Building a vertically integrated genomic learning health system: The biobank at the Colorado Center for Personalized Medicine.

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.

Time-varying associations of patient and tumor characteristics with cancer survival: an analysis of SEER data across 14 cancer sites, 2004-2017.

PURPOSE: Surveillance, Epidemiology, and End Results (SEER) cancer registries provides information about survival duration and cause of death for cancer patients. Baseline demographic and tumor characteristics such as age, sex, race, year of diagnosis, and tumor stage can inform the expected survival time of patients, but their associations with survival may not be constant over the post-diagnosis period. METHODS: Using SEER data, we examined if there were time-varying associations of patient and tumor characteristics on survival, and we assessed how these relationships differed across 14 cancer sites. Standard Cox proportional hazards models were extended to allow for time-varying associations and incorporated into a competing-risks framework, separately modeling cancer-specific and other-cause deaths. For each cancer site and for each of the five factors, we estimated the relative hazard ratio and absolute hazard over time in the presence of competing risks. RESULTS: Our comprehensive consideration of patient and tumor characteristics when estimating time-varying hazards showed that the associations of age, tumor stage at diagnosis, and race/ethnicity with risk of death (cancer-specific and other-cause) change over time for many cancers; characteristics of sex and year of diagnosis exhibit some time-varying patterns as well. Stage at diagnosis had the largest associations with survival. CONCLUSION: These findings suggest that proportional hazards assumptions are often violated when examining patient characteristics on cancer survival post-diagnosis. We discuss several interesting results where the relative hazards are time-varying and suggest possible interpretations. Based on the time-varying associations of several important covariates on survival after cancer diagnosis using a pan-cancer approach, the likelihood of the proportional hazards assumption being met or corresponding interpretation should be considered in survival analyses, as flawed inference may have implications for cancer care and policy.

Surrogacy validation for time-to-event outcomes with illness-death frailty models.

A common practice in clinical trials is to evaluate a treatment effect on an intermediate outcome when the true outcome of interest would be difficult or costly to measure. We consider how to validate intermediate outcomes in a causally-valid way when the trial outcomes are time-to-event. Using counterfactual outcomes, those that would be observed if the counterfactual treatment had been given, the causal association paradigm assesses the relationship of the treatment effect on the surrogate outcome with the treatment effect on the true, primary outcome. In particular, we propose illness-death models to accommodate the censored and semicompeting risk structure of survival data. The proposed causal version of these models involves estimable and counterfactual frailty terms. Via these multistate models, we characterize what a valid surrogate would look like using a causal effect predictiveness plot. We evaluate the estimation properties of a Bayesian method using Markov chain Monte Carlo and assess the sensitivity of our model assumptions. Our motivating data source is a localized prostate cancer clinical trial where the two survival outcomes are time to distant metastasis and time to death.

Solutions for surrogacy validation with longitudinal outcomes for a gene therapy.

Valid surrogate endpoints S can be used as a substitute for a true outcome of interest T to measure treatment efficacy in a clinical trial. We propose a causal inference approach to validate a surrogate by incorporating longitudinal measurements of the true outcomes using a mixed modeling approach, and we define models and quantities for validation that may vary across the study period using principal surrogacy criteria. We consider a surrogate-dependent treatment efficacy curve that allows us to validate the surrogate at different time points. We extend these methods to accommodate a delayed-start treatment design where all patients eventually receive the treatment. Not all parameters are identified in the general setting. We apply a Bayesian approach for estimation and inference, utilizing more informative prior distributions for selected parameters. We consider the sensitivity of these prior assumptions as well as assumptions of independence among certain counterfactual quantities conditional on pretreatment covariates to improve identifiability. We examine the frequentist properties (bias of point and variance estimates, credible interval coverage) of a Bayesian imputation method. Our work is motivated by a clinical trial of a gene therapy where the functional outcomes are measured repeatedly throughout the trial.

A multi-phase intervention study of sports bra prescription for elite UK female athletes preparing for the Tokyo Olympics and Paralympics.

Athletes report poor breast/bra knowledge, breast pain, sports bras causing lacerations and chafing, negatively affecting sports performance. No bra interventions to address these issues are reported. Working with 142 UK female athletes preparing for Tokyo Olympics/Paralympics (27 sports), this multi-phase intervention assessed breast/bra knowledge, preferences, issues via surveys and breast/bra assessments. Data were used to develop two sports bras. A total of 112 athletes were prescribed one of the new bras through individual assessments. After four weeks, wear athletes completed evaluations. Pre-intervention breast/bra knowledge was low (83% ≤average), multiple breast/bra issues were reported and most athletes wore ill-fitting, loose bras, offering limited support. Post-intervention, 63% reported improved knowledge and 97% reported their prescribed bra as better than their original bra. Eighty-seven per cent reported benefitting from this intervention, with 17% reporting improved performance. This intervention effectively assessed sports bra needs, developed and implemented solutions, which improved knowledge and potentially performance for some UK athletes.

Incorporating baseline covariates to validate surrogate endpoints with a constant biomarker under control arm.

A surrogate endpoint S in a clinical trial is an outcome that may be measured earlier or more easily than the true outcome of interest T. In this work, we extend causal inference approaches to validate such a surrogate using potential outcomes. The causal association paradigm assesses the relationship of the treatment effect on the surrogate with the treatment effect on the true endpoint. Using the principal surrogacy criteria, we utilize the joint conditional distribution of the potential outcomes T, given the potential outcomes S. In particular, our setting of interest allows us to assume the surrogate under the placebo, S(0) , is zero-valued, and we incorporate baseline covariates in the setting of normally distributed endpoints. We develop Bayesian methods to incorporate conditional independence and other modeling assumptions and explore their impact on the assessment of surrogacy. We demonstrate our approach via simulation and data that mimics an ongoing study of a muscular dystrophy gene therapy.

Intertidal Canopy-forming Seaweeds Modulate Understory Seaweed Photoprotective Compounds.

Foundation species provide physical structure that enhances the diversity and abundance of associated organisms. Canopy-forming seaweeds are known to act as foundation species on rocky shores by lowering temperature and desiccation stress. Direct solar radiation, including ultraviolet (UV) light, can also reduce photosynthetic rates in algae, cause oxidative stress and DNA damage. The reduction in UV exposure provided by an algal canopy could therefore be important for understory organisms, including the red alga Chondrus crispus on New England's (USA) rocky shores, and this relationship may be more important at higher tidal elevations with increased low-tide exposure time. In field experiments, we investigated the relationship between tidal elevation and an index of C. crispus UV exposure, the concentration of UV-absorbing pigments. Low on the shore, C. crispus grew without a canopy. Higher on the shore, in the mid-intertidal zone, C. crispus was found under the canopy-forming rockweed, Fucus distichus subsp. evanescens. At this elevation, C. crispus was shaded (>50%; >1 m above MLLW). We performed a canopy removal experiment that spanned the mid-zone where C. crispus and F. distichus subsp. evanescens co-occur and the low-zone (no canopy). Following canopy removal in the mid-zone, UV pigment concentrations increased with tidal elevation. After accounting for the effect of elevation, removal of the algal canopy resulted in UV-protective pigment concentrations 2-fold higher than in un-manipulated control plots. These results suggest that amelioration of solar UV exposure might be another mechanism by which canopy seaweeds, acting as foundation species, facilitate understory seaweeds on rocky shores.

Research participant understanding and engagement in an institutional, self-consent biobank model.

The number of institutional and governmental biobanks and the target enrollment sizes of modern biobanks are increasing, affording more opportunities for the public to participate in biobanking efforts. In parallel with these expansions are pressures to increase the efficiency of obtaining informed consent using shorter consent forms that cover a broader scope of research and increasingly include provisions for return of research or clinical genetic test results to participants. Given these changes, how well these participants understand genetics, their level of understanding of what they are consenting to, and their wishes to engage longitudinally and receive biobank results are not well understood. We surveyed participants in a large, medical system-based biobank who had enrolled through a two-page, self-consent process about their baseline knowledge of genetics, understanding and recall of the consent process, wishes for future contact and engagement, and level of interest in receiving clinical genetic testing results. A total of 856 consented persons participated in the survey (67% women; 67% white). Participants' general reported genetics knowledge was relatively high (mean 11.60 of 15 questions answered correctly) as was recall of key elements from the two-page consent form. Overall participant enthusiasm for future contact by the biobank and for receiving clinical genetic testing results was high. The use of a two-page, self-consent process in a large, institutional biobank resulted in high levels of consent recall and enthusiasm for future ongoing engagement and receipt of genetic testing results by participants.

Current Key Challenges in Managing Maternal Sepsis.

Sepsis resulting from maternal infection is the second leading cause of pregnancy-related death. Although screening and initial care of a septic nonpregnant patient is standardized in nonpregnant adults, many challenges exist for early recognition and management of sepsis and septic shock in the obstetric population. Because most sepsis research excludes pregnant patients, there are many challenges that contribute to a lack of standardized approach to maternal sepsis. These challenges include inconsistent early warning sign criteria, lack of validated screening tools, adaptation of bundle components for maternal physiology, delivery considerations, and knowing when to transfer the patient to a higher level of care. To overcome these challenges, reduce variation in care, and improve patient outcomes, it is important for clinicians to plan, practice, and implement a maternal sepsis bundle.

Revealing the diversity of amber source plants from the Early Cretaceous Crato Formation, Brazil.

BACKGROUND: Amber has been reported from the Early Cretaceous Crato Formation, as isolated clasts or within plant tissues. Undescribed cones of uncertain gymnosperm affinity have also been recovered with amber preserved in situ. Here, we provide multiple lines of evidence to determine the botanical affinity of this enigmatic, conspicuous cone type, and to better understand the diversity of amber-source plants present in the Crato Formation and beyond. RESULTS: A new taxon of amber-bearing pollen cone Araripestrobus resinosus gen. nov. et sp. nov. is described here from complete cones and characteristic disarticulated portions. The best-preserved cone portion has both in situ amber infilling the resin canals inside the preserved microsporophyll tissues and pollen of the Eucommiidites-type. This places this genus within the Erdtmanithecales, an incompletely known gymnosperm group from the Mesozoic. FTIR analysis of the in situ amber indicates a potential araucariacean conifer affinity, although affinity with cupressacean conifers cannot be definitely ruled out. Pyr-GC-MS analysis of the Araripestrobus resinosus gen. nov. et sp. nov. in situ fossil resin shows that it is a mature class Ib amber, thought to indicate affinities with araucariacean and cupressacean, but not pinaceous, conifers. This is the first confirmed occurrence of this class of amber in the Crato Formation flora and in South America, except for an archaeological sample from Laguna Guatavita, Colombia. CONCLUSIONS: The combined results of the cones' novel gross morphology and the analyses of the in situ amber and pollen clearly indicate that the new taxon of resinous gymnosperm pollen cones from the Crato Formation is affiliated with Erdtmanithecales. The cone morphology is very distinct from all known pollen cone types of this extinct plant group. We therefore assume that the plant group that produced Eucommiidites-type pollen is much more diverse in habits than previously thought. Moreover, the diversity of potential amber source plants from the Crato Formation is now expanded beyond the Araucariaceae and the Cheirolepidiaceae to include this member of the Erdtmanithecales. Despite dispersed Eucommiidites pollen being noted from the Crato Formation, this is the first time macrofossils of Erdtmanithecales have been recognized from the Early Cretaceous of South America.

An Exceptionally Mild and Scalable Solution-Phase Synthesis of Molybdenum Carbide Nanoparticles for Thermocatalytic CO2 Hydrogenation.

Transition metal carbides (TMCs) have demonstrated outstanding potential for utilization in a wide range of catalytic applications because of their inherent multifunctionality and tunable composition. However, the harsh conditions required to prepare these materials have limited the scope of synthetic control over their physical properties. The development of low-temperature, carburization-free routes to prepare TMCs would unlock the versatility of this class of materials, enhance our understanding of their physical properties, and enable their cost-effective production at industrial scales. Here, we report an exceptionally mild and scalable solution-phase synthesis route to phase-pure molybdenum carbide (α-MoC1-x) nanoparticles (NPs) in a continuous flow millifluidic reactor. We exploit the thermolytic decomposition of Mo(CO)6 in the presence of a surface-stabilizing ligand and a high boiling point solvent to yield MoC1-x NPs that are colloidally stable and resistant to bulk oxidation in air. To demonstrate the utility of this synthetic route to prepare catalytically active TMC NPs, we evaluated the thermochemical CO2 hydrogenation performance of α-MoC1-x NPs dispersed on an inert carbon support. The α-MoC1-x/C catalyst exhibited a 2-fold increase in both activity on a per-site basis and selectivity to C2+ products as compared to the bulk α-MoC1-x analogue.

Multicentre retrospective study of intravascular large B-cell lymphoma treated at academic institutions within the United States.

Intravascular large B-cell lymphoma (IVLBCL) is a rare entity, with a generally aggressive course that may vary based on geographic presentation. While a United States (US) registry study showed relatively good outcomes with IVLBCL, clinicopathological and treatment data were unavailable. We performed a detailed retrospective review of cases identified at 8 US medical centres, to improve understanding of IVLBCL and inform management. We compiled data retrieved via an Institutional Review Board-approved review of IVLBCL cases identified from 1999 to 2015 at nine academic institutions across the US. We characterized the cohort's clinical status at time of diagnosis, presenting diagnostic and clinical features of the disease, treatment modalities used and overall prognostic data. Our cohort consisted of 54 patients with varying degrees of clinical features. Adjusting for age, better performance status at presentation was associated with increased survival time for the patients diagnosed in vivo (hazard ratio: 2·12, 95% confidence interval 1·28, 3·53). Based on the data we have collected, it would appear that the time interval to diagnosis is a significant contributor to outcomes of patients with IVLBCL.

Collapse of Cytolytic Potential in SIV-Specific CD8+ T Cells Following Acute SIV Infection in Rhesus Macaques.

Poor maintenance of cytotoxic factor expression among HIV-specific CD8+ T cells, in part caused by dysregulated expression of the transcription factor T-bet, is associated with HIV disease progression. However, the precise evolution and context in which CD8+ T cell cytotoxic functions become dysregulated in HIV infection remain unclear. Using the rhesus macaque (RM) SIV infection model, we evaluated the kinetics of SIV-specific CD8+ T cell cytolytic factor expression in peripheral blood, lymph node, spleen, and gut mucosa from early acute infection through chronic infection. We identified rapid acquisition of perforin and granzyme B expression in SIV-specific CD8+ T cells in blood, secondary lymphoid tissues and gut mucosa that collapsed rapidly during the transition to chronic infection. The evolution of this expression profile was linked to low expression of T-bet and occurred independent of epitope specificity, viral escape patterns and tissue origin. Importantly, during acute infection SIV-specific CD8+ T cells that maintained T-bet expression retained the ability to express granzyme B after stimulation, but this relationship was lost in chronic infection. Together, these data demonstrate the loss of cytolytic machinery in SIV-specific CD8+ T cells in blood and at tissue sites of viral reservoir and active replication during the transition from acute to chronic infection. This phenomenon occurs despite persistent high levels of viremia suggesting that an inability to maintain properly regulated cytotoxic T cell responses in all tissue sites enables HIV/SIV to avoid immune clearance, establish persistent viral reservoirs in lymphoid tissues and gut mucosa, and lead ultimately to immunopathogenesis and death.

An investigation of toxicities and survival in Hispanic children and adolescents with ALL: Results from the Dana-Farber Cancer Institute ALL Consortium protocol 05-001.

PURPOSE: This study compared the relative incidence of treatment-related toxicities and the event-free and overall survival between Hispanic and non-Hispanic children undergoing therapy for acute lymphoblastic leukemia (ALL) on Dana-Farber Cancer Institute ALL Consortium protocol 05-001. PATIENTS AND METHODS: Secondary analysis of prospectively collected data from a phase III multicenter study in children and adolescents of 1-18 years with previously untreated ALL. RESULTS: Between 2005 and 2011, 794 eligible patients enrolled on DFCI 05-001, 730 of whom were included in this analysis (19% [N = 150] Hispanic, 73% [N = 580] non-Hispanic). Hispanic patients were more likely to be ≥10 years of age (32% vs. 24%, P = 0.045) at diagnosis. Toxicity analyses revealed that Hispanic patients had significantly lower cumulative incidence of bone fracture (P < 0.001) and osteonecrosis (ON; P = 0.047). In multivariable risk regression, the risk of ON was significantly lower in Hispanic patients ≥10 years (HR 0.23; P = 0.006). Hispanic patients had significantly lower 5-year event-free survival (EFS) (79.4%; 95% CI: 71.6-85.2) and overall survival (OS) (89.2%; 95% CI: 82.7-93.4) than non-Hispanic patients (EFS: 87.5%; 95% CI: 84.5-90.0, P = 0.004; OS: 92.7%; 95% CI: 90.2-94.6, P = 0.006). Exploratory analyses revealed differences between Hispanic and non-Hispanic patients in the frequency of common variants in genes related to toxicity or ALL outcome. CONCLUSION: Hispanic children treated for ALL on DFCI 05-001 had fewer bone-related toxicities and inferior survival than non-Hispanic patients. While disease biology is one explanatory variable for outcome disparities, these findings suggest that biologic and non-biologic mechanisms affecting drug delivery and exposure in this population may be important contributing factors as well.

A rapid triage protocol to optimize cold ischemic time for breast resection specimens.

Prolonged time from specimen excision to adequate formalin exposure, or cold ischemic time (CIT), negatively impacts estrogen receptor (ER), progesterone receptor (PR) and HER-2 biomarker studies routinely performed on breast specimens. Current guidelines recommend CIT of ≤1 h. Since formalin penetrates resections slowly, optimal fixation requires incision. We evaluated the efficacy of a rapid triage protocol developed to optimize CIT. We identified 2821 specimens: 650 (23.0%) excisional biopsies (EB), 1051 (37.3%) lumpectomies, and 1120 (39.7%) mastectomies. CIT was available for 2362 (83.7%), with 1845 (78.1%) ≤1 h and 2323 (98.3%) ≤4 h. IHC was performed in 533/2821 (18.9%) and was associated with lumpectomy and mastectomy procedures when compared to EB. However, IHC was also performed on 11.1% (72/650) of EB specimens despite EB being significantly less likely to have CIT recorded (468/650; 72% for EB vs. 1894/2171; 87.2% for lumpectomies/mastectomies). Our study highlights the need for rapid triage of breast resections with known or suspected malignant diagnoses and outlines our procedure for optimizing CIT. Additionally, we advocate treating ALL breast resections as having the potential of being malignant and requiring biomarker studies for which optimal CIT is of great importance.

Clinicopathological findings in female-to-male gender-affirming breast surgery.

AIMS: Gender dysphoria is a diagnosis whereby an individual identifies as the opposite gender. The management of patients seeking female-to-male (FTM) transition includes hormonal therapy and surgical intervention, including mastectomy. The aim of this study was to characterize the immunohistological findings in resection specimens from FTM patients. METHODS AND RESULTS: We reviewed 68 cases (67 patients, one with re-excision) of FTM breast tissue resection by collecting clinical data, reviewing breast imaging and pathology reports (gross fibrous density, specimen weight, and number of cassettes submitted), and reviewing pathology slides [number of tissue pieces submitted, number of terminal duct lobule units (TDLUs), and the presence of histological findings]. Significant histological findings were present in 51 of 68 (75.0%) cases, including one case (1.5%) of flat epithelial atypia. Fibrocystic changes were the most common finding (27/68, 39.7%), followed by gynaecomastoid change, fibrotic stage, (22/68, 32.4%), and fibroadenomatoid change (11/68, 16.2%). Fibrocystic change was associated with increased numbers of TDLUs, and gynaecomastoid change was associated with lower body mass index and decreased numbers of TDLUs. Gynaecomastoid change showed a moderate proportion of luminal epithelial cells with strong-intensity immunohistochemical staining for oestrogen receptor, progesterone receptor, and androgen receptor, and a three-layered epithelium demonstrated by the use of cytokeratin 5/6 immunohistochemistry. CONCLUSIONS: We identified gynaecomastoid change at a significantly higher rate than previously reported in female patients. We support the continued gross and histological evaluation of FTM specimens in light of the identification of atypia in one case.

Student Opposition to University Pouring Rights Contracts.

Introduction: The majority of large public universities have exclusive pouring rights contracts with beverage companies that produce and market sugar-sweetened beverages. Pouring rights contracts contain provisions that conflict with recommendations from major public health organizations that institutions reduce sugar-sweetened beverage availability, marketing, and consumption. This study assessed the following among students at 3 public universities: student perception of pouring rights contracts (the extent to which they favored or opposed pouring rights contracts), the association between student socioeconomic characteristics and perception of pouring rights contracts, student estimates of pouring rights contract revenue, and the association between student pouring rights contract revenue estimates and perception of pouring rights contracts. To contextualize results, actual pouring rights contract revenue as a percentage of total revenues was estimated. Methods: A cross-sectional exploratory study was conducted among a convenience sample of 1,311 undergraduate sugar-sweetened beverages-consuming students recruited from 3 large and diverse public universities in Northern California. On an online questionnaire, undergraduate students indicated the extent to which they favored or opposed pouring rights contracts on a 10-point scale (oppose=1-5, favor=6-10) and provided a numeric estimate of the percentage of total university revenue they thought their university's pouring rights contract generated. Regression models were used to analyze differences in perception of pouring rights contracts by student socioeconomic characteristics and estimates of university revenues generated by pouring rights contracts. In addition, pouring rights contracts and financial reports were obtained from the 3 universities to estimate actual pouring rights contract revenue as a percentage of total revenues. Survey data were collected between August and November 2018 and analyzed in August 2022. Results: A large majority of students (81%) opposed pouring rights contracts, and the opposition did not significantly differ by student socioeconomic characteristics, including by levels of food security, need-based financial aid, participation in federal food assistance or healthcare programs, parental education, or parental income (all ps>0.14). The median student estimate for pouring rights contract revenue as a percentage of total university revenue was 10%. In contrast, the estimated actual annual revenue generated from the pouring rights contracts ranged from 0.01% to 0.04% at these schools. Revenue estimates were not significantly associated with participants' opposition or favoring of pouring rights contracts (p=0.65). Conclusions: A large majority of students opposed pouring rights contracts, and this opposition was similar regardless of student socioeconomic characteristics or student estimates of pouring rights contract revenues. Students markedly overestimated (by >100-1,000-fold) the percentage of university revenue that came from pouring rights contracts. University administration should consider student views on pouring rights contracts when deciding whether to exit or continue with pouring rights contracts.

Spinal cord injury-induced neurogenic bowel: A role for host-microbiome interactions in bowel pain and dysfunction.

Background and aims: Spinal cord injury (SCI) affects roughly 300,000 Americans with 17,000 new cases added annually. In addition to paralysis, 60% of people with SCI develop neurogenic bowel (NB), a syndrome characterized by slow colonic transit, constipation, and chronic abdominal pain. The knowledge gap surrounding NB mechanisms after SCI means that interventions are primarily symptom-focused and largely ineffective. The goal of the present studies was to identify mechanism(s) that initiate and maintain NB after SCI as a critical first step in the development of evidence-based, novel therapeutic treatment options. Methods: Following spinal contusion injury at T9, we observed alterations in bowel structure and function reflecting key clinical features of NB. We then leveraged tissue-specific whole transcriptome analyses (RNAseq) and fecal 16S rRNA amplicon sequencing in combination with histological, molecular, and functional (Ca2+ imaging) approaches to identify potential mechanism(s) underlying the generation of the NB phenotype. Results: In agreement with prior reports focused on SCI-induced changes in the skin, we observed a rapid and persistent increase in expression of calcitonin gene-related peptide (CGRP) expression in the colon. This is suggestive of a neurogenic inflammation-like process engaged by antidromic activity of below-level primary afferents following SCI. CGRP has been shown to disrupt colon homeostasis and negatively affect peristalsis and colon function. As predicted, contusion SCI resulted in increased colonic transit time, expansion of lymphatic nodules, colonic structural and genomic damage, and disruption of the inner, sterile intestinal mucus layer corresponding to increased CGRP expression in the colon. Gut microbiome colonization significantly shifted over 28 days leading to the increase in Anaeroplasma, a pathogenic, gram-negative microbe. Moreover, colon specific vagal afferents and enteric neurons were hyperresponsive after SCI to different agonists including fecal supernatants. Conclusions: Our data suggest that SCI results in overexpression of colonic CGRP which could alter colon structure and function. Neurogenic inflammatory-like processes and gut microbiome dysbiosis can also sensitize vagal afferents, providing a mechanism for visceral pain despite the loss of normal sensation post-SCI. These data may shed light on novel therapeutic interventions targeting this process to prevent NB development in patients.

Virtual 3D Specimen Mapping in Head & Neck Oncologic Surgery.

OBJECTIVES: Virtual 3D specimen mapping of oncologic surgical specimens provides a visual record of the specimen and margin sampling sites which can be utilized in a variety of cancer care settings. Our objective was to perform a retrospective review of head and neck surgical oncology cases where the specimen was mapped post-operatively and to evaluate the utility of these 3D specimen maps amongst the multidisciplinary cancer care team. METHODS: A retrospective review of our 3D specimen model biorepository was performed. Surgical specimens were 3D scanned and then graphically annotated (or "mapped") during routine pathologic processing. The resulting 3D specimen maps were distributed to the multidisciplinary oncologic care team. Final margin status and any use of the 3D specimen maps were recorded. RESULTS: A total of 28 cases were included. Virtual 3D specimen maps were utilized by the cancer care team in 8 cases (29%), including 2 positive margin cases, 2 close margin cases, and 4 indeterminate margin cases. 3D specimen maps were used to visualize positive margin sites for pathologist-surgeon communication as a visual reference during tumor board discussions and to inform radiation treatment planning. CONCLUSION: Post-operative virtual 3D specimen mapping of oncologic specimens creates a permanent visual record of the specimen and the margins sampled and may serve as a beneficial tool for communication amongst the multidisciplinary cancer care team. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:191-197, 2024.

Optic disk pit morphology and retinal detachment: optical coherence tomography with intraoperative correlation.

BACKGROUND: The pathogenesis of optic nerve head pits and associated retinal detachment, and the most effective surgical intervention when visual loss develops, remains unclear. METHODS: The morphology of the optic disk in patients with pits was investigated with optical coherence tomography. For those who underwent surgical treatment for pit-associated retinal detachment, the efficacy of treatment by vitrectomy and separation of the posterior hyaloid, with and without additional peeling of peripapillary tissue, was assessed. RESULTS: On optical coherence tomography imaging, 14 of 18 pits (78%) demonstrated a localized pit-like invagination, whereas 3 (17%) had disks with a generally excavated structure. For 16 of 18 pits (89%), there was evidence of condensed vitreous or glial tissue seen extending from the pit or inside the optic disk. Nine eyes with retinal detachment underwent vitrectomy, posterior hyaloid separation, and endolaser. The retinal detachment completely resolved in 6 of 6 cases where the surgeon additionally peeled the fibrous tissue from the pit and 2 of 3 cases where this was not performed. CONCLUSION: Spectral domain optical coherence tomography demonstrates the varying morphology of optic pit anatomy. Condensed vitreous strands or glial tissue in the optic nerve pit may also contribute to retinal detachment development.