Implementing an osteoarthritis management program to deliver guideline-driven care for knee and hip osteoarthritis in a U.S. academic health system.

Objective: Assess implementation feasibility and outcomes for an Osteoarthritis Management Program (OAMP) at an academic center. Design: This open study assessed an OAMP designed to deliver care in 1-5 individual or group visits across ≤12 months. Eligibility included adults with knee or hip osteoarthritis with ≥1 visit from 7/1/2017-1/15/2021. A multidisciplinary care team provided: education on osteoarthritis, self-management, exercise, weight loss; pharmacologic management; assessments of mood, sleep, quality of life, and diet. Clinic utilization and growth are reported through 2022. Patient outcomes of body mass index (BMI), pain, and function were analyzed using multivariable general linear models. OAMP outcomes were feasibility and sustainability. Results: Most patients were locally referred by primary care. 953 patients attended 2531 visits (average visits 2.16, treatment duration 187.9 days). Most were female (72.6%), older (62.1), white (91.1%), and had medical insurance (95.4%). Obesity was prevalent (84.7% BMI ≥30, average BMI 40.9), mean Charlson Comorbidity Index was 1.89, and functional testing was below average. Longitudinal modeling revealed statistically but not clinically significant pain reduction (4.4-3.9 on 0-10 scale, p â€‹= â€‹0.002). BMI did not significantly change (p â€‹= â€‹0.87). Higher baseline pain and BMI correlated with greater reductions in each posttreatment. Uninsured patients had shorter treatment duration. Increasing clinic hours (4-24 â€‹h weekly) and serving 953 patients over four years demonstrated OAMP sustainability. Conclusions: OAMP implementation was feasible and sustainable. Patients with high baseline pain and BMI were more likely to improve. Noninsurance was a barrier. These results contribute to understanding OAMP outcomes in U.S. healthcare.

Hydrogen/Deuterium Exchange Mass Spectrometry Provides Insights into the Role of Drosophila Testis-Specific Myosin VI Light Chain AndroCaM.

In Drosophila testis, myosin VI plays a special role, distinct from its motor function, by anchoring components to the unusual actin-based structures (cones) that are required for spermatid individualization. For this, the two calmodulin (CaM) light-chain molecules of myosin VI are replaced by androcam (ACaM), a related protein with 67% identity to CaM. Although ACaM has a similar bi-lobed structure to CaM, with two EF hand-type Ca2+ binding sites per lobe, only one functional Ca2+ binding site operates in the amino-terminus. To understand this light chain substitution, we used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to examine dynamic changes in ACaM and CaM upon Ca2+ binding and interaction with the two CaM binding motifs of myosin VI (insert2 and IQ motif). HDX-MS reveals that binding of Ca2+ to ACaM destabilizes its N-lobe but stabilizes the entire C-lobe, whereas for CaM, Ca2+ binding induces a pattern of alternating stabilization/destabilization throughout. The conformation of this stable holo-C-lobe of ACaM seems to be a "prefigured" version of the conformation adopted by the holo-C-lobe of CaM for binding to insert2 and the IQ motif of myosin VI. Strikingly, the interaction of holo-ACaM with either peptide converts the holo-N-lobe to its Ca2+-free, more stable, form. Thus, ACaM in vivo should bind the myosin VI light chain sites in an apo-N-lobe/holo-C-lobe state that cannot fulfill the Ca2+-related functions of holo-CaM required for myosin VI motor assembly and activity. These findings indicate that inhibition of myosin VI motor activity is a precondition for transition to an anchoring function.

Deficits in basal and evoked striatal dopamine release following alpha-synuclein preformed fibril injection: An in vivo microdialysis study.

Parkinson's disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) protein, forming intraneuronal Lewy body (LB) inclusions. The α-syn preformed fibril (PFF) model of PD recapitulates α-syn aggregation, progressive nigrostriatal degeneration and motor dysfunction; however, little is known about the time course of PFF-induced alterations in basal and evoked dopamine (DA). In vivo microdialysis is well suited for identifying small changes in neurotransmitter levels over extended periods. In the present study, adult male Fischer 344 rats received unilateral, intrastriatal injections of either α-syn PFFs or phosphate-buffered saline (PBS). At 4 or 8 months post-injection (p.i.), animals underwent in vivo microdialysis to evaluate basal extracellular striatal DA and metabolite levels, local KCl-evoked striatal DA release and the effects of systemic levodopa (l-DOPA). Post-mortem analysis demonstrated equivalent PFF-induced reductions in tyrosine hydroxylase (TH) immunoreactive nigral neurons (~50%) and striatal TH (~20%) at both time points. Compared with reduction in striatal TH, reduction in striatal dopamine transporter (DAT) was more pronounced and progressed between the 4- and 8-month p.i. intervals (36% âž” 46%). Significant PFF-induced deficits in basal and evoked striatal DA, as well as deficits in motor performance, were not observed until 8 months p.i. Responses to l-DOPA did not differ regardless of PBS or PFF treatment. These results suggest that basal and evoked striatal DA are maintained for several months following PFF injection, with loss of both associated with motor dysfunction. Our studies provide insight into the time course and magnitude of PFF-induced extracellular dopaminergic deficits in the striatum.

Transcriptomic profiling of early synucleinopathy in rats induced with preformed fibrils.

Examination of early phases of synucleinopathy when inclusions are present, but long before neurodegeneration occurs, is critical to both understanding disease progression and the development of disease modifying therapies. The rat alpha-synuclein (α-syn) preformed fibril (PFF) model induces synchronized synucleinopathy that recapitulates the pathological features of Parkinson's disease (PD) and can be used to study synucleinopathy progression. In this model, phosphorylated α-syn (pSyn) inclusion-containing neurons and reactive microglia (major histocompatibility complex-II immunoreactive) peak in the substantia nigra pars compacta (SNpc) months before appreciable neurodegeneration. However, it remains unclear which specific genes are driving these phenotypic changes. To identify transcriptional changes associated with early synucleinopathy, we used laser capture microdissection of the SNpc paired with RNA sequencing (RNASeq). Precision collection of the SNpc allowed for the assessment of differential transcript expression in the nigral dopamine neurons and proximal glia. Transcripts upregulated in early synucleinopathy were mainly associated with an immune response, whereas transcripts downregulated were associated with neurotransmission and the dopamine pathway. A subset of 29 transcripts associated with neurotransmission/vesicular release and the dopamine pathway were verified in a separate cohort of males and females to confirm reproducibility. Within this subset, fluorescent in situ hybridization (FISH) was used to localize decreases in the Syt1 and Slc6a3 transcripts to pSyn inclusion-containing neurons. Identification of transcriptional changes in early synucleinopathy provides insight into the molecular mechanisms driving neurodegeneration.

Development and Implementation of a Medical School Course Integrating Basic, Clinical, and Health Systems Sciences.

OBJECTIVE: In recent years, significant steps have been made in integrating basic science and clinical medicine. There remains a gap in adding the third pillar of education: health systems science (HSS). Core clerkships represent an ideal learning venue to integrate all three. Students can experience the value of integrating basic science as they learn clinical medicine in environments where HSS is occurring all around them. METHODS: We outline the creation of Sciences and Art of Medicine Integrated (SAMI), a course that runs parallel with the clerkship year and integrates basic science and HSS with clinical medicine. A complete description of the planning and implementation of SAMI is provided. We include the participants and educational setting, the goals and objectives, and the structure of each session. To encourage the integration of basic science, HSS, and clinical medicine, students utilize a series of tools, described in detail. Examples of each tool are provided utilizing a case of a patient presenting with obstructive sleep apnea. RESULTS: We successfully implemented this course with positive reception from students. CONCLUSION: This course represents a step not only toward the integration of HSS with basic science and clinical medicine but also an advancement in training future clinicians to provide high-value care. Future curricular development must consider the validation of a measure of clinical reasoning that assesses a student's ability to think in a cognitively integrated fashion about basic science, HSS, and clinical medicine demonstrated by enhanced justification of clinical reasoning and a more holistic approach to planning patient care.

Assessing the feasibility of an intervention for adolescents and parents transitioning out of paediatric eating disorder services: A mixed methods study.

OBJECTIVE: To assess the feasibility of a new intervention designed to support adolescents and parents in the transition from paediatric eating disorder (ED) treatment to adult mental health services. METHOD: Pre-transition adolescents with EDs, and their parents, were invited to complete up to five transition intervention components over 3 months. A mixed methods design was used to assess intervention feasibility, comprised of acceptability and preliminary effectiveness. A single-arm pre-post design was used to collect and analyse quantitative survey and feasibility data. Individual qualitative interviews and written reflections were collected and analysed using content analysis. RESULTS: This study yielded a 33% (10/31) recruitment rate and 68% (13/19) retention rate. On average, participants completed 75% of the expected components in under 3 months, with varied completion of each expected intervention component (40%-100%). Participants found the intervention convenient and helpful. Parents reported a significant decrease in guilt (Z = -2.02, p = 0.04, d = -0.83). By 1-month post-transition, three adolescents transitioned to interim supports and none started specialist adult treatment. CONCLUSIONS: Although this transition intervention did not demonstrate adequate feasibility, its acceptability and effectiveness should be evaluated after an update based on participant feedback. Other solutions to bridge the transition gap for adolescents with EDs should continue to be identified. CLINICAL TRIAL REGISTRATION NUMBER: NCT04888273.

Assessing the Genomic Landscape of Cervical Cancers: Clinical Opportunities and Therapeutic Targets.

PURPOSE: Tumor genomic profiling is increasingly used to guide treatment strategy in patients with cancer. We integrated tumor genomic, clinical demographic, and treatment response data to assess how prospective tumor-normal sequencing impacted treatment selection in patients with cervical cancer. EXPERIMENTAL DESIGN: Cervical cancers were prospectively analyzed using the MSK-IMPACT (Memorial Sloan Kettering Cancer Center - Integrated Mutation Profiling of Actionable Cancer Targets) next-generation sequencing panel. Clinical data, including histology, stage at diagnosis, treatment history, clinical trial enrollment and outcomes, date of last follow-up, and survival status were obtained from medical records. RESULTS: A total of 177 patients with cervical cancer (squamous, 69; endocervical adenocarcinoma, 50; gastric type, 22; adenosquamous, 21; and other, 15) underwent MSK-IMPACT testing. The most prevalent genomic alterations were somatic mutations or amplifications in PIK3CA (25%), ERBB2 (12%), KMT2C (10%), and KMT2D (9%). Furthermore, 13% of patients had high tumor mutational burden (TMB >10 mut/Mb), 3 of which were also microsatellite instability-high (MSI-H). Thirty-seven percent of cases had at least one potentially actionable alteration designated as a level 3B mutational event according to the FDA-recognized OncoKB tumor mutation database and treatment classification system. A total of 30 patients (17%) were enrolled on a therapeutic clinical trial, including 18 (10%) who were matched with a study based on their MSK-IMPACT results. Twenty patients (11%) participated in an immune checkpoint inhibition study for metastatic disease; 2 remain progression free at >5 years follow-up. CONCLUSIONS: Tumor genomic profiling can facilitate the selection of targeted/immunotherapies, as well as clinical trial enrollment, for patients with cervical cancer.

Ethical Considerations of Genome Sequencing for Pediatric Patients.

Advancements in genetic testing in the healthcare setting, most recently genomic sequencing, has enhanced our ability to diagnose genetic conditions. These advances include increased accessibility and affordability of genomic technologies. With expanded use comes the potential for significant ethical challenges for clinicians, particularly considering the implications of testing a child for one condition and incidentally finding a different condition or health risk. In this focused review, we address various ethical considerations from informed consent to the rights of a child undergoing genetic testing.

Overabundant deer and invasive plants drive widespread regeneration debt in eastern United States national parks.

Advanced regeneration, in the form of tree seedlings and saplings, is critical for ensuring the long-term viability and resilience of forest ecosystems in the eastern United States. Lack of regeneration and/or compositional mismatch between regeneration and canopy layers, called regeneration debt, can lead to shifts in forest composition, structure, and, in extreme cases, forest loss. In this study, we examined status and trends in regeneration across 39 national parks from Virginia to Maine, spanning 12 years to apply the regeneration debt concept. We further refined the concept by adding new metrics and classifying results into easily interpreted categories adapted from the literature: imminent failure, probable failure, insecure, and secure. We then used model selection to determine the potential drivers most influencing patterns of regeneration debt. Status and trends indicated widespread regeneration debt in eastern national parks, with 27 of 39 parks classified as imminent or probable failure. Deer browse impact was consistently the strongest predictor of regeneration abundance. The most pervasive component of regeneration debt observed across parks was a sapling bottleneck, characterized by critically low sapling density of native canopy species and significant declines in native canopy sapling basal area or density for most parks. Regeneration mismatches also threaten forest resilience in many parks, where native canopy seedlings and saplings were outnumbered by native subcanopy species, particularly species that are less palatable deer browse. The devastating impact of emerald ash borer eliminating ash as a native canopy tree also drove regeneration mismatches in many parks that contain abundant ash regeneration, demonstrating the vulnerability of forests that lack diverse understories to invasive pests and pathogens. These findings underscore the critical importance of an integrated forest management approach that promotes an abundant and diverse regeneration layer. In most cases, this can only be achieved through long-term (i.e., multidecadal) management of white-tailed deer and invasive plants. Small-scale disturbances that increase structural complexity may also promote regeneration where stress from deer and invasive plants is minimal. Without immediate and sustained management intervention, the forest loss we are already observing may become a widespread pattern in eastern national parks and the broader region.

Feasibility and Acceptability of a Model Disaster Teleconsultation System for Regional Disaster Health Response.

Introduction: The federally funded Region 1 Regional Disaster Health Response System (RDHRS) and the American Burn Association partnered to develop a model regional disaster teleconsultation system within a Medical Emergency Operations Center (MEOC) to support triage and specialty consultation during a no-notice mass casualty incident. Our objective was to test the acceptability and feasibility of a prototype model system in simulated disasters as proof of concept. Methods: We conducted a mixed-methods simulation study using the Technology Acceptance Model framework. Participating physicians completed the Telehealth Usability Questionnaire (TUQ) and semistructured interviews after simulations. Results: TUQ item scores rating the model system were highest for usefulness and satisfaction, and lowest for interaction quality and reliability. Conclusions: We found high model acceptance, but desire for a simpler, more reliable technology interface with better audiovisual quality for low-frequency, high-stakes use. Future work will emphasize technology interface quality and reliability, automate coordinator roles, and field test the model system.

Bifunctional Blockade: A Novel Immunotherapy Approach for Cervical Cancer.

SHR-1701, a bispecific fusion protein directed against PD-L1 and TGFß, demonstrates promising clinical activity in advanced/recurrent cervical cancer. A recent study serves as a proof of principle that the TGFß pathway may be successfully targeted, and that bispecific antibodies offer a novel therapeutic approach to do so. See related article by Feng et al., p. 5297.

Adaptive body image can be contagious: An examination of college women facing situational body image threats.

The present research examined whether and which adaptive body image displays in peers can promote more adaptive body image in self. In two studies, female-identified undergraduates recalled a personally distressing body image event. In Study 1, participants (N = 158) then heard an alleged female-identified peer responding to her own distressing body image event with either self-compassion, self-esteem enhancement, or distraction. Participants across conditions reported increased body acceptance and body image-related self-compassion, and decreased body image distress, but changes did not vary by condition. Study 2 sought to determine which component(s) common to Study 1's conditions explained the benefits participants experienced. Participants (N = 207) listened to an alleged peer: describe body image distress with which she coped adaptively; express body image distress but no adaptive coping; or deny body image distress and relate positively to her body. Hearing a peer cope adaptively with body image distress yielded the greatest body image benefits, whereas hearing a peer deny body image distress was generally least helpful. Results suggest that learning how a peer copes adaptively with body image distress may be most helpful in the face of personal body image distress, and support the overarching theory that adaptive body image may be socially transmissible.

Dopaminergic Positron Emission Tomography Imaging in the Alpha-Synuclein Preformed Fibril Model Reveals Similarities to Early Parkinson's Disease.

BACKGROUND: Positron emission tomography (PET) imaging in early Parkinson's disease (PD) subjects reveals that increased dopamine (DA) turnover and reduced dopamine transporter (DAT) density precede decreases in DA synthesis and storage. The rat α-synuclein preformed fibril (α-syn PFF) model provides a platform to investigate DA dynamics during multiple stages of α-syn inclusion-triggered nigrostriatal degeneration. OBJECTIVES: We investigated multiple aspects of in vivo dopaminergic deficits longitudinally and similarities to human PD using translational PET imaging readouts. METHODS: Longitudinal imaging was performed every 2 months in PFF and control rats for 7 months. [18 F]-Fluoro-3,4-dihydroxyphenyl-L-alanine (FDOPA) imaging was performed to investigate DA synthesis and storage (Kocc ) and DA turnover, estimated by its inverse, the effective distribution volume ratio (EDVR). 11 C-Methylphenidate (MP) was used to estimate DAT density (BPND ). RESULTS: Early DA turnover increases and DAT binding decreases were observed in the ipsilateral striatum of PFF rats, progressing longitudinally. EDVR decreased 26%, 38%, and 47%, and BPND decreased 36%, 50%, and 65% at the 2-, 4-, and 6-month time points, respectively, compared to ipsilateral control striatum. In contrast, deficits in DA synthesis and storage were not observed in the ipsilateral striatum of PFF rats compared to control injections and were relatively preserved up to 6 months (Kocc decreased 20% at 6 months). CONCLUSIONS: The relative preservation of DA synthesis and storage compared to robust progressive deficits in DAT density and increases in DA turnover in the rat α-syn PFF model display remarkable face validity to dopaminergic alterations in human PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Primary characteristics and outcomes of newly diagnosed low-grade endometrial stromal sarcoma.

OBJECTIVE: To assess potential predictive variables for nodal metastasis and survival outcomes in patients with newly diagnosed, low-grade endometrial stromal sarcoma. METHODS: We performed a single-institution, retrospective analysis of consecutive patients with newly diagnosed, low-grade endometrial stromal sarcoma who presented between January 1, 1980 and December 31, 2019 and underwent hysterectomy at our institution or presented within 3 months of primary surgery elsewhere before recurrence. Patients who presented to our institution only at recurrence were excluded. Patients with <3 months of follow-up were excluded from survival analyses. RESULTS: We identified 127 consecutive patients for analysis. Median age at diagnosis was 48 years (range 19-88 years); 91 (74.6%) of 127 were pre-menopausal; and 74 (58.3%) of 127 had uterine-confined, stage I tumors. Of 56 patients (44.1%) who underwent lymph node sampling, 10 (17.9%) had nodal metastasis. Of the 10 with nodal metastasis, 1 (10%) did not have lymphadenopathy or extra-uterine disease, 4 (40%) had lymphadenopathy only, 1 (10%) had extra-uterine disease only, and 4 (40%) had both. Among the 29 patients without apparent extra-uterine disease or gross lymphadenopathy, there was one occult lymph node metastasis (3.4%). Gross lymphadenopathy at time of surgery was predictive for lymph node metastasis (p<0.001). Median follow-up was 69 months (range 4-336) for the 95 patients included in the survival analyses. The 5-year progression-free survival and disease-specific survival rates were 79.8% and 90.8%, respectively. Patients with stage I tumors had longer progression-free survival than those with stage II-IV disease (p<0.001); there was no difference in disease-specific survival (p=0.63). Post-operative observation versus adjuvant therapy with hormone blockade or radiation therapy did not result in progression-free survival differences for stage I or completely resected stage II-IV disease (p=0.50 and p=0.81, respectively). Similarly, there was no disease-specific survival difference for completely resected stage II-IV disease (p=0.3). CONCLUSIONS: Lymph node dissection in patients with low-grade endometrial stromal sarcoma should be reserved for those with clinically suspicious lymphadenopathy. Disease stage correlated with progression-free survival but not disease-specific survival. Post-operative therapy did not improve progression-free survival or disease-specific survival.

Evaluating the role of aromatase inhibitors in the treatment of low-grade endometrial stromal sarcomas.

Objectives: Endometrial stromal sarcomas (ESS) are rare, accounting for < 1% of all uterine malignancies. Treatment has been guided by small case series and retrospective studies. Endocrine therapy is used in both adjuvant and metastatic settings. Aromatase inhibitors (AIs) are widely used in clinical practice. We sought to evaluate clinical outcomes of AI use in the largest cohort of patients with LGESS to date. Methods: We performed a retrospective study of patients with LGESS treated with an AI at our institution from 1/1998-12/2020. Response was evaluated using RECIST 1.1. The Kaplan-Meier method was used to estimate median progression-free (PFS) and overall (OS) survival. Results: Forty patients were identified. Treatment was well tolerated, with 57.5% experiencing adverse effects. The most common were arthralgias (12 patients, 30%) and hot flashes (9, 22.5%). Two of 11 patients with RECIST-evaluable imaging experienced a partial response to treatment. Median PFS for the entire cohort was 79.2 months (95% CI 39.7 months to NE); the 5-year PFS rate was 59.6% (95% CI 41.8% to 73.6, p = 0.065). Median follow-up for the 29 survivors was 97.9 months (range: 12.6-226.7). The 5-year OS rate was 81.5% (95% CI 64.9-90.7%). One patient who discontinued AI after 10 years of treatment recurred 1 year later. Conclusion: AIs were well tolerated and offered periods of prolonged disease stability, even in the metastatic setting. Our study suggests, however, that response rates may be lower than previously reported. Data on optimal duration of treatment is needed, but the rarity of LGESS is an obstacle to conducting large clinical trials.

PFTAIRE Kinase L63 Interactor 1A (Pif1A Protein) Is Required for Actin Cone Movement during Spermatid Individualization in Drosophila melanogaster.

A useful model for determining the mechanisms by which actin and actin binding proteins control cellular architecture is the Drosophila melanogaster process of spermatogenesis. During the final step of spermatogenesis, 64 syncytial spermatids individualized as stable actin cones move synchronously down the axonemes and remodel the membranes. To identify new genes involved in spermatid individualization, we screened a collection of Drosophila male-sterile mutants and found that, in the line Z3-5009, actin cones formed near to the spermatid nuclei but failed to move, resulting in failed spermatid individualization. However, we show by phalloidin actin staining, electron microscopy and immunocytochemical localization of several actin binding proteins that the early cones had normal structure. We sequenced the genome of the Z3-5009 line and identified mutations in the PFTAIRE kinase L63 interactor 1A (Pif1A) gene. Quantitative real-time PCR showed that Pif1A transcript abundance was decreased in the mutant, and a transgene expressing Pif1A fused to green fluorescent protein (GFP) was able to fully rescue spermatid individualization and male fertility. Pif1A-GFP localized to the front of actin cones before initiation of movement. We propose that Pif1A plays a pivotal role in directing actin cone movement.

Characterization of Axon Guidance Phenotypes in Wnt/PCP Mutant Mice.

Our lab showed that the Wnt family proteins can function as axon guidance molecules and the planar cell polarity (PCP) pathway mediates the function of Wnts in axon guidance. One of the key evidences was by identifying the axon guidance defects in knockout or conditional knockout animals. We utilized a variety of axon tracing and labeling techniques, including immunohistochemistry (IHC), DiI, BDA, and fluorescent reporters (GFP or tdTomato). These studies have primarily been conducted in spinal cord commissural axons, but have been applied to retinal ganglion cell axons, corticospinal tract axons, dopaminergic and serotonergic projections.

In Vitro Explant Assays and Cultures to Study PCP Signaling in Axon Guidance.

In vitro studies have provided valuable insights to the function and mechanisms in axon guidance. In this chapter, we will introduce the rodent "open-book" assay, pre- or postcrossing explant culture and the dissociated neuron culture. They have been used to discover mechanism which we have gone on to validate or will confirm using in vivo genetic approaches.

Biochemical and Cellular Assays to Study Mechanisms of PCP Signaling in Axon Guidance.

Understanding biochemical and cellular mechanisms of how PCP components regulate axon guidance is important for understanding brain development and may lead to new therapeutic approaches for neural repair. Meanwhile, axonal growth cones are a highly polarized structure and are a great experimental system. Therefore, some of these novel mechanisms we are uncovering for axon guidance may be applicable for PCP signaling in general. In this chapter, we introduce some of the techniques we used or developed: (1) protein localization and trafficking; (2) protein phosphorylation; and (3) protein-protein interactions in the same cell and across the two neighboring cells.