The circadian regulator PER1 promotes cell reprogramming by inhibiting inflammatory signaling from macrophages.

Circadian regulation of gene expression is prevalent and plays critical roles in cell differentiation. However, its roles in the reprogramming of differentiated cells remain largely unknown. Here, we found that one of the master circadian regulators PER1 promoted virus-mediated reprogramming of mouse embryonic fibroblasts (MEFs) to induced neurons (iNs) and induced pluripotent stem cells (iPSCs). Unexpectedly, PER1 achieved this by repressing inflammatory activation of contaminating macrophages in the MEF culture, rather than by directly modulating the reprogrammability of MEFs. More specifically, we found that transduced viruses activated inflammatory genes in macrophages, such as Tnf encoding TNFα, one of the central inflammatory regulators and an autocrine activator of macrophages. TNFα inhibited iN reprogramming, whereas a TNFα inhibitor promoted iN reprogramming, connecting the inflammatory responses to iN reprogramming. In addition, macrophages were induced to proliferate and mature by non-macrophage cells serving as feeders, which also supported up-regulation of TNFα in macrophages without virus transduction. Furthermore, the 2 inflammatory responses were repressed by the circadian regulator PER1 in macrophages, making reprogrammability dependent on time-of-day of virus transduction. Similar results were obtained with iPSC reprogramming, suggesting a wide occurrence of macrophage-mediated inhibition of cell reprogramming. This study uncovers mechanistic links between cell reprogramming, bystander inflammatory macrophages, and circadian rhythms, which are particularly relevant to in vivo reprogramming and organoid formation incorporating immune cells.

Impact of Teprotumumab on Clinical Practice in Thyroid Eye Disease.

BACKGROUND: Following its FDA approval in January 2020, we examined the impact of teprotumumab on thyroid eye disease (TED) clinical practices. METHODS: Across three referral centers from January 1, 2018, to December 30, 2022, we retrospectively analyzed demographics, clinical features, treatment choices, and insurance status of patients with active, moderate to severe TED. RESULTS: Of 74 patients recommended for medical therapy, 53% received collaborative recommendations from endocrinologists and ophthalmologists in a TED clinic. Prior to teprotumumab availability, 19 patients were recommended medical therapy, and all received medical therapy (100%), which consists of corticosteroids (14, 73.7%) or tocilizumab (5, 26.3%). After teprotumumab became available, out of 55 patients that were recommended medical therapy, only 41 (74.6%) received medical therapy, mostly teprotumumab (33, 60%), followed by corticosteroids (5, 9.1%) or tocilizumab (3, 5.4%), while 14 (25.4%) did not receive medical therapy. Discordance between physicians' recommendations and therapy received or lack thereof was explained by patients' refusal (9, 64.3%), mostly due to side effect concerns (8, 88.9%), and insurance denial (5, 35.7%). Teprotumumab use was mostly associated with otic changes (10, 30.3%), weight loss (9, 27.3%), and hyperglycemia (6, 18.2%), but 2 (6.1%) patients developed serious infections. Corticosteroids were associated with insomnia (4, 21.1%), and one patient in the tocilizumab group had an infusion reaction requiring hospitalization. CONCLUSION: Teprotumumab introduction increased TED therapy evaluations, yet not all received recommended treatment due to safety concerns or accessibility issues. Enhancing collaborative care, medication accessibility, and adverse effect management is crucial.

Obstructive Sleep Apnea Associated With Increased Failure Rate of Ptosis Repair.

PURPOSE: This study investigates how Obstructive sleep apnea (OSA) affects the outcomes of ptosis repair. We hypothesized that patients with OSA have an increased rate of reoperation after ptosis repair. METHODS: This retrospective cohort study included patients age >18 from the Mayo Clinic who underwent ptosis repair by levator advancement or Müller muscle-conjunctiva resection between 2018 and 2021. Outcomes were measured at 1 to 3 months of follow-up with surgical failure defined as asymmetry or unsatisfactory eyelid height requiring revision surgery within 1 year. RESULTS: A total of 577 patients met the inclusion criteria. There was a statistically significant difference in surgical failure between patients with OSA and those without (20.5% vs. 13.1%, p = 0.02). Patients with OSA showed a statistically significant difference in risk of revision by a factor of 1.70 (95% CI: 1.06-2.07). Revisions were attributed to unsatisfactory eyelid height in 72.6% of patients and eyelid asymmetry in 21.1%. All patients who had revision surgery had satisfactory outcomes. On logistic regression analysis, when adjusting for age and sex, OSA was significantly associated with ptosis revision ( p = 0.007). CONCLUSIONS: OSA increases risk of surgical failure and need for revision surgery in patients undergoing blepharoptosis repair but is not a sole risk factor.

Mohs Micrographic Surgery With Immunohistochemistry for the Treatment of Periocular Melanoma In Situ.

PURPOSE: Mohs micrographic surgery with immunohistochemistry allows for same-day comprehensive margin assessment of melanoma in situ prior to subspecialty reconstruction. This study describes the oncologic and reconstructive outcomes of eyelid and periorbital melanoma in situ and identifies risk factors for complex reconstructive demands. METHODS: Retrospective case series of all patients treated with Mohs micrographic surgery with immunohistochemistry for melanoma in situ affecting the eyelids or periorbital region from 2008 to 2018 at a single institution. Tumors were assigned to the eyelid group if the clinically visible tumor involved the skin inside the orbital rim. Reconstructive variables were compared between the eyelid and periorbital cohorts. RESULTS: There were 24 eyelid and 141 periorbital tumors included. The initial surgical margin for all tumors was 5.34 ± 1.54 mm and multiple Mohs stages were required in 24.2% of cases. Eyelid tumors included more recurrences (p = 0.003), and the average defect size was larger (14.0 ± 13.3 cm2 vs. 7.7 ± 5.4 cm2, p = 0.03). Risk factors for complex reconstruction included: initial tumor diameter >2 cm (odds ratio [OR]: 3.84, 95% confidence interval [CI]: 1.95-7.57) and eyelid involved by initial tumor (OR: 4.88, 95% CI: 1.94-12.28). At an average follow-up of 4.8 years, there were no melanoma-related deaths and 1 local recurrence (0.6% recurrence rate). CONCLUSIONS: Mohs micrographic surgery with immunohistochemistry achieves excellent local control rates for periocular melanoma in situ. An initial surgical margin of 5 mm is frequently insufficient to achieve clear margins. The resulting defects are large, and the complexity of reconstruction can be predicted by tumor size and clinical involvement of eyelid skin.

Alemtuzumab-Induced Thyroid Eye Disease: A Comprehensive Case Series and Review of the Literature.

PURPOSE: To present 5 cases of alemtuzumab-induced thyroid eye disease (AI-TED) and review the literature to highlight the natural history, severity, and outcomes as compared with conventional thyroid eye disease (TED). METHODS: A multi-institutional retrospective case series of patients with AI-TED was compiled. Chart review evaluated for clinical characteristics, imaging findings, and treatment for AI-TED. Additionally, a comprehensive review of the literature identified all previously published cases of AI-TED. RESULTS: Five new patients with AI-TED were included in this series. The average clinical activity score on presentation was 2.8 (range 1-4) and reached an average peak of 5.0 during the active phase of the disease (4-7). Patients were treated medically with selenium (40%) or monoclonal antibodies including teprotumumab or tocilizumab (40%). Surgical treatment with orbital decompression for compressive optic neuropathy was performed on 2 (40%) patients. Combined with 11 previously reported cases, these 16 patients with AI-TED had an average clinical activity score on presentation of 3.3. The average length of the AI-TED phase was 14.0 months, and all patients were treated with medical and/or surgical interventions for their disease. CONCLUSIONS: Clinical and imaging findings in AI-TED mirror that of conventional TED, however, AI-TED may present with greater severity. AI-TED may develop many months after Graves' disease; therefore, providers should be aware of this association and monitor patients for the development of severe TED.

Predictors of Surgical Versus Medical Management of Eyes in the Setting of Orbital Fracture at an Academic Level I Trauma Center.

We present clinical and imaging predictors of ocular injuries that required medical management versus surgical intervention in cases of orbital fractures. From 2014 to 2020, a retrospective review of patients with orbital fractures who received ophthalmologic consultation and computed scan (CT) analysis at a level I trauma center was performed. Inclusion criteria were patients with confirmed orbital fracture on CT and ophthalmology consultation. Patient demographics, associated injuries, comorbidities, management, and outcomes were collected. Two hundred and one patients and 224 eyes (11.4% bilateral orbital fractures) were included. Overall, 21.9% of orbital fractures presented with a significant concomitant ocular injury. Associated facial fractures were present in 68.8% of eyes. Management included surgical treatment in 33.5% of eyes and ophthalmology-directed medical treatment in 17.4%. On multivariate analysis, clinical predictors of surgical intervention were retinal hemorrhage (OR=4.7 (1.0-21.0), P =0.0437), motor vehicle accident injury (OR=2.7 (1.4-5.1), P =0.0030) and diplopia (OR=2.8 (1.5-5.3), P =0.0011). Imaging predictors of surgical intervention were herniation of orbital contents (OR=2.1 (1.1-4.0), P =0.0281) and multiple wall fractures (OR=1.9 (1.01-3.6), P =0.0450). Predictors of medical management were corneal abrasion (OR=7.7 (1.9-31.4), P =0.0041), periorbital laceration (OR=5.7 (2.1-15.6), P =0.0006), and traumatic iritis (OR=4.7 (1.1-20.3), P =0.0444). We demonstrated a 22% incidence of concomitant ocular trauma in orbital fracture patients at our level I trauma center. Predictors of the surgical intervention included multiple wall fractures, herniation of orbital contents, retinal hemorrhage, diplopia, and motor vehicle accident injury. These findings emphasize the importance of a multidisciplinary team in managing ocular and facial trauma.

Conditional Loss of MEF2C Expression in Osteoclasts Leads to a Sex-Specific Osteopenic Phenotype.

Myocyte enhancement factor 2C (MEF2C) is a transcription factor studied in the development of skeletal and smooth muscles. Bone resorption studies have exhibited that the reduced expression of MEF2C contributes to osteopetrosis and the dysregulation of pathological bone remodeling. Our current study aims to determine how MEF2C contributes to osteoclast differentiation and to analyze the skeletal phenotype of Mef2c-cKO mice (Cfms-cre; Mef2cfl/fl). qRT-PCR and Western blot demonstrated that Mef2c expression is highest during the early days of osteoclast differentiation. Osteoclast genes, including c-Fos, c-Jun, Dc-stamp, Cathepsin K, and Nfatc1, had a significant reduction in expression, along with a reduction in osteoclast size. Despite reduced CTX activity, female Mef2c cKO mice were osteopenic, with decreased bone formation as determined via a P1NP ELISA, and a reduced number of osteoblasts. There was no difference between male WT and Mef2c-cKO mice. Our results suggest that Mef2c is critical for osteoclastogenesis, and that its dysregulation leads to a sex-specific osteopenic phenotype.

Macrophages and Intervertebral Disc Degeneration.

The intervertebral disc (IVD) aids in motion and acts to absorb energy transmitted to the spine. With little inherent regenerative capacity, degeneration of the intervertebral disc results in intervertebral disc disease, which contributes to low back pain and significant disability in many individuals. Increasing evidence suggests that IVD degeneration is a disease of the whole joint that is associated with significant inflammation. Moreover, studies show elevated macrophage accumulation within the IVD with increasing levels of disease severity; however, we still need to understand the roles, be they causative or consequential, of macrophages during the degenerative process. In this narrative review, we discuss hallmarks of IVD degeneration, showcase evidence of macrophage involvement during disc degeneration, and explore burgeoning research aimed at understanding the molecular pathways regulating macrophage functions during intervertebral disc degeneration.

Histone Deacetylases in Bone Development and Skeletal Disorders.

Histone deacetylases (Hdacs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins. Eleven of the 18 Hdacs encoded by the human and mouse genomes depend on Zn(2+) for enzymatic activity, while the other 7, the sirtuins (Sirts), require NAD2(+). Collectively, Hdacs and Sirts regulate numerous cellular and mitochondrial processes including gene transcription, DNA repair, protein stability, cytoskeletal dynamics, and signaling pathways to affect both development and aging. Of clinical relevance, Hdacs inhibitors are United States Food and Drug Administration-approved cancer therapeutics and are candidate therapies for other common diseases including arthritis, diabetes, epilepsy, heart disease, HIV infection, neurodegeneration, and numerous aging-related disorders. Hdacs and Sirts influence skeletal development, maintenance of mineral density and bone strength by affecting intramembranous and endochondral ossification, as well as bone resorption. With few exceptions, inhibition of Hdac or Sirt activity though either loss-of-function mutations or prolonged chemical inhibition has negative and/or toxic effects on skeletal development and bone mineral density. Specifically, Hdac/Sirt suppression causes abnormalities in physiological development such as craniofacial dimorphisms, short stature, and bone fragility that are associated with several human syndromes or diseases. In contrast, activation of Sirts may protect the skeleton from aging and immobilization-related bone loss. This knowledge may prolong healthspan and prevent adverse events caused by epigenetic therapies that are entering the clinical realm at an unprecedented rate. In this review, we summarize the general properties of Hdacs/Sirts and the research that has revealed their essential functions in bone forming cells (e.g., osteoblasts and chondrocytes) and bone resorbing osteoclasts. Finally, we offer predictions on future research in this area and the utility of this knowledge for orthopedic applications and bone tissue engineering.

Concordance of Narrative Comments with Supervision Ratings Provided During Entrustable Professional Activity Assessments.

BACKGROUND: Use of EPA-based entrustment-supervision ratings to determine a learner's readiness to assume patient care responsibilities is expanding. OBJECTIVE: In this study, we investigate the correlation between narrative comments and supervision ratings assigned during ad hoc assessments of medical students' performance of EPA tasks. DESIGN: Data from assessments completed for students enrolled in the clerkship phase over 2 academic years were used to extract a stratified random sample of 100 narrative comments for review by an expert panel. PARTICIPANTS: A review panel, comprised of faculty with specific expertise related to their roles within the EPA program, provided a "gold standard" supervision rating using the comments provided by the original assessor. MAIN MEASURES: Interrater reliability (IRR) between members of review panel and correlation coefficients (CC) between expert ratings and supervision ratings from original assessors. KEY RESULTS: IRR among members of the expert panel ranged from .536 for comments associated with focused history taking to .833 for complete physical exam. CC (Kendall's correlation coefficient W) between panel members' assignment of supervision ratings and the ratings provided by the original assessors for history taking, physical examination, and oral presentation comments were .668, .697, and .735 respectively. The supervision ratings of the expert panel had the highest degree of correlation with ratings provided during assessments done by master assessors, faculty trained to assess students across clinical contexts. Correlation between supervision ratings provided with the narrative comments at the time of observation and supervision ratings assigned by the expert panel differed by clinical discipline, perhaps reflecting the value placed on, and perhaps the comfort level with, assessment of the task in a given specialty. CONCLUSIONS: To realize the full educational and catalytic effect of EPA assessments, assessors must apply established performance expectations and provide high-quality narrative comments aligned with the criteria.

Structural quality of labor and delivery care in government hospitals of Ethiopia: a descriptive analysis.

BACKGROUND: Ethiopia has low skilled birth attendance rates coupled with low quality of care within health facilities contributing to one of the highest maternal mortality rates in Sub-Saharan Africa, at 412 deaths per 100,000 live births. There is lack of evidence on the readiness of health facilities to deliver quality labor and delivery (L&D) care. This paper describes the structural quality of routine L&D care in government hospitals of Ethiopia. METHODS: A facility-based cross-sectional study design, involving census of all government hospitals in Southern Nations Nationalities and People's Region (SNNPR) (N = 20) was conducted in November 2016 through facility audit using a structured checklist. Data collectors verified the availability and functioning of the required items through observation and interview with the heads of labor and delivery case team. An overall mean score of structural quality was calculated considering domain scores such as general infrastructure, human resource and essential drugs, supplies, equipment and laboratory services. Summary statistics such as proportion, mean and standard deviation were computed to describe the degree of adherence of the hospitals to the standards related to structural quality of routine labor and delivery care. RESULTS: One third of hospitals had low readiness to provide quality routine L&D care, with only two approaching near fulfilment of all the standards. Hospitals had fulfilled 68.2% of the standards for the structural aspects of quality of L&D care. Of the facility audit criteria, the availability of essential equipment and supplies for infection prevention scored the highest (88.8%), followed by safety, comfort and woman friendliness of the environment (76.4%). Availability skilled health professionals and quality management practices scored 72.5% each, while availability of the required items of general infrastructure was 64.6%. The two critical domains with the lowest score were availability of essential drugs, supplies and equipment (52.2%); and laboratory services and safe blood supply (50%). CONCLUSION: Substantial capacity gaps were observed in the hospitals challenging the provision of quality routine L&D care services, with only two thirds of required resources available. The largest gaps were in laboratory services and safe blood, and essential drugs, supplies and equipment. The results suggest the need to ensure that all public hospitals in SNNPR meet the required structure to enable the provision of quality routine L&D care with emphases on the identified gaps.

A nutrition and lifestyle-focused shared medical appointment in a resource-challenged community setting: a mixed-methods study.

BACKGROUND: In order to address disparities in preventable chronic diseases, we adapted a nutrition and lifestyle-focused shared medical appointment (SMA) program to be delivered in an underserved community setting. The objective was to evaluate a community-based nutrition and lifestyle-focused SMA as it relates to acceptability and health and behavior-related outcomes. METHODS: A mixed-methods study was performed to evaluate pre-post changes in wellness indices, biometrics, self-efficacy, and trust in medical researchers as part of a community-based SMA. To understand program acceptability including barriers and facilitators for implementation and scalability, we conducted two participant focus groups and five stakeholder interviews and used content analysis to determine major themes. RESULTS: Fifteen participants attended 10 weekly sessions. The majority were older adult, African American women. There were pre-post improvements in mean [SD] systolic (-10.5 [7.7] mmHg, p = 0.0001) and diastolic (-4.7 [6.7] mmHg, p = 0.17) blood pressures and weight (-5.7 [6.3] pounds, p = 0.003) at 3 months though these were not significant at 6 months. More individuals reported improvements in health status, daily fruit and vegetable intake, and sleep than at baseline. There were no significant pre-post changes in other wellness indices, self-efficacy, trust in medical researchers, hemoglobin A1c, insulin, or LDL cholesterol. Participants discussed positive health changes as a result of the SMA program, program preferences, and facilitators and barriers to continuing program recommendations in focus groups. SMA implementation was facilitated by clinical staff who adjusted content to a low health literacy group and partnership with a trusted community partner. Sustainability barriers include heavy personnel time and in-kind resources to deliver the program. CONCLUSIONS: Nutrition and lifestyle-focused SMAs in a resource-challenged community setting may be an acceptable intervention for underserved patients.

Telemedicine for Preoperative Evaluation of Upper Eyelid Malposition: Reliability of Diagnosis and Surgical Plan.

PURPOSE: Outpatient visits and surgeries for nonurgent indications in ophthalmology have intermittently been restricted during the COVID-19 pandemic. Telemedicine services have rapidly gained acceptance during this period, and could improve patient access for routine oculoplastic evaluations in the future. The objective of this study is to investigate interobserver and intraobserver reliability of eyelid and brow position assessment and surgical plan when comparing photography-based and face-to-face evaluation. METHODS: This was an observational study conducted at a single academic center. Thirty randomly selected patients who had completed an in-office evaluation for chief complaint of "drooping eyelids" between June 2019 and March 2020 were included. Virtual assessment of brow position, dermatochalasis, blepharoptosis, and margin-reflex distance 1 was performed by 2 oculoplastic surgeons based on external photographs, and a surgical plan was formulated. Fraction of agreement and Cohen's κ were determined to evaluate reliability of the virtual assessment compared to face-to-face examination. RESULTS: For 60 eyes from 30 study subjects, diagnostic reliability for observer A was near perfect for brow ptosis, substantial for blepharoptosis and moderate for dermatochalasis (κ = 0.86, 0.67, and 0.57, respectively); for observer B, reliability was moderate for brow and blepharoptosis and substantial for dermatochalasis (0.47, 0.59, and 0.79). Fraction of agreement for blepharoptosis was 94% in eyes where the eyelid margin was visible, and 66% in eyes where the eyelid margin was obscured by overhanging skin. Virtual margin-reflex distance 1 measurements were highly correlated with those obtained face to face (r = 0.77, p < 0.01). Fraction of agreement for surgical plan after virtual examination by observer A/B, respectively, was 100%/94% for brow lift, 90%/87% for blepharoptosis repair and 83%/83% for functional upper blepharoplasty. CONCLUSIONS: Virtual evaluation of upper eyelid and brow malposition can be performed with acceptable reliability. Co-existing dermatochalasis or brow ptosis may require special photographic technique or video examination to ensure an appropriate diagnosis. A photography-based preliminary surgical plan offers a viable alternative to face-to-face encounters.

Endoscopic Browlift in Patients With Receding Hairlines.

ABSTRACT: Patients with receding or high hairlines have traditionally been considered unfavorable candidates for endoscopic brow lift as this can further lengthen the hairline. We analyzed outcomes in patients that underwent a novel endoscopic brow lift technique with placement of incisions and anchoring Endotine Forehead Devices (CoApt Systems Inc, Palo Alto, CA, USA) directly at the natural forehead crease lines, in an effort to minimize elevation of the hairline, whereas providing well-hidden scars. We retrospectively reviewed all patients who underwent this new Endotine and incision placement between 2016 and 2020. Preoperative and postoperative photographs of all patients were analyzed to determine the postoperative changes in brow elevation and forehead length proportion (defined as length from cranium to chin).The forehead length proportion was unchanged pre- and post-operatively, with no statistically significant differences noted (P = 0.48). The average brow position elevation ranged from 2.78 mm in the medial location to 5.05 mm in the lateral location. All patients were happy with their appearance and had improved visual fields postoperatively. The forehead scars healed well and were well hidden in forehead rhytids at long term follow-up.This novel endoscopic brow lift technique provides an option to utilize a minimally invasive approach in patients with receding hairline. With this technique, visible scars were minimized, whereas still being able to achieve reasonable brow elevation. Thus, our approach enables long term maintenance of brow elevation with inconspicuous scars in the forehead.

Musculoskeletal Development and Skeletal Pathophysiology's.

Musculoskeletal (MSK) disorders are one of the leading causes of disability for people of all ages and impart significant socio-economic burdens on society [...].

Survival benefit of pancreatic enzyme replacement therapy in patients undergoing treatment of pancreatic neuroendocrine tumours.

BACKGROUND: Treatment with somatostatin analogues (SSAs) or pancreaticoduodenectomy frequently causes malnutrition-inducing pancreatic exocrine insufficiency. This single-centre retrospective cohort study aimed to establish whether pancreatic enzyme replacement therapy (PERT) improves survival or nutritional status in SSA or pancreaticoduodenectomy-treated patients with pancreatic neuroendocrine tumours (pNETs). METHODS: SSA and/or pancreaticoduodenectomy-treated patients with pNETs, diagnosed between 2009 and 2019, (n = 77) were retrospectively identified from departmental databases. Data was sourced from clinical records. Overall survival and percentage monthly weight changes were compared between PERT-treated (n = 45) and non-PERT-treated (n = 32) patients. RESULTS: PERT-treated patients experienced significantly greater median monthly weight gain (+0.01% vs -0.10%, p = 0.038) and 5-year survival (81% vs 51%, p = 0.007). PERT was not, however, independently associated with survival (Hazard ratio 0.47, 95% CI 0.14-1.62, p = 0.232). Considering SSA-treated patients (n = 50) only, PERT-treated patients (n = 24) showed numerically but non-significantly improved monthly weight gain (+0.04% vs -0.18%, p = 0.139) and median survival (55.5, 95% CI 10.2-100.7 vs 42.4, 95% CI 11.7-73.2 months, p = 0.082). CONCLUSION: PERT may improve survival and nutrition in SSA and pancreaticoduodenectomy-treated patients with pNETs, however, low patient numbers precluded the reliable mitigation of confounding in this study. A further multi-centre study is required to define the benefits of PERT in this population.

Hdac3 regulates bone modeling by suppressing osteoclast responsiveness to RANKL.

Hdac3 is a lysine deacetylase that removes acetyl groups from histones and additional proteins. Although Hdac3 functions within mesenchymal lineage skeletal cells are defined, little is known about Hdac3 activities in bone-resorbing osteoclasts. In this study we conditionally deleted Hdac3 within Ctsk-expressing cells and examined the effects on bone modeling and osteoclast differentiation in mice. Hdac3 deficiency reduced femur and tibia periosteal circumference and increased cortical periosteal osteoclast number. Trabecular bone was likewise reduced and was accompanied by increased osteoclast number per trabecular bone surface. We previously showed that Hdac3 deacetylates the p65 subunit of the NF-κB transcriptional complex to decrease DNA-binding and transcriptional activity. Hdac3-deficient osteoclasts demonstrate increased K310 NF-κB acetylation and NF-κB transcriptional activity. Hdac3-deficient osteoclast lineage cells were hyper-responsive to RANKL and showed elevated ex vivo osteoclast number and size and enhanced bone resorption in pit formation assays. Osteoclast-directed Hdac3 deficiency decreased cortical and trabecular bone mass parameters, suggesting that Hdac3 regulates coupling of bone resorption and bone formation. We surveyed a panel of osteoclast-derived coupling factors and found that Hdac3 suppression diminished sphingosine-1-phosphate production. Osteoclast-derived sphingosine-1-phosphate acts in paracrine to promote bone mineralization. Mineralization of WT bone marrow stromal cells cultured with conditioned medium from Hdac3-deficient osteoclasts was markedly reduced. Expression of alkaline phosphatase, type 1a1 collagen, and osteocalcin was also suppressed, but no change in Runx2 expression was observed. Our results demonstrate that Hdac3 controls bone modeling by suppressing osteoclast lineage cell responsiveness to RANKL and coupling to bone formation.

Oscillatory spreading and inertia in power grids.

The increase in variable renewable generators (VRGs) in power systems has altered the dynamics from a historical experience. VRGs introduce new sources of power oscillations, and the stabilizing response provided by synchronous generators (SGs, e.g., natural gas, coal, etc.), which help avoid some power fluctuations, will lessen as VRGs replace SGs. These changes have led to the need for new methods and metrics to quickly assess the likely oscillatory behavior for a particular network without performing computationally expensive simulations. This work studies the impact of a critical dynamical parameter-the inertia value-on the rest of a power system's oscillatory response to representative VRG perturbations. We use a known localization metric in a novel way to quantify the number of nodes responding to a perturbation and the magnitude of those responses. This metric allows us to relate the spread and severity of a system's power oscillations with inertia. We find that as inertia increases, the system response to node perturbations transitions from localized (only a few close nodes respond) to delocalized (many nodes across the network respond). We introduce a heuristic computed from the network Laplacian to relate this oscillatory transition to the network structure. We show that our heuristic accurately describes the spread of oscillations for a realistic power-system test case. Using a heuristic to determine the likely oscillatory behavior of a system given a set of parameters has wide applicability in power systems, and it could decrease the computational workload of planning and operation.

Toward automated extraction and characterization of scaling regions in dynamical systems.

Scaling regions-intervals on a graph where the dependent variable depends linearly on the independent variable-abound in dynamical systems, notably in calculations of invariants like the correlation dimension or a Lyapunov exponent. In these applications, scaling regions are generally selected by hand, a process that is subjective and often challenging due to noise, algorithmic effects, and confirmation bias. In this paper, we propose an automated technique for extracting and characterizing such regions. Starting with a two-dimensional plot-e.g., the values of the correlation integral, calculated using the Grassberger-Procaccia algorithm over a range of scales-we create an ensemble of intervals by considering all possible combinations of end points, generating a distribution of slopes from least squares fits weighted by the length of the fitting line and the inverse square of the fit error. The mode of this distribution gives an estimate of the slope of the scaling region (if it exists). The end points of the intervals that correspond to the mode provide an estimate for the extent of that region. When there is no scaling region, the distributions will be wide and the resulting error estimates for the slope will be large. We demonstrate this method for computations of dimension and Lyapunov exponent for several dynamical systems and show that it can be useful in selecting values for the parameters in time-delay reconstructions.

Implementing Systematic Faculty Development to Support an EPA-Based Program of Assessment: Strategies, Outcomes, and Lessons Learned.

Problem: Development of a novel, competency-based program of assessment requires creation of a plan to measure the processes that enable successful implementation. The principles of implementation science outline the importance of considering key drivers that support and sustain transformative change within an educational program. The introduction of Entrustable Professional Activities (EPAs) as a framework for assessment has underscored the need to create a structured plan to prepare assessors to engage in a new paradigm of assessment. Although approaches to rater training for workplace-based assessments have been described, specific strategies to prepare assessors to apply standards related to the level of supervision a student needs have not been documented. Intervention: We describe our systematic approach to prepare assessors, faculty and postgraduate trainees, to complete EPA assessments for medical students during the clerkship phase of our curriculum. This institution-wide program is designed to build assessors' skills in direct observation of learners during authentic patient encounters. Assessors apply new knowledge and practice skills in using established performance expectations to determine the level of supervision a learner needs to perform clinical tasks. Assessors also learn to provide feedback and narrative comments to coach students and promote their ongoing clinical development. Data visualizations for assessors facilitate reinforcement of the tenets learned during training. Collaborative learning and peer feedback during faculty development sessions promote the formation of a community of practice among assessors. Context: Faculty development for assessors was implemented in advance of implementation of the EPA program. Assessors in the program include residents/fellows who work closely with students, faculty with discipline-specific expertise and a group of experienced clinicians who were selected to serve as experts in competency-based EPA assessments, the Master Assessors. Training focused on creating a shared understanding about the application of criteria used to evaluate student performance. EPA assessments based on the AAMC's Core Entrustable Professional Activities for Entering Residency, were completed in nine core clerkships. EPA assessments included a supervision rating based on a modified scale for use in undergraduate medical education. Impact: Data from EPA assessments completed during the first year of the program were analyzed to evaluate the effectiveness of the faculty development activities implemented to prepare assessors to consistently apply standards for assessment. A systematic approach to training and attention to critical drivers that enabled institution-wide implementation, led to consistency in the supervision rating for students' first EPA assessment completed by any type of assessor, ratings by assessors done within a specific clinical context, and ratings assigned by a group of specific assessors across clinical settings. Lessons learned: A systematic approach to faculty development with a willingness to be flexible and reach potential participants using existing infrastructure, can facilitate assessors' engagement in a new culture of assessment. Interaction among participants during training sessions not only promotes learning but also contributes to community building. A leadership group responsible to oversee faculty development can ensure that the needs of stakeholders are addressed and that a change in assessment culture is sustained.