemical modification of proteins6. In short, protein stabilization is a challenge with no universal solution7,8. Here we designed a stiff hydrogel that stabilizes proteins against thermal denaturation even at 50 °C, and that can, unlike present technologies, deliver pure, excipient-free protein by mechanically releasing it from a syringe. Macromolecules can be loaded at up to 10 wt% without affecting the mechanism of release. This unique stabilization and excipient-free release synergy offers a practical, scalable and versatile solution to enable the low-cost, cold-chain-free and equitable delivery of therapies worldwide.

Spinal cord lesion MRI and behavioral outcomes in a miniature pig model of spinal cord injury: exploring preclinical potential through an ad hoc comparison with human SCI.

STUDY DESIGN: prospective case series of Yucatan miniature pig spinal cord contusion injury model with comparison to human cases of spinal cord injury (SCI). OBJECTIVES: to describe magnetic resonance imaging (MRI) measures of spinal cord lesion severity along with estimates of lateral corticospinal tracts spared neural tissue in both a less severe and more severe contusion SCI model, as well as to describe their corresponding behavioral outcome changes. SETTING: University laboratory setting. METHODS: Following a more severe and less severe SCI, each pig underwent spinal cord MRI to measure lesion characteristics, along with locomotor and urodynamics outcomes testing. RESULTS: In the pig with more severe SCI, locomotor and urodynamic outcomes were poor, and both the spinal cord lesion volume and damage estimates to the lateral corticospinal tracts were large. Conversely, in the pig with less severe SCI, locomotor and urodynamic outcomes were favorable, with the spinal cord lesion volume and damage estimates to the lateral corticospinal tracts being less pronounced. For two human cases matched on estimates of damage to the lateral corticospinal tract regions, the clinical presentations were similar to the pig outcomes, with more limited mobility and more limited bladder functional independence in the more severe case. CONCLUSIONS: Our initial findings contribute valuable insights to the emergent field of MRI-based evaluation of spinal cord lesions in pig models, offering a promising avenue for understanding and potentially improving outcomes in spinal cord injuries.

Localization of protoporphyrin IX during glioma-resection surgery via paired stimulated Raman histology and fluorescence microscopy.

The most widely used fluorophore in glioma-resection surgery, 5-aminolevulinic acid (5-ALA), is thought to cause the selective accumulation of fluorescent protoporphyrin IX (PpIX) in tumour cells. Here we show that the clinical detection of PpIX can be improved via a microscope that performs paired stimulated Raman histology and two-photon excitation fluorescence microscopy (TPEF). We validated the technique in fresh tumour specimens from 115 patients with high-grade gliomas across four medical institutions. We found a weak negative correlation between tissue cellularity and the fluorescence intensity of PpIX across all imaged specimens. Semi-supervised clustering of the TPEF images revealed five distinct patterns of PpIX fluorescence, and spatial transcriptomic analyses of the imaged tissue showed that myeloid cells predominate in areas where PpIX accumulates in the intracellular space. Further analysis of external spatially resolved metabolomics, transcriptomics and RNA-sequencing datasets from glioblastoma specimens confirmed that myeloid cells preferentially accumulate and metabolize PpIX. Our findings question 5-ALA-induced fluorescence in glioma cells and show how 5-ALA and TPEF imaging can provide a window into the immune microenvironment of gliomas.

PRC2-AgeIndex as a universal biomarker of aging and rejuvenation.

DNA methylation (DNAm) is one of the most reliable biomarkers of aging across mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, DNAm gain is less characterized. Studies have demonstrated that CpGs which gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, whole-genome examination of all PRC2 targets as well as determination of the pan-tissue or tissue-specific nature of these associations is lacking. Here, we show that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. We estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the "PRC2-AgeIndex," defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells which can distinguish the effect of different anti-aging interventions.