Leveraging faculty development to support validation of entrustable professional activities assessment tools in anatomic and clinical pathology training.

Entrustable professional activities (EPAs) are observable activities that define the practice of medicine and provide a framework of evaluation that has been incorporated into US medical school curricula in both undergraduate and graduate medical education. This manuscript describes the development of an entrustment scale and formative and summative evaluations for pathology EPAs, outlines a process for faculty development that was employed in a pilot study implementing two Anatomic Pathology and two Clinical Pathology EPAs in volunteer pathology residency programs, and provides initial validation data for the proposed pathology entrustment scales. Prior to implementation, faculty development was necessary to train faculty on the entrustment scale for each given activity. A "train the trainer" model used performance dimension training and frame of reference training to train key faculty at each institution. The session utilized vignettes to practice determination of entrustment ratings and development of feedback for trainees as to strengths and weaknesses in the performance of these activities. Validity of the entrustment scale is discussed using the Messick framework, based on concepts of content, response process, and internal structure. This model of entrustment scales, formative and summative assessments, and faculty development can be utilized for any pathology EPA and provides a roadmap for programs to design and implement EPA assessments into pathology residency training.

National pilot of entrustable professional activities in pathology residency training.

Entrustable professional activities (EPAs) are observable clinical skills and/or procedures that have been introduced into medical education at the student and resident levels in most specialties to determine readiness to advance into residency or independent practice, respectively. This publication describes the process and outcomes of a pilot study looking at the feasibility of using two anatomic pathology and two clinical pathology EPAs in pathology residency in 6 pathology residency programs that volunteered for the study. Faculty development on EPAs and their assessment was provided to pilot program faculty, and EPA assessment tools were developed and used by the pilot programs. Pre- and post-study surveys were given to participating residents, faculty, and program directors to gauge baseline practices and to gather feedback on the EPA implementation experience. Results demonstrated overall good feasibility in implementing EPAs. Faculty acceptance of EPAs varied and was less than that of program directors. Residents reported a significant increase in the frequency with which faculty provided formative assessments that included specific examples of performance and specific ways to improve, as well as increased frequency with which faculty provided summative assessments that included specific ways to improve. EPAs offered the most benefit in setting clear expectations for performance of each task, for providing more specific feedback to residents, and in increasing Program director's understanding of resident strengths abilities and weaknesses.

Fluorescence Lifetime Imaging of Human Retinal Pigment Epithelium in Pentosan Polysulfate Toxicity Using Adaptive Optics Scanning Light Ophthalmoscopy.

Purpose: Fluorescence lifetime ophthalmoscopy (FLIO) is an emerging clinical modality that could provide biomarkers of retinal health beyond fluorescence intensity. Adaptive optics (AO) ophthalmoscopy provides the confocality to measure fluorescence lifetime (FL) primarily from the retinal pigment epithelium (RPE) whereas clinical FLIO has greater influence from fluorophores in the inner retina and lens. Adaptive optics fluorescence lifetime ophthalmoscopy (AOFLIO) measures of FL in vivo could provide insight into RPE health at different stages of disease. In this study, we assess changes in pentosan polysulfate sodium (PPS) toxicity, a recently described toxicity that has clinical findings similar to advanced age-related macular degeneration. Methods: AOFLIO was performed on three subjects with PPS toxicity (57-67 years old) and six age-matched controls (50-64 years old). FL was analyzed with a double exponential decay curve fit and with phasor analysis. Regions of interest (ROIs) were subcategorized based on retinal features on optical coherence tomography (OCT) and compared to age-matched controls. Results: Twelve ROIs from PPS toxicity subjects met the threshold for analysis by curve fitting and 15 ROIs met the threshold for phasor analysis. Subjects with PPS toxicity had prolonged FL compared to age-matched controls. ROIs of RPE degeneration had the longest FLs, with individual pixels extending longer than 900 ps. Conclusions: Our study shows evidence that AOFLIO can provide meaningful information in outer retinal disease beyond what is obtainable from fluorescence intensity alone. More studies are needed to determine the prognostic value of AOFLIO.

Continued Positive Job Search Experience for New Pathologists Seeking First Employment During the COVID-19 Pandemic (2020-2022).

CONTEXT.­: As pathologists retire and leave the field, it is critical to accurately capture employment trends for new-in-practice pathologists. There is always interest in the job market for newly graduated pathology trainees and prospective pathology trainees, but it is unclear how the COVID-19 pandemic may have affected the job search experience. OBJECTIVE.­: To provide an update on trends gleaned from a survey of pathology graduates' job search experiences during the COVID-19 pandemic. DESIGN.­: We analyzed data from an annual job search survey sent by the College of American Pathologists Graduate Medical Education Committee between 2020 and 2022 to College of American Pathologists junior members and fellows in practice 3 years or less actively looking for a nonfellowship position. Various indicators of the job search experience were compared year to year and with the data previously published 2017 to 2019 and 2012 to 2016. RESULTS.­: Analysis revealed continued positive trends between the 2020 to 2022 data and the data from 2017 to 2019 and 2012 to 2016. This includes continued ease in finding positions, continued availability of jobs in the subspecialty of choice, continued satisfaction with the positions accepted, and, notably, higher starting salaries. CONCLUSIONS.­: Despite the many challenges of the COVID-19 pandemic, job market trends for newly graduated pathology trainees continue to be favorable with respect to multiple indicators compared with 2 prior periods, 2017 to 2019 and 2012 to 2016.

Leadership perspectives on osteopathic medical school applicants to pathology residency training.

The number of graduating allopathic (MD) medical students matching into pathology has declined in recent years, while the number of osteopathic (DO) medical students has increased modestly, given the rapid expansion of osteopathic medical schools. Nonscholarly publications and materials on the internet often perpetuate negative perceptions of osteopathic physicians. Anecdotally, perspectives exist that some pathology residency programs are not DO-friendly; however, the reasons and how widespread an effect this might be are unclear. Our survey queried pathology chairs and residency program directors about their perceptions of osteopathic applicants and their knowledge of osteopathic medical school/training in general. This study utilized two similar, parallel surveys of pathology chairs and residency program directors with general questions structured around the perceptions and knowledge of both allopathic and osteopathic physicians, their medical training, and the consideration of osteopathic applicants to pathology residency. Pathology residency leaders acknowledge some negative perceptions of osteopathic physicians in the medical profession, the news, and social media. They also have some knowledge and perception gaps regarding osteopathic training and applicants, although experience with training osteopathic physicians as residents has been equivalent to that with allopathic physicians, and consideration appears to be fairly equal for osteopathic applicants. Even though negative perceptions of osteopathic physicians persist in news and social media, our surveys demonstrate that the leadership of pathology residency programs does not hold the same degree of bias and that DOs perform well in allopathic pathology residency programs without evidence of inferior outcomes.

Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor.

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC50: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.

PI(4,5)P2 binding sites in the Ebola virus matrix protein VP40 modulate assembly and budding.

Ebola virus (EBOV) causes severe hemorrhagic fever in humans and is lethal in a large percentage of those infected. The EBOV matrix protein viral protein 40 kDa (VP40) is a peripheral binding protein that forms a shell beneath the lipid bilayer in virions and virus-like particles (VLPs). VP40 is required for virus assembly and budding from the host cell plasma membrane. VP40 is a dimer that can rearrange into oligomers at the plasma membrane interface, but it is unclear how these structures form and how they are stabilized. We therefore investigated the ability of VP40 to form stable oligomers using in vitro and cellular assays. We characterized two lysine-rich regions in the VP40 C-terminal domain (CTD) that bind phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) and play distinct roles in lipid binding and the assembly of the EBOV matrix layer. The extensive analysis of VP40 with and without lipids by hydrogen deuterium exchange mass spectrometry revealed that VP40 oligomers become extremely stable when VP40 binds PI(4,5)P2. The PI(4,5)P2-induced stability of VP40 dimers and oligomers is a critical factor in VP40 oligomerization and release of VLPs from the plasma membrane. The two lysine-rich regions of the VP40 CTD have different roles with respect to interactions with plasma membrane phosphatidylserine (PS) and PI(4,5)P2. CTD region 1 (Lys221, Lys224, and Lys225) interacts with PI(4,5)P2 more favorably than PS and is important for VP40 extent of oligomerization. In contrast, region 2 (Lys270, Lys274, Lys275, and Lys279) mediates VP40 oligomer stability via lipid interactions and has a more prominent role in release of VLPs.

Pharmacological inhibition of CLK2 activates YAP by promoting alternative splicing of AMOTL2.

Yes-associated protein (YAP), the downstream effector of the evolutionarily conserved Hippo pathway, promotes cellular proliferation and coordinates certain regenerative responses in mammals. Small molecule activators of YAP may, therefore, display therapeutic utility in treating disease states involving insufficient proliferative repair. From a high-throughput chemical screen of the comprehensive drug repurposing library ReFRAME, here we report the identification of SM04690, a clinical stage inhibitor of CLK2, as a potent activator of YAP-driven transcriptional activity in cells. CLK2 inhibition promotes alternative splicing of the Hippo pathway protein AMOTL2, producing an exon-skipped gene product that can no longer associate with membrane-bound proteins, resulting in decreased phosphorylation and membrane localization of YAP. This study reveals a novel mechanism by which pharmacological perturbation of alternative splicing inactivates the Hippo pathway and promotes YAP-dependent cellular growth.

Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis.

Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds. High-throughput screening (HTS) with 11,948 clinical-stage compounds was performed using a reporter cell line detecting endogenous KLF4 activation. Eighteen compounds were identified through the HTS and confirmed in a secondary screen. After testing in SW1353 chondrosarcoma cells and human chondrocytes, mocetinostat - a class I selective histone deacetylase (HDAC) inhibitor - had the best profile of biological activities. Mocetinostat upregulated cartilage signature genes in human chondrocytes, meniscal cells, and BM-derived mesenchymal stem cells, and it downregulated hypertrophic, inflammatory, and catabolic genes in those cells and synoviocytes. I.p. administration of mocetinostat into mice reduced severity of OA-associated changes and improved pain behaviors. Global gene expression and proteomics analyses revealed that regenerative and protective effects of mocetinostat were dependent on peroxisome proliferator-activated receptor γ coactivator 1-α. These findings show therapeutic and protective activities of mocetinostat against OA, qualifying it as a candidate to be used as a DMOAD.

Pharmacological inhibition of CLK2 activates YAP by promoting alternative splicing of AMOTL2.

Yes-associated protein (YAP), the downstream effector of the evolutionarily conserved Hippo pathway, promotes cellular proliferation and coordinates certain regenerative responses in mammals. Small molecule activators of YAP may therefore display therapeutic utility in treating disease states involving insufficient proliferative repair. From a high-throughput chemical screen of the comprehensive drug repurposing library ReFRAME, here we report the identification of SM04690, a clinical stage inhibitor of CLK2, as a potent activator of YAP driven transcriptional activity in cells. CLK2 inhibition promotes alternative splicing of the Hippo pathway protein AMOTL2, producing an exon-skipped gene product that can no longer associate with membrane-bound proteins, resulting in decreased phosphorylation and membrane localization of YAP. This study reveals a novel mechanism by which pharmacological perturbation of alternative splicing inactivates the Hippo pathway and promotes YAP dependent cellular growth.

Experiential exposure as the key to recruiting medical students into pathology.

Medical student interest and pursuit of a career in pathology have been steadily declining since 2015. We conducted three separate surveys of medical students to better understand these trends. In our first survey, we focused on assessing U.S. allopathic medical students understanding and perceptions of pathology. We later surveyed U.S. osteopathic medical students as a companion to the allopathic medical student survey, in which many similarities were discovered with some key differences. In our final survey, we specifically looked at curriculum differences between the U.S. allopathic medical schools that graduate the most students who enter pathology training programs (Group 1) versus those schools that graduate the fewest future pathologists (Group 2) to determine if the curriculum had an impact on medical student matriculation into pathology. Together, through these surveys, we were able to identify several remarkable recurring trends, presenting areas of targetable action. Here, we summarize themes from the three studies as well as a review of pertinent literature to offer best practices for exposing and engaging medical students to pathology and possibly recruiting students to consider pathology as a career.

How influential are medical school curriculum and other medical school characteristics in students' selecting pathology as a specialty?

There has been a significant decline in the number of United States allopathic medical students matching to pathology residency programs. Data acquired from the American Association of Medical Colleges (AAMC) show sustained variation in the medical school production of students who go on to pathology residency. When divided into groups based on the medical school's historical volume of graduates entering pathology, the schools in groups labeled Group 1 and Group 2 produced significantly higher and lower proportions of pathology residents, respectively. This study aimed to identify what medical school curriculum elements and other medical school characteristics might explain the differences observed in the AAMC data. The Dean or another undergraduate medical education contact from the Group 1 and Group 2 schools was invited to participate in an interview. Pathology Program Directors and Pathology Department Chairs were also included in communications. Thirty interviews were completed with equal numbers from each group. Interview questions probed pathology experiences, existence, and structure of a pathology interest group, options for post-sophomore fellowships, recent curriculum changes, and the extent of mentoring programs. Surprisingly, the curriculum does not appear to be a predictor of a medical school's production of students who enter pathology residency. A significantly greater percentage of Group 1 schools are public institutions compared to Group 2 schools. Other factors that may increase the number of students who go into pathology include mentoring, active learning versus observation, and post-sophomore fellowships or other opportunities to work in the capacity of a new pathology resident.

Reducing Gadolinium Exposure in Patients Undergoing Monitoring for Meningiomas.

Background Due to the non-malignant and slow-growing nature of many meningiomas, surveillance with serial magnetic resonance imaging (MRI) serves as an acceptable management plan. However, repeated imaging with gold-standard contrast-based studies may lead to contrast-associated adverse effects. Non-gadolinium T2 sequences may serve as a suitable alternative without the risk of adverse effects of contrast. Thus, this study sought to investigate the agreement between post-contrast T1 and non-gadolinium T2 MRI sequences in the measurement of meningioma growth. Methodology The Virginia Commonwealth University School of Medicine (VCU SOM) brain tumor database was used to create a cohort of meningioma patients and determine the number of patients who had T1 post-contrast imaging accompanied by readily measurable imaging from either T2 fast spin echo (FSE) or T2 fluid-attenuated inversion recovery (FLAIR) sequences. Measurements of the largest axial and perpendicular diameters of each tumor were conducted by two independent observers using T1 post-contrast, T2 FSE, and T2 FLAIR imaging series. Lin's concordance correlation coefficient (CCC) was calculated to assess inter-rater reliability between observers and agreement between measurements of tumor diameter among the different imaging sequences. Results In total, 33 patients (average age = 72.1 ± 12.9 years, 90% female) with meningiomas were extracted from our database, with 22 (66.7%) undergoing T1 post-contrast imaging accompanied with readily measurable imaging from T2 FSE and/or T2 FLAIR sequences. The inter-rater reliability between the measurements of T1 axial and perpendicular diameters was 0.96 (95% confidence interval (CI) = 0.92-0.98) and 0.92 (95% CI = 0.83-0.97), respectively. The inter-rater reliability between the measurements of T2 axial perpendicular diameters was 0.93 (95% = CI 0.92-0.97) and 0.89 (95% CI = 0.74-0.95), respectively. The agreements between the measurement of T1 and T2 FSE axial diameter by each observer were 0.97 (95% CI = 0.93-0.98) and 0.92 (95% CI = 0.81-0.97). The agreements between the measurements of T1 and T2 FSE perpendicular diameter measurements by each observer were 0.98 (95% CI = 0.95-0.99) and 0.88 (95% CI = 0.73-0.95). Conclusions Two-thirds of our patients had meningiomas that were readily measurable on either T2 FSE or T2 FLAIR sequences. Additionally, there was excellent inter-rater reliability between the observers in our study as well as an agreement between individual measurements of T1 post-contrast and T2 FSE tumor diameters. These findings suggest that T2 FSE may serve as a safe and similarly effective surveillance method for the long-term management of meningioma patients.

Erratum: Adaptive optics fluorescence lifetime imaging ophthalmoscopy of in vivo human retinal pigment epithelium: erratum.

[This corrects the article on p. 1737 in vol. 13, PMID: 35414970.].

The Type I Interferon Signature Reflects Multiple Phenotypic and Activity Measures in Dermatomyositis.

OBJECTIVE: The type 1 interferon (IFN) pathway is up-regulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic type I IFN activity in adult patients with DM. METHODS: RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed up during the course of their clinical care. A previously defined 13-gene type I IFN score was modeled as a function of demographic, serologic, and clinical variables using both cross-sectional and longitudinal data. RESULTS: The pattern of type I IFN-driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to systemic lupus erythematosus. The median type I IFN score was higher or lower in patients with anti-melanoma differentiation-associated protein 5 (anti-MDA-5) or anti-Mi-2 antibodies, respectively, compared to patients without these antibodies. Absolute type I IFN score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti-MDA-5 antibodies. Changes in the type I IFN score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation between changes in the type I IFN score and skin disease activity (Spearman's ρ = 0.84-0.95). CONCLUSION: The type I IFN score is independently associated with skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti-MDA-5 status revealed that the type I IFN score is strongly correlated with skin disease activity, providing support for type I IFN blockade as a therapeutic strategy for DM.

Working With Rural Producers to Expand EBT in Farmers' Markets: A Case Study in Hardeman County, Tennessee.

Rural residents tend to eat less fruits and vegetables, placing them at higher risk of chronic diseases compared with urban residents. Farmers' markets can provide increased access to fresh produce for rural communities. Encouraging markets to accept Supplemental Nutrition Assistance Program (SNAP) benefits through Electronic Benefit Transfer (EBT) can expand access to healthy foods to low-income residents. Rural markets are less likely to accept SNAP compared with urban markets. Rural producers have identified lack of knowledge and limited support about the application process as barriers for accepting SNAP. This case study details how our Extension program helped a rural producer through the SNAP application process. We started with a workshop to inform rural producers about the benefits of accepting SNAP. After the workshop, we provided hands-on support and assistance to help one producer navigate the EBT application process as well as how to implement and advertise SNAP at the market. Implications for practitioners about tips to help producers overcome challenges and barriers for EBT acceptance are discussed.

Ras-dependent activation of BMAL2 regulates hypoxic metabolism in pancreatic cancer.

To identify novel drivers of malignancy in pancreatic ductal adenocarcinoma (PDAC), we employed regulatory network analysis, which calculates the activity of transcription factors and other regulatory proteins based on the integrated expression of their positive and negative target genes. We generated a regulatory network for the malignant epithelial cells of human PDAC using gene expression data from a set of 197 laser capture microdissected human PDAC samples and 45 low-grade precursors, for which we had matched histopathological, clinical, and epidemiological annotation. We then identified the most highly activated and repressed regulatory proteins (e.g. master regulators or MRs) associated with four malignancy phenotypes: precursors vs. PDAC (initiation), low-grade vs. high grade histopathology (progression), survival post resection, and association with KRAS activity. Integrating across these phenotypes, the top MR of PDAC malignancy was found to be BMAL2, a member of the PAS family of bHLH transcription factors. Although the canonical function of BMAL2 is linked to the circadian rhythm protein CLOCK, annotation of BMAL2 target genes highlighted a potential role in hypoxia response. We previously demonstrated that PDAC is hypovascularized and hypoperfused, and here show that PDAC from the genetically engineered KPC model exists in a state of extreme hypoxia, with a partial oxygen pressure of <1mmHg. Given the close homology of BMAL2 to HIF1ß (ARNT) and its potential to heterodimerize with HIF1A and HIF2A, we investigated whether BMAL2 plays a role in the hypoxic response of PDAC. Indeed, BMAL2 controlled numerous hypoxia response genes and could be inhibited following treatment with multiple RAF, MEK, and ERK inhibitors, validating its association with RAS activity. Knockout of BMAL2 in four human PDAC cell lines led to defects in growth and invasion in the setting of hypoxia. Strikingly, BMAL2 null cells failed to induce glycolysis upon exposure to severe hypoxia and this was associated with a loss of expression of the glycolytic enzyme LDHA. Moreover, HIF1A was no longer stabilized under hypoxia in BMAL2 knockout cells. By contrast, HIF2A was hyper-stabilized under hypoxia, indicating a dysregulation of hypoxia metabolism in response to BMAL2 loss. We conclude that BMAL2 is a master regulator of hypoxic metabolism in PDAC, serving as a molecular switch between the disparate metabolic roles of HIF1A- and HIF2A-dependent hypoxia responses.

A concerted mechanism involving ACAT and SREBPs by which oxysterols deplete accessible cholesterol to restrict microbial infection.

Most of the cholesterol in the plasma membranes (PMs) of animal cells is sequestered through interactions with phospholipids and transmembrane domains of proteins. However, as cholesterol concentration rises above the PM's sequestration capacity, a new pool of cholesterol, called accessible cholesterol, emerges. The transport of accessible cholesterol between the PM and the endoplasmic reticulum (ER) is critical to maintain cholesterol homeostasis. This pathway has also been implicated in the suppression of both bacterial and viral pathogens by immunomodulatory oxysterols. Here, we describe a mechanism of depletion of accessible cholesterol from PMs by the oxysterol 25-hydroxycholesterol (25HC). We show that 25HC-mediated activation of acyl coenzyme A: cholesterol acyltransferase (ACAT) in the ER creates an imbalance in the equilibrium distribution of accessible cholesterol between the ER and PM. This imbalance triggers the rapid internalization of accessible cholesterol from the PM, and this depletion is sustained for long periods of time through 25HC-mediated suppression of SREBPs and continued activation of ACAT. In support of a physiological role for this mechanism, 25HC failed to suppress Zika virus and human coronavirus infection in ACAT-deficient cells, and Listeria monocytogenes infection in ACAT-deficient cells and mice. We propose that selective depletion of accessible PM cholesterol triggered by ACAT activation and sustained through SREBP suppression underpins the immunological activities of 25HC and a functionally related class of oxysterols.

Targeting FoxO transcription factors with HDAC inhibitors for the treatment of osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) features ageing-related defects in cellular homeostasis mechanisms in articular cartilage. These defects are associated with suppression of forkhead box O (FoxO) transcription factors. FoxO1 or FoxO3 deficient mice show early onset OA while FoxO1 protects against oxidative stress in chondrocytes and promotes expression of autophagy genes and the essential joint lubricant proteoglycan 4 (PRG4). The objective of this study was to identify small molecules that can increase FoxO1 expression. METHODS: We constructed a reporter cell line with FoxO1 promoter sequences and performed high-throughput screening (HTS) of the Repurposing, Focused Rescue and Accelerated Medchem (ReFRAME) library . Hits from the HTS were validated and function was assessed in human chondrocytes, meniscus cells and synoviocytes and following administration to mice. The most promising hit, the histone deacetylase inhibitor (HDACI) panobinostat was tested in a murine OA model. RESULTS: Among the top hits were HDACI and testing in human chondrocytes, meniscus cells and synoviocytes showed that panobinostat was the most promising compound as it increased the expression of autophagy genes and PRG4 while suppressing the basal and IL-1ß induced expression of inflammatory mediators and extracellular matrix degrading enzymes. Intraperitoneal administration of panobinostat also suppressed the expression of mediators of OA pathogenesis induced by intra-articular injection of IL-1ß. In a murine OA model, panobinostat reduced the severity of histological changes in cartilage, synovium and subchondral bone and improved pain behaviours. CONCLUSION: Panobinostat has a clinically relevant activity profile and is a candidate for OA symptom and structure modification.

Balance Confidence and Balance Performance, But Not Fall History Are Associated With Quality of Life in Community-Dwelling Older Adults: A Cross Sectional Study.

BACKGROUND AND PURPOSE: Fear of falling (FoF) is highly prevalent in community-dwelling older adults and is associated with low health-related quality of life (QoL). Low QoL is associated with increased health care utilization and is a predictor of future falls, but few studies have examined the relationship between high-level balance and dynamic gait performance and QoL in community-dwelling older adults. The purpose of this cross-sectional study was to determine whether there is a relationship between FoF avoidance behaviors, balance confidence, performance on measures of high-level mobility, and QoL in community-dwelling older adults. The secondary purpose was to determine whether older adults who fall have a different QoL than older adults who have not fallen in the past year. METHODS: Eighty-nine community-dwelling older adults (76.33 ± 6.84 years, 54 female, 34 fallers) completed the World Health Organization Quality of Life-BREF (WHOQOL-BREF), Activities-specific Balance Confidence Scale (ABC), Fear of Falling Avoidance Behavior Questionnaire (FFABQ), Functional Gait Assessment (FGA), and Community Balance and Mobility Scale (CB&M). Correlation and multiple regression analyses were calculated to determine the relationship between the outcome measures and domains on the WHOQOL-BREF. RESULTS AND DISCUSSION: Significant correlations were observed between the WHOQOL-BREF physical health domain and the ABC, FFABQ, FGA, and CB&M (ρ= 0.524, -0.509, 0.348, and r = 0.423, respectively), the WHOQOL-BREF psychological domain and the ABC (ρ= 0.284) and FFABQ (ρ=-0.384), and the WHOQOL-BREF environment domain and the ABC (ρ= 0.343) and FFABQ (ρ=-0.406). No correlations were found between WHOQOL-BREF domain scores and a history of falls. CONCLUSIONS: Performance-based outcome measures that measure high-level mobility such as the CB&M and FGA, and patient-reported outcome measures for balance confidence and FoF avoidance behavior such as the ABC and FFABQ, are correlated with the physical health QoL domain on the WHOQOL-BREF. The ABC and FFABQ are correlated with psychological and environment QoL. Fall history was not correlated with QoL. Interventions to decrease FoF or improve high-level mobility may improve QoL in community-dwelling older adults.