The Alzheimer's Knowledge Base: A Knowledge Graph for Alzheimer Disease Research.

BACKGROUND: As global populations age and become susceptible to neurodegenerative illnesses, new therapies for Alzheimer disease (AD) are urgently needed. Existing data resources for drug discovery and repurposing fail to capture relationships central to the disease's etiology and response to drugs. OBJECTIVE: We designed the Alzheimer's Knowledge Base (AlzKB) to alleviate this need by providing a comprehensive knowledge representation of AD etiology and candidate therapeutics. METHODS: We designed the AlzKB as a large, heterogeneous graph knowledge base assembled using 22 diverse external data sources describing biological and pharmaceutical entities at different levels of organization (eg, chemicals, genes, anatomy, and diseases). AlzKB uses a Web Ontology Language 2 ontology to enforce semantic consistency and allow for ontological inference. We provide a public version of AlzKB and allow users to run and modify local versions of the knowledge base. RESULTS: AlzKB is freely available on the web and currently contains 118,902 entities with 1,309,527 relationships between those entities. To demonstrate its value, we used graph data science and machine learning to (1) propose new therapeutic targets based on similarities of AD to Parkinson disease and (2) repurpose existing drugs that may treat AD. For each use case, AlzKB recovers known therapeutic associations while proposing biologically plausible new ones. CONCLUSIONS: AlzKB is a new, publicly available knowledge resource that enables researchers to discover complex translational associations for AD drug discovery. Through 2 use cases, we show that it is a valuable tool for proposing novel therapeutic hypotheses based on public biomedical knowledge.

Sociodemographic factors and research experience impact MD-PhD program acceptance.

The 2014 NIH Physician-Scientist Workforce Working Group predicted a future shortage of physician-scientists. Subsequent studies have highlighted disparities in MD-PhD admissions based on race, income, and education. Our analysis of data from the Association of American Medical Colleges covering 2014-2021 (15,156 applicants and 6,840 acceptees) revealed that acceptance into US MD-PhD programs correlates with research experience, family income, and research publications. The number of research experiences associated with parental education and family income. Applicants were more likely to be accepted with a family income greater than $50,000 or with one or more publications or presentations. Applicants were less likely to be accepted if they had parents without a graduate degree, were Black/African American, were first-generation college students, or were reapplicants, irrespective of the number of research experiences, publications, or presentations. These findings underscore an admissions bias that favors candidates from affluent and highly educated families, while disadvantaging underrepresented minorities.

Biomechanical analysis of complications following T10-Pelvis spinal fusion: A population based computational study.

Proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) are challenging complications of long fusion constructs for the treatment of adult spinal deformity. The objective of this study is to understand the biomechanical stresses proximal to the upper instrumentation of a T10-pelvis fusion in a large patient cohort. The pre-fusion models were subject-specific thoracolumbar spine models that incorporate the height, weight, spine curvature, and muscle morphology of 250 individuals from the Framingham Heart Study Multidetector CT Study. To create post-fusion models, the subject-specific models were further modified to eliminate motion between the intervertebral joints from T10 to the pelvis. OpenSim analysis tools were used to calculate the medial lateral shear force, anterior posterior shear force, and compressive force on the T9 vertebra during the static postures. Differences between pre-fusion and post-fusion T9 biomechanics were consistent between increased segmental mobility and unchanged segmental mobility conditions. For all static postures, compression decreased (p < 0. 0005). Anterior-posterior shear force significantly increased (p < 0. 0005) during axial twist and significantly increased (p < 0. 0005) during trunk flexion. Medial lateral shear force significantly increased (p < 0. 0005) during axial twist. This computational study provided the first use of subject-specific models to investigate the biomechanics of long spinal fusions. Patients undergoing T10-Pelvis fusion were predicted to have increased shear forces and decreased compressive force at the T9 vertebra, independent of change in segmental mobility. The computational model shows potential for the investigation of spinal fusion biomechanics to reduce the risk of PJK or PJF.

Executive Summary of the American Radium Society Appropriate Use Criteria for Neoadjuvant Therapy for Nonmetastatic Pancreatic Adenocarcinoma: Systematic Review and Guidelines.

For patients with locoregionally confined pancreatic ductal adenocarcinoma (PDAC), margin-negative surgical resection is the only known curative treatment; however, the majority of patients are not operable candidates at initial diagnosis. Among patients with resectable disease who undergo surgery alone, the 5-year survival remains poor. Adjuvant therapies, including systemic therapy or chemoradiation, are utilized as they improve locoregional control and overall survival. There has been increasing interest in the use of neoadjuvant therapy to obtain early control of occult metastatic disease, allow local tumor response to facilitate margin-negative resection, and provide a test of time and biology to assist with the selection of candidates most likely to benefit from radical surgical resection. However, limited guidance exists regarding the relative effectiveness of treatment options. In this systematic review, the American Radium Society multidisciplinary gastrointestinal expert panel convened to develop Appropriate Use Criteria evaluating the evidence regarding neoadjuvant treatment for patients with PDAC, including surgery, systemic therapy, and radiotherapy, in terms of oncologic outcomes and quality of life. The evidence was assessed using the Population, Intervention, Comparator, Outcome, and Study (PICOS) design framework and "Preferred Reporting Items for Systematic Reviews and Meta-analyses" 2020 methodology. Eligible studies included phases 2 to 3 trials, meta-analyses, and retrospective analyses published between January 1, 2012 and December 30, 2022 in the Ovid Medline database. A summary of recommendations based on the available literature is outlined to guide practitioners in the management of patients with PDAC.

American Radium Society Appropriate Use Criteria for the use of liver-directed therapies for nonsurgical management of liver metastases: Systematic review and guidelines.

The liver is a common site of cancer metastases. Systemic therapy is widely accepted as the standard treatment for liver metastases (LM), although select patients with liver oligometastases may be candidates for potentially curative liver resection. Recent data support the role of nonsurgical local therapies such as ablation, external beam radiotherapy, embolization, and hepatic artery infusion therapy for management of LM. Additionally, for patients with advanced, symptomatic LM, local therapies may provide palliative benefit. The American Radium Society gastrointestinal expert panel, including members representing radiation oncology, interventional radiology, surgical oncology, and medical oncology, performed a systemic review and developed Appropriate Use Criteria for the use of nonsurgical local therapies for LM. Preferred Reporting Items for Systematic reviews and Meta-Analyses methodology was used. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in seven representative clinical scenarios through a well-established consensus methodology (modified Delphi). A summary of recommendations is outlined to guide practitioners on the use of nonsurgical local therapies for patients with LM.

Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial.

Importance: Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial. Objective: To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone. Design, Setting, Participants: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022. Interventions: Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. Main Outcomes and Measures: The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing. Results: The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm. Conclusions and Relevance: In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals. Trial Registration: ClinicalTrials.gov Identifier: NCT03599765.

American Radium Society (ARS) Appropriate Use Criteria (AUC) for Extrahepatic Cholangiocarcinoma.

Although uncommon, extrahepatic cholangiocarcinoma (EHCC) is a deadly malignancy, and the treatment approaches remain controversial. While surgery remains the only cure, few patients are candidates for resection up front, and there are high rates of both local and distant failure following resection. Herein, we systematically review the available evidence regarding treatment approaches for patients with EHCC, including surgery, radiation, and chemotherapy. The evidence regarding treatment outcomes was assessed using the Population, Intervention, Comparator, Outcome, and Study design (PICOS) framework. A summary of recommendations based on the available literature is outlined for specific clinical scenarios encountered by providers in the clinic to guide the management of these patients.

Intraoperative Hypotension Is Not Correlated With Acute Kidney Injury During Spinal Fusion Surgery.

BACKGROUND: Intraoperative hypotension (IOH) has been found to be associated with organ damage, including cardiac injury and acute kidney injury (AKI). However, to our knowledge, this relationship has not been studied in a neurosurgery-specific patient population. In this report, we review our institutional experience to understand the magnitude of association between IOH in spinal fusion operations and incidence of postoperative AKI. METHODS: This retrospective cohort study included 910 patients who underwent posterior spinal fusion procedures performed in the prone position. Intraoperative variables collected and analyzed include minute-by-minute mean arterial pressure (MAP) from an arterial catheter, intermittent blood pressure cuff readings, volume of administered intravenous fluids, urine output, and all relevant vitals and administered medications. The electronic medical record was queried for additional patient data. IOH was defined as MAP <65 mm Hg for greater than 10 minutes. The primary endpoints of the study were presence and staging of AKI ( [Kidney Disease: Improving Global Outcomes] consensus classification), postoperative ileus, and postoperative troponin leak. RESULTS: Using a partial correlation analysis, no association was found between IOH metrics (IOH occurrence, IOH duration >10 minutes, and total IOH time) and any outcome metrics, including AKI, except for vasopressor usage and estimated blood loss. Patient age at surgery was not associated with any outcome variables. The lack of association between IOH and AKI contrasts with existing literature; this could be due to underlying differences in our patient population or could highlight a more complex relationship between IOH and AKI than previously understood. CONCLUSION: Occurrence and duration of IOH were not associated with AKI, postoperative ileus, troponin leak, length of stay, or any other major outcome variables in spinal fusion patients. CLINICAL RELEVANCE: These findings depart from previous literature showing a correlation between IOH and AKI and provide level 3 evidence clinically relevant to spinal surgery. Further research is needed to better understand the exact nature of this relationship.

Quality Control Procedures for Genome-Wide Association Studies.

Genome-wide association studies (GWAS) are being conducted at an unprecedented rate in population-based cohorts and have increased our understanding of the pathophysiology of many complex diseases. Regardless of the context, the practical utility of this information ultimately depends upon the quality of the data used for statistical analyses. Quality control (QC) procedures for GWAS are constantly evolving. Here, we enumerate some of the challenges in QC of genotyped GWAS data and describe the approaches involving genotype imputation of a sample dataset along with post-imputation quality assurance, thereby minimizing potential bias and error in GWAS results. We discuss common issues associated with QC of the GWAS data (genotyped and imputed), including data file formats, software packages for data manipulation and analysis, sex chromosome anomalies, sample identity, sample relatedness, population substructure, batch effects, and marker quality. We provide detailed guidelines along with a sample dataset to suggest current best practices and discuss areas of ongoing and future research. © 2022 Wiley Periodicals LLC.

The Virtual Summer Research Program: supporting future physician-scientists from underrepresented backgrounds.

Introduction: Physician-scientist training programs expect applicants to have had extensive research experience prior to applying. Even at the best of times, this leaves individuals from underserved and underrepresented backgrounds at a competitive disadvantage, especially those remote from major academic centers. The COVID-19 pandemic exacerbated that disadvantage by closing research laboratories and suspending summer research opportunities. Methods: The Virtual Summer Research Program (VSRP) was designed to combat this shortfall by helping participating students become better informed and better prepared for applying to MD/DO-PhD programs. 156 participants were recruited from historically black colleges and universities and from national organizations for underrepresented trainees. Participants were paired with medical school faculty members and current MD/DO-PhD students from 35 participating institutions. The program lasted for at least 4 weeks and included a short research project, interactive sessions, journal clubs, social events, and attendance at a regional American Physician Scientists Association conference. Results: In follow-up surveys, participants reported improvements in their science-related skills and in their confidence in becoming a physician-scientist, applying to training programs, and navigating mentorship relationships. A follow-up study completed one year later indicated that participants felt they had benefited from an enhanced skill set, long-term relationships with their mentors, and connections to the physician-scientist community at large. Discussion: The results suggest that VSRP met its primary goals, which were to provide a diverse group of trainees with mentors, provide skills and resources for MD/DO-PhD application and matriculation and to support the development of longitudinal relationships between VSRP mentees and APSA. VSRP provides an approach that can be applied at an even larger scale when the constraints caused by a global pandemic have lifted.

American Radium Society (ARS) Appropriate Use Criteria (AUC) for Locoregional Gastric Adenocarcinoma: Systematic Review and Guidelines.

OBJECTIVE: The objective of this study was to systematically evaluate the data regarding the use of neoadjuvant, perioperative, surgical, and adjuvant treatment options in localized gastric cancer patients and to develop Appropriate Use Criteria recommended by a panel of experts convened by the American Radium Society. METHODS: Preferred reporting items for systematic reviews and meta-analyses methodology was used to develop an extensive analysis of peer-reviewed phase 2/2R/3 trials, as well as meta-analyses found within the Ovid Medline database between 2010 and 2020. The expert panel then rated the appropriateness of various treatments in 5 representative clinical scenarios through a well-established consensus methodology (modified Delphi). RESULTS: For patients with medically operable locally advanced gastric cancer, the strongest recommendation was for perioperative chemotherapy based on high-quality data. Acceptable alternatives included surgery followed by either chemotherapy or concurrent chemoradiotherapy (CRT). For patients with upfront resection of stages I to III gastric cancer (no neoadjuvant therapy), the group strongly recommended adjuvant therapy with either chemotherapy alone or CRT, based on high-quality data. For patients with locally advanced disease who received preoperative chemotherapy without tumor regression, the group strongly recommended postoperative chemotherapy or postoperative CRT. Finally, for medically inoperable gastric cancer patients, there was moderate consensus recommending definitive concurrent CRT. CONCLUSIONS: The addition of chemotherapy and/or radiation, either in the neoadjuvant, adjuvant, or perioperative setting, results in improved survival rates for patients compared with surgery alone. For inoperable patients, definitive CRT is a reasonable treatment option, though largely palliative.

Factors Associated With Image-Guided Radiation Therapy Image Rejection in a Multisite Institution.

PURPOSE: Nonclinical factors and cognitive biases have been shown to significantly affect clinical decision making. In this study, we aimed to identify clinical and environmental factors that might influence the decision to approve or reject image-guided radiation therapy (IGRT) images in a large multisite institution. METHODS: We identified all IGRT image approval and rejection decisions recorded within an electronic imaging system from July 1, 2016, to June 30, 2018. For each decision, we tabulated the following parameters: the attending physician of the patient, the physician reviewing the image, total images reviewed by the physician that day, time of day, day of week, treatment site, and imaging modality (kilovoltage or cone beam computed tomography [CBCT]). We created a binary multivariable logistic regression model to identify factors associated with IGRT image rejection. RESULTS: Overall, of 51,797 total image records evaluated, 881 (1.70%) were rejected and 50,916 (98.30%) were approved. Univariable analysis revealed that images reviewed by physicians with high rejection rates (odds ratio [OR], 3.16; P < .001) and by physicians reviewing fewer IGRT images (OR, 0.99; P = .024), images from various anatomic sites (particularly skin, breast, and head and neck), and CBCT imaging compared with kilovoltage imaging (OR, 1.49; P < .001) were associated with the increased rate of rejection. On multivariable analysis, images reviewed by physicians with high rejection rates (OR, 3.28; P < .001), images from specific anatomic sites including breast (P < .001), and CBCT imaging (P < .001) persisted as independent predictors of image rejection. CONCLUSION: These data provide important insight into the clinical, cognitive, and environmental factors that might influence the routine clinical decision of IGRT image approval. Recognition of these factors may not only improve the quality of individual decisions but also identify opportunities for systems-based quality improvement in IGRT.

Environmental enrichment leads to behavioral circadian shifts enhancing brain-wide functional connectivity between sensory cortices and eliciting increased hippocampal spiking.

Environmental enrichment induces widespread neuronal changes, but the initiation of the cascade is unknown. We ascertained the critical period of divergence between environmental enriched (EE) and standard environment (SE) mice using continuous infrared (IR) videography, functional magnetic resonance imaging (fMRI), and neuron level calcium imaging. Naïve adult male mice (n = 285, C57BL/6J, postnatal day 60) were divided into SE and EE groups. We assessed the linear time-series of motion activity using a novel structural break test which examined the dataset for change in circadian and day-by-day motion activity. fMRI was used to map brain-wide response using a functional connectome analysis pipeline. Awake calcium imaging was performed on the dorsal CA1 pyramidal layer. We found the preeminent behavioral feature in EE was a forward shift in the circadian rhythm, prolongation of activity in the dark photoperiod, and overall decreased motion activity. The crepuscular period of dusk was seen as the critical period of divergence between EE and SE mice. The functional processes at dusk in EE included increased functional connectivity in the visual cortex, motor cortex, retrosplenial granular cortex, and cingulate cortex using seed-based analysis. Network based statistics found a modulated functional connectome in EE concentrated in two hubs: the hippocampal formation and isocortical network. These hubs experienced a higher node degree and significant enhanced edge connectivity. Calcium imaging revealed increased spikes per second and maximum firing rate in the dorsal CA1 pyramidal layer, in addition to location (anterior-posterior and medial-lateral) effect size differences between EE and SE. The emergence of functional-neuronal changes due to enrichment consisted of enhanced hippocampal-isocortex functional connectivity and CA1 neuronal increased spiking linked to a circadian shift during the dusk period. Future studies should explore the molecular consequences of enrichment inducing shifts in the circadian period.

PSA: Declining utilization of prostate brachytherapy.

PURPOSE: To analyze rates of brachytherapy use for prostate cancer over time and evaluate patient characteristics, demographics and factors predictive for its utilization. METHODS: Data was retrospectively analyzed from the National Cancer Database (NCDB) for patients with localized prostate cancer treated between 2010 and 2015. Patients were included if they had biopsy confirmed localized adenocarcinoma of the prostate, were treated with radiation as definitive local therapy, and were at least 18 years old. Utilization rates of external beam radiation (EBRT), brachytherapy (BT) and combination (EBRT + BT) were evaluated over time. Univariable (UVA) and backwards elimination multivariable (MVA) analysis were performed to determine characteristics predictive for brachytherapy use. RESULTS: We analyzed 178,837 patients with localized adenocarcinoma of the prostate treated between 2010 and 2015 with radiation therapy. During this period, the use of EBRT increased from 67% to 78%, BT (both monotherapy and combination with EBRT) decreased from 33% to 22%, BT monotherapy decreased from 25% to 16% and EBRT + BT decreased from 8% to 6%. Age >70, government funded insurance or lack of insurance, intermediate or high-risk disease and treatment at an academic center were associated with significantly lower utilization of brachytherapy (all p <0.001), while higher median zip code income was associated with increased use (p = 0.02). On multivariable analysis patients who were younger, had private insurance, were lower NCCN risk category and treated in non-academic cancer centers, had a higher rate of brachytherapy utilization. Notably, on both UVA and MVA brachytherapy practice decreased with increasing year of diagnosis (OR 0.881, 95% CI 0.853-0.910, p <0.001). CONCLUSION: Rates of brachytherapy utilization for the treatment of prostate cancer continue to decrease over time. Treatment at an academic center was associated with reduced likelihood of brachytherapy use. This has significant implications for the training of future radiation oncology residents/fellows and direct consequences for both our patients and healthcare expenditure.

Supporting Equity and Inclusion of Deaf and Hard-of-Hearing Individuals in Professional Organizations.

Disability is an important and often overlooked component of diversity. Individuals with disabilities bring a rare perspective to science, technology, engineering, mathematics, and medicine (STEMM) because of their unique experiences approaching complex issues related to health and disability, navigating the healthcare system, creatively solving problems unfamiliar to many individuals without disabilities, managing time and resources that are limited by physical or mental constraints, and advocating for themselves and others in the disabled community. Yet, individuals with disabilities are underrepresented in STEMM. Professional organizations can address this underrepresentation by recruiting individuals with disabilities for leadership opportunities, easing financial burdens, providing equal access, fostering peer-mentor groups, and establishing a culture of equity and inclusion spanning all facets of diversity. We are a group of deaf and hard-of-hearing (D/HH) engineers, scientists, and clinicians, most of whom are active in clinical practice and/or auditory research. We have worked within our professional societies to improve access and inclusion for D/HH individuals and others with disabilities. We describe how different models of disability inform our understanding of disability as a form of diversity. We address heterogeneity within disabled communities, including intersectionality between disability and other forms of diversity. We highlight how the Association for Research in Otolaryngology has supported our efforts to reduce ableism and promote access and inclusion for D/HH individuals. We also discuss future directions and challenges. The tools and approaches discussed here can be applied by other professional organizations to include individuals with all forms of diversity in STEMM.

Structural Alterations in a Rat Model of Short-Term Conductive Hearing Loss Are Associated With Reduced Resting State Functional Connectivity.

Conductive hearing loss (CHL) results in attenuation of air conducted sound reaching the inner ear. How a change in air conducted sound alters the auditory system resulting in cortical alterations is not well understood. Here, we have assessed structural and functional magnetic resonance imaging (MRI) in an adult (P60) rat model of short-term conductive hearing loss (1 week). Diffusion tensor imaging (DTI) revealed fractional anisotropy (FA) and axial diffusivity alterations after hearing loss that circumscribed the auditory cortex (AC). Tractography found the lateral lemniscus tract leading to the bilateral inferior colliculus (IC) was reduced. For baseline comparison, DTI and tractography alterations were not found for the somatosensory cortex. To determine functional connectivity changes due to hearing loss, seed-based analysis (SBA) and independent component analysis (ICA) were performed. Short term conductive hearing loss altered functional connectivity in the AC and IC, but not the somatosensory cortex. The results present an exploratory neuroimaging assessment of structural alterations coupled to a change in functional connectivity after conductive hearing loss. The results and implications for humans consist of structural-functional brain alterations following short term hearing loss in adults.

Hearing loss impacts gray and white matter across the lifespan: Systematic review, meta-analysis and meta-regression.

Hearing loss is a heterogeneous disorder thought to affect brain reorganization across the lifespan. Here, structural alterations of the brain due to hearing loss are assessed by using unique effect size metrics based on Cohen's d and Hedges' g. These metrics are used to map coordinates of gray matter (GM) and white matter (WM) alterations from bilateral congenital and acquired hearing loss populations. A systematic review and meta-analysis revealed m = 72 studies with structural alterations measured with magnetic resonance imaging (MRI) (bilateral = 64, unilateral = 8). The bilateral studies categorized hearing loss into congenital and acquired cases (n = 7,445) and control cases (n = 2,924), containing 66,545 datapoint metrics. Hearing loss was found to affect GM and underlying WM in nearly every region of the brain. In congenital hearing loss, GM decreased most in the frontal lobe. Similarly, acquired hearing loss had a decrease in frontal lobe GM, albeit the insula was most decreased. In congenital, WM underlying the frontal lobe GM was most decreased. In congenital, the right hemisphere was more negatively impacted than the left hemisphere; however, in acquired, this was the opposite. The WM alterations most frequently underlined GM alterations in congenital hearing loss, while acquired hearing loss studies did not frequently assess the WM metric. Future studies should use the endophenotype of hearing loss as a prognostic template for discerning clinical outcomes.

Structural and Functional Hippocampal Correlations in Environmental Enrichment During the Adolescent to Adulthood Transition in Mice.

Environmental enrichment is known to induce neuronal changes; however, the underlying structural and functional factors involved are not fully known and remain an active area of study. To investigate these factors, we assessed enriched environment (EE) and standard environment (SE) control mice over 30 days using structural and functional MRI methods. Naïve adult male mice (n = 30, ≈20 g, C57BL/B6J, postnatal day 60 initial scan) were divided into SE and EE groups and scanned before and after 30 days. Structural analyses included volumetry based on manual segmentation as well as diffusion tensor imaging (DTI). Functional analyses included seed-based analysis (SBA), independent component analysis (ICA), the amplitude of low-frequency fluctuation (ALFF), and fractional ALFF (fALFF). Structural results indicated that environmental enrichment led to an increase in the volumes of cornu ammonis 1 (CA1) and dentate gyrus. Structural results indicated changes in radial diffusivity and mean diffusivity in the visual cortex and secondary somatosensory cortex after EE. Furthermore, SBA and ICA indicated an increase in resting-state functional MRI (rsfMRI) functional connectivity in the hippocampus. Using parallel structural and functional analyses, we have demonstrated coexistent structural and functional changes in the hippocampal subdivision CA1. Future research should map alterations temporally during environmental enrichment to investigate the initiation of these structural and functional changes.

Executive Summary of the American Radium Society Appropriate Use Criteria for Operable Esophageal and Gastroesophageal Junction Adenocarcinoma: Systematic Review and Guidelines.

PURPOSE: Limited guidance exists regarding the relative effectiveness of treatment options for nonmetastatic, operable patients with adenocarcinoma of the esophagus or gastroesophageal junction (GEJ). In this systematic review, the American Radium Society (ARS) gastrointestinal expert panel convened to develop Appropriate Use Criteria (AUC) evaluating how neoadjuvant and/or adjuvant treatment regimens compared with each other, surgery alone, or definitive chemoradiation in terms of response to therapy, quality of life, and oncologic outcomes. METHODS AND MATERIALS: Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology was used to develop an extensive analysis of peer-reviewed phase 2R and phase 3 randomized controlled trials as well as meta-analyses found within the Ovid Medline, Cochrane Central, and Embase databases between 2009 to 2019. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in 4 broadly representative clinical scenarios through a well-established consensus methodology (modified Delphi). RESULTS: For a medically operable nonmetastatic patient with a cT3 and/or cN+ adenocarcinoma of the esophagus or GEJ (Siewert I-II), the panel most strongly recommends neoadjuvant chemoradiation. For a cT2N0M0 patient with high-risk features, the panel recommends neoadjuvant chemoradiation as usually appropriate. For patients found to have pathologically involved nodes (pN+) who did not receive any neoadjuvant therapy, the panel recommends adjuvant chemoradiation as usually appropriate. These guidelines assess the appropriateness of various dose-fractionating schemes and target volumes. CONCLUSIONS: Chemotherapy and/or radiation regimens for esophageal cancer are still evolving with many areas of active investigation. These guidelines are intended for the use of practitioners and patients who desire information about the management of operable esophageal adenocarcinoma.