Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

Longitudinal molecular trajectories of diffuse glioma in adults.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

The neuromodulatory role of dopamine in improved reaction time by acute cardiovascular exercise.

Acute cardiovascular physical exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Here, using positron emission tomography (PET) with [11 C]raclopride, in a multi-experiment study we investigated whether acute exercise releases endogenous dopamine (DA) in the brain. We hypothesized that acute exercise augments the brain DA system, and that RT improvement is correlated with this endogenous DA release. The PET study (Experiment 1: n = 16) demonstrated that acute physical exercise released endogenous DA, and that endogenous DA release was correlated with improvements in RT of the Go/No-Go task. Thereafter, using two electrical muscle stimulation (EMS) studies (Experiments 2 and 3: n = 18 and 22 respectively), we investigated what triggers RT improvement. The EMS studies indicated that EMS with moderate arm cranking improved RT, but RT was not improved following EMS alone or EMS combined with no load arm cranking. The novel mechanistic findings from these experiments are: (1) endogenous DA appears to be an important neuromodulator for RT improvement and (2) RT is only altered when exercise is associated with central signals from higher brain centres. Our findings explain how humans rapidly alter their behaviour using neuromodulatory systems and have significant implications for promotion of cognitive health. KEY POINTS: Acute cardiovascular exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Using the neurochemical specificity of [11 C]raclopride positron emission tomography, we demonstrated that acute supine cycling released endogenous dopamine (DA), and that this release was correlated with improved RT. Additional electrical muscle stimulation studies demonstrated that peripherally driven muscle contractions (i.e. exercise) were insufficient to improve RT. The current study suggests that endogenous DA is an important neuromodulator for RT improvement, and that RT is only altered when exercise is associated with central signals from higher brain centres.

Differential roles for ACBD4 and ACBD5 in peroxisome-ER interactions and lipid metabolism.

Peroxisomes and the endoplasmic reticulum (ER) are intimately linked subcellular organelles, physically connected at membrane contact sites. While collaborating in lipid metabolism, for example, of very long-chain fatty acids (VLCFAs) and plasmalogens, the ER also plays a role in peroxisome biogenesis. Recent work identified tethering complexes on the ER and peroxisome membranes that connect the organelles. These include membrane contacts formed via interactions between the ER protein VAPB (vesicle-associated membrane protein-associated protein B) and the peroxisomal proteins ACBD4 and ACBD5 (acyl-coenzyme A-binding domain protein). Loss of ACBD5 has been shown to cause a significant reduction in peroxisome-ER contacts and accumulation of VLCFAs. However, the role of ACBD4 and the relative contribution these two proteins make to contact site formation and recruitment of VLCFAs to peroxisomes remain unclear. Here, we address these questions using a combination of molecular cell biology, biochemical, and lipidomics analyses following loss of ACBD4 or ACBD5 in HEK293 cells. We show that the tethering function of ACBD5 is not absolutely required for efficient peroxisomal ß-oxidation of VLCFAs. We demonstrate that loss of ACBD4 does not reduce peroxisome-ER connections or result in the accumulation of VLCFAs. Instead, the loss of ACBD4 resulted in an increase in the rate of ß-oxidation of VLCFAs. Finally, we observe an interaction between ACBD5 and ACBD4, independent of VAPB binding. Overall, our findings suggest that ACBD5 may act as a primary tether and VLCFA recruitment factor, whereas ACBD4 may have regulatory functions in peroxisomal lipid metabolism at the peroxisome-ER interface.

PEX11ß and FIS1 cooperate in peroxisome division independently of mitochondrial fission factor.

Peroxisome membrane dynamics and division are essential to adapt the peroxisomal compartment to cellular needs. The peroxisomal membrane protein PEX11ß (also known as PEX11B) and the tail-anchored adaptor proteins FIS1 (mitochondrial fission protein 1) and MFF (mitochondrial fission factor), which recruit the fission GTPase DRP1 (dynamin-related protein 1, also known as DNML1) to both peroxisomes and mitochondria, are key factors of peroxisomal division. The current model suggests that MFF is essential for peroxisome division, whereas the role of FIS1 is unclear. Here, we reveal that PEX11ß can promote peroxisome division in the absence of MFF in a DRP1- and FIS1-dependent manner. We also demonstrate that MFF permits peroxisome division independently of PEX11ß and restores peroxisome morphology in PEX11ß-deficient patient cells. Moreover, targeting of PEX11ß to mitochondria induces mitochondrial division, indicating the potential for PEX11ß to modulate mitochondrial dynamics. Our findings suggest the existence of an alternative, MFF-independent pathway in peroxisome division and report a function for FIS1 in the division of peroxisomes. This article has an associated First Person interview with the first authors of the paper.

Quantitative Assessment of Preanalytic Variables on Clinical Evaluation of PI3/AKT/mTOR Signaling Activity in Diffuse Glioma.

Biomarker-driven therapeutic clinical trials require the implementation of standardized, evidence-based practices for sample collection. In diffuse glioma, phosphatidylinositol 3 (PI3)-kinase/AKT/mTOR (PI3/AKT/mTOR) signaling is an attractive therapeutic target for which window-of-opportunity clinical trials could facilitate the identification of promising new agents. Yet, the relevant preanalytic variables and optimal tumor sampling methods necessary to measure pathway activity are unknown. To address this, we used a murine model for isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) and human tumor tissue, including IDH-wildtype GBM and IDH-mutant diffuse glioma. First, we determined the impact of delayed time-to-formalin fixation, or cold ischemia time (CIT), on the quantitative assessment of cellular expression of 6 phosphoproteins that are readouts of PI3K/AK/mTOR activity (phosphorylated-proline-rich Akt substrate of 40 kDa (p-PRAS40, T246), -mechanistic target of rapamycin (p-mTOR; S2448); -AKT (p-AKT, S473); -ribosomal protein S6 (p-RPS6, S240/244 and S235/236), and -eukaryotic initiation factor 4E-binding protein 1 (p-4EBP1, T37/46). With CITs ≥ 2 hours, typical of routine clinical handling, all had reduced or altered expression with p-RPS6 (S240/244) exhibiting relatively greater stability. A similar pattern was observed using patient tumor samples from the operating room with p-4EBP1 more sensitive to delayed fixation than p-RPS6 (S240/244). Many clinical trials utilize unstained slides for biomarker evaluation. Thus, we evaluated the impact of slide storage conditions on the detection of p-RPS6 (S240/244), p-4EBP1, and p-AKT. After 5 months, storage at -80°C was required to preserve the expression of p-4EBP1 and p-AKT, whereas p-RPS6 (240/244) expression was not stable regardless of storage temperature. Biomarker heterogeneity impacts optimal tumor sampling. Quantification of p-RPS6 (240/244) expression in multiple regionally distinct human tumor samples from 8 patients revealed significant intratumoral heterogeneity. Thus, the accurate assessment of PI3K/AKT/mTOR signaling in diffuse glioma must overcome intratumoral heterogeneity and multiple preanalytic factors, including time-to-formalin fixation, slide storage conditions, and phosphoprotein of interest.

Controlling contacts-Molecular mechanisms to regulate organelle membrane tethering.

In recent years, membrane contact sites (MCS), which mediate interactions between virtually all subcellular organelles, have been extensively characterized and shown to be essential for intracellular communication. In this review essay, we focus on an emerging topic: the regulation of MCS. Focusing on the tether proteins themselves, we discuss some of the known mechanisms which can control organelle tethering events and identify apparent common regulatory hubs, such as the VAP interface at the endoplasmic reticulum (ER). We also highlight several currently hypothetical concepts, including the idea of tether oligomerization and redox regulation playing a role in MCS formation. We identify gaps in our current understanding, such as the identity of the majority of kinases/phosphatases involved in tether modification and conclude that a holistic approach-incorporating the formation of multiple MCS, regulated by interconnected regulatory modulators-may be required to fully appreciate the true complexity of these fascinating intracellular communication systems.

Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage.

Most glioblastomas (GBMs) achieve cellular immortality by acquiring a mutation in the telomerase reverse transcriptase (TERT) promoter. TERT promoter mutations create a binding site for a GA binding protein (GABP) transcription factor complex, whose assembly at the promoter is associated with TERT reactivation and telomere maintenance. Here, we demonstrate increased binding of a specific GABPB1L-isoform-containing complex to the mutant TERT promoter. Furthermore, we find that TERT promoter mutant GBM cells, unlike wild-type cells, exhibit a critical near-term dependence on GABPB1L for proliferation, notably also posttumor establishment in vivo. Up-regulation of the protein paralogue GABPB2, which is normally expressed at very low levels, can rescue this dependence. More importantly, when combined with frontline temozolomide (TMZ) chemotherapy, inducible GABPB1L knockdown and the associated TERT reduction led to an impaired DNA damage response that resulted in profoundly reduced growth of intracranial GBM tumors. Together, these findings provide insights into the mechanism of cancer-specific TERT regulation, uncover rapid effects of GABPB1L-mediated TERT suppression in GBM maintenance, and establish GABPB1L inhibition in combination with chemotherapy as a therapeutic strategy for TERT promoter mutant GBM.

miRNA-independent function of long noncoding pri-miRNA loci.

Among the large, diverse set of mammalian long noncoding RNAs (lncRNAs), long noncoding primary microRNAs (lnc-pri-miRNAs) are those that host miRNAs. Whether lnc-pri-miRNA loci have important biological function independent of their cognate miRNAs is poorly understood. From a genome-scale lncRNA screen, lnc-pri-miRNA loci were enriched for function in cell proliferation, and in glioblastoma (i.e., GBM) cells with DGCR8 or DROSHA knockdown, lnc-pri-miRNA screen hits still regulated cell growth. To molecularly dissect the function of a lnc-pri-miRNA locus, we studied LOC646329 (also known as MIR29HG), which hosts the miR-29a/b1 cluster. In GBM cells, LOC646329 knockdown reduced miR-29a/b1 levels, and these cells exhibited decreased growth. However, genetic deletion of the miR-29a/b1 cluster (LOC646329-miR29Δ) did not decrease cell growth, while knockdown of LOC646329-miR29Δ transcripts reduced cell proliferation. The miR-29a/b1-independent activity of LOC646329 corresponded to enhancer-like activation of a neighboring oncogene (MKLN1), regulating cell propagation. The LOC646329 locus interacts with the MKLN1 promoter, and antisense oligonucleotide knockdown of the lncRNA disrupts these interactions and reduces the enhancer-like activity. More broadly, analysis of genome-wide data from multiple human cell types showed that lnc-pri-miRNA loci are significantly enriched for DNA looping interactions with gene promoters as well as genomic and epigenetic characteristics of transcriptional enhancers. Functional studies of additional lnc-pri-miRNA loci demonstrated cognate miRNA-independent enhancer-like activity. Together, these data demonstrate that lnc-pri-miRNA loci can regulate cell biology via both miRNA-dependent and miRNA-independent mechanisms.

Varying Complication Rates and Increased Costs in Technology-Assisted Total Hip Arthroplasty Versus Conventional Instrumentation in 1,372,300 Primary Total Hips.

BACKGROUND: The use of technology allows surgeons increased precision in component positioning in total hip arthroplasty (THA). The objective of this study was to compare (1) perioperative complications and (2) resource utilizations between robotic-assisted (RA) and computer-navigated (CN) versus conventional instrumenttaion (CI) THA. METHODS: A retrospective cohort study was performed using a large national database to identify patients undergoing unilateral, primary elective THA from January 1, 2016 to December 31, 2019 using RA, CN, or CI. There were 1,372,300 total patients identified and included RA (29,735), CN (28,480), and CI (1,314,085) THA. Demographics, complications, lengths of stay, dispositions, and costs were compared between the cohorts. Binary logistic regression analyses were performed. RESULTS: The use of RA THA led to lower rates of intraoperative fracture (0.22% versus 0.39%), delirium (0.1% versus 0.2%), postoperative anemia (14.4% versus 16.7%), higher myocardial infarction (0.13% versus 0.08%), renal failure (1.7% versus 1.6%), blood transfusion (2.0% versus 1.9%), and wound dehiscence (0.02% versus 0.01%) compared to CI THA. The use of CN led to lower rates of respiratory complication (0.5% versus 0.8%), renal failure (1.1% versus 1.6%), blood transfusion (1.3% versus 1.9%), and pulmonary embolism (0.02% versus 0.1%) compared to CI THA. Total costs were increased in RA ($17,729 versus $15,977) and CN ($22,529 versus $15,977). Lengths of hospital stay were decreased in RA (1.8 versus 1.9 days) and CN (1.7 versus 1.9 days). CONCLUSIONS: Perioperative complication rates vary in technology-assisted THA, with higher rates in RA THA and lower rates in CN THA, relative to CI THA. Both RA THA and CN THA were associated with more costs, shorter postoperative hospital stays, and higher rates of discharge home compared to CI THA.

Lower Perioperative Complication Rates and Shorter Lengths of Hospital Stay Associated With Technology-Assisted Total Knee Arthroplasty Versus Conventional Instrumentation in Primary Total Knee Arthroplasty.

BACKGROUND: The use of technology allows increased precision in component positioning in total knee arthroplasty (TKA). The objectives of this study were to compare (1) perioperative complications and (2) resource utilization between robotic-assisted (RA) and computer-navigated (CN) versus conventional (CI) TKA. METHODS: A retrospective cohort study was performed using a national database to identify patients undergoing unilateral, primary elective TKA from January 2016 to December 2019. A total of 2,174,685 patients were identified and included RA (69,445), CN (112,225), or CI (1,993,015) TKA. Demographics, complications, lengths of stay, dispositions, and costs were compared between the cohorts. Binary logistic regression analysis was performed. RESULTS: The RA TKA cohort had lower rates of intraoperative fracture (0.05 versus 0.08%, P < .05), respiratory complications (0.6 versus 1.1%, P < .05), renal failure (1.3 versus 1.7%, P < .05), delirium (0.1 versus 0.2%, P < .05), gastrointestinal complications (0.04 versus 0.09%, P < .05), postoperative anemia (8.9 versus 13.9%, P < .05), blood transfusion (0.4 versus 0.9%, P < .05), pulmonary embolism, and deep vein thrombosis (0.1 versus 0.2%, P < .05), and mortality (0.01 versus 0.02%, P < .05) compared to conventional TKA, though the cohort did have higher rates of myocardial infarction (0.09 versus 0.07%, P < .05). The CN cohort had lower rates of myocardial infarction (0.02 versus 0.07%, P < .05), respiratory complications (0.8 versus 1.1%, P < .05), renal failure (1.5 versus 1.7%, P < .05), blood transfusion (0.8 versus 0.9%, P < .05), pulmonary embolism (0.08 versus 0.2%, P < .05), and deep vein thrombosis (0.2 versus 0.2%, P < .05) over CI TKA. Total cost was increased in RA (16,190 versus $15,133, P < .05) and CN (17,448 versus $15,133, P < .05). However, the length of hospital stay was decreased in both RA (1.8 versus 2.2 days, P < .05) and CN (2.1 versus 2.2 days, P < .05). CONCLUSIONS: Technology-assisted TKA was associated with lower perioperative complication rates and faster recovery.

Effects of COVID-19 on Rate of Injury and Position-Specific Injury During the 2020 National Football League Season.

ABSTRACT: Costello II, JP, Wagner, JD, Dahl, VA, Cohen, JL, Reuter, AM, and Kaplan, LD. Effects of COVID-19 on rate of injury and position-specific injury during the 2020 National Football League season. J Strength Cond Res 38(1): 97-104, 2024-Because of the COVID-19 pandemic, the National Football League (NFL) made changes to its operations for the 2020 season. We hypothesize an increase in the rate of injuries during the 2020 season. Publicly available data were reviewed to identify NFL injuries from the 2015-2020 seasons. Player position, description of injury, date of injury, and injury setting were recorded. p ≤ 0.05 was considered statistically significant. For the 2020 season, compared with the 2015-2019 seasons, there was an increased risk of injury during the regular season overall relative risk (RR) = 1.308 ( p < 0.05), week (W)1 RR = 7.33 ( p < 0.05), W1-6 RR = 1.964 ( p < 0.05), W7-12 RR = 1.8909 ( p < 0.05), and during the postseason overall RR = 1.1444 ( p < 0.05), calculated using analysis of variance. There was an overall increased risk of abdominal or core injuries RR = 1.248 ( p < 0.05), groin or hip injuries RR = 2.534 ( p < 0.05), and hamstring injuries RR = 3.644 ( p < 0.05). There was an increased risk of hamstring injuries in cornerbacks RR = 3.219 ( p < 0.05) and running backs RR = 1.1394 ( p < 0.05), hip or groin injuries in guards RR = 1.105 ( p < 0.05), Achilles tendon injuries in safeties RR = 1.6976 ( p < 0.05), quadriceps injuries in running backs RR = 1.6191 ( p < 0.05), and arm injuries in defensive tackles RR = 1.221 ( p < 0.05). There was an increase in the overall rate of injuries in the 2020 NFL season, both in the regular season and postseason, compared with the 2015-2019 seasons. The overall rate of abdominal or core, groin or hip, and hamstring injuries increased. Specific player positions saw unique increases in rates of injuries. These findings may be due to numerous operational changes implemented, such as reduced in-person training and the elimination of the preseason, leading to suboptimal, sports-specific conditioning and increased risk of musculoskeletal injury.

The Surgical Management of NCAA Division 1 College Football Injuries Post COVID-19: A Single Institution Retrospective Review.

ABSTRACT: Cohen, JL, Cade, WH, Harrah, TC, Costello II, JP, and Kaplan, LD. The surgical management of NCAA Division 1 college football injuries post COVID-19: A single institution retrospective review. J Strength Cond Res 38(5): 906-911, 2024-The unprecedented COVID-19 pandemic had a significant impact on college football operations, including athletes' training regimens. As a result of these changes, concern for increased injury susceptibility post COVID-19 regulations has become a point of discussion. The current study sought to evaluate the incidence of surgical injury among NCAA Division 1 college football players at the authors' institution during the first full season after start of the COVID-19 pandemic compared with previous years. Retrospective chart review was performed for all players who sustained injuries requiring surgery while a member of the NCAA Division 1 football program during the 2009-2021 seasons. A p -value of ≤0.05 was used to determine significance. A total of 23 surgical injuries occurred in 22 players during the 2021 season compared with 121 in 118 players in the 12 previous seasons combined ( p = 0.0178; RR = 1.47). There was a significant increase in shoulder injuries ( n = 13 vs. n = 31; p = <0.0001; RR = 3.05) and specifically a significant increase in labral tears ( n = 10 vs. n = 30; p = 0.0003; RR = 2.74). No difference was seen in knee injuries ( n = 10 vs. n = 77; p = 0.27; RR = 1.35) and specifically no difference in anterior cruciate ligament injuries ( n = 3 vs. n = 31; p = 0.77; RR = 1.17). This phenomenon is multifactorial in nature, but alterations to players' training and preparations because of the COVID-19 pandemic likely resulted in suboptimal conditioning, leading to the increased incidence of surgical injuries emphasizing the importance of adequate strength training and conditioning.

"De novo replication repair deficient glioblastoma, IDH-wildtype" is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade.

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

The voices of medical education scholarship: Describing the published landscape.

INTRODUCTION: The voices of authors who publish medical education literature have a powerful impact on the field's discourses. Researchers have identified a lack of author diversity, which suggests potential epistemic injustice. This study investigates author characteristics to provide an evidence-based starting point for communal discussion with the intent to move medical education towards a future that holds space for, and values, diverse ways of knowing. METHOD: The authors conducted a bibliometric analysis of all articles published in 24 medical education journals published between 2000 and 2020 to identify author characteristics, with an emphasis on author gender and geographic location and their intersection. Article metadata was downloaded from Web of Science. Genderize.io was used to predict author gender. RESULTS: The journals published 37 263 articles authored by 62 708 unique authors. Males were more prevalent across all authorship positions (n = 62 828; 55.7%) than females (n = 49 975; 44.3%). Authors listed affiliations in 146 countries of which 95 were classified as Global South. Few articles were written by multinational teams (n = 3765; 16.2%). Global South authors accounted for 12 007 (11.4%) author positions of which 3594 (3.8%) were female. DISCUSSION: This study provides an evidence-based starting point to discuss the imbalance of author voices in medical education, especially when considering the intersection of gender and geographical location, which further suggests epistemic injustice in medical education. If the field values a diversity of perspectives, there is considerable opportunity for improvement by engaging the community in discussions about what knowledge matters in medical education, the role of journals in promoting diversity, how to best use this baseline data and how to continue studying epistemic injustice in medical education.

The effects of manipulating the visual environment on thermal perception: A structured narrative review.

When exposed to ambient temperatures that cause thermal discomfort, a human's behavioral responses are more effective than autonomic ones at compensating for thermal imbalance. These behavioral thermal responses are typically directed by an individual's perception of the thermal environment. Perception of the environment is a holistic amalgamation of human senses, and in some circumstances, humans prioritize visual information. Existing research has considered this in the specific case of thermal perception, and this review investigates the state of the literature examining this effect. We identify the frameworks, research rationales, and potential mechanisms that underpin the evidence base in this area. Our review identified 31 experiments, comprising 1392 participants that met the inclusion criteria. Methodological heterogeneity was observed in the assessment of thermal perception, and a variety of methods were employed to manipulate the visual environment. However, the majority of the included experiments (80%) reported a difference in thermal perception after the visual environment was manipulated. There was limited research exploring any effects on physiological variables (e.g. skin and core temperature). This review has wide-ranging implications for the broad discipline of (thermo)physiology, psychology, psychophysiology, neuroscience, ergonomics, and behavior.

Thalamic Segmentation and Neural Activation Modeling Based on Individual Tissue Microstructure in Deep Brain Stimulation for Essential Tremor.

OBJECTIVE: Thalamic deep brain stimulation (DBS) is the primary surgical therapy for essential tremor (ET). Thalamic DBS traditionally uses an atlas-based targeting approach, which, although nominally accurate, may obscure individual anatomic differences from population norms. The objective of this study was to compare this traditional atlas-based approach with a novel quantitative modeling methodology grounded in individual tissue microstructure (N-of-1 approach). MATERIALS AND METHODS: The N-of-1 approach uses individual patient diffusion tensor imaging (DTI) data to perform thalamic segmentation and volume of tissue activation (VTA) modeling. For each patient, the thalamus was individually segmented into 13 nuclei using DTI-based k-means clustering. DBS-induced VTAs associated with tremor suppression and side effects were then computed for each patient with finite-element electric-field models incorporating DTI microstructural data. Results from N-of-1 and traditional atlas-based modeling were compared for a large cohort of patients with ET treated with thalamic DBS. RESULTS: The size and shape of individual N-of-1 thalamic nuclei and VTAs varied considerably across patients (N = 22). For both methods, tremor-improving therapeutic VTAs showed similar overlap with motor thalamic nuclei and greater motor than sensory nucleus overlap. For VTAs producing undesirable sustained paresthesia, 94% of VTAs overlapped with N-of-1 sensory thalamus estimates, whereas 74% of atlas-based segmentations overlapped. For VTAs producing dysarthria/motor contraction, the N-of-1 approach predicted greater spread beyond the thalamus into the internal capsule and adjacent structures than the atlas-based method. CONCLUSIONS: Thalamic segmentation and VTA modeling based on individual tissue microstructure explain therapeutic stimulation equally well and side effects better than a traditional atlas-based method in DBS for ET. The N-of-1 approach may be useful in DBS targeting and programming, particularly when patient neuroanatomy deviates from population norms.

Multiplatform molecular analyses refine classification of gliomas arising in patients with neurofibromatosis type 1.

Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology "pilocytic astrocytoma, arising in the setting of NF1". The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.

Delineating the field of medical education: Bibliometric research approach(es).

BACKGROUND: The field of medical education remains poorly delineated such that there is no broad consensus of articles or journals that comprise 'the field'. This lack of consensus indicates a missed opportunity for researchers to generate insights about the field that could facilitate conducting bibliometric studies and other research designs (e.g., systematic reviews) and also enable individuals to identify themselves as 'medical education researchers'. Other fields have utilised bibliometric field delineation, which is the assigning of articles or journals to a certain field in an effort to define that field. PROCESS: In this Research Approach, three bibliometric field delineation approaches-information retrieval, core journals, and journal co-citation-are introduced. For each approach, the authors describe attempts to apply it in medical education and identify related strengths and weaknesses. Based on co-citation, the authors propose the Medical Education Journal List 24 (MEJ-24), as a starting point for delineating medical education and invite the community to collaborate on improving and potentially expanding this list. PEARLS: As a research approach, field delineation is complicated, and there is no clear best way to delineate the field of medical education. However, recent advances in information science provide potentially fruitful approaches to deal with the field's complexity. When considering these approaches, researchers should consider collaborating with bibliometricians. Bibliometric approaches rely on available metadata for articles and journals, which necessitates that researchers examine the metadata prior to analysis to understand its strengths and weaknesses, and to assess how this might affect data interpretation. While using bibliometric approaches for field delineation is valuable, it is important to remember that these techniques are only as good as the research team's interpretation of the data, which suggests that an expanded approach is needed to better delineate medical education, an approach that includes active discussion within the medical education community.

A Light-Tolerant Wireless Neural Recording IC for Motor Prediction With Near-Infrared-Based Power and Data Telemetry.

Miniaturized and wireless near-infrared (NIR) based neural recorders with optical powering and data telemetry have been introduced as a promising approach for safe long-term monitoring with the smallest physical dimension among state-of-the-art standalone recorders. However, a main challenge for the NIR based neural recording ICs is to maintain robust operation in the presence of light-induced parasitic short circuit current from junction diodes. This is especially true when the signal currents are kept small to reduce power consumption. In this work, we present a light-tolerant and low-power neural recording IC for motor prediction that can fully function in up to 300 µW/mm2 of light exposure. It achieves best-in-class power consumption of 0.57 µW at 38° C with a 4.1 NEF pseudo-resistorless amplifier, an on-chip neural feature extractor, and individual mote level gain control. Applying the 20-channel pre-recorded neural signals of a monkey, the IC predicts finger position and velocity with correlation coefficient up to 0.870 and 0.569, respectively, with individual mote level gain control enabled. In addition, wireless measurement is demonstrated through optical power and data telemetry using a custom PV/LED GaAs chip wire bonded to the proposed IC.