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Amanda M Farr,1 John Jack Sheehan,2 Brian M Davis,1 David M Smith1 1Life Sciences, Truven Health Analytics, an IBM Company, Cambridge, MA, 2Health Economics and Outcomes Research – Diabetes, AstraZeneca, Fort Washington, PA, USA Background: Adherence and persistence to antidiabetes medications are important to control blood glucose levels among individuals with type 2 diabetes mellitus (T2D).Objectives: The objective of this study was to compare adherence and persistence over a 12-month period between patients initiating saxagliptin and patients initiating linagliptin, two dipeptidyl peptidase-4 inhibitors.Methods: This retrospective cohort study was conducted in MarketScan® Commercial and Medicare Supplemental claims databases. Patients with T2D initiating saxagliptin or linagliptin between January 1, 2009, and June 30, 2013, were selected. Patients were required to be at least 18 years old and have 12 months of continuous enrollment prior to and following initiation. Adherence and persistence to initiated medication were measured over the 12 months after initiation using outpatient pharmacy claims. Patients were considered adherent if the proportion of days covered was ≥0.80. Patients were considered nonpersistent (or to have discontinued) if there was a gap of >60 days without initiated medication on hand. Multivariable logistic regression and multivariable Cox proportional hazard models were fit to compare adherence and persistence, respectively, between the two cohorts.Results: There were 21,599 saxagliptin initiators (mean age 55 years; 53% male) and 5,786 linagliptin initiators (mean age 57 years; 54% male) included in the study sample. Over the 12-month follow-up, 46% of saxagliptin initiators and 42% of linagliptin initiators were considered adherent and 47% of saxagliptin initiators and 51% of linagliptin initiators discontinued their initiated medication. After controlling for patient characteristics, saxagliptin initiation was associated with significantly greater odds of being adherent (adjusted odds ratio =1.212, 95% CI 1.140–1.289) and significantly lower hazards of discontinuation (adjusted hazard ratio =0.887, 95% CI 0.850–0.926) compared with linagliptin initiation.Conclusion: Compared with patients with T2D who initiated linagliptin, patients with T2D who initiated saxagliptin had significantly better adherence and persistence. Keywords: type 2 diabetes, dipeptidyl peptidase-4 inhibitors, saxagliptin, linagliptin, adherence, discontinuation

Background: During the influenza A(H1N1) pandemic, antiviral prescribing was limited, vaccines were not available early, and the effectiveness of nonpharmaceutical interventions (NPIs) was uncertain. Our study examined whether use of face masks and hand hygiene reduced the incidence of influenza-like illness (ILI).Methods: A randomized intervention trial involving 1437 young adults living in university residence halls during the 2006-2007 influenza season was designed. Residence halls were randomly assigned to 1 of 3 groups-face mask use, face masks with hand hygiene, or control- for 6 weeks. Generalized models estimated rate ratios for clinically diagnosed or survey-reported ILI weekly and cumulatively.Results: We observed significant reductions in ILI during weeks 4-6 in the mask and hand hygiene group, compared with the control group, ranging from 35% (confidence interval [CI], 9%-53%) to 51% (CI, 13%-73%), after adjusting for vaccination and other covariates. Face mask use alone showed a similar reduction in ILI compared with the control group, but adjusted estimates were not statistically significant. Neither face mask use and hand hygiene nor face mask use alone was associated with a significant reduction in the rate of ILI cumulatively.Conclusions: These findings suggest that face masks and hand hygiene may reduce respiratory illnesses in shared living settings and mitigate the impact of the influenza A(H1N1) pandemic.Trial Registration: ClinicalTrials.gov identifier: NCT00490633. [ABSTRACT FROM AUTHOR]

The prevalence of dysmenorrhea, the pain while menstruating, is high. Although most cases are benign, there should be a high suspicion of other etiologies such as endometriosis with recurrent episodes. Inaccurate or delayed diagnosis and treatment of endometriosis can lead to increased hospital visits and costs. We report the case of a 46-year-old female with a history of frequent hospital visits due to dysmenorrhea and menorrhagia, presented with clinical, laboratory, and image findings of pancreatitis with biopsy revealing endometriosis. This case report aims to highlight pancreatic endometriosis, a different and rare cause of pancreatitis, which should be suspected in cases of recurrent hospital visits with recurrent menstrual pain and abnormal presentation of pancreatitis., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Naseer et al.)

Background: Persistent human papillomavirus (HPV) infection can cause anogenital and oropharyngeal cancers. Many HPV infections and HPV-associated cancers are vaccine-preventable. Studies suggest long-term persistence of vaccine-induced antibodies. However, data are limited among Alaska Native people., Methods: During 2011-2014, we enrolled Alaska Native children aged 9-14 years who received a 3-dose series of quadrivalent HPV vaccine (4vHPV). We collected sera at 1 month and 1, 2, 3, and 5 years post-vaccination to evaluate trends in type-specific immunoglobulin G antibody concentrations for the 4vHPV types (HPV 6/11/16/18)., Results: All participants (N = 469) had detectable antibodies against all 4vHPV types at all timepoints post-vaccination. For all 4vHPV types, antibody levels peaked by 1 month post-vaccination and gradually declined in subsequent years. At 5 years post-vaccination, antibody levels were higher among children who received 4vHPV at a younger age., Conclusions: Alaska Native children maintained antibodies against all 4vHPV types at 5 years post-vaccination., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Purpose: Resveratrol is a natural polyphenol which has a very low bioavailability but whose antioxidant, anti-inflammatory and anti-apoptotic properties may have therapeutic potential for the treatment of neurodegenerative diseases such as multiple sclerosis (MS). Previously, we reported the oral administration of resveratrol nanoparticles (RNs) elicited a neuroprotective effect in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, at significantly lower doses than unconjugated resveratrol (RSV) due to enhanced bioavailability. Furthermore, we demonstrated that the intranasal administration of a cell-derived secretome-based therapy at low concentrations leads to the selective neuroprotection of the optic nerve in EAE mice. The current study sought to assess the potential selective efficacy of lower concentrations of intranasal RNs for attenuating optic nerve damage in EAE mice., Methods: EAE mice received either a daily intranasal vehicle, RNs or unconjugated resveratrol (RSV) for a period of thirty days beginning on the day of EAE induction. Mice were assessed daily for limb paralysis and weekly for visual function using the optokinetic response (OKR) by observers masked to treatment regimes. After sacrifice at day 30, spinal cords and optic nerves were stained to assess inflammation and demyelination, and retinas were immunostained to quantify retinal ganglion cell (RGC) survival., Results: Intranasal RNs significantly increased RGC survival at half the dose previously shown to be required when given orally, reducing the risk of systemic side effects associated with prolonged use. Both intranasal RSV and RN therapies enhanced RGC survival trends, however, only the effects of intranasal RNs were significant. RGC loss was prevented even in the presence of inflammatory and demyelinating changes induced by EAE in optic nerves., Conclusions: The intranasal administration of RNs is able to reduce RGC loss independent of the inflammatory and demyelinating effects on the optic nerve and the spinal cord. The concentration of RNs needed to achieve neuroprotection is lower than previously demonstrated with oral administration, suggesting intranasal drug delivery combined with nanoparticle conjugation warrants further exploration as a potential neuroprotective strategy for the treatment of optic neuritis, alone as well as in combination with glucocorticoids.

The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Oncogenic EGFR has been successfully targeted by tyrosine kinase inhibitors, but acquired drug resistance eventually overcomes the efficacy of these treatments. Attempts to surmount this therapeutic challenge are hindered by a poor understanding of how and why cancer mutations specifically amplify ligand-independent EGFR auto-phosphorylation signals to enhance cell survival and how this amplification is related to ligand-dependent cell proliferation. Here we show that drug-resistant EGFR mutations manipulate the assembly of ligand-free, kinase-active oligomers to promote and stabilize the assembly of oligomer-obligate active dimer sub-units and circumvent the need for ligand binding. We reveal the structure and assembly mechanisms of these ligand-free, kinase-active oligomers, uncovering oncogenic functions for hitherto orphan transmembrane and kinase interfaces, and for the ectodomain tethered conformation of EGFR. Importantly, we find that the active dimer sub-units within ligand-free oligomers are the high affinity binding sites competent to bind physiological ligand concentrations and thus drive tumor growth, revealing a link with tumor proliferation. Our findings provide a framework for future drug discovery directed at tackling oncogenic EGFR mutations by disabling oligomer-assembling interactions., (© 2024. The Author(s).)

A woman in her mid-60s presented to the hospital due to a history of nausea, vomiting, shortness of breath, dyspnoea on exertion and polyuria. She was receiving medical therapy for advanced non-small cell lung cancer and recently initiated immune checkpoint inhibitor (ICI) immunotherapy. Investigations revealed lab results consistent with diabetic ketoacidosis (DKA), elevated cardiac biomarkers, multiple cardiac arrhythmias and reduced ejection fraction on transthoracic echocardiogram. Cardiac catheterisation showed non-obstructive coronary arteries.The patient was diagnosed with an ICI-associated myocarditis and type I diabetes due to recent initiation of the ICI durvalumab. She was treated with the institutional DKA protocol and received corticosteroid therapy for drug toxicity according to guidelines. She was discharged with marked improvement in symptoms. The patient had good recovery after discharge with further investigations showing improvement in her cardiac ejection fraction on cardiac MRI. She remains on medical therapy with an insulin regimen for diabetes management., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Resveratrol is a natural polyphenol which may be useful for treating neurodegenerative diseases such as multiple sclerosis (MS). To date, current immunomodulatory treatments for MS aim to reduce inflammation with limited effects on the neurodegenerative component of this disease. The purpose of the current study is to develop a novel nanoparticle formulation of resveratrol to increase its solubility, and to assess its ability to prevent optic nerve and spinal cord degeneration in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Resveratrol nanoparticles (RNs) were made using a thin rehydration technique. EAE mice received a daily oral administration of vehicle, RNs or unconjugated resveratrol for one month. They were assessed daily for clinical signs of paralysis and weekly for their visual acuity with optokinetic responses (OKR). After one month, their spinal cords and optic nerves were stained for inflammation and demyelination and retinal ganglion cells immunostained for Brn3a. RNs were stable for three months. The administration of RNs did not have any effect on clinical manifestation of EAE and did not preserve OKR scores but reduced the intensity of the disease. It did not reduce inflammation and demyelination in the spinal cord and the optic nerve. However, RNs were able to decrease RGC loss compared to the vehicle. Results demonstrate that resveratrol is neuroprotective by reducing RGC loss. Interestingly, neuroprotective effects and decreased disease severity occurred without reduction of inflammation or demyelination, suggesting this therapy may fill an unmet need to limit the neurodegenerative component of MS., (© 2023. The American Society for Experimental Neurotherapeutics, Inc.)

Purpose: To evaluate the novel Rose Plot Analysis (RPA) in the analysis and presentation of glaucoma structural progression data., Design: Case-control image analysis study using retrospective retinal imaging series., Subjects: Subjects with open-angle glaucoma with at least 5 registered spectral-domain OCT scans., Methods: Glaucoma RPA was developed, combining a novel application of angular histograms and dynamic cluster analysis of circumpapillary retinal nerve fiber layer (cRNFL) OCT data. Rose Plot Analysis plots were created for each eye and each visit. Significant clusters of progression were indicated in red. Three masked clinicians categorized all RPA plots (progressing, not progressing), in addition to measuring the significant RPA area. A masked OCT series assessment with linear regression of averaged global and sectoral cRNFL thicknesses was conducted as the clinical imaging standard., Main Outcome Measures: Interobserver agreement was compared between RPA and the clinical imaging standard. Discriminative ability was assessed using receiver-operating characteristic curves. The time to detection of progression was compared using a Kaplan-Meier survival analysis, and the agreement of RPA with the clinical imaging standard was calculated., Results: Seven hundred fourty-three scans from 98 eyes were included. Interobserver agreement was significantly greater when categorizing RPA (κ, 0.86; 95% confidence interval [CI], 0.81-0.91) compared with OCT image series (κ, 0.66; 95% CI, 0.54-0.77). The discriminative power of RPA to differentiate between eyes that were progressing and not progressing (area under the curve [AUC], 0.97; 95% CI, 0.92-1.00) was greater than that of global cRNFL thickness (AUC, 0.71; 95% CI, 0.59-0.82; P < 0.0001) and equivalent to that of sectoral cRNFL regression (AUC, 0.97; 95% CI, 0.92-1.00). A Kaplan-Meier survival analysis showed that progression was detected 8.7 months sooner by RPA than by global cRNFL linear regression (P < 0.0001) in progressing eyes but was not sooner than with sectoral cRNFL (P = 0.06). Rose Plot Analysis showed substantial agreement with the presence of significant thinning on sectoral cRNFL linear regression (κ, 0.715; 95% CI, 0.578-0.853)., Conclusions: Rose Plot Analysis has been shown to provide accurate and intuitive, at-a-glance data analysis and presentation that improve interobserver agreement and may aid early diagnosis of glaucomatous disease progression., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

PDL1 is a protein that induces immunosuppression by binding to PD1 expressed on immune cells. In line with historical studies, we found that membrane-bound PD1 expression was largely restricted to immune cells; PD1 was not detectable at either the mRNA or protein level in peripheral neurons using single neuron qPCR, immunolabeling and flow cytometry. However, we observed widespread expression of PDL1 in both sensory and sympathetic neurons that could have important implications for patients receiving immunotherapies targeting this pathway that include unexpected autonomic and sensory related effects. While signaling pathways downstream of PD1 are well established, little to no information is available regarding the intracellular signaling downstream of membrane-bound PDL1 (also known as reverse signaling). Here, we administered soluble PD1 to engage neuronally expressed PDL1 and found that PD1 significantly reduced nocifensive behaviors evoked by algogenic capsaicin. We used calcium imaging to examine the underlying neural mechanism of this reduction and found that exogenous PD1 diminished TRPV1-dependent calcium transients in dissociated sensory neurons. Furthermore, we observed a reduction in membrane expression of TRPV1 following administration of PD1. Exogenous PD1 had no effect on pain-related behaviors in sensory neuron specific PDL1 knockout mice. These data indicate that neuronal PDL1 activation is sufficient to modulate sensitivity to noxious stimuli and as such, may be an important homeostatic mechanism for regulating acute nociception., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JLS: Research Funding— Cygnal Therapeutics. DAAV: cofounder and stock holder – Novasenta, Potenza, Tizona, Trishula; stock holder – Oncorus, Werewolf, Apeximmune; patents licensed and royalties - Astellas, Bristol Myers Squibb, Novasenta; scientific advisory board member - Tizona, Werewolf, F-Star, Bicara, Apeximmune; consultant - Astellas, Bristol Myers Squibb, Almirall, Incyte, G1 Therapeutics; research funding – Bristol Myers Squibb, Astellas and Novasenta.., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Valgus extension overload syndrome (VEOS) of the elbow is a condition associated with overhead athletes. However, the non-surgical management of these individuals is not well documented., Purpose: To discuss the unique presentation, management, and outcomes of an adolescent baseball player with a chronic history of VEOS experienced during hitting., Case Description: A 15-year-old right-handed high school baseball catcher presented with a six-month history of right-sided ulnar elbow pain. Elbow MRI w/ contrast was consistent with VEOS. The initial examination demonstrated excessive resting right-sided humeral external rotation compared to his left. Valgus stress testing in the subject's hitting position reproduced symptoms, which were alleviated with retest while correcting excessive humeral external rotation. Weakness of the humeral internal rotators and stiffness/shortness of the posterior shoulder were found and thought to relate to the humeral contribution to his elbow movement dysfunction. Rehabilitation emphasized addressing impairments contributing to excessive humeral external rotation with reintegration into batting., Outcomes: After five weeks of physical therapy, the subject returned to soft toss hitting at approximately 75% velocity for the first time since symptom onset, without pain. At seven months after discharge, a phone conversation confirmed that the subject had returned to baseball without limitations., Discussion: Despite the concept of 'regional interdependence', common proximal impairments are often assumed to contribute to elbow pain without a clear biomechanical rationale. Future research demonstrating the specific biomechanical effects of the shoulder on the elbow is needed, in addition to more accessible examination strategies to assess their relationship., Level of Evidence: 5., Competing Interests: The authors of this case report have no conflicts of interest.

Lithography based additive manufacturing techniques, specifically digital light processing (DLP), are considered innovative manufacturing techniques for orthopaedic implants because of their potential for construction of complex geometries using polymers, metals, and ceramics. Hydroxyapatite (HA) coupons, printed using DLP, were evaluated for biological performance in supporting viability, proliferation, and osteogenic differentiation of the human cell line U2OS and human mesenchymal stem cells (MSCs) up to 35 days in culture to determine feasibility for future use in development of complex scaffold geometries. Contact angle, profilometry, and scanning electron microscopy (SEM) measurements showed the HA coupons to be hydrophilic, porous, and having micro size surface roughness, all within favourable cell culture ranges. The study found no impact of leachable and extractables form the DLP printing process. Cells seeded on coupons exhibited morphologies comparable to conventional tissue culture polystyrene plates. Cell proliferation rates, as determined by direct cell count and the RealTime-GloTM MT Cell Viability Assay, were similar on HA coupons and standard tissue culture polystyrene plates). Osteogenic differentiation of human MSCs on HA coupons was confirmed using alkaline phosphatase, Alizarin Red S and von Kossa staining. The morphology of MSCs cultured in osteogenic medium for 14 to 35 days was similar on HA coupons and tissue culture polystyrene plates, with osteogenic (geometric, cuboidal morphology with dark nodules) and adipogenic (lipid vesicles and deposits) features. We conclude that the DLP process and LithaBone HA400 slurry are biocompatible and are suitable for osteogenic applications. Coupons served as an effective evaluation design in the characterization and visualization of cell responses on DLP printed HA material. Results support the feasibility of future technical development for 3D printing of sophisticated scaffold designs, which can be constructed to meet the mechanical, chemical, and porosity requirements of an artificial bone scaffold., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: all authors received research support from GE Research and are employees. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. All authors declare no competing interests.

Objective: To investigate the factor structure of the verbal paired-associates (VPA) subtest in the WMS-III using a theoretically driven model of semantic processing previously found to be well-fitting for the WMS-IV version of the test., Method: Archival data were used from 267 heterogeneous neurosciences patients and 223 seizure disorder patients who completed the WMS-III as part of a standard neuropsychological evaluation. Confirmatory factor analysis was used to test theoretically driven models for VPA based on principles of semantic processing. Four nested models of different complexities were examined and compared for goodness-of-fit using chi-squared difference testing. Measurement invariance testing was conducted across heterogeneous neuroscience and seizure disorder samples to test generality of the factor model., Results: After removing items with limited variability (very easy or very hard; 12 of 40 items), a four-factor model was found to be best-fitting in the present patient samples. The four factors were "recreational", "functional", "material", and "symbolic", each representing semantic knowledge associated with the function of the target word referent. This model subsequently met the criteria for the strict measurement invariance, showing good overall fit when factor loadings, thresholds, and residuals were held to equality across samples., Conclusions: The results of this study provide further evidence that "arbitrary" associations between word pairs in VPA items have an underlying semantic structure, challenging the idea that unrelated hard-pairs are semantic-free. These results suggest that a semantic-structure model may be implemented as an alternative scoring in future editions of the WMS to facilitate interpretation., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Temperature-controlled radiofrequency neurolysis of the posterior nasal nerve has been shown to reduce the symptom burden of patients with chronic rhinitis., Objectives: To evaluate the long-term safety and effectiveness of temperature-controlled radiofrequency neurolysis of the posterior nasal nerve for the treatment of chronic rhinitis., Methods: A prospective extension of a 12-month single-arm study, where reflective total nasal symptom score (rTNSS) and the responses to a study-specific quality of life questionnaire and patient satisfaction survey were collected at 24 months., Results: Forty-seven patients completed initial 12-month follow-up after treatment with the study device, of which 34 patients were reconsented and completed 24-month follow-up. The mean rTNSS of the long-term follow-up patients improved from 8.4 (95% confidence interval (CI), 7.7 to 9.0) at baseline to 2.9 (95% CI, 2.1 to 3.6), P  < .001 at 24 months, a 65.5% improvement. On a 6-point scale (0-5), postnasal drip improved from a mean of 4.1 (95% CI, 3.6 to 4.6) to 2.1 (95% CI, 1.7 to 2.5) and chronic cough improved from 3.2 (95% CI, 2.7 to 3.6) to 0.9 (95% CI, 0.5 to 1.3) from baseline through 24 months; P  < .001 for both measures. The proportion of patients achieving a minimal clinically important difference of 30% improvement from baseline at 24 months was 88.2% (95% CI, 73.4%-95.3%). At 24 months, 24% of patients were taking overall fewer and 15% taking overall more rhinitis medication classes than at baseline. Patients reported a higher quality of life in terms of sleep, well-being, and lower oral medication/nasal spray use at 24 months. There were no serious adverse events considered related to the procedure in the 12-24-month period., Conclusion: Temperature-controlled radiofrequency neurolysis results in a significant and durable reduction in the symptom burden of chronic rhinitis and patients reported improved quality of life through 24 months postprocedure., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Xxxxxxx. Dale Ehmer and V. Vasu Kakarlapudi are consultants for Aerin Medical. The authors have no other funding, financial relationships, or conflicts of interest to disclose., (© The Author(s) 2022.)

Objectives: This study aimed to identify a well-fitting and theoretically justified item-level latent factor structure for the Wechsler Memory Scales (WMS)-IV verbal paired associates (VerbalPA) subtest to facilitate the ease and accuracy of score interpretations for patients with lateralized temporal lobe epilepsy (TLE)., Methods: Archival data were used from 250 heterogeneous neurosciences patients who were administered the WMS-IV as part of a standard neuropsychological assessment. Three theoretically motivated models for the latent structure of VerbalPA were tested using confirmatory factor analysis. The first model, based on cognitive principles of semantic processing from hub-and-spoke theory, tested whether performance is related to specific semantic features of target words. The second, motivated by the Cattell-Horn-Carroll (CHC) model of cognitive abilities, investigated whether the associative properties of items influence performance. A third, Hybrid model tested whether performance is related to both semantic and associative properties of items. The best-fitting model was tested for diagnostic group effects contrasting the heterogeneous neuroscience patients with subsets of left and right TLE (n = 51, n = 26, respectively) patients., Results: The Hybrid model was found to have the best fit. Patients with left TLE scored significantly less well than the heterogeneous neurosciences sample on selected semantic factor scores, although the effect size was small., Conclusions: Future editions of the WMS may consider implementing a semantic scoring structure for the VerbalPA to facilitate test score interpretation. Additionally, these results suggest that principles of hub-and-spoke theory may be integrated into CHC cognitive ability taxonomy.

The enteric nervous system not only innervates the colon to execute various functions in a semi-autonomous manner but also receives neural input from three extrinsic sources, (1) vagal, (2) thoracolumbar (splanchnic), and (3) lumbosacral (pelvic) pathways, that permit bidirectional communication between the colon and central nervous system. Extrinsic pathways signal sensory input via afferent fibers, as well as motor autonomic output via parasympathetic or sympathetic efferent fibers, but the shared and unique roles for each pathway in executing sensory-motor control of colon function have not been well understood. Here, we describe the recently developed approaches that have provided new insights into the diverse mechanisms utilized by extrinsic pathways to influence colon functions related to visceral sensation, motility, and inflammation. Based on the cumulative results from anatomical, molecular, and functional studies, we propose pathway-specific functions for vagal, thoracolumbar, and lumbosacral innervation of the colon., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background & Aims: Colonic motor patterns have been described by a number of different groups, but the neural connectivity and ganglion architecture supporting patterned motor activity have not been elucidated. Our goals were to describe quantitatively, by region, the structural architecture of the mouse enteric nervous system and use functional calcium imaging, pharmacology, and electrical stimulation to show regional underpinnings of different motor patterns., Methods: Excised colon segments from mice expressing the calcium indicator GCaMP6f or GCaMP6s were used to examine spontaneous and evoked (pharmacologic or electrical) changes in GCaMP-mediated fluorescence and coupled with assessment of colonic motor activity, immunohistochemistry, and confocal imaging. Three-dimensional image reconstruction and statistical methods were used to describe quantitatively mouse colon myenteric ganglion structure, neural and vascular network patterning, and neural connectivity., Results: In intact colon, regionally specific myenteric ganglion size, architecture, and neural circuit connectivity patterns along with neurotransmitter-receptor expression underlie colonic motor patterns that define functional differences along the colon. Region-specific effects on spontaneous, evoked, and chemically induced neural activity contribute to regional motor patterns, as does intraganglionic functional connectivity. We provide direct evidence of neural circuit structural and functional regional differences that have only been inferred in previous investigations. We include regional comparisons between quantitative measures in mouse and human colon that represent an important advance in showing the usefulness and relevance of the mouse system for translation to the human colon., Conclusions: There are several neural mechanisms dependent on myenteric ganglion architecture and functional connectivity that underlie neurogenic control of patterned motor function in the mouse colon., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)