Genetic variants for head size share genes and pathways with cancer.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Identifying dementia from cognitive footprints in hospital records among Chinese older adults: a machine-learning study.

Background: By combining theory-driven and data-driven methods, this study aimed to develop dementia predictive algorithms among Chinese older adults guided by the cognitive footprint theory. Methods: Electronic medical records from the Clinical Data Analysis and Reporting System in Hong Kong were employed. We included patients with dementia diagnosed at 65+ between 2010 and 2018, and 1:1 matched dementia-free controls. We identified 51 features, comprising exposures to established modifiable factors and other factors before and after 65 years old. The performances of four machine learning models, including LASSO, Multilayer perceptron (MLP), XGBoost, and LightGBM, were compared with logistic regression models, for all patients and subgroups by age. Findings: A total of 159,920 individuals (40.5% male; mean age [SD]: 83.97 [7.38]) were included. Compared with the model included established modifiable factors only (area under the curve [AUC] 0.689, 95% CI [0.684, 0.694]), the predictive accuracy substantially improved for models with all factors (0.774, [0.770, 0.778]). Machine learning and logistic regression models performed similarly, with AUC ranged between 0.773 (0.768, 0.777) for LASSO and 0.780 (0.776, 0.784) for MLP. Antipsychotics, education, antidepressants, head injury, and stroke were identified as the most important predictors in the total sample. Age-specific models identified different important features, with cardiovascular and infectious diseases becoming prominent in older ages. Interpretation: The models showed satisfactory performances in identifying dementia. These algorithms can be used in clinical practice to assist decision making and allow timely interventions cost-effectively. Funding: The Research Grants Council of Hong Kong under the Early Career Scheme 27110519.

Informing the Exposure Landscape: The Fate of Microplastics in a Large Pelagic In-Lake Mesocosm Experiment.

Understanding microplastic exposure and effects is critical to understanding risk. Here, we used large, in-lake closed-bottom mesocosms to investigate exposure and effects on pelagic freshwater ecosystems. This article provides details about the experimental design and results on the transport of microplastics and exposure to pelagic organisms. Our experiment included three polymers of microplastics (PE, PS, and PET) ranging in density and size. Nominal concentrations ranged from 0 to 29,240 microplastics per liter on a log scale. Mesocosms enclosed natural microbial, phytoplankton, and zooplankton communities and yellow perch (Perca flavescens). We quantified and characterized microplastics in the water column and in components of the food web (biofilm on the walls, zooplankton, and fish). The microplastics in the water stratified vertically according to size and density. After 10 weeks, about 1% of the microplastics added were in the water column, 0.4% attached to biofilm on the walls, 0.01% within zooplankton, and 0.0001% in fish. Visual observations suggest the remaining >98% were in a surface slick and on the bottom. Our study suggests organisms that feed at the surface and in the benthos are likely most at risk, and demonstrates the value of measuring exposure and transport to inform experimental designs and achieve target concentrations in different matrices within toxicity tests.

Claustrum projections to the anterior cingulate modulate nociceptive and pain-associated behavior.

The anterior cingulate cortex (ACC) is critical for the perception and unpleasantness of pain.1,2,3,4,5,6 It receives nociceptive information from regions such as the thalamus and amygdala and projects to several cortical and subcortical regions of the pain neuromatrix.7,8 ACC hyperexcitability is one of many functional changes associated with chronic pain, and experimental activation of ACC pyramidal cells produces hypersensitivity to innocuous stimuli (i.e., allodynia).9,10,11,12,13,14 A less-well-studied projection to the ACC arises from a small forebrain region, the claustrum.15,16,17,18,19,20 Stimulation of excitatory claustrum projection neurons preferentially activates GABAergic interneurons, generating feed-forward inhibition onto excitatory cortical networks.21,22,23,24 Previous work has shown that claustrocingulate projections display altered activity in prolonged pain25,26,27; however, it remains unclear whether and how the claustrum participates in nociceptive processing and high-order pain behaviors. Inhibition of ACC activity reverses mechanical allodynia in animal models of persistent and neuropathic pain,1,9,28 suggesting claustrum inputs may function to attenuate pain processing. In this study, we sought to define claustrum function in acute and chronic pain. We found enhanced claustrum activity after a painful stimulus that was attenuated in chronic inflammatory pain. Selective inhibition of claustrocingulate projection neurons enhanced acute nociception but blocked pain learning. Inversely, chemogenetic activation of claustrocingulate neurons had no effect on basal nociception but rescued inflammation-induced mechanical allodynia. Together, these results suggest that claustrocingulate neurons are a critical component of the pain neuromatrix, and dysregulation of this connection may contribute to chronic pain.

Educational Mobility, Pace of Aging, and Lifespan Among Participants in the Framingham Heart Study.

Importance: People who complete more education live longer lives with better health. New evidence suggests that these benefits operate through a slowed pace of biological aging. If so, measurements of the pace of biological aging could offer intermediate end points for studies of how interventions to promote education will affect healthy longevity. Objective: To test the hypothesis that upward educational mobility is associated with a slower pace of biological aging and increased longevity. Design, Setting, and Participants: This prospective cohort study analyzed data from 3 generations of participants in the Framingham Heart Study: (1) the original cohort, enrolled beginning in 1948; (2) the Offspring cohort, enrolled beginning in 1971; and (3) the Gen3 cohort, enrolled beginning in 2002. A 3-generation database was constructed to quantify intergenerational educational mobility. Mobility data were linked with blood DNA-methylation data collected from the Offspring cohort in 2005 to 2008 (n = 1652) and the Gen3 cohort in 2009 to 2011 (n = 1449). Follow-up is ongoing. Data analysis was conducted from June 2022 to November 2023 using data obtained from the National Institutes of Health database of Genotypes and Phenotypes (dbGaP). Exposure: Educational mobility was measured by comparing participants' educational outcomes with those of their parents. Main Outcomes and Measures: The pace of biological aging was measured from whole-blood DNA-methylation data using the DunedinPACE epigenetic clock. For comparison purposes, the analysis was repeated using 4 other epigenetic clocks. Survival follow-up was conducted through 2019. Results: This study analyzed data from 3101 participants from the Framingham Heart Study; 1652 were in the Offspring cohort (mean [SD] age, 65.57 [9.22] years; 764 [46.2%] male) and 1449 were in the Gen3 cohort (mean [SD] age, 45.38 [7.83] years; 691 [47.7%] male). Participants who were upwardly mobile in educational terms tended to have slower pace of aging in later life (r = -0.18 [95% CI, -0.23 to -0.13]; P < .001). This pattern of association was similar across generations and held in within-family sibling comparisons. There were 402 Offspring cohort participants who died over the follow-up period. Upward educational mobility was associated with lower mortality risk (hazard ratio, 0.89 [95% CI, 0.81 to 0.98]; P = .01). Slower pace of aging accounted for approximately half of this association. Conclusions and Relevance: This cohort study's findings support the hypothesis that interventions to promote educational attainment may slow the pace of biological aging and promote longevity. Epigenetic clocks have potential as near-term outcome measures of intervention effects on healthy aging. Experimental evidence is needed to confirm findings.

A retrospective analysis of molecular testing in cytologically indeterminate thyroid nodules with histologic correlation: Experience at a heterogenous multihospital system.

INTRODUCTION: Thyroid malignancy is one of the most common types of cancer in developed nations. Currently, fine-needle aspiration cytology (FNAC) is the most practical screening test for thyroid nodules. However, cytologically indeterminate samples comprise approximately 15%-30% of cases. These include cases classified as atypia of undetermined significance (AUS), follicular neoplasm (FN), and suspicious for malignancy (SFM). Indeterminate cases can be sent for molecular testing for more definitive classification to help guide management and prevent overtreatment of benign thyroid nodules. We conducted a retrospective review on molecular testing of indeterminate thyroid FNAC and reviewed subsequent histologic diagnoses in resection specimens to assess how molecular testing supported a diagnosis and its effect on clinical management of patients at our institution. METHODS: A retrospective chart review was performed on all thyroid FNAC specimens, corresponding molecular testing, and subsequent surgical resection specimens over a 6-year period. RESULTS: A total of 10,253 thyroid FNAC were performed in our hospital system during our study period, of which 10% (n = 1102/10,253) had indeterminate FNAC results. Molecular testing was performed in 16% (n = 178/1102) of indeterminate cytology cases. Genetic alterations were identified in 39% (n = 69/178) of the cases sent for molecular testing. The majority of cytologically indeterminate cases sent for molecular testing were follicular-patterned lesions and their corresponding resection specimens revealed mostly low grade follicular derived neoplasms (i.e., follicular adenoma, non-invasive follicular thyroid neoplasm with papillary-like nuclear features, and follicular variant of papillary thyroid carcinoma). Of the cases with identified genetic alterations, 75% (n = 52/69) were treated surgically. In cases with no genetic alterations identified, only 18% (n = 20/109) were treated surgically. DISCUSSION/CONCLUSION: Molecular testing on cytologically indeterminate thyroid nodules can help provide a more accurate risk of malignancy assessment in patients with lesions that are difficult to diagnosis based solely on FNAC morphology. The types of genetic alterations identified in the resected thyroid lesions were consistent with what has been previously described in the literature. Additionally, we found that in the patients with indeterminate thyroid FNAC with adjunct molecular testing, more than half did not undergo surgical resection. This finding emphasizes the value of adding molecular testing in patients, particularly when attempting to reduce unnecessary surgical intervention.

Spoken discourse in episodic autobiographical and verbal short-term memory in Chinese people with dementia: the roles of global coherence and informativeness.

Introduction: Memory and discourse production are closely related in healthy populations. A few studies in people with amnestic mild cognitive impairment and people with dementia (PWD) suggested similar links, although empirical evidence is insufficient to inform emerging intervention design and natural language processing research. Fine-grained discourse assessment is needed to understand their complex relationship in PWD. Methods: Spoken samples from 104 PWD were elicited using personal narrative and sequential picture description and assessed using Main Concept Analysis and other content-based analytic methods. Discourse and memory performance data were analyzed in bivariate correlation and linear multiple regression models to determine the relationship between discourse production and episodic autobiographical memory and verbal short-term memory (vSTM). Results: Global coherence was a significant predictor of episodic autobiographical memory, explaining over half of the variance. Both episodic autobiographical memory and vSTM were positively correlated with global coherence and informativeness, and negatively with empty speech indices. Discussion: Coherence in personal narrative may be supported by episodic autobiographical memory and vice versa, suggesting potential mechanism of interventions targeting personhood through conversation. Indices of global coherence, informativeness, and empty speech can be used as markers of memory functions in PWD.

Patient Health Questionnaire-9 Item Pairing Predictiveness for Prescreening Depressive Symptomatology: Machine Learning Analysis.

BACKGROUND: Anhedonia and depressed mood are considered the cardinal symptoms of major depressive disorder. These are the first 2 items of the Patient Health Questionnaire (PHQ)-9 and comprise the ultrabrief PHQ-2 used for prescreening depressive symptomatology. The prescreening performance of alternative PHQ-9 item pairings is rarely compared with that of the PHQ-2. OBJECTIVE: This study aims to use machine learning (ML) with the PHQ-9 items to identify and validate the most predictive 2-item depressive symptomatology ultrabrief questionnaire and to test the generalizability of the best pairings found on the primary data set, with 6 external data sets from different populations to validate their use as prescreening instruments. METHODS: All 36 possible PHQ-9 item pairings (each yielding scores of 0-6) were investigated using ML-based methods with logistic regression models. Their performances were evaluated based on the classification of depressive symptomatology, defined as PHQ-9 scores ≥10. This gave each pairing an equal opportunity and avoided any bias in item pairing selection. RESULTS: The ML-based PHQ-9 items 2 and 4 (phq2&4), the depressed mood and low-energy item pairing, and PHQ-9 items 2 and 8 (phq2&8), the depressed mood and psychomotor retardation or agitation item pairing, were found to be the best on the primary data set training split. They generalized well on the primary data set test split with area under the curves (AUCs) of 0.954 and 0.946, respectively, compared with an AUC of 0.942 for the PHQ-2. The phq2&4 had a higher AUC than the PHQ-2 on all 6 external data sets, and the phq2&8 had a higher AUC than the PHQ-2 on 3 data sets. The phq2&4 had the highest Youden index (an unweighted average of sensitivity and specificity) on 2 external data sets, and the phq2&8 had the highest Youden index on another 2. The PHQ-2≥2 cutoff also had the highest Youden index on 2 external data sets, joint highest with the phq2&4 on 1, but its performance fluctuated the most. The PHQ-2≥3 cutoff had the highest Youden index on 1 external data set. The sensitivity and specificity achieved by the phq2&4 and phq2&8 were more evenly balanced than the PHQ-2≥2 and ≥3 cutoffs. CONCLUSIONS: The PHQ-2 did not prove to be a more effective prescreening instrument when compared with other PHQ-9 item pairings. Evaluating all item pairings showed that, compared with alternative partner items, the anhedonia item underperformed alongside the depressed mood item. This suggests that the inclusion of anhedonia as a core symptom of depression and its presence in ultrabrief questionnaires may be incompatible with the empirical evidence. The use of the PHQ-2 to prescreen for depressive symptomatology could result in a greater number of misclassifications than alternative item pairings.

Phase II study of trifluridine/tipiracil in metastatic breast cancers with or without prior exposure to fluoropyrimidines.

BACKGROUND: Fluoropyrimidines are commonly used in the treatment of metastatic breast cancer (MBC), and trifluridine/tipiracil (FTD/TPI) has shown activity in patients with colorectal and gastric cancers despite prior exposure to fluoropyrimidines. We investigate the role of FTD/TPI in patients with MBC with or without prior fluoropyridines in a single-arm phase II study. METHODS: Patients with MBC were enroled first into a run-in dose confirmation phase, followed by two parallel cohorts including patients with (Cohort A) and without (Cohort B) prior exposure to fluoropyrimidines, where they were treated with FTD/TPI. Primary objectives for each cohort included determination of progression-free survival (PFS), and secondary objectives included determination of objective response rates (ORR), safety, and tolerability. RESULTS: Seventy-four patients (42 Cohort A, 32 Cohort B) were enroled, all of whom were evaluable for toxicity and survival, with 72 evaluable for response. Median PFS was 5.7 months (95% confidence interval 3.8-8.3) and 9.4 months (95% CI 5.5-14.0) respectively in Cohorts A and B. Responses were observed regardless of prior exposure to fluoropyrimidines, with ORR of 19.5% (95% CI 8.8-34.9) and 16.1% (95% CI 5.5-33.7) in Cohorts A and B, and 6-month clinical benefit rates of 56.1% (95% CI 39.7-71.5) and 61.3% (95% CI 42.2-78.2) respectively. The safety profile was consistent with known toxicities of FTD/TPI, including neutropenia, fatigue, nausea, and anorexia, mitigated with dose modifications. CONCLUSION: FTD/TPI showed promising antitumour activity with manageable toxicity and is a clinically valid option in patients with MBC.

Pre-analytical effects on whole transcriptome and targeted RNA sequencing analysis in cytology: The effects of prolonged time in storage of effusion specimens prior to preservation.

OBJECTIVES: To investigate the pre-analytics of the molecular testing of cytology specimens, we studied the effects of time in refrigerator storage (4°C) of malignant effusions on RNA sequencing (RNAseq) results. METHODS: Ten effusion specimens were stored in a refrigerator (4°C) for different durations (day 0, 1, 4, and 7). All specimens were prepared as cytospins fixed in either Carnoy's solution or 95% ethanol (EtOH) and in an RNA preservative for a fresh frozen (FF) high-quality reference. Whole transcriptome (wt) and targeted (t)RNAseq of two multigene expression signatures were performed. We then compared transcript expression levels (including mutant allele fraction) according to pre-analytical variables using a concordance correlation coefficient (CCC) and a mixed effect model. RESULTS: Sequencing results were mostly stable over increasing time in storage. Cytospins fixed in Carnoy's solution were more concordant with FF samples than cytospins fixed in 95% EtOH at all timepoints. This finding was consistent for both wtRNAseq (averages: day 0 CCC = 0.98 vs 0.91; day 7 CCC = 0.88 vs 0.78) and tRNAseq methods (averages: day 0 CCC = 0.98 vs 0.81; day 7 CCC = 0.98 vs 0.90). Cytospins fixed in Carnoy's solution did not show significant changes in expression over timepoints or between expression signatures, whereas 95% EtOH did. CONCLUSION: RNAseq can be accurately performed on effusion specimens after prolonged refrigerator storage. RNA extracted from scraped cytospin slides fixed in Carnoy's solution was marginally superior to 95% EtOH fixation, but either method had comparable analytic performance to high-quality FF RNA samples.

Differential Associations Between Depressive Symptom-Domains With Anxiety, Loneliness, and Cognition in a Sample of Community Older Chinese Adults: A Multiple Indicators Multiple Causes Approach.

Background and Objectives: Depressive symptoms are common in older adults, and often co-occur with other mental health problems. However, knowledge about depressive symptom-domains and their associations with other conditions is limited. This study examined depressive symptom-domains and associations with anxiety, cognition, and loneliness. Research Design and Methods: A sample of 3,795 participants aged 60 years and older were recruited from the community in Hong Kong. They were assessed for depressive symptoms (Patient Health Questionnaire-9 [PHQ-9]), anxiety (Generalized Anxiety Disorder 7-item), loneliness (UCLA 3-item), and cognition (Montreal Cognitive Assessment 5-Minute Protocol). Summary descriptive statistics were calculated, followed by confirmatory factor analysis of PHQ-9. Multiple Indicators Multiple Causes analysis was used to examine the associations between mental health conditions in the general sample and subgroups based on depressive symptom severity. Results: A 4-factor model based on the Research Domain Criteria showed the best model fit of PHQ-9 (χ2/df = 10.63, Root-Mean-Square Error of Approximation = 0.05, Comparative Fit Index = 0.96, Tucker-Lewis Index = 0.93). After adjusting for demographics, 4 depressive symptom-domains were differentially associated with anxiety, loneliness, and cognition across different depression severity groups. The Negative Valance Systems and Internalizing domain (NVS-I; guilt and self-harm) were consistently associated with anxiety (ß = 0.45, 0.44) and loneliness (ß = 0.11, 0.27) regardless of depression severity (at risk/mild vs moderate and more severe, respectively, all p < .001). Discussion and Implications: The consistent associations between the NVS-I domain of depression with anxiety and loneliness warrant attention. Simultaneous considerations of depressive symptom-domains and symptom severity are needed for designing more personalized care. Clinical Trials Registration Number: NCT03593889.

Social Fitness and the Social Domain: A Holistic Approach Based on Total Force Fitness.

The Total Force Fitness (TFF) framework was envisioned as a holistic framework of interrelated domains, whereby impact in one domain could have cascading implications for the others. For this reason, definitional clarity surrounding how to achieve fitness in the various domains is crucial. Social fitness definitions tend to focus on individual efforts and overlook the powerful impact of the social group and the social environment on the individual. In this article, various definitions of social fitness are analyzed in an effort to broaden the current understanding of the social domain. Some of the knowledge gaps in understanding social fitness and the resulting challenges are addressed before reviewing a few existing social fitness interventions. Finally, this study offers recommendations for improvement, along with future directions for the increased integration of the social domain into the TFF framework.

Total Force Fitness Education: A Critical Enabler of Human Performance Optimization.

INTRODUCTION: Military health education has historically been focused on conveying the consequences of risky behaviors, informing about external resources, and addressing disease through mitigation and prevention. Total Force Fitness (TFF) and Human Performance Optimization (HPO) provide a broad and holistic framework for preventing health issues and bolstering performance. The Consortium for Health and Military Performance convened a workgroup at the TFF Summit in 2021 to discuss the current state of TFF/HPO in military health education efforts and to identify areas for improvement. METHODS: An education workgroup of 42 attendees gathered to discuss the current state of TFF/HPO-based health education in the military. Four questions were posed to all members for discussion. Notes were taken and consolidated to obtain feedback and promote discussion from the attendees in a larger audience at the TFF Summit. RESULTS AND DISCUSSION: The education workgroup identified several education formats, goals, initiatives, and opportunities for improving the development and dissemination of TFF/HPO-based health education throughout the Services. Workgroup members reached a consensus on health education formats (development, dissemination, and audience) and that the primary goal of education is knowledge dissemination and increasing awareness. They also identified several stellar examples of existing TFF/HPO initiatives and explored how health education can increase impact and be more sustainable. The workgroup outcomes were shared with the TFF Summit audience to generate further discussion and to outline action items. Seven action items were identified to improve the development and dissemination of TFF/HPO resources and ensure productive and effective initiatives and programs throughout the Department of Defense. CONCLUSIONS: The TFF Summit outlined several actionable items that would improve the development and dissemination of TFF/HPO-based health education throughout the Department of Defense's initiatives and programs. A broader approach to military health education that uses a TFF/HPO framework will directly impact the health and performance of the force. Ultimately, embedding TFF/HPO information into the fabric of military health education would shift the focus toward a holistic, proactive, preventive, and performance-based culture.

Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition.

The objective was to correlate CD47 gene expression with resistance to immune checkpoint inhibitors (ICI) in tumor tissue of gynecological cancer (GC). Further, we sought to assess the efficacy of targeting CD47 pathway alone and in combination in pre-clinical ovarian cancer (OC) models. We performed transcriptomic analyses in GC treated with ICI. Signaling pathway enrichment analysis was performed using Ingenuity Pathway Analysis. Immune cell abundance was estimated. CD47 expression was correlated with other pathways, objective response, and progression-free survival (PFS). Anti-tumor efficacy of anti-CD47 therapy alone and in combination was investigated both in-vitro and in-vivo using cell-line derived xenograft (CDX) and patient-derived xenograft (PDX) models. High CD47 expression associated with lower response to ICI and trended toward lower PFS in GC patients. Higher CD47 associated negatively with PDL1 and CTLA4 expression, as well as cytotoxic T-cells and dendritic cells but positively with TGF-ß, BRD4 and CXCR4/CXCL12 expression. Anti-CD47 significantly enhanced macrophage-mediated phagocytosis of OC cells in-vitro and exhibited potent anti-tumor activity in-vivo in OC CDX and PDX models. In-vitro treatment with PARPi increased CD47 expression. Anti-CD47 led to significantly enhanced in-vitro phagocytosis, enhanced STING pathway and synergized in-vivo when combined with PARP inhibitors in BRCA-deficient OC models. This study provides insight on the potential role of CD47 in mediating immunotherapy resistance and its association with higher TGF-ß, BRD4 and CXCR4/CXCL12 expression. Anti-CD47 showed potent anti-tumor activity and synergized with PARPi in OC models. These data support clinical development of anti-CD47 therapy with PARPi in OC.

Gene Therapy with p14/tBID Induces Selective and Synergistic Apoptosis in Mutant Ras and Mutant p53 Cancer Cells In Vitro and In Vivo.

Any gene therapy for cancer will be predicated upon its selectivity against cancer cells and non-toxicity to normal cells. Therefore, safeguards are needed to prevent its activation in normal cells. We designed a minimal p14ARF promoter with upstream Ap1 and E2F enhancer elements and a downstream MDR1 inhibitory element, TATA box, and a transcription initiation site (hereafter p14ARFmin). The modified p14ARFmin promoter was linked to bicistronic P14 and truncated BID (tBID) genes, which led to synergistic apoptosis via the intrinsic and extrinsic pathways of apoptosis when expressed. The promoter was designed to be preferentially activated by mutant Ras and completely inhibited by wild-type p53 so that only cells with both mutant Ras and mutant p53 would activate the construct. In comparison to most p53 gene therapies, this construct has selective advantages: (1) p53-based gene therapies with a constitutive CMV promoter cannot differentiate between normal cells and cancer cells, and can be toxic to normal cells; (2) our construct does not induce p21WAF/CIPI in contrast to other p53-based gene therapies, which can induce cell cycle arrest leading to increased chemotherapy resistance; (3) the modified construct (p14ARFmin-p14-tBID) demonstrates bidirectional control of its promoter, which is completely repressed by wild-type p53 and activated only in cells with both RAS and P53 mutations; and (4) a novel combination of genes (p14 and tBID) can synergistically induce potent intrinsic and extrinsic apoptosis in cancer cells.

Applying motivational framework in medical education: a self-determination theory perspectives.

BACKGROUND: The application of self-determination theory in explaining student achievement has been well-established in various contexts. However, its application to medical education, particularly in interprofessional education (IPE) remains underexplored. Understanding how students' motivation plays a role in students' engagement and achievement is essential to optimize efforts to improve learning and instruction. OBJECTIVE: This two-stage study aims to contextualize the SDT framework to IPE through the adaptation of the Basic Psychological Need Satisfaction to IPE (Study 1) and to demonstrate how SDT can be applied in IPE by examining a model of SDT constructs (Study 2) in predicting outcomes (behavioral engagement, team effectiveness, collective dedication, goal achievement). DESIGN: In Study 1 (n=996), we adapted and validated BPNS-IPE using confirmatory factor analysis and multiple linear regression using data from 996 IPE students (Chinese Medicine, Medicine, Nursing, and Pharmacy). In Study 2 (n=271), we implemented an IPE program where we integrated SDT approaches and examined the relationship of SDT constructs with IPE outcomes using multiple linear regression. RESULTS: Our data supported the three-factor structure (autonomy, competence, and relatedness) of BPNS-IPE, meeting the required model fit. Autonomy predicted team effectiveness (F=51.290, p<.05, R2=.580); competence predicted behavioral engagement (F=55.181, p<.05, R2=.598); while relatedness predicted significantly four IPE outcomes: behavioral engagement (F=55.181, p<.01, R2=.598), team effectiveness (F=51.290, p<.01, R2=.580), collective dedication (F=49.858, p<.01, R2=.573), goal achievement (F=68.713, p<.01, R2=.649). CONCLUSIONS: The SDT motivational framework can be adapted and applied in the IPE context to understand and enhance student motivation in medical education. Potential studies with the use of the scale are provided to guide researchers.

Molecular testing opportunities on cytology effusion specimens: the pre-analytic effects of various body fluid cytology preparation methods on RNA extraction quality and targeted sequencing.

INTRODUCTION: RNA sequencing (RNAseq) analysis is emerging as a clinical research or diagnostic approach for cytologic samples, but there is need for formal comparison of different sample preparation methods in the cytology laboratory to identify which pre-analytic methods could provide alternatives to formalin-fixed paraffin-embedded (FFPE) sections. MATERIALS AND METHODS: We prepared 13 malignant effusions (metastatic estrogen receptor-positive breast cancer) in the cytology laboratory using 6 routine cytologic methods: FFPE cell block, Carnoy's solution, 95% ethanol (EtOH), air-dried and Diff-Quik, ThinPrep, and SurePath preparations. Measurements of RNA quality, expression of 2 multigene expression signatures, molecular subtype, and 4 common activating mutation sites in each preparation were compared with fresh frozen (FF) cell pellet in RNA preservative using distribution of fragment length and concordance correlation coefficient (CCC). RESULTS: The fraction of RNA fragments measuring 200 bases or more (DV200) were 24% higher from cytospins fixed in Carnoy's solution or 95% EtOH than DV200 from FFPE cell blocks. SurePath samples failed RNAseq quality control. There was high concordance of gene expression measurements with FF samples using cytospins fixed in Carnoy's solution, 95% EtOH, Diff-Quik (CCC = 0.829, 0.812, 0.760, respectively), or ThinPrep (CCC = 0.736), but lower using FFPE cell block (CCC = 0.564). The proportion of mutant transcripts was concordant between FF and any cytologic preparation methods. CONCLUSIONS: Cytospin preparations fixed with Carnoy's or 95% ETOH then Papanicolaou stained produced RNAseq results that were equivalent to FF samples and superior to FFPE cell block sections.

Steroids Significantly Decrease Postoperative Postural Hypotension in Total Knee Replacement.

Total knee replacement (TKR) is one of the most common orthopaedic procedures performed, and enhanced recovery after surgery (ERAS) has been developed and incorporated into inpatient surgical pathways to improve patient outcomes. Under ERAS recommendations, multimodal prophylaxis has been used to help manage postoperative nausea and vomiting (PONV) following TKR. Dexamethasone is one of the commonly used for this and the anti-inflammatory properties could depress vagal activity, reducing postural hypotension (PH). The hypothesis of this study is that postoperative dexamethasone use is associated with lower rates of early postoperative PH following TKR surgery. In our institution, patients who undergo elective primary TKR are admitted on the day of surgery and follow a standardized ERAS protocol. Data on patients who underwent elective primary TKR under a single adult reconstruction team from September 2017 to March 2020 were reviewed and analyzed. A review of demographic characteristics, surgical data, postoperative medications, and postoperative notes was performed. Binary logistic regression was used to assess the effect of the use of dexamethasone on PH, with an adjusted odds ratio (OR) calculated after accounting for potential confounders. Of the 149 patients were included in the study, 78 had dexamethasone postoperatively, and 71 did not. Patients who had received dexamethasone were statistically less likely to suffer from PH (OR = 0.31, p = 0.03) and less likely to develop PONV (OR = 0.21, p = 0.006). Patients who had received dexamethasone were more likely able to participate in early physiotherapy (OR = 2.42, p = 0.14), and this result was statistically insignificant. The use of postoperative intravenous dexamethasone is significantly associated with lower rates of postoperative PH after TKR. However, more studies are required to assess the optimal dosing amount and frequency, as well as to assess other factors which can enhance early postoperative patient mobilization as part of our goals for ERAS. This therapeutic study reflects level of evidence III.