A very complicated UTI: malakoplakia following E. coli urinary tract infection.

Malakoplakia is a rare inflammatory disorder believed to result from a defect in macrophage phagocytic function triggering a granulomatous reaction. It can present with genitourinary, gastrointestinal, or cutaneous manifestations in immunocompromised or, less commonly, immunocompetent hosts. We describe a case of renal malakoplakia in a young, otherwise healthy patient presenting with nephromegaly and sepsis following an E. coli urinary tract infection. We discuss diagnosis and management, including antibiotic selection and the decision to pursue nephrectomy. This case highlights the potential for kidney recovery with prolonged antibiotic therapy in conjunction with adjunct immunomodulatory therapies and source control.

Perspective: Nutrition Health Disparities Framework: A Model to Advance Health Equity.

Disparities in nutrition, such as poor diet quality and inadequate nutrient intake, arise from multiple factors and are related to adverse health outcomes such as obesity, diabetes, cardiovascular disease, and some cancers. The aim of the current perspective is to present a nutrition-centric socioecological framework that delineates determinants and factors that contribute to diet and nutrition-related disparities among disadvantaged populations. The Nutrition Health Disparities Framework (NHDF) describes the domains (biological, behavioral, physical/built environment, sociocultural environment, and healthcare system) that influence nutrition-related health disparities through the lens of each level of influence (that is, individual, interpersonal, community, and societal). On the basis of the scientific literature, the authors engaged in consensus decision making in selecting nutrition-related determinants of health within each domain and socioecological level when creating the NHDF. The framework identifies how neighborhood food availability and access (individual/built environment) intersect with cultural norms and practices (interpersonal/sociocultural environment) to influence dietary behaviors, exposures, and risk of diet-related diseases. In addition, the NHDF shows how factors such as genetic predisposition (individual/biology), family dietary practices (interpersonal/behavioral), and food marketing policies (societal) may impact the consumption of unhealthy foods and beverages and increase chronic disease risk. Family and peer norms (interpersonal/behavior) related to breastfeeding and early childhood nutrition interact with resource-poor environments such as lack of access to preventive healthcare settings (societal/healthcare system) and low usage of federal nutrition programs (societal/behavioral), which may increase risk of poor nutrition during childhood and food insecurity. The NHDF describes the synergistic interrelationships among factors at different levels of the socioecological model that influence nutrition-related outcomes and exacerbate health disparities. The framework is a useful resource for nutrition researchers, practitioners, food industry leaders, and policymakers interested in improving diet-related health outcomes and promoting health equity in diverse populations.

Methodological examination of the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Score.

The objective of this study was to examine the impact of methodological changes to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Score on associations with risk for all-cause mortality, cancer mortality, and cancer risk jointly among older adults in the NIH-AARP Diet and Health Study. Weights were incorporated for each Score component; a continuous point scale was developed in place of the Score's fully discrete cut-points; and cut-point values were changed for physical activity and red meat based on evidence-based recommendations. Exploratory aims also examined the impact of separating components with more than one sub-component and whether all components were necessary to retain within this population utilizing a penalized scoring approach. Findings suggested weighting the original 2018 WCRF/AICR Score improved the score's predictive performance in association with all-cause mortality and provided more precise estimates in relation to cancer risk and mortality outcomes. The importance of healthy weight, physically activity, and plant-based foods in relation to cancer and overall mortality risk were highlighted in this population of older adults. Further studies are needed to better understand the consistency and generalizability of these findings across other populations.

Appropriateness of Information Provided by ChatGPT Regarding Breast Pathologic Diagnoses.

A multidisciplinary physician team rated information provided by ChatGPT regarding breast pathologic diagnoses. ChatGPT responses were mostly appropriate regarding accuracy, consistency, definitions provided, and clinical significance conveyed. Responses were scored lower in terms of management recommendations provided, primarily related to low agreement with recommendations for high-risk lesions.

Conceptualization and Assessment of 24-H Timing of Eating and Energy Intake: A Methodological Systematic Review of the Chronic Disease Literature.

Timing of eating (TOE) and energy intake (TOEI) has important implications for chronic disease risk beyond diet quality. The 2020 Dietary Guidelines Advisory Committee recommended developing consistent terminology to address the lack of TOE/TOEI standardization. The primary objective of this methodological systematic review was to characterize the conceptualization and assessment of TOE/TOEI within the chronic disease literature (International Prospective Register of Systematic Reviews registration number: CRD42021236621). Literature searches in Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus, Embase, PubMed, and Scopus were limited to English language publications from 2000 to August 2022. Eligible studies reported the association between TOE/TOEI and obesity, cardiovascular disease, type 2 diabetes mellitus, cancer, or a related clinical risk factor among adults (≥19 y) in observational and intervention studies. A qualitative synthesis described and compared TOE/TOEI conceptualization, definitions, and assessment methods across studies. Of the 7579 unique publications identified, 259 studies (observational [51.4 %], intervention [47.5 %], or both [1.2 %]) were eligible for inclusion. Key findings indicated that most studies (49.6 %) were conducted in the context of obesity and body weight. TOE/TOEI variables or assigned conditions conceptualized interrelated aspects of time and eating or energy intake in varying ways. Common TOE/TOEI conceptualizations included the following: 1) timepoint (specific time to represent when intake occurs, such as time of breakfast [74.8 %]); 2) duration (length of time or interval when intake does/does not occur, such as "eating window" [56.5 %]); 3) distribution (proportion of daily intake at a given time interval, such as "percentage of energy before noon" [29.8 %]); and 4) cluster (grouping individuals based on temporal ingestive characteristics [5.0 %]). Assessment, definition, and operationalization of 24-h TOE/TOEI variables varied widely across studies. Observational studies most often used surveys or questionnaires (28.9 %), whereas interventions used virtual or in-person meetings (23.8 %) to assess TOE/TOEI adherence. Overall, the diversity of terminology and methods solidifies the need for standardization to guide future research in chrononutrition and to facilitate inter-study comparisons.

Associations between actigraphy-measured sleep duration, continuity, and timing with mortality in the UK Biobank.

STUDY OBJECTIVES: To examine the associations between sleep duration, continuity, timing, and mortality using actigraphy among adults. METHODS: Data were from a cohort of 88 282 adults (40-69 years) in UK Biobank that wore a wrist-worn triaxial accelerometer for 7 days. Actigraphy data were processed to generate estimates of sleep duration and other sleep characteristics including wake after sleep onset (WASO), number of 5-minute awakenings, and midpoint for sleep onset/wake-up and the least active 5 hours (L5). Data were linked to mortality outcomes with follow-up to October 31, 2021. We implemented Cox models (hazard ratio, confidence intervals [HR, 95% CI]) to quantify sleep associations with mortality. Models were adjusted for demographics, lifestyle factors, and medical conditions. RESULTS: Over an average of 6.8 years 2973 deaths occurred (1700 cancer, 586 CVD deaths). Overall sleep duration was significantly associated with risk for all-cause (p < 0.01), cancer (p < 0.01), and CVD (p = 0.03) mortality. For example, when compared to sleep durations of 7.0 hrs/d, durations of 5 hrs/d were associated with a 29% higher risk for all-cause mortality (HR: 1.29 [1.09, 1.52]). WASO and number of awakenings were not associated with mortality. Individuals with L5 early or late midpoints (<2:30 or ≥ 3:30) had a ~20% higher risk for all-cause mortality, compared to those with intermediate L5 midpoints (3:00-3:29; p ≤ 0.01; e.g. HR ≥ 3:30: 1.19 [1.07, 1.32]). CONCLUSIONS: Shorter sleep duration and both early and late sleep timing were associated with a higher mortality risk. These findings reinforce the importance of public health efforts to promote healthy sleep patterns in adults.

Evaluation of putative signatures of consciousness using specific definitions of responsiveness, connectedness, and consciousness.

BACKGROUND: Understanding the neural correlates of consciousness has important ramifications for the theoretical understanding of consciousness and for clinical anaesthesia. A major limitation of prior studies is the use of responsiveness as an index of consciousness. We identified a collection of measures derived from unresponsive subjects and more specifically their association with consciousness (any subjective experience) or connectedness (specific experience of environmental stimuli). METHODS: Using published data generated through the UNderstanding Consciousness Connectedness and Intra-Operative Unresponsiveness Study (NCT03284307), we evaluated 10 previously published resting-state EEG-based measures that were derived using unresponsiveness as a proxy for unconsciousness. Measures were tested across dexmedetomidine and propofol sedation and natural sleep. These markers represent the complexity, connectivity, cross-frequency coupling, graph theory, and power spectrum measures. RESULTS: Although many of the proposed markers were associated with consciousness per se (reported subjective experience), none were specific to consciousness alone; rather, each was also associated with connectedness (i.e. awareness of the environment). In addition, multiple markers showed no association with consciousness and were associated only with connectedness. Of the markers tested, loss of normalised-symbolic transfer entropy (front to back) was associated with connectedness across all three experimental conditions, whereas the transition from disconnected consciousness to unconsciousness was associated with significant decreases in permutation entropy and spectral exponent (P<0.05 for all conditions). CONCLUSIONS: None of the proposed EEG-based neural correlates of unresponsiveness corresponded solely to consciousness, highlighting the need for a more conservative use of the term (un)consciousness when assessing unresponsive participants. CLINICAL TRIAL REGISTRATION: NCT03284307.

Actigraphy-derived measures of sleep and risk of prostate cancer in the UK Biobank.

BACKGROUND: Studies of sleep and prostate cancer are almost entirely based on self-report, with limited research using actigraphy. Our goal was to evaluate actigraphy-measured sleep and prostate cancer and to expand on findings from prior studies of self-reported sleep. METHODS: We prospectively examined 34 260 men without a history of prostate cancer in the UK Biobank. Sleep characteristics were measured over 7 days using actigraphy. We calculated sleep duration, onset, midpoint, wake-up time, social jetlag (difference in weekend-weekday sleep midpoints), sleep efficiency (percentage of time spent asleep between onset and wake-up time), and wakefulness after sleep onset. Cox proportional hazards models were used to estimate covariate-adjusted hazards ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over 7.6 years, 1152 men were diagnosed with prostate cancer. Sleep duration was not associated with prostate cancer risk. Sleep midpoint earlier than 4:00 am was not associated with prostate cancer risk, though sleep midpoint of 5:00 am or later was suggestively associated with lower prostate cancer risk but had limited precision (earlier than 4:00 am vs 4:00-4:59 am HR = 1.00, 95% CI = 0.87 to 1.16; 5:00 am or later vs 4:00-4:59 am HR = 0.79, 95% CI = 0.57 to 1.10). Social jetlag was not associated with greater prostate cancer risk (1 to <2 hours vs <1 hour HR = 1.06, 95% CI = 0.89 to 1.25; ≥2 hours vs <1 hour HR = 0.90, 95% CI = 0.65 to 1.26). Compared with men who averaged less than 30 minutes of wakefulness after sleep onset per day, men with 60 minutes or more had a higher risk of prostate cancer (HR = 1.20, 95% CI = 1.00 to 1.43). CONCLUSIONS: Of the sleep characteristics studied, higher wakefulness after sleep onset-a measure of poor sleep quality-was associated with greater prostate cancer risk. Replication of our findings between wakefulness after sleep onset and prostate cancer are warranted.

Time-Restricted Eating in Community-Dwelling Adults: Correlates of Adherence and Discontinuation in a Cross-Sectional Online Survey Study.

BACKGROUND: Time-restricted eating (TRE), a type of intermittent fasting in which all daily calories are consumed within a window of ≤12 hours, is hypothesized to promote long-term weight management because of its relative simplicity. OBJECTIVE: This study reports correlates of adherence among community-dwelling adults currently or formerly following a TRE dietary strategy. DESIGN: A 25-minute cross-sectional online survey was developed, including questions about TRE perceptions, behaviors, motivators and drivers, and demographics. The survey was administered in February 2021 via Prolific, an online platform for sample recruitment and survey dissemination. PARTICIPANTS: Eligibility criteria included US adult ages 18+ who currently or formerly (past 3 months) followed TRE (ie, consumed all daily calories within a window of ≤12 hours) for a minimum of 1 week. STATISTICAL ANALYSES: χ2 tests and analysis of covariance (ANCOVA; adjusting for sex and age) compared responses between current and former followers. RESULTS: Current followers (n = 296, mean [SD]: 34.2 ± 12.2y) were older than former followers (n = 295, mean [SD]: 31.1 ± 10.9 y) and practiced TRE for longer (median: 395 vs 90 days, P < 0.001). Current followers reported more success with meeting TRE goals (P ≤ 0.015), were less likely to report TRE concerns (P < 0.001), and more likely to report TRE satisfaction (P < 0.001). Four TRE motivators were more important among current (vs former) followers: weight maintenance, health (not weight), improved sleep, and preventing disease (P ≤ 0.017); weight loss was more important among former (vs current) followers (P = 0.003). Among adherence drivers, ability to work from home and the impact of COVID-19 were reported as more helpful for TRE adherence among current compared with former followers (P ≤ 0.028). CONCLUSIONS: TRE motivators and drivers differed between current and former followers; interventions tailored to individuals' preferences and circumstances may benefit TRE adherence.

Metaplastic carcinoma with osteosarcomatous differentiation in the breast: Case report.

Metaplastic breast carcinoma is rare and may present as a highly aggressive subtype of breast cancer. In this case report of metastatic metaplastic breast carcinoma with osteosarcomatous differentiation in a female patient previously treated for invasive ductal carcinoma, we describe the new presentation of a palpable mass with associated calcifications on imaging near the site of prior partial mastectomy. This article will detail the clinical presentation, imaging findings, histopathology, and clinical course following treatment of our case. Knowledge of the clinical and imaging presentation of this rare subtype, which can present with benign features on mammography and ultrasound, can facilitate timely diagnosis as treatment paradigms evolve.

Healthy Eating Index-2020: Review and Update Process to Reflect the Dietary Guidelines for Americans,2020-2025.

The purpose of this review is to share the process for reviewing, updating, and developing the most recent version of the Healthy Eating Index-2020 (HEI-2020) for ages 2 and older, following the release of the Dietary Guidelines for Americans (DGA), 2020-2025. The overall review process included: 1) gathering information from the updated DGA, experts, and federal stakeholders; 2) considering substantive changes and needs for new development, keeping in mind the HEI's key features and guiding principles, the US Department of Agriculture's Dietary Patterns that serve as the foundation for the HEI, and scoring considerations; and 3) completing evaluation analyses, including the examination of content validity. The review process led to the development of the HEI-2020; a separate HEI-Toddlers-2020 was developed for ages 12 through 23 months. The 13 components and scoring standards of the HEI-2020 fully align with the HEI-2015, although the index was renamed to clarify that it aligned with the most recent 2020-2025 DGA. As the evidence informing the DGA continues to evolve, various aspects of the HEI may need to evolve in the future as well. Further methodological research is encouraged to add to the scientific evidence base on dietary patterns, to examine needs specific to each life stage, and to model optimal trajectories of healthy dietary patterns over the lifespan.

Evaluation of the Healthy Eating Index-Toddlers-2020.

BACKGROUND: With the addition of new guidance for children from birth to 24 months in the Dietary Guidelines for Americans, 2020-2025 (DGA), a Healthy Eating Index (HEI) was developed for toddlers. OBJECTIVE: To evaluate the psychometric properties of the HEI-Toddlers-2020, 5 analyses relevant to construct and concurrent validity and 2 related to reliability were examined. DESIGN: Twenty-four-hour diet recall data from the cross-sectional National Health and Nutrition Examination Survey (2011-2018) were used. In addition, exemplary menus were analyzed. PARTICIPANTS/SETTING: The main analytic sample included toddlers aged 12 through 23 months (n = 838), with additional analyses of toddlers aged 12 through 35 months (n = 1,717) from the United States. Included participants had valid diet recalls and available weight-for-age data. MAIN OUTCOME MEASURES: Outcomes measures included HEI-Toddlers-2020 total and component scores on menus, population distributions, and correlations. STATISTICAL ANALYSES: HEI total and component scores were calculated using menus from the American Academy of Pediatrics and Healthy Eating Research. Score means and distributions were estimated using a Markov Chain Monte Carlo approach with National Health and Nutrition Examination Survey data (2011-2018). Principal component analysis explored dimensions and Pearson correlations examined components, energy, and Cronbach α. In addition, HEI-Toddlers-2020 and HEI-2020 scores were compared for identical intakes at age 24 months. RESULTS: For validity, exemplary menus received high scores with the HEI-Toddlers-2020. The mean ± SE total HEI-Toddlers-2020 score for toddlers aged 12 through 23 months was 62.9 ± 0.78 and ranged from 40.1 to 84.4 (1st to 99th percentile). Correlation between diet quality and diet quantity was low (-0.15); the scree plot revealed multiple factors. In addition, total scores for identical intakes were approximately 1.5 points higher for HEI-Toddlers-2020 compared with HEI-2020 (difference range for component scores, -4.97 to 4.89). For reliability, most of the intercorrelations among components were low to moderate (0 to 0.49), with a few exceptions among related components. Cronbach α was .48. These results indicate that the index is multidimensional, with no single component driving the total score, and no unnecessary components that are highly correlated with another component. CONCLUSIONS: The results demonstrated evidence supportive of validity and reliability. The HEI-Toddlers-2020 can be used to assess alignment with the DGA for toddlers.

Continuity, Considerations, and Future Directions for the Healthy Eating Index-Toddlers-2020.

The Dietary Guidelines for Americans, 2020-2025 includes guidance for infants and toddlers aged birth to 24 months. To assess alignment with this new guidance, the Healthy Eating Index (HEI)-Toddlers-2020 was developed for toddlers 12 through 23 months old. This monograph focuses on the continuity, considerations, and future directions of this new index for toddlers in the context of evolving dietary guidance. There is considerable continuity between the HEI-Toddlers-2020 and previous versions of the HEI. The same process, guiding principles, and features (with caveats) are repeated in the new index. However, there are unique considerations for measurement, analysis, and interpretation for the HEI-Toddlers-2020 that this article addresses, while identifying future directions for the HEI-Toddlers-2020. The continued evolution of dietary guidance for infants, toddlers, and young children will provide additional opportunities for index-based metrics: considering inclusion of multidimensional layers in dietary patterns, defining a healthy eating trajectory, bridging healthy eating across different life stages, and communicating the constructs of balance among dietary constituents.

Development of the Healthy Eating Index-Toddlers-2020.

The Healthy Eating Index-Toddlers-2020 (HEI-Toddlers-2020) is a measure for assessing how well a set of foods aligns with new guidance in the Dietary Guidelines for Americans, 2020-2025 (DGA) for toddlers aged 12 through 23 months. This new tool was developed using consistent features and the guiding principles of the HEI. The HEI-Toddlers-2020, like HEI-2020, has 13 components reflecting all constituents of dietary intake, except for human milk or infant formula. These components include the following: Total Fruits, Whole Fruits, Total Vegetables, Greens and Beans, Whole Grains, Dairy, Total Protein Foods, Seafood and Plant Proteins, Fatty Acids, Refined Grains, Sodium, Added Sugars, and Saturated Fats. Healthy dietary patterns for toddlers have unique considerations reflected in the scoring standards for Added Sugars and Saturated Fats. Toddlers have lower energy intake relative to high nutrient needs and added sugars should be avoided. Another distinctive difference is that there is no recommendation to limit saturated fats to <10% of energy intake in this age group; however, saturated fats cannot be unlimited without displacing the energy available to achieve other food group and subgroup goals. Calculations using the HEI-Toddlers-2020, like the HEI-2020, result in a total score and a set of individual component scores that reveal a dietary pattern. The release of a HEI-Toddlers-2020 will enable assessment of diet quality that aligns with the DGA and support additional methodological research to examine needs specific to each life stage and how to model trajectories of healthy dietary patterns.

A New Landscape of Testing and Therapeutics in Metastatic Breast Cancer.

Predictive biomarker testing on metastatic breast cancer is essential for determining patient eligibility for targeted therapeutics. The National Comprehensive Cancer Network currently recommends assessment of specific biomarkers on metastatic tumor subtypes, including hormone receptors, HER2, and BRCA1/2 mutations, on all newly metastatic breast cancers subtypes; programmed death-ligand 1 on metastatic triple-negative carcinomas; and PIK3CA mutation status on estrogen receptor-positive carcinomas. In select circumstances mismatch repair protein deficiency and/or microsatellite insufficiency, tumor mutation burden, and NTRK translocation status are also testing options. Novel biomarker testing, such as detecting PIK3CA mutations in circulating tumor DNA, is expanding in this rapidly evolving arena.

A Decade of Dietary Assessment Methodology Research at the National Institutes of Health, 2012-2021.

BACKGROUND: Assessment of individual and population-level dietary intake is critical for public health surveillance, epidemiology, and dietary intervention research. In recognition of that need, the National Insitutes of Health (NIH) has a history of funding research projects designed to support the development, implementation, and refinement of tools to assess dietary intake in humans. OBJECTIVES: This report provides data and information on NIH-funded dietary intake assessment methodological research over the period of 2012-2021. METHODS: Data were extracted from an internal NIH data system using the Research, Condition, and Disease Categorization (RCDC) spending category for Nutrition. Data were then examined to identify research focused on dietary assessment tools or methods to capture or analyze dietary intake. RESULTS: Over the decade of 2012-2021, NIH supported 46 grants and 2 large contracts specific to dietary assessment methods development. The top 6 Institutes and Offices funding dietary assessment methods research were identified. Most projects were limited to adults. Projects ranged from novel methods to capture dietary intake, and refinement of analytical methods, to biomarkers of dietary intake. One key contract supported the automated self-administered 24-h dietary assessment tool (ASA24), a widely used, free tool available to the research community for assessing dietary intake. CONCLUSIONS: NIH's support for dietary assessment methods development over this 10-y period was small but grew over time with an expanding number and variety of methods, data sources, and technological advancements in the assessment of dietary intake. NIH remains committed to supporting research seeking to advance the field of dietary assessment methods research.

Operationalisation of a standardised scoring system to assess adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations in the UK biobank.

Introduction: In 2018, The World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) published ten evidence-based Cancer Prevention Recommendations designed to reduce the risk of cancer via improved lifestyle behaviours. In 2019, Shams-White and colleagues created the "2018 WCRF/AICR Score" which aimed to standardise how adherence to these recommendations is assessed. The standardised scoring system includes seven of the recommendations concerning weight, physical activity and diet, with an optional eighth recommendation on breastfeeding. To promote transparency and reproducibility, the present paper describes the methodology for operationalisation of the standardised scoring system in the UK Biobank. Methods: UK Biobank recruited >500,000 individuals aged 37-73 years, between 2006 and 2010. In 2021, we held a workshop with experts which aimed to reach consensus on how to operationalise the scoring system using data available within UK Biobank. We used data on anthropometric measurements, physical activity and diet to calculate adherence scores. 24 h dietary assessment data were used to measure adherence to the following recommendations: "Eat a diet rich in wholegrains, vegetables, fruit, and beans", "Limit consumption of "fast foods" and other processed foods high in fat, starches or sugars" and "Limit consumption of sugar-sweetened drinks"; food frequency questionnaire data were used to assess adherence to "Limit consumption of red and processed meat" and "Limit alcohol consumption". Participants were allocated points for meeting, partially meeting or not meeting each recommendation, using cut-offs defined in the standardised scoring system. Results: At our workshop, discussions included the use of national guidelines to assess adherence to the recommendation on alcohol consumption, as well as challenges faced including defining the adapted ultra-processed food variables. A total score was calculated for 158,415 participants (mean 3.9 points, range 0-7 points). We also describe the methodology to derive a partial 5-point adherence score using data from the food frequency questionnaire in 314,616 participants. Conclusion: We describe the methodology used to estimate adherence to the 2018 WCRF/AICR Cancer Prevention Recommendations for participants in the UK Biobank, including some of the challenges faced operationalising the standardised scoring system.

Web-based pathology modules with virtual slides are effective for teaching introductory gastrointestinal pathology concepts.

Pathology interns face a steep learning curve as they transition from medical school to residency. Innovative teaching tools are needed to effectively and efficiently bridge this gap. We created four online learning modules geared toward pathology interns, for use at the beginning of the gastrointestinal pathology rotation at our institution. Our modules covered introductory esophageal, gastric, small bowel, and colonic pathology. Each module incorporated photomicrographs and annotated virtual slides, and included pre- and post-module assessment questions and a link to an anonymous survey. Twelve interns completed the modules between 9/20/2019 and 12/31/2021, including 80% of the 2020-2021 intern class. Significant improvement in performance was seen between the pre- and post-module questions for the stomach, small bowel, and colon modules (p < 0.05 for all), with a trend toward improved performance with the esophageal module. Interns rated the modules highly and indicated that they would recommend the modules to their peers. While the modules were geared toward interns, due to the coronavirus-19 pandemic we expanded access to the modules to include medical students. Medical students also found the learning modules valuable and requested more modules in the future. We conclude that online learning modules are an effective tool for teaching pathology interns and are well-received by this group. Online modules can also be seamlessly incorporated into asynchronous medical student teaching.

Greater tau pathology is associated with altered predictive coding.

Altered predictive coding may underlie the reduced auditory mismatch negativity amplitude observed in patients with dementia. We hypothesized that accumulating dementia-associated pathologies, including amyloid and tau, lead to disturbed predictions of our sensory environment. This would manifest as increased reliance on 'observed' sensory information with an associated increase in feedforward, and decrease in feedback, signalling. To test this hypothesis, we studied a cross-sectional cohort of participants who underwent PET imaging and high-density EEG during an oddball paradigm, and used dynamic casual modelling and Bayesian statistics to make inferences about the neuronal architectures (generators) and mechanisms (effective connectivity) underlying the observed auditory-evoked responses. Amyloid-ß imaging with [C-11] Pittsburgh Compound-B PET was qualitatively rated using established criteria. Tau-positive PET scans, with [F-18]MK-6240, were defined by an MK-6240 standardized uptake value ratio positivity threshold at 2 standard deviations above the mean of the Amyloid(-) group in the entorhinal cortex (entorhinal MK-6240 standardized uptake value ratio > 1.27). The cross-sectional cohort included a total of 56 participants [9 and 13 participants in the Tau(+) and Amyloid(+) subgroups, respectively: age interquartile range of (73.50-75.34) and (70.5-75.34) years, 56 and 69% females, respectively; 46 and 43 participants in the Tau(-) and Amyloid(-) subgroups, respectively: age interquartile range of (62.72-72.5) and (62.64-72.48) years, 67 and 65% females, respectively]. Mismatch negativity amplitudes were significantly smaller in Tau+ subgroup than Tau- subgroup (cluster statistics corrected for multiple comparisons: P = 0.028). Dynamic causal modelling showed that tau pathology was associated with increased feedforward connectivity and decreased feedback connectivity, with increased excitability of superior temporal gyrus but not inferior frontal regions. This effect on superior temporal gyrus was consistent with the distribution of tau disease on PET in these participants, indicating that the observed differences in mismatch negativity reflect pathological changes evolving in preclinical dementia. Exclusion of participants with diagnosed mild cognitive impairment or dementia did not affect the results. These observational data provide proof of concept that abnormalities in predictive coding may be detected in the preclinical phase of Alzheimer's disease. This framework also provides a construct to understand how progressive impairments lead to loss of orientation to the sensory world in dementia. Based on our modelling results, plus animal models indicating that Alzheimer's disease pathologies produce hyperexcitability of higher cortical regions through local disinhibition, mismatch negativity might be a useful monitor to deploy as strategies that target interneuron dysfunction are developed.

Dynamic causal modelling of auditory surprise during disconnected consciousness: The role of feedback connectivity.

The neural mechanisms through which individuals lose sensory awareness of their environment during anesthesia remains poorly understood despite being of vital importance to the field. Prior research has not distinguished between sensory awareness of the environment (connectedness) and consciousness itself. In the current study, we investigated the neural correlates of sensory awareness by contrasting neural responses to an auditory roving oddball paradigm during consciousness with sensory awareness (connected consciousness) and consciousness without sensory awareness (disconnected consciousness). These states were captured using a serial awakening paradigm with the sedative alpha2 adrenergic agonist dexmedetomidine, chosen based on our published hypothesis that suppression of noradrenaline signaling is key to induce a state of sensory disconnection. High-density electroencephalography was recorded from 18 human subjects before and after administration of dexmedetomidine. By investigating event-related potentials and taking advantage of advances in Dynamic Causal Modeling (DCM), we assessed alterations in effective connectivity between nodes of a previously established auditory processing network. We found that during disconnected consciousness, the scalp-level response to standard tones produced a P3 response that was absent during connected consciousness. This P3 response resembled the response to oddball tones seen in connected consciousness. DCM showed that disconnection produced increases in standard tone feedback signaling throughout the auditory network. Simulation analyses showed that these changes in connectivity, most notably the increase in feedback from right superior temporal gyrus to right A1, can explain the new P3 response. Together these findings show that during disconnected consciousness there is a disruption of normal predictive coding processes, so that all incoming auditory stimuli become similarly surprising.