Ocean mixing and heat transport processes observed under the Ross Ice Shelf control its basal melting.

The stability of large Antarctic ice shelves has important implications for global sea level, sea ice area, and ocean circulation. A significant proportion of ice mass loss from these ice shelves is through ocean-driven melting which is controlled by largely unobserved oceanic thermodynamic and circulatory processes in the cavity beneath the ice shelf. Here we use direct measurements to provide evidence of the changing water column structure in the cavity beneath the Ross Ice Shelf, the planet's largest ice shelf by area. The cavity water column data exhibit both basal and benthic boundary layers, along with evidence of tidally modulated and diffusively convecting internal mixing processes. A region of thermohaline interleaving in the upper-middle water column indicates elevated diffusion and the potential to modify the cavity circulation. The measurements were recorded using the Aotearoa New Zealand Ross Ice Shelf Program hot water drill borehole melted in the central region of the shelf in December 2017 (HWD2), only the second borehole through the central region of the ice shelf, following J9 in 1977. These data, and comparison with the 1977 data, provide valuable insight into ice shelf cavity circulation and aid understanding of the evolution of the presently stable Ross Ice Shelf.

Receptor-centric solutions for the opioid epidemic: Making the opioid user impervious to overdose death.

This mini-review presents the view that contemporary approaches to stem the tide of opioid overdose deaths are insufficient to make a significant impact. Instead, a focus on the opioid receptor as the ultimate molecular target to directly abolish opioid overdose death is explored. After identifying the key brainstem neurons that control respiration which are inhibited by opioid drugs, genetic techniques targeting the mu opioid receptor are detailed which prevent opioid overdose. This receptor-centric solution for the opioid overdose epidemic can be realized with existing technology and, with sufficient effort, could enter clinical trials within 5 to 10 years.

MR-based synthetic CT image for intensity-modulated proton treatment planning of nasopharyngeal carcinoma patients.

PURPOSE: To develop an advanced deep convolutional neural network (DCNN) architecture to generate synthetic CT (SCT) images from MR images for intensity-modulated proton therapy (IMPT) treatment planning of nasopharyngeal cancer (NPC) patients. METHODS: T1-weighted MR images and paired CT (PCT) images were obtained from 206 NPC patients. For each patient, deformable image registration was performed between MR and PCT images to create an MR-CT image pair. Thirty pairs were randomly chosen as the independent test set and the remaining 176 pairs (14 for validation and 162 for training) were used to build two conditional generative adversarial networks (GANs): 1) GAN3D: using a 3D U-net enhanced with residual connections and attentional mechanism as the generator and 2) GAN2D: using a 2D U-net as the generator. For each test patient, SCT images were generated using the generators with the MR images as input and were compared with respect to the corresponding PCT image. A clinical IMPT plan was created and optimized on the PCT image. The dose was recalculated on the SCT images and compared with the one calculated on the PCT image. RESULTS: The mean absolute errors (MAEs) between the PCT and SCT, within the body, were (64.89 ± 5.31) HU and (64.31 ± 4.61) HU for the GAN2D and GAN3D. Within the high-density bone (HU > 600), the GAN3D achieved a smaller MAE compared with the GAN2D (p < 0.001). Within the body, the absolute point dose deviation was reduced from (0.58 ± 1.61) Gy for the GAN2D to (0.47 ± 0.94) Gy for the GAN3D. The (3 mm/3%) gamma passing rates were above 97.32% for all SCT images. CONCLUSIONS: The SCT images generated using GANs achieved clinical acceptable dosimetric accuracy for IMPT of NPC patients. Using advanced DCNN architecture design, such as residual connections and attention mechanism, SCT image quality was further improved and resulted in a small dosimetric improvement.

Using previously registered cone beam computerized tomography images to facilitate online computerized tomography to cone beam computerized tomography image registration in lung stereotactic body radiation therapy.

PURPOSE: In our conventional image registration workflow, the four-dimensional (4D) CBCT was directly registered to the reference helical CT (HCT) using a dual registration approach within the Elekta XVI software. In this study, we proposed a new HCT-CBCT auto-registration strategy using a previously registered CBCT (CBCTpre) as the reference image and tested its clinical feasibility. METHODS: From a previous CBCT session, the registered average 4D CBCT was selected as CBCTpre and the HCT-CBCTpre registration vector from the clinician's manual registration result was recorded. In the new CBCT session, auto-registration was performed between the new average 4D CBCT (CBCTtx) and CBCTpre (CBCTpre-CBCTtx). The overall HCT-CBCTtx registration result was then derived by combing the results from two registrations (i.e., HCT-CBCTpre + CBCTpre-CBCTtx). The results from the proposed method were compared with clinician's manually adjusted HCT-CBCTtx registration results ("ground truth") to evaluate its accuracy using a test dataset consisting of 32 challenging registration cases. RESULTS: The uncertainty of the proposed auto-registration method was -0.1 ± 0.5, 0.1 ± 1.0, and -0.1 ± 0.7 mm in three translational directions (lateral, longitudinal, and vertical) and 0.0° ± 0.9°, 0.3° ± 0.9°, and 0.4° ± 0.7° in three rotation directions, respectively. Two patients (6.3%) had translational uncertainty > 2 mm (max = 3.1 mm) and both occurred in the longitudinal direction. Meanwhile, the uncertainty of the conventional direct HCT-CBCTtx auto-registration was -0.4 ± 2.6, -0.2 ± 7.4, -1.4 ± 3.6 mm for translations and -0.3° ± 1.2°, 0.0° ± 1.6°, and 0.1 ± 1.1° for rotations. Eleven patients (34.4%) had translation uncertainty > 2 mm (max = 26.2 mm) in at least one direction. Accuracy in translation was improved with the new method, while rotation accuracy stayed in the same order. CONCLUSION: We demonstrated the feasibility of incorporating prior clinical registration knowledge into the online HCT-CBCT registration process. The proposed auto-registration method provides a quick and reliable starting solution for online HCT-CBCT registration.

Models of Osteoarthritis: Relevance and New Insights.

Osteoarthritis (OA) is a progressive and disabling musculoskeletal disease affecting millions of people and resulting in major healthcare costs worldwide. It is the most common form of arthritis, characterised by degradation of the articular cartilage, formation of osteophytes, subchondral sclerosis, synovial inflammation and ultimate loss of joint function. Understanding the pathogenesis of OA and its multifactorial aetiology will lead to the development of effective treatments, which are currently lacking. Two-dimensional (2D) in vitro tissue models of OA allow affordable, high-throughput analysis and stringent control over specific variables. However, they are linear in fashion and are not representative of physiological conditions. Recent in vitro studies have adopted three-dimensional (3D) tissue models of OA, which retain the advantages of 2D models and are able to mimic physiological conditions, thereby allowing investigation of additional variables including interactions between the cells and their surrounding extracellular matrix. Numerous spontaneous and induced animal models are used to reproduce the onset and monitor the progression of OA based on the aetiology under investigation. This therefore allows elucidation of the pathogenesis of OA and will ultimately enable the development of novel and specific therapeutic interventions. This review summarises the current understanding of in vitro and in vivo OA models in the context of disease pathophysiology, classification and relevance, thus providing new insights and directions for OA research.

Direct Oral Anticoagulants Versus Warfarin in the Treatment of Left Ventricular Thrombus.

BACKGROUND: Use of direct oral anticoagulants (DOACs) for the treatment of left ventricular (LV) thrombus has gained considerable interest. OBJECTIVE: We aimed to evaluate if DOACs are effective in the treatment of LV thrombus compared with warfarin. METHODS: We evaluated the medical records of patients diagnosed with a new LV thrombus at a tertiary medical center. The primary outcome was the composite of thrombus persistence, stroke, or systemic embolism. We adjusted for potential confounders using multiple logistic regression. The safety outcome was the composite of hemorrhagic stroke or bleeding requiring blood transfusion. RESULTS: A total of 129 patients were treated with warfarin and 22, with a DOAC. In unadjusted analysis, 54.3% of patients treated with warfarin met criteria for the efficacy outcome as compared with 40.9% of patients treated with a DOAC (P = 0.25). In adjusted analysis, no difference between groups was observed (odds ratio = 0.39; 95% CI = 0.14-1.06; P = 0.07 for DOAC vs warfarin). In all, 3.9% of patients treated with warfarin met safety criteria as compared with 4.5% of patients treated with a DOAC. A total of 8 patients in the warfarin group had a stroke or systemic embolism as compared with 0 patients in the DOAC group (P = 0.37). CONCLUSION AND RELEVANCE: Our data suggest that DOACs may be reasonable alternatives for treatment of LV thrombus. When added to the totality of available studies, this study demonstrates that the effectiveness of DOACs in LV thrombus remains uncertain. Randomized clinical trials are needed.

Impact of Protocolized Pharmacist Intervention on Critical Activated Partial Thromboplastin Time Values With Heparin Infusions.

Background: Unfractionated heparin (UFH) infusions are commonly managed with nurse-driven nomograms titrated to activated partial thromboplastin time (aPTT). In some patients, anti-Xa values may be more appropriate measures of anticoagulation. At the present institution, an update to the nurse-driven aPTT nomogram requires pharmacist notification and clinical assessment for critically supratherapeutic aPTT results. Objective: The purpose of this study was to evaluate the efficacy and safety of the nomogram update. Methods: A single-center, retrospective, pre-post analysis was conducted in patients treated with UFH who experienced a critical aPTT during the 6 months preceding and following the nomogram update. Patients with erroneous critical aPTT results were excluded. The primary endpoint was the time in therapeutic range (Rosendaal method) from the first critical aPTT until UFH discontinuation. Secondary endpoints included the proportion of patients transitioned to anti-Xa monitoring and the incidence of Bleeding Academic Research Consortium (BARC) 2, 3, 5 bleeding. Data were analyzed by the χ2 test. The study was institutional review board approved. Results: Of 277 UFH infusions, 142 belonged to the pre-implementation group and 135 to the post-implementation group. Baseline aPTTs were similar between the 2 groups. Time in therapeutic range was 58.1% versus 62.4% of between groups (P = .467). UFH was transitioned to pharmacist-driven anti-Xa monitoring in 16.2% versus 40.3% of patients (P < .001). BARC 2, 3, 5 bleeding occurred in 23.2% versus 13.4% of patients (P < .001). Conclusions: Application of these data suggest improved safety and efficacy outcomes with directed pharmacist management of UFH in patients with critically elevated aPTTs.

A novel energy sequence optimization algorithm for efficient spot-scanning proton arc (SPArc) treatment delivery.

BACKGROUND: Spot-scanning proton arc therapy (SPArc) has been proposed to improve dosimetric outcome and to simplify treatment workflow. To efficiently deliver a SPArc plan, it's crucial to minimize the number of energy layer switches (ELS) a sending because of the magnetic hysteresis effect. In this study, we introduced a new SPArc energy sequence optimization algorithm (SPArc_seq) to reduce ascended ELS and to investigate its impact on the beam delivery time (BDT). METHOD AND MATERIALS: An iterative energy layer sorting and re-distribution mechanism following the direction of the gantry rotation was implemented in the original SPArc algorithm (SPArc_orig). Five disease sites, including prostate, lung, brain, head neck cancer (HNC) and breast cancer were selected to evaluate this new algorithm. Dose-volume histogram (DVH) and plan robustness were used to assess the plan quality for both SPArc_seq and SPArc_orig plans. The BDT evaluations were analyzed through two methods: 1. fixed gantry angle delivery (BDTfixed) and 2. An in-house dynamic arc scanning controller simulation which considered of gantry rotation speed, acceleration and deceleration (BDTarc). RESULTS: With a similar total number of energy layers, SPArc_seq plans provided a similar nominal plan quality and plan robustness compared to SPArc_orig plans. SPArc_seq significantly reduced the number of ascended ELS by 83% (19 vs.115), 70% (16 vs. 64), 82% (19 vs. 104), 80% (19 vs. 94) and 70% (9 vs. 30), which effectively shortened the BDTfixed by 65% (386 vs. 1091 s), 61% (235 vs. 609 s), 64% (336 vs. 928 s), 48% (787 vs.1521 s) and 25% (384 vs. 511 s) and shortened BDTarc by 54% (522 vs.1128 s), 52% (310 vs.645 s), 53% (443 vs. 951 s), 49% (803 vs.1583 s) and 26% (398 vs. 534 s) in prostate, lung, brain, HNC and breast cancer, respectively. CONCLUSIONS: The SPArc_seq optimization algorithm could effectively reduce the BDT compared to the original SPArc algorithm. The improved efficiency of the SPArc_seq algorithm has the potential to increase patient throughput, thereby reducing the operation cost of proton therapy.

Improving dosimetric outcome for hippocampus and cochlea sparing whole brain radiotherapy using spot-scanning proton arc therapy.

This feasibility study shows that Spot-scanning Proton Arc therapy (SPArc) is able to significantly reduce the dose to the hippocampus and cochlea compared to both Volumetric Modulated Arc Photon Therapy (VMAT) and the robust optimized Intensity Modulated Proton Therapy (ro-IMPT) plans in whole brain radiotherapy. Furthermore, SPArc not only improves plan robustness but could potentially deliver a treatment as efficient as ro-IMPT when proton system's energy layer switch time is less than 1 s.

The optimal number of options for multiple-choice questions on high-stakes tests: application of a revised index for detecting nonfunctional distractors.

Research suggests that the three-option format is optimal for multiple choice questions (MCQs). This conclusion is supported by numerous studies showing that most distractors (i.e., incorrect answers) are selected by so few examinees that they are essentially nonfunctional. However, nearly all studies have defined a distractor as nonfunctional if it is selected by fewer than 5% of examinees. A limitation of this definition is that the proportion of examinees available to choose a distractor depends on overall item difficulty. This is especially problematic for mastery tests, which consist of items that most examinees are expected to answer correctly. Based on the traditional definition of nonfunctional, a five-option MCQ answered correctly by greater than 90% of examinees will be constrained to have only one functional distractor. The primary purpose of the present study was to evaluate an index of nonfunctional that is sensitive to item difficulty. A secondary purpose was to extend previous research by studying distractor functionality within the context of professionally-developed credentialing tests. Data were analyzed for 840 MCQs consisting of five options per item. Results based on the traditional definition of nonfunctional were consistent with previous research indicating that most MCQs had one or two functional distractors. In contrast, the newly proposed index indicated that nearly half (47.3%) of all items had three or four functional distractors. Implications for item and test development are discussed.

Azathioprine Has a Deleterious Effect on the Bone Health of Mice with DSS-Induced Inflammatory Bowel Disease.

Patients with inflammatory bowel disease (IBD) often present poor bone health and are 40% more at risk of bone fracture. Studies have implicated autophagy in IBD pathology and drugs used to treat IBD stimulate autophagy in varying degrees, however, their effect on the skeleton is currently unknown. Here, we have utilised the dextran sulphate sodium (DSS) model of colitis in mice to examine the effects of the thiopurine drug azathioprine on the skeleton. Ten-week-old male mice (n = 6/group) received 3.0% DSS in their drinking water for four days, followed by a 14-day recovery period. Mice were treated with 10 mg/kg/day azathioprine or vehicle control. Histopathological analysis of the colon from DSS mice revealed significant increases in scores for inflammation severity, extent, and crypt damage (p < 0.05). Azathioprine provided partial protection to the colon, as reflected by a lack of significant difference in crypt damage and tissue regeneration with DSS treatment. MicroCT of vehicle-treated DSS mice revealed azathioprine treatment had a significant detrimental effect on the trabecular bone microarchitecture, independent of DSS treatment. Specifically, significant decreases were observed in bone volume/tissue volume (p < 0.01), and trabecular number (p < 0.05), with a concurrent significant increase in trabecular pattern factor (p < 0.01). Immunohistochemical labelling for LC3 revealed azathioprine to induce autophagy in the bone marrow. Together these data suggest that azathioprine treatment may have a deleterious effect on IBD patients who may already be at increased risk of osteoporotic bone fractures and thus will inform on future treatment strategies for patient stratification.

Text mining-based in silico drug discovery in oral mucositis caused by high-dose cancer therapy.

INTRODUCTION: Oral mucositis (OM) is a major dose-limiting side effect of chemotherapy and radiation used in cancer treatment. Due to the complex nature of OM, currently available drug-based treatments are of limited efficacy. OBJECTIVES: Our objectives were (i) to determine genes and molecular pathways associated with OM and wound healing using computational tools and publicly available data and (ii) to identify drugs formulated for topical use targeting the relevant OM molecular pathways. METHODS: OM and wound healing-associated genes were determined by text mining, and the intersection of the two gene sets was selected for gene ontology analysis using the GeneCodis program. Protein interaction network analysis was performed using STRING-db. Enriched gene sets belonging to the identified pathways were queried against the Drug-Gene Interaction database to find drug candidates for topical use in OM. RESULTS: Our analysis identified 447 genes common to both the "OM" and "wound healing" text mining concepts. Gene enrichment analysis yielded 20 genes representing six pathways and targetable by a total of 32 drugs which could possibly be formulated for topical application. A manual search on ClinicalTrials.gov confirmed no relevant pathway/drug candidate had been overlooked. Twenty-five of the 32 drugs can directly affect the PTGS2 (COX-2) pathway, the pathway that has been targeted in previous clinical trials with limited success. CONCLUSIONS: Drug discovery using in silico text mining and pathway analysis tools can facilitate the identification of existing drugs that have the potential of topical administration to improve OM treatment.

Retinoic Acid Signaling Regulates Differential Expression of the Tandemly-Duplicated Long Wavelength-Sensitive Cone Opsin Genes in Zebrafish.

The signaling molecule retinoic acid (RA) regulates rod and cone photoreceptor fate, differentiation, and survival. Here we elucidate the role of RA in differential regulation of the tandemly-duplicated long wavelength-sensitive (LWS) cone opsin genes. Zebrafish embryos were treated with RA from 48 hours post-fertilization (hpf) to 75 hpf, and RNA was isolated from eyes for microarray analysis. ~170 genes showed significantly altered expression, including several transcription factors and components of cellular signaling pathways. Of interest, the LWS1 opsin gene was strongly upregulated by RA. LWS1 is the upstream member of the tandemly duplicated LWS opsin array and is normally not expressed embryonically. Embryos treated with RA 48 hpf to 100 hpf or beyond showed significant reductions in LWS2-expressing cones in favor of LWS1-expressing cones. The LWS reporter line, LWS-PAC(H) provided evidence that individual LWS cones switched from LWS2 to LWS1 expression in response to RA. The RA signaling reporter line, RARE:YFP indicated that increased RA signaling in cones was associated with this opsin switch, and experimental reduction of RA signaling in larvae at the normal time of onset of LWS1 expression significantly inhibited LWS1 expression. A role for endogenous RA signaling in regulating differential expression of the LWS genes in postmitotic cones was further supported by the presence of an RA signaling domain in ventral retina of juvenile zebrafish that coincided with a ventral zone of LWS1 expression. This is the first evidence that an extracellular signal may regulate differential expression of opsin genes in a tandemly duplicated array.

A clinical 3D/4D CBCT-based treatment dose monitoring system.

To monitor delivered dose and trigger plan adaptation when deviation becomes unacceptable, a clinical treatment dose (Tx-Dose) reconstruction system based on three-dimensional (3D)/four-dimensional (4D)-cone beam computed tomograpy (CBCT) images was developed and evaluated on various treatment sites, particularly for lung cancer patient treated by stereotactic body radiation therapy (SBRT). This system integrates with our treatment planning system (TPS), Linacs recording and verification system (R&V), and CBCT imaging system, consisting of three modules: Treatment Schedule Monitoring module (TSM), pseudo-CT Generating module (PCG), and Treatment Dose Reconstruction/evaluation module (TDR). TSM watches the treatment progress in the R&V system and triggers the PCG module when new CBCT is available. PCG retrieves the CBCTs and performs planning CT to CBCT deformable registration (DIR) to generate pseudo-CT. The 4D-CBCT images are taken for target localization and correction in lung cancer patient before treatment. To take full advantage of the valuable information carried by 4D-CBCT, a novel phase-matching DIR scheme was developed to generate 4D pseudo-CT images for 4D dose reconstruction. Finally, TDR module creates TPS scripts to automate Tx-Dose calculation on the pseudo-CT images. Both initial quantitative commissioning and patient-specific qualitative quality assurance of the DIR tool were utilized to ensure the DIR quality. The treatment doses of ten patients (six SBRT-lung, two head and neck (HN), one breast and one prostate cancer patients) were retrospectively constructed and evaluated. The target registration error (mean ± STD: 1.05 ± 1.13 mm) of the DIR tool is comparable to the interobserver uncertainty (0.88 ± 1.31 mm) evaluated by a publically available lung-landmarks dataset. For lung SBRT patients, the D99 of the final cumulative Tx-Dose of GTV is 93.8 ± 5.5% (83.7-100.1%) of the originally planned D99 . CTV D99 decreases by 3% and mean ipsilateral parotid dose increases by 11.5% for one of the two HN patients. In conclusion, we have demonstrated the feasibility and effectiveness of a treatment dose verification system in our clinical setting.

Abnormal retinal development in Cloche mutant zebrafish.

BACKGROUND: Functions for the early embryonic vasculature in regulating development of central nervous system tissues, such as the retina, have been suggested by in vitro studies and by in vivo manipulations that caused additional ocular vessels to develop. Here, we use an avascular zebrafish embryo, cloche-/- (clo-/-), to begin to identify necessary developmental functions of the ocular vasculature in regulating development and patterning of the neural retina, in vivo. These studies are possible in zebrafish embryos, which do not yet rely upon the vasculature for tissue oxygenation. RESULTS: clo-/- embryos lacked early ocular vasculature and were microphthalmic, with reduced retinal cell proliferation and cell survival. Retinas of clo mutants were disorganized, with irregular synaptic layers, mispatterned expression domains of retinal transcription factors, morphologically abnormal Müller glia, reduced differentiation of specific retinal cell types, and sporadically distributed cone photoreceptors. Blockade of p53-mediated cell death did not completely rescue this phenotype and revealed ectopic cones in the inner nuclear layer. clo-/- embryos did not upregulate a molecular marker for hypoxia. CONCLUSIONS: The disorganized retinal phenotype of clo-/- embryos is consistent with a neural and glial developmental patterning role for the early ocular vasculature that is independent of its eventual function in gas exchange.

Comparison of Time to Therapeutic aPTT in Patients Who Received Continuous Unfractionated Heparin After Implementation of Pharmacy-wide Intervention Alerts.

Background: For patients on continuous IV unfractionated heparin (UFH), failing to achieve a therapeutic aPTT by 24 hours can be associated with increased morbidity. A pharmacy clinical surveillance system (PCSS) subtherapeutic aPTT alert was implemented at our institution to improve achievement of therapeutic aPTT goals by 24 hours. Objective: The primary objective was the time to achieve the minimum goal aPTT before and after the alert implementation. The secondary objectives were to examine the percentage of patients who achieved the minimum goal aPTT by 24 hours and the number of dose changes to achieve the minimum goal aPTT. Methods: A single-center retrospective study was conducted to include all adult inpatients receiving a continuous UFH infusion during a 3-month period prior to the implementation of a subtherapeutic aPTT alert and a 3-month period after implementation. Results: 317 patients were included in the analysis. The average time to achieve the minimum goal aPTT was 21.8 hours prior to alert implementation and 15.4 hours after implementation (p = .002). The percent of patients who achieved the minimum goal aPTT by 24 hours was 65.7% prior to alert implementation and 82.4% after implementation (p = .035). The average number of dose changes necessary to achieve aPTT value to the minimum goal aPTT prior to alert implementation was 1.67 and 1. 98 after implementation (p = .68). Conclusion: This analysis showed that implementation of a PCSS subtherapeutic aPTT alert for patients on continuous UFH infusions may ensure patients reach goal aPTT faster and facilitate a higher percent of patients who achieve the minimum goal aPTT by 24 hours.

The intermediate filament protein, vimentin, is a regulator of NOD2 activity.

OBJECTIVE: Mutations in the nucleotide-binding oligomerisation domain-containing protein 2 (NOD2) gene remain the strongest genetic determinants for Crohn's disease (CD). Having previously identified vimentin as a novel NOD2-interacting protein, the authors aimed to investigate the regulatory effects of vimentin on NOD2 function and the association of variants in Vim with CD susceptibility. DESIGN: Coimmunoprecipitation, fluorescent microscopy and fractionation were used to confirm the interaction between NOD2 and vimentin. HEK293 cells stably expressing wild-type NOD2 or a NOD2 frameshift variant (L1007fs) and SW480 colonic epithelial cells were used alongside the vimentin inhibitor, withaferin A (WFA), to assess effects on NOD2 function using the nuclear factor-kappaB (NF-κB) reporter gene, green fluorescent protein-LC3-based autophagy, and bacterial gentamicin protection assays. International genome-wide association meta-analysis data were used to test for associations of single-nucleotide polymorphisms in Vim with CD susceptibility. RESULTS: The leucine-rich repeat domain of NOD2 contained the elements required for vimentin binding; CD-associated polymorphisms disrupted this interaction. NOD2 and vimentin colocalised at the cell plasma membrane, and cytosolic mislocalisation of the L1007fs and R702W variants correlated with an inability to interact with vimentin. Use of WFA demonstrated that vimentin was required for NOD2-dependent NF-κB activation and muramyl dipeptide-induced autophagy induction, and that NOD2 and vimentin regulated the invasion and survival properties of a CD-associated adherent-invasive Escherichia coli strain. Genetic analysis revealed an association signal across the haplotype block containing Vim. CONCLUSION: Vimentin is an important regulator of NOD2 function and a potential novel therapeutic target in the treatment of CD. In addition, Vim is a candidate susceptibility gene for CD, supporting the functional data.

Relationship between publication of a postgraduate year 1 residency research project and subsequent career type at a large academic medical center.

PURPOSE: The study objectives were to (1) quantify the overall incidence of residency publications of postgraduate year 1 (PGY1) residency alumni; (2) evaluate annual fluctuations in publications over time; and (3) compare the career types of residency alumni who published their PGY1 residency research projects to those for alumni who did not. METHODS: A retrospective cohort study was performed among individuals who completed a PGY1 acute/ambulatory care residency between 2010 and 2021. A list of residency alumni was obtained along with the corresponding titles of their research projects. Each resident's name was entered into PubMed and Google Scholar to find the corresponding publication. LinkedIn and other publicly available resources were used to determine the career types of residents immediately after residency as well as their current career types. RESULTS: In total, 178 residency alumni completed an acute/ambulatory care PGY1 residency, of whom 16.7% (30/178) published their residency research project. Publication was associated with career type among those who pursued a postgraduate year 2 residency but was not associated with career type immediately after the PGY1 residency or current career type. The presence of an academic preceptor was associated with a higher probability of publishing compared to residents who did not have an academic preceptor (31.5% vs 10.5%; P < 0.01). CONCLUSION: The frequency of publications was within the range reported elsewhere, with fluctuations over time. Presence of an academic preceptor improved the probability of publication.