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OBJECTIVES/GOALS: Patient-specific definition of extent of surgical excision is foundational to the safety offered by computer assisted interventions. Consequently, this study aims to develop a pipeline for automated segmentation of bone removed during cortical mastoidectomy, a technically complex otologic surgery. METHODS/STUDY POPULATION: A simulator, previously developed in our lab, allows fully immersive simulation of mastoidectomy using segmented temporal bones generated from CT data. Using the simulator, one attending surgeon will perform three trials of mastoidectomy on 20 different temporal bones. From the simulator we will obtain data on the volume of bone removed for a specific anatomy, averaged between trials. No new U-net (nnU-net), an open-source three-dimensional segmentation network, will then be trained to predict the volume of bone removed using segmented pre-operative CT imaging. Segmentation accuracy will be evaluated with the Dice coefficient, modified Hausdorff distance (mHD), sensitivity and specificity. RESULTS/ANTICIPATED RESULTS: We expect the mean pairwise Dice coefficient to be high indicating relative similarity of volume removed between trials. Moreover, we predict that following five-fold cross-validation the best model will result in a Dice coefficient, mHD, sensitivity, and specificity indicative of volume removed predictions consistent with surgeon-generated data. Finally, given that network training will penalize overlap of the predicted excised bone segment and previously segmented anatomic structures, we expect that no critical anatomical structures will be marked as tissue removed. DISCUSSION/SIGNIFICANCE: We hope to show that deep learning architectures can accurately predict bone removed during mastoidectomy. These predictions can be used for preoperative planning, as clinical endpoints in surgical simulators, or be used in conjunction with surgical robots, all ultimately improving patient safety.

Objective: To map literature on research ethics committees, institutional review boards and ethics review framework in Pakistan to identify key insights during public health emergencies and normal times. Method: The systematic scoping review was conducted in April 22, and comprised literature search on PubMed, World Health Organisation Global Index Medicus and Summons databases for articles published between January 2005 and February 2022. Information extracted included authors’ names, year of publication, title, study methodology, and key insights under the heads of challenges and solutions. Due to data heterogeneity, key themes were identified and analysed. Results: Of the 2,190 studies initially identified, 21(0.95%) were subjected to full-text review, and, from among them, 9(45%) were analysed in detail. There were 4 key insights identified: research ethics committees and institutional review boards in Pakistan remain unregulated as they are currently not registered or accredited by a competent national-level authority; most members of such committees are not formally trained to implement the mandate; internal and external pressures hinder independent decision-making of such committees; and other issues hindering the functionality and performance of research ethics committees and institutional review boards. Conclusion: Despite existing publications calling for urgent policy and regulatory reforms, there is a dearth of literature and minimal policy actions underline the fact that ethics review remains a neglected area in Pakistan. Key Words: Ethics, Pakistan, Bioethics, Ethics committees, Institutional review board.

IntroductionThis study aimed to assess whether psychiatric disorders predict the onset of fibromyalgia and chronic fatigue syndrome (CFS) which develop in the presence of pre-existing muscle pain or fatigue.MethodsThe population-based Lifelines cohort study included 148,614 adults with relevant data for the fibromyalgia study and 136,423 for the CFS study. Participants with prior self-reported fibromyalgia (or CFS) at baseline were excluded from the relevant analysis. At follow-up (mean 2.4 years), new onsets of each syndrome were identified by self-report. Logistic regression was used to identify which of the baseline variables predicted new onsets of each syndrome. The total number of psychiatric disorders (depression, anxiety, burnout, panic disorder, social phobia, agoraphobia, obsessive–compulsive, and eating disorders) was used as a predictor. Prior to the analyses the samples were divided into those with and without marked muscle pain (for fibromyalgia analysis) or persistent fatigue (for CFS).ResultsDuring follow-up, there were 685/136,423 (0.5%) new onsets of self-reported FM in participants without marked muscle pain and 281/7481 (3.75%) in those with such pain; for CFS it was 292/124,223 (0.2%) for those without and 192/10,025 (1.9%) for those with baseline fatigue. In both univariate and logistic regression analyses of participants with prior persistent fatigue psychiatric disorder was clearly associated with onset of CFS. This was not so for onset of fibromyalgia in participants with prior muscle pain.DiscussionAlthough psychiatric disorders did not predict self-reported fibromyalgia or CFS in participants free of pain or fatigue at baseline, in this study psychiatric disorder did predict self-reported CFS in the presence of pre-existing fatigue. Progress in understanding the etiology of these disorders may require studying separately onsets with and without pre-existing key symptoms.

ObjectiveIt is not clear why psychiatric disorders are more prevalent in the functional somatic syndromes than other general medical illnesses. This study assessed the correlates of psychiatric disorders in 3 functional syndromes and 3 general medical illnesses in a population-based sample.MethodsThe Lifelines cohort study included 122,366 adults with relevant data for 6 self-reported conditions: irritable bowel syndrome (IBS), fibromyalgia, chronic fatigue syndrome (CFS), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and diabetes. For each condition the proportion with a DSM-IV psychiatric disorder was assessed. In a cross-sectional design, logistic regression identified at baseline the variables most closely associated with current psychiatric disorder in participants with a pre-existing medical or functional condition. In a separate analysis the prevalence of psychiatric disorder prior to onset of these conditions was assessed. This was a longitudinal study with psychiatric disorder assessed at baseline in participants who subsequently developed a general medical or functional condition between baseline and follow-up.ResultsThe prevalence of psychiatric disorder was higher (17-27%) in the functional somatic syndromes than the general medical illnesses (10.4-11.7%). The variables closely associated with psychiatric disorder were similar in the functional syndromes and general medical illnesses: stressful life events, chronic personal health difficulties, neuroticism, poor perception of general health, impairment of function due to physical illness and reported previous (lifetime) psychiatric disorder. The prevalence of psychiatric disorder prior to development of these disorder was similar to that of established disorders.ConclusionDespite the difference in prevalence, the correlates of psychiatric disorders were similar in functional and general medical disorders and included predisposing and environmental factors. The increased rate of psychiatric disorder in functional somatic syndromes appears to be evident before onset of the syndrome.

Objective: To investigate whether stress, anxiety and depression predict preterm birth in twin pregnancies. Methods: A prospective cohort study with a convenience sample of women pregnant with dichorionic, diamniotic twins. They were interviewed at 24–28 weeks using the Life Events and Difficulties Schedule and the Hospital Anxiety and Depression Scale. Corticotrophin-releasing hormone, ACTH and cortisol levels were assessed at 28 weeks. The main outcome was premature delivery; there were 42 preterm and 73 term births. Results: Preterm births (

The terracotta figurines of the Aphrodision of Argos comprise a very rich corpus that sheds light on the creation of archaic Argive sculpture. This is especially the case for the type of the “seated female” that has a modeled body with a molded head. The study of these figurines reveals that more than 20 different facial types were developed by Argive craftsmen throughout the course of the 6th century B.C.E. This not only documents the creativity of the Argive workshops, but it also gives rise to the question of their relationship with artisans working in bronze. In any case, the parallel development in the Argive corpus of both techniques of modeling and molding can be observed during the 6th century B.C.E.

Children with Attention Deficit/Hyperactivity Disorder (ADHD) receive approximately 80% of instruction in the general education classroom, where individualized behavioral management strategies may be difficult for teachers to consistently deliver. Mobile device apps provide promising platforms to manage behavior. This pilot study evaluated the utility of a web-based application (iSelfControl) designed to support classroom behavior management. iSelfControl prompted students every 'Center' (30-minutes) to self-evaluate using a universal token-economy classroom management system focused on compliance, productivity, and positive relationships. Simultaneously, the teacher evaluated each student on a separate iPad. Using Multi Level Modeling, we examined 13 days of data gathered from implementation with 5th grade students (N = 12) at a school for children with ADHD and related executive function difficulties. First, an unconditional growth model evaluated the overall amount of change in aggregated scores over time as well as the degree of systematic variation in scores within and across teacher-student dyads. Second, separate intercepts and slopes were estimated for teacher and student to estimate degree of congruency between trajectories. Finally, differences between teacher and student scores were tested at each time-point in separate models to examine unique 'Center' effects. 51% of the total variance in scores was attributed to differences between dyads. Trajectories of student and teacher scores remained relatively stable across seven time-points each day and did not statistically differ from each other. On any given day, students tended to evaluate their behaviors more positively (entered higher scores for themselves) compared to corresponding teacher scores. In summary, iSelfControl provides a platform for self and teacher evaluation that is an important adjunct to conventional classroom management strategies. The application captured teacher/student discrepancies and significant variations across the day. Future research with a larger, clinically diagnosed sample in multiple classrooms is needed to assess generalizability to a wider variety of classroom settings.

Objective: Endocytosis is a process vital to angiogenesis and vascular homeostasis. In pathologies where supraphysiological growth factor signaling underlies disease etiology, such as in diabetic retinopathy and solid tumors, strategies to limit chronic growth factor signaling by way of blunting endocytic processes have been shown to have tremendous clinical value. ADP ribosylation factor 6 (Arf6) is a small GTPase that promotes the assembly of actin necessary for clathrin-mediated and clathrin-independent endocytosis. In its absence, growth factor signaling is greatly diminished, which has been shown to ameliorate pathological signaling input in diseased vasculature. However, it is less clear if there are bystander effects related to loss of Arf6 on angiogenic behaviors. Our goal was to provide an analysis of Arf6's function in angiogenic endothelium, focusing on its role in actin and endocytosis as well as sprouting morphogenesis., Methods: Primary endothelial cells were cultured in both 2D and 3D environments. Here, endothelial cells were fixed and stained for various proteins or transfected with fluorescently-tagged constructs for live-cell imaging., Results: We found that Arf6 localized to both filamentous actin and sites of endocytosis in two-dimensional culture. Loss of Arf6 distorted both apicobasal polarity and reduced the total cellular filamentous actin content, which may be the primary driver underlying gross sprouting dysmorphogenesis in its absence., Conclusions: Our findings highlight that endothelial Arf6 is a potent mediator of both actin regulation and endocytosis and is required for proper sprout formation., (© 2023 John Wiley & Sons Ltd.)

Clathrin-mediated endocytosis (CME) is a process vital to angiogenesis as well as general vascular homeostasis. In pathologies where supraphysiological growth factor signaling underlies disease etiology, such as in diabetic retinopathy and solid tumors, strategies to limit chronic growth factor signaling by way of CME have been shown to have tremendous clinical value. ADP ribosylation factor 6 (Arf6) is a small GTPase that promotes the assembly of actin necessary for CME. In its absence, growth factor signaling is greatly diminished, which has been shown to ameliorate pathological signaling input in diseased vasculature. However, it is less clear if there are bystander effects related to loss of Arf6 on angiogenic behaviors. Our goal was to provide a analysis of Arf6’s function in angiogenic endothelium, focusing on its role in lumenogenesis as well as its relation to actin and CME. We found that Arf6 localized to both filamentous actin and sites of CME in 2-dimensional culture. Loss of Arf6 distorted both apicobasal polarity and reduced the total cellular filamentous actin content, and this may be the primary driver underlying gross dysmorphogenesis during angiogenic sprouting in its absence. Our findings highlight that endothelial Arf6 is a potent mediator of both actin regulation and CME.

Objectives: Vesicular trafficking dictates protein localization, functional activity, and half-life, providing a critically important regulatory step in tissue development; however, there is little information detailing endothelial-specific trafficking signatures. This is due, in part, to limitations in visualizing trafficking events in endothelial tissues. Our aim in this investigation was to explore the use of a 3-dimensional (3D) in vitro sprouting model to image endothelial membrane trafficking events., Methods: Endothelial cells were challenged to grow sprouts in a fibrin bead assay. Thereafter, spouts were transfected with fluorescent proteins and stained for various cell markers. Sprouts were then imaged for trafficking events using live and fixed-cell microscopy., Results: Our results demonstrate that fibrin bead sprouts have a strong apicobasal polarity marked by apical localization of proteins moesin and podocalyxin. Comparison of trafficking mediators Rab27a and Rab35 between 3D sprouts and 2D culture showed that vesicular carriers can be imaged at high resolution, exhibiting proper membrane polarity solely in 3D sprouts. Lastly, we imaged exocytic events of von Willebrand Factor and demonstrated a distinct imaging advantage for monitoring secretion events in 3D sprouts as compared with 2D culture., Conclusions: Our results establish that the fibrin bead sprouting assay is well-suited for imaging of trafficking events during angiogenic growth., (© 2021 The Authors. Microcirculation published by John Wiley & Sons Ltd.)

In early blood vessel development, trafficking programs, such as those using Rab GTPases, are tasked with delivering vesicular cargo with high spatiotemporal accuracy. However, the function of many Rab trafficking proteins remain ill-defined in endothelial tissue; therefore, their relevance to blood vessel development is unknown. Rab35 has been shown to play an enigmatic role in cellular behaviors which differs greatly between tissue-type and organism. Importantly, Rab35 has never been characterized for its potential contribution in sprouting angiogenesis; thus, our goal was to map Rab35's primary function in angiogenesis. Our results demonstrate that Rab35 is critical for sprout formation; in its absence, apicobasal polarity is entirely lost in vitro and in vivo. To determine mechanism, we systematically explored established Rab35 effectors and show that none are operative in endothelial cells. However, we find that Rab35 partners with DENNd1c, an evolutionarily divergent guanine exchange factor, to localize to actin. Here, Rab35 regulates actin polymerization through limiting Rac1 and RhoA activity, which is required to set up proper apicobasal polarity during sprout formation. Our findings establish that Rab35 is a potent brake of actin remodeling during blood vessel development., (© 2022. The Author(s).)

Blood vessels demonstrate a multitude of complex signaling programs that work in concert to produce functional vasculature networks during development. A known, but less widely studied, area of endothelial cell regulation is vesicular trafficking, also termed sorting. After moving through the Golgi apparatus, proteins are shuttled to organelles, plugged into membranes, recycled, or degraded depending on the internal and extrinsic cues. A snapshot of these protein-sorting systems can be viewed as a trafficking signature that is not only unique to endothelial tissue, but critically important for blood vessel form and function. In this review, we will cover how vesicular trafficking impacts various aspects of angiogenesis, such as sprouting, lumen formation, vessel stabilization, and secretion, emphasizing the role of Rab GTPase family members and their various effectors., (© 2022. The Author(s).)

Objective: Despite the absolute requirement of Delta/Notch signaling to activate lateral inhibition during early blood vessel development, many mechanisms remain unclear about how this system is regulated. Our objective was to determine the involvement of Epsin 15 Homology Domain Containing 2 (EHD2) in delta-like ligand 4 (Dll4) endocytosis during Notch activation., Approach and Results: Using both in vivo and in vitro models, we demonstrate that EHD2 is a novel modulator of Notch activation in endothelial cells through controlling endocytosis of Dll4. In vitro, EHD2 localized to plasma membrane-bound Dll4 and caveolae. Chemical disruption of caveolae complexes resulted in EHD2 failing to organize around Dll4 as well as loss of Dll4 internalization. Reduced Dll4 internalization blunted Notch activation in endothelial cells. In vivo, EHD2 is primarily expressed in the vasculature, colocalizing with junctional marker VE-cadherin and Dll4. Knockout of EHD2 in zebrafish produced a significant increase in dysmorphic sprouts in zebrafish intersomitic vessels during development and a reduction in downstream Notch signaling., Conclusions: Overall, we demonstrate that EHD2 is necessary for Dll4 transcytosis and downstream Notch activation., (© 2021 The Authors. Microcirculation published by John Wiley & Sons Ltd.)

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A typology of physically abusive parents was developed based upon personality characteristics measured by the 16-PF. Cluster analysis revealed five distinct patterns, accounting for 81 of 82 profiles submitted. Significant differences among the clusters were found on 14 of the 16 factors. The following types were described: (a) Shy, withdrawn, apprehensive, sober, and restrained; tending to have the least education, the greatest number of children. (b) Parents presenting as "normal" in personality features; tending to have relatively more education, fewer children. (c) Compulsive, bold, dominant, and assertive; tending to be highly manipulative in self-presentations, have high educational levels, and be older than other types. (d) Basically passive and submissive; tending to come from families where both parents are abusive. (e) Isolated, withdrawn, suspicious, tense, and apprehensive; tending to be more psychologically disturbed. Significance tests on external variables performed to validate the solution found differences among clusters in age, education, number of children, number of parents involved in abuse, 16-PF Faking Good and Faking Bad scores, and MMPI Scales L, F, K, 4, 5, 6, 7, and 0. Distinguishing personality features and demographic characteristics of the types are discussed with a focus upon possible treatment approaches for each type. Limitations of the study and suggestions for future research are addressed.