Pandemic Action Plan: Phase 3-Lessons Learned from Implementation. "What Did We Learn?"

The COVID-19 pandemic created critical challenges for hospitals and health care providers. Suddenly clinics were forced to close; elective procedures were delayed; scheduled visits were canceled; emergency rooms were overcrowded; hospital beds, equipment, and personal protective equipment (PPE) were in short supply; and staff were faced with rapidly changing circumstances, care protocols, trauma, and personal risk. To better address challenges of the ongoing COVID-19 pandemic and prepare for future pandemics, the National Telemedicine Technology Assessment Resource Center (TTAC) was asked to develop a Pandemic Response Action Plan that would allow its users to address critical issues with available telemedicine and related technologies. The project was constructed in 3 phases. Phase 1-Develop a Pandemic Response Action Plan and a Pandemic Response Action Plan Policy and Regulatory Summary, which identifies the regulatory challenges as well as policy recommendations. Phase 2-Publish the Action Plan and the Policy and Regulatory Summary. Phase 3-Look at health care providers who used the approaches, tools, and technology in the Pandemic Action Plan and document the results. This document represents Phase 3. This document is Phase 3. In this report we look back at health care providers who used the approaches in the Phase 1 Pandemic Response Action Plan as published in Phase 2. In this document we report on the challenges and results of implementing parts of the Pandemic Action Plan. It records the findings, conclusions, and recommendations resulting from the experience of health care providers and the professional experiences of the team and their organizations in implementing parts or all of the plan. Methods: The same multidisciplinary team that constructed Phase 1 and Phase 2 were engaged to develop this Phase 3 report. The members of the team represent leadership expertise and key stakeholders in health care delivery during a pandemic (administration, infection control, physicians, nurses, public health, contingency planning, disaster response, and information technology) as well as a facilitator. For Phase 3, the group used structured brainstorming to define the findings, issues, and results of their own organizations' digital health response to the pandemic. In addition, eight health care providers (hospitals) identified by the Telemedicine Resource Centers' (TRCs) organizations, who used the Pandemic response Plan (created in Phases 1 and 2), were interviewed. All interviews were conducted by the same facilitator with leaders (CEO, and leaders of the telemedicine programs) in each of the eight programs, using a standard questionnaire created by the team. Current literature references are included in this report to illustrate when findings are known to have broader applicability. Conclusions: The impact of the COVID-19 Pandemic was severe and identified multiple critical challenges and weaknesses. Applying the approaches, tools, and technology outlined in the Pandemic Response Action Plan proved to be effective in addressing critical provider challenges. However, implementing these tools during a crisis was difficult unless the organization had experience with the tools and necessary workflows in advance. Implementing these tools as part of standard workflows and everyday operations increased the capabilities and resilience of these organizations in the provision of care during this and for future pandemics.

Optimization of physicochemical properties of pyrrolidine GPR40 AgoPAMs results in a differentiated profile with improved pharmacokinetics and reduced off-target activities.

GPR40 AgoPAMs are highly effective antidiabetic agents that have a dual mechanism of action, stimulating both glucose-dependent insulin and GLP-1 secretion. The early lipophilic, aromatic pyrrolidine and dihydropyrazole GPR40 AgoPAMs from our laboratory were highly efficacious in lowering plasma glucose levels in rodents but possessed off-target activities and triggered rebound hyperglycemia in rats at high doses. A focus on increasing molecular complexity through saturation and chirality in combination with reducing polarity for the pyrrolidine AgoPAM chemotype resulted in the discovery of compound 46, which shows significantly reduced off-target activities as well as improved aqueous solubility, rapid absorption, and linear PK. In vivo, compound 46 significantly lowers plasma glucose levels in rats during an oral glucose challenge yet does not demonstrate the reactive hyperglycemia effect at high doses that was observed with earlier GPR40 AgoPAMs.

Dorsal Subluxation of the First Metacarpal During Thumb Flexion is an Indicator of Carpometacarpal Osteoarthritis Progression.

BACKGROUND: Measurable changes in patients with progression of thumb carpometacarpal (CMC) osteoarthritis (OA) include joint space narrowing, osteophyte formation, subluxation, and adjacent-tissue changes. Subluxation, an indication of mechanical instability, is postulated as an early biomechanical indicator of progressing CMC OA. Various radiographic views and hand postures have been proposed to best assess CMC subluxation, but 3D measurements derived from CT images serve as the optimal metric. However, we do not know which thumb pose yields subluxation that most indicates OA progression. QUESTIONS/PURPOSES: Using osteophyte volume as a quantitative measure of OA progression, we asked: (1) Does dorsal subluxation vary by thumb pose, time, and disease severity in patients with thumb CMC OA? (2) In which thumb pose(s) does dorsal subluxation most differentiate patients with stable CMC OA from those with progressing CMC OA? (3) In those poses, what values of dorsal subluxation indicate a high likelihood of CMC OA progression? METHODS: Between 2011 and 2014, 743 patients were seen at our institutions for trapeziometacarpal pain. We considered individuals who were between the ages of 45 and 75 years, had tenderness to palpation or a positive grind test result, and had modified Eaton Stage 0 or 1 radiographic thumb CMC OA as potentially eligible for enrollment. Based on these criteria, 109 patients were eligible. Of the eligible patients, 19 were excluded because of a lack of interest in study participation, and another four were lost before the minimum study follow-up or had incomplete datasets, leaving 86 (43 female patients with a mean age of 53 ± 6 years and 43 male patients with a mean age of 60 ± 7 years) patients for analysis. Twenty-five asymptomatic participants (controls) aged 45 to 75 years were also prospectively recruited to participate in this study. Inclusion criteria for controls included an absence of thumb pain and no evidence of CMC OA during clinical examination. Of the 25 recruited controls, three were lost to follow-up, leaving 22 for analysis (13 female patients with a mean age of 55 ± 7 years and nine male patients with a mean age of 58 ± 9 years). Over the 6-year study period, CT images were acquired of patients and controls in 11 thumb poses: neutral, adduction, abduction, flexion, extension, grasp, jar, pinch, grasp loaded, jar loaded, and pinch loaded. CT images were acquired at enrollment (Year 0) and Years 1.5, 3, 4.5, and 6 for patients and at Years 0 and 6 for controls. From the CT images, bone models of the first metacarpal (MC1) and trapezium were segmented, and coordinate systems were calculated from their CMC articular surfaces. The volar-dorsal location of the MC1 relative to the trapezium was computed and normalized for bone size. Patients were categorized into stable OA and progressing OA subgroups based on trapezial osteophyte volume. MC1 volar-dorsal location was analyzed by thumb pose, time, and disease severity using linear mixed-effects models. Data are reported as the mean and 95% confidence interval. Differences in volar-dorsal location at enrollment and rate of migration during the study were analyzed for each thumb pose by group (control, stable OA, and progressing OA). A receiver operating characteristic curve analysis of MC1 location was used to identify thumb poses that differentiated patients whose OA was stable from those whose OA was progressing. The Youden J statistic was used to determine optimized cutoff values of subluxation from those poses to be tested as indicators of OA progression. Sensitivity, specificity, negative predictive values, and positive predictive values were calculated to assess the performance of pose-specific cutoff values of MC1 locations as indicators of progressing OA. RESULTS: In flexion, the MC1 locations were volar to the joint center in patients with stable OA (mean -6.2% [95% CI -8.8% to -3.6%]) and controls (mean -6.1% [95% CI -8.9% to -3.2%]), while patients with progressing OA exhibited dorsal subluxation (mean 5.0% [95% CI 1.3% to 8.6%]; p < 0.001). The pose associated with the most rapid MC1 dorsal subluxation in the progressing OA group was thumb flexion (mean 3.2% [95% CI 2.5% to 3.9%] increase per year). In contrast, the MC1 migrated dorsally much slower in the stable OA group (p < 0.001), at only a mean of 0.1% (95% CI -0.4% to 0.6%) per year. A cutoff value of 1.5% for the volar MC1 position during flexion at enrollment (C-statistic: 0.70) was a moderate indicator of OA progression, with a high positive predictive value (0.80) but low negative predictive value (0.54). Positive and negative predictive values of subluxation rate in flexion (2.1% per year) were high (0.81 and 0.81, respectively). The metric that most indicated a high likelihood of OA progression (sensitivity 0.96, negative predictive value 0.89) was a dual cutoff that combined the subluxation rate in flexion (2.1% per year) with that of loaded pinch (1.2% per year). CONCLUSION: In the thumb flexion pose, only the progressing OA group exhibited MC1 dorsal subluxation. The MC1 location cutoff value for progression in flexion was 1.5% volar to the trapezium , which suggests that dorsal subluxation of any amount in this pose indicates a high likelihood of thumb CMC OA progression. However, volar MC1 location in flexion alone was not sufficient to rule out progression. The availability of longitudinal data improved our ability to identify patients whose disease will likely remain stable. In patients whose MC1 location during flexion changed < 2.1% per year and whose MC1 location during pinch loading changed < 1.2% per year, the confidence that their disease would remain stable throughout the 6-year study period was very high. These cutoff rates were a lower limit, and any patients whose dorsal subluxation advanced faster than 2% to 1% per year in their respective hand poses, were highly likely to experience progressive disease. CLINICAL RELEVANCE: Our findings suggest that in patients with early signs of CMC OA, nonoperative interventions aimed to reduce further dorsal subluxation or operative treatments that spare the trapezium and limit subluxation may be effective. It remains to be determined whether our subluxation metrics can be rigorously computed from more widely available technologies, such as plain radiography or ultrasound.

SHP2 regulates the development of intestinal epithelium by modifying OSTERIX+ crypt stem cell self-renewal and proliferation.

The protein tyrosine phosphatase SHP2, encoded by PTPN11, is ubiquitously expressed and essential for the development and/or maintenance of multiple tissues and organs. SHP2 is involved in gastrointestinal (GI) epithelium development and homeostasis, but the underlying mechanisms remain elusive. While studying SHP2's role in skeletal development, we made osteoblast-specific SHP2 deficient mice using Osterix (Osx)-Cre as a driver to excise Ptpn11 floxed alleles. Phenotypic characterization of these SHP2 mutants unexpectedly revealed a critical role of SHP2 in GI biology. Mice lacking SHP2 in Osx+ cells developed a fatal GI pathology with dramatic villus hypoplasia. OSTERIX, an OB-specific zinc finger-containing transcription factor is for the first time found to be expressed in GI crypt cells, and SHP2 expression in the crypt Osx+ cells is critical for self-renewal and proliferation. Further, immunostaining revealed the colocalization of OSTERIX with OLFM4 and LGR5, two bona fide GI stem cell markers, at the crypt cells. Furthermore, OSTERIX expression is found to be associated with GI malignancies. Knockdown of SHP2 expression had no apparent influence on the relative numbers of enterocytes, goblet cells or Paneth cells. Given SHP2's key regulatory role in OB differentiation, our studies suggest that OSTERIX and SHP2 are indispensable for gut homeostasis, analogous to SOX9's dual role as a master regulator of cartilage and an important regulator of crypt stem cell biology. Our findings also provide a foundation for new avenues of inquiry into GI stem cell biology and of OSTERIX's therapeutic and diagnostic potential.

Evaluation of the PROMIS Upper Extremity Against Validated Patient-Reported Outcomes in Patients With Early Carpometacarpal Osteoarthritis.

PURPOSE: Internal consistency, construct, and criterion validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity (UE) v1.2 were evaluated in patients with early-stage carpometacarpal (CMC) osteoarthritis (OA). We hypothesized that in patients with early CMC OA, PROMIS UE scores would: (1) be lower than those in asymptomatic controls; (2) correlate with established patient-reported outcomes; (3) correlate with pinch and grip strengths; and (4) not correlate with radiographic disease progression. METHODS: Patients with early CMC OA (modified Eaton stage 0 or 1) and matched asymptomatic control patients completed the PROMIS UE, Australian and Canadian Osteoarthritis Hand Index, and Patient-Rated Wrist-Hand Evaluation at 2 time points. The PROMIS UE's internal consistency was evaluated by Cronbach's alpha, construct validity by Spearman correlation coefficients among the patient-reported outcome measures, and criterion validity using measures of strength. A floor or ceiling effect was indicated if more than 15% of patients achieved the lowest or highest possible score. RESULTS: The PROMIS UE had high internal consistency. Patients with early CMC OA had a lower score than healthy controls (average, 42 vs 54, respectively). We observed moderate to high correlations between the PROMIS UEv1.2, Australian and Canadian Osteoarthritis Hand Index, and Patient-Rated Wrist-Hand Evaluation and good criterion validity when compared to key pinch and grip strengths. The PROMIS UE did not correlate to radiographic disease severity. CONCLUSIONS: The PROMIS UE had a high correlation with Australian and Canadian Osteoarthritis Hand Index and a moderate correlation with Patient-Rated Wrist-Hand Evaluation. The PROMIS UE had high internal consistency and good criterion validity. CLINICAL RELEVANCE: The PROMIS UE is a valid assessment for disability in patients with early CMC OA and can serve as a clinical adjunct to an outcome assessment.

Pandemic Telemedicine Technology Response Plan and Technology Assessment Phase 2: Pandemic Action Plan Key Issues and Technology Solutions for Health Care Delivery Organizations in a Pandemic.

Introduction: The Covid-19 pandemic created critical challenges for hospitals and healthcare providers. Suddenly clinics were forced to close; scheduled visits were cancelled; emergency rooms were overcrowded; hospital beds, equipment and personal protective equipment (PPE) was in short supply; and staff were faced with rapidly changing circumstances, care protocols, trauma and personal risk. In order to better address the ongoing the Covid-19 pandemic and prepare for future pandemics, the National Telemedicine Technology Assessment resource Center (TTAC) was asked to develop an Pandemic Response Action Plan that would allow its user to address critical issues with available telemedicine and related technologies. The project was constructed into three phases: Phase 1. Develop a Pandemic Response Action Plan (this document) and a Policy document which identifies the regulatory challenges in the Pandemic Response as well as policy recommendations (published separately). Phase 2. Publish the plan and policy documents. Phase 3 Look at healthcare providers who used the approaches, tools and technology in the Pandemic Action Plan and document the results (to be published separately). TTAC will also assess selected technology and publish results as part of their normal course of services. Materials and Methods: A multi-disciplinary team was created representing leadership expertise and key stakeholders in healthcare delivery during a pandemic (administration, infection control, physicians, nurses, public health, contingency planning, disaster response, information technology) as well as a facilitator. The group used structured brainstorming, current literature and iterative review to identify the most critical challenges facing healthcare providers during the current Covid 19 pandemic. The team then used structured brainstorming, professional experience and current literature to take a deeper look into these impacts, identify applicable solutions and develop a plan to address the critical challenges using telemedicine and related technologies. Result: A Pandemic Action Response Plan that describes the critical challenges and then identifies approaches, tools and technology to address them as well as identifying samples of the technology. Conclusions: The impact of the Covid 19 Pandemic was severe and identified multiple critical challenges and weaknesses in most healthcare providers. Applying the approaches, tools and technology in this Pandemic Action Plan will help providers address these challenges and increase the capabilities and resilience of their organizations in the provision of care during this and future pandemics.

Pandemic Action Plan Policy and Regulatory Summary Telehealth Policy and Regulatory Considerations During a Pandemic.

Reports, studies, and surveys have demonstrated telehealth provides opportunities to make health care more efficient, better coordinated, convenient, and affordable. Telehealth can also help address health income and access disparities in underserved communities by removing location and transportation barriers, unproductive time away from work, childcare expenses, and so on. Despite evidence showing high-quality outcomes, satisfaction, and success rates (e.g., 95% patient satisfaction rate and 84% success rate in which patients were able to completely resolve their medical concerns during a telehealth visit), nationwide adoption of telehealth has been quite low due to policy and regulatory barriers, constraints, and complexities.

Formalising the Pathways to Life Using Assembly Spaces.

Assembly theory (referred to in prior works as pathway assembly) has been developed to explore the extrinsic information required to distinguish a given object from a random ensemble. In prior work, we explored the key concepts relating to deconstructing an object into its irreducible parts and then evaluating the minimum number of steps required to rebuild it, allowing for the reuse of constructed sub-objects. We have also explored the application of this approach to molecules, as molecular assembly, and how molecular assembly can be inferred experimentally and used for life detection. In this article, we formalise the core assembly concepts mathematically in terms of assembly spaces and related concepts and determine bounds on the assembly index. We explore examples of constructing assembly spaces for mathematical and physical objects and propose that objects with a high assembly index can be uniquely identified as those that must have been produced using directed biological or technological processes rather than purely random processes, thereby defining a new scale of aliveness. We think this approach is needed to help identify the new physical and chemical laws needed to understand what life is, by quantifying what life does.

An Approach to Robotic Testing of the Wrist Using Three-Dimensional Imaging and a Hybrid Testing Methodology.

Robotic technology is increasingly used for sophisticated in vitro testing designed to understand the subtleties of joint biomechanics. Typically, the joint coordinate systems in these studies are established via palpation and digitization of anatomic landmarks. We are interested in wrist mechanics in which overlying soft tissues and indistinct bony features can introduce considerable variation in landmark localization, leading to descriptions of kinematics and kinetics that may not appropriately align with the bony anatomy. In the wrist, testing is often performed using either load or displacement control with standard material testers. However, these control modes either do not consider all six degrees-of-freedom (DOF) or reflect the nonlinear mechanical properties of the wrist joint. The development of an appropriate protocol to investigate complexities of wrist mechanics would potentially advance our understanding of normal, pathological, and artificial wrist function. In this study, we report a novel methodology for using CT imaging to generate anatomically aligned coordinate systems and a new methodology for robotic testing of wrist. The methodology is demonstrated with the testing of 9 intact cadaver specimens in 24 unique directions of wrist motion to a resultant torque of 2.0 N·m. The mean orientation of the major principal axis of range of motion (ROM) envelope was oriented 12.1 ± 2.7 deg toward ulnar flexion, which was significantly different (p < 0.001) from the anatomical flexion/extension axis. The largest wrist ROM was 98 ± 9.3 deg in the direction of ulnar flexion, 15 deg ulnar from pure flexion, consistent with previous studies [1,2]. Interestingly, the radial and ulnar components of the resultant torque were the most dominant across all directions of wrist motion. The results of this study showed that we can efficiently register anatomical coordinate systems from CT imaging space to robotic test space adaptable to any cadaveric joint experiments and demonstrated a combined load-position strategy for robotic testing of wrist.

Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling.

The tyrosine phosphatase SHP2, encoded by PTPN11, is required for the survival, proliferation and differentiation of various cell types. Germline activating mutations in PTPN11 cause Noonan syndrome, whereas somatic PTPN11 mutations cause childhood myeloproliferative disease and contribute to some solid tumours. Recently, heterozygous inactivating mutations in PTPN11 were found in metachondromatosis, a rare inherited disorder featuring multiple exostoses, enchondromas, joint destruction and bony deformities. The detailed pathogenesis of this disorder has remained unclear. Here we use a conditional knockout (floxed) Ptpn11 allele (Ptpn11(fl)) and Cre recombinase transgenic mice to delete Ptpn11 specifically in monocytes, macrophages and osteoclasts (lysozyme M-Cre; LysMCre) or in cathepsin K (Ctsk)-expressing cells, previously thought to be osteoclasts. LysMCre;Ptpn11(fl/fl) mice had mild osteopetrosis. Notably, however, CtskCre;Ptpn11(fl/fl) mice developed features very similar to metachondromatosis. Lineage tracing revealed a novel population of CtskCre-expressing cells in the perichondrial groove of Ranvier that display markers and functional properties consistent with mesenchymal progenitors. Chondroid neoplasms arise from these cells and show decreased extracellular signal-regulated kinase (ERK) pathway activation, increased Indian hedgehog (Ihh) and parathyroid hormone-related protein (Pthrp, also known as Pthlh) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased fibroblast growth factor-evoked ERK activation and enhanced Ihh and Pthrp expression, whereas fibroblast growth factor receptor (FGFR) or mitogen-activated protein kinase kinase (MEK) inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Importantly, smoothened inhibitor treatment ameliorated metachondromatosis features in CtskCre;Ptpn11(fl/fl) mice. Thus, in contrast to its pro-oncogenic role in haematopoietic and epithelial cells, Ptpn11 is a tumour suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production.

Kinematic Accuracy in Tracking Total Wrist Arthroplasty With Biplane Videoradiography Using a Computed Tomography-Generated Model.

Total wrist arthroplasty (TWA) for improving the functionality of severe wrist joint pathology has not had the same success, in parameters such as motion restoration and implant survival, as hip, knee, and shoulder arthroplasty. These other arthroplasties have been studied extensively, including the use of biplane videoradiography (BVR) that has allowed investigators to study the in vivo motion of the total joint replacement during dynamic activities. The wrist has not been a previous focus, and utilization of BVR for wrist arthroplasty presents unique challenges due to the design characteristics of TWAs. Accordingly, the aims of this study were (1) to develop a methodology for generating TWA component models for use in BVR and (2) to evaluate the accuracy of model-image registration in a single cadaveric model. A model of the carpal component was constructed from a computed tomography (CT) scan, and a model of the radial component was generated from a surface scanner. BVR was acquired for three anatomical tasks from a cadaver specimen. Optical motion capture (OMC) was used as the gold standard. BVR's bias in flexion/extension, radial/ulnar deviation, and pronosupination was less than 0.3 deg, 0.5 deg, and 0.6 deg. Translation bias was less than 0.2 mm with a standard deviation of less than 0.4 mm. This BVR technique achieved a kinematic accuracy comparable to the previous studies on other total joint replacements. BVR's application to the study of TWA function in patients could advance the understanding of TWA, and thus, the implant's success.

Climate sensitivity functions and net primary production: A framework for incorporating climate mean and variability.

Understanding controls on net primary production (NPP) has been a long-standing goal in ecology. Climate is a well-known control on NPP, although the temporal differences among years within a site are often weaker than the spatial pattern of differences across sites. Climate sensitivity functions describe the relationship between an ecological response (e.g., NPP) and both the mean and variance of its climate driver (e.g., aridity index), providing a novel framework for understanding how climate trends in both mean and variance vary with NPP over time. Nonlinearities in these functions predict whether an increase in climate variance will have a positive effect (convex nonlinearity) or negative effect (concave nonlinearity) on NPP. The influence of climate variance may be particularly intense at ecosystem transition zones, if species reach physiological thresholds that create nonlinearities at these ecotones. Long-term data collected at the confluence of three dryland ecosystems in central New Mexico revealed that each ecosystem exhibited a unique climate sensitivity function that was consistent with long-term vegetation change occurring at their ecotones. Our analysis suggests that rising temperatures in drylands could alter the nonlinearities that determine the relative costs and benefits of variance in precipitation for primary production.

Criticality Distinguishes the Ensemble of Biological Regulatory Networks.

The hypothesis that many living systems should exhibit near-critical behavior is well motivated theoretically, and an increasing number of cases have been demonstrated empirically. However, a systematic analysis across biological networks, which would enable identification of the network properties that drive criticality, has not yet been realized. Here, we provide a first comprehensive survey of criticality across a diverse sample of biological networks, leveraging a publicly available database of 67 Boolean models of regulatory circuits. We find all 67 networks to be near critical. By comparing to ensembles of random networks with similar topological and logical properties, we show that criticality in biological networks is not predictable solely from macroscale properties such as mean degree ⟨K⟩ and mean bias in the logic functions ⟨p⟩, as previously emphasized in theories of random Boolean networks. Instead, the ensemble of real biological circuits is jointly constrained by the local causal structure and logic of each node. In this way, biological regulatory networks are more distinguished from random networks by their criticality than by other macroscale network properties such as degree distribution, edge density, or fraction of activating conditions.

SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion.

Genes that regulate osteoclast (OC) development and function in both physiologic and disease conditions remain incompletely understood. Shp2 (the Src homology-2 domain containing protein tyrosine phosphatase 2), a ubiquitously expressed cytoplasmic protein tyrosine phosphatase, is implicated in regulating M-CSF and receptor activator of nuclear factor-κB ligand (RANKL)-evoked signaling; its role in osteoclastogenesis and bone homeostasis, however, remains unknown. Using a tissue-specific gene knockout approach, we inactivated Shp2 expression in murine OCs. Shp2 mutant mice are phenotypically osteopetrotic, featuring a marked increase of bone volume (BV)/total volume (TV) (+42.8%), trabeculae number (Tb.N) (+84.1%), structure model index (+119%), and a decrease of trabecular thickness (Tb.Th) (-34.1%) and trabecular spacing (Tb.Sp) (-41.0%). Biochemical analyses demonstrate that Shp2 is required for RANKL-induced formation of giant multinucleated OCs by up-regulating the expression of nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1), a master transcription factor that is indispensable for terminal OC differentiation. Shp2 deletion, however, has minimal effect on M-CSF-dependent survival and proliferation of OC precursors. Instead, its deficiency aborts the fusion of OC precursors and formation of multinucleated OCs and decreases bone matrix resorption. Moreover, pharmacological intervention of Shp2 is sufficient to prevent preosteoclast fusion in vitro. These findings uncover a novel mechanism through which Shp2 regulates osteoclastogenesis by promoting preosteoclast fusion. Shp2 or its signaling partners could potentially serve as pharmacological targets to regulate the population of OCs locally and/or systematically, and thus treat OC-related diseases, such as periprosthetic osteolysis and osteoporosis.

Matrilin-3 inhibits chondrocyte hypertrophy as a bone morphogenetic protein-2 antagonist.

Increased chondrocyte hypertrophy is often associated with cartilage joint degeneration in human osteoarthritis patients. Matrilin-3 knock-out (Matn3 KO) mice exhibit these features. However, the underlying mechanism is unknown. In this study, we sought a molecular explanation for increased chondrocyte hypertrophy in the mice prone to cartilage degeneration. We analyzed the effects of Matn3 on chondrocyte hypertrophy and bone morphogenetic protein (Bmp) signaling by quantifying the hypertrophic marker collagen type X (Col X) gene expression and Smad1 activity in Matn3 KO mice in vivo and in Matn3-overexpressing chondrocytes in vitro. The effect of Matn3 and its specific domains on BMP activity were quantified by Col X promoter activity containing the Bmp-responsive element. Binding of MATN3 with BMP-2 was determined by immunoprecipitation, solid phase binding, and surface plasmon resonance assays. In Matn3 KO mice, Smad1 activity was increased more in growth plate chondrocytes than in wild-type mice. Conversely, Matn3 overexpression in hypertrophic chondrocytes led to inhibition of Bmp-2-stimulated, BMP-responsive element-dependent Col X expression and Smad1 activity. MATN3 bound BMP-2 in a dose-dependent manner. Multiple epidermal growth factor (EGF)-like domains clustered together by the coiled coil of Matn3 is required for Smad1 inhibition. Hence, as a novel BMP-2-binding protein and antagonist in the cartilage extracellular matrix, MATN3 may have the inherent ability to inhibit premature chondrocyte hypertrophy by suppressing BMP-2/Smad1 activity.

The Envelope of Physiological Motion of the First Carpometacarpal Joint.

Much of the hand's functional capacity is due to the versatility of the motions at the thumb carpometacarpal (CMC) joint, which are presently incompletely defined. The aim of this study was to develop a mathematical model to completely describe the envelope of physiological motion of the thumb CMC joint and then to examine if there were differences in the kinematic envelope between women and men. In vivo kinematics of the first metacarpal with respect to the trapezium were computed from computed tomography (CT) volume images of 44 subjects (20M, 24F, 40.3 ± 17.7 yr) with no signs of CMC joint pathology. Kinematics of the first metacarpal were described with respect to the trapezium using helical axis of motion (HAM) variables and then modeled with discrete Fourier analysis. Each HAM variable was fit in a cyclic domain as a function of screw axis orientation in the trapezial articular plane; the RMSE of the fits was 14.5 deg, 1.4 mm, and 0.8 mm for the elevation, location, and translation, respectively. After normalizing for the larger bone size in men, no differences in the kinematic variables between sexes could be identified. Analysis of the kinematic data also revealed notable coupling of the primary rotations of the thumb with translation and internal and external rotations. This study advances our basic understanding of thumb CMC joint function and provides a complete description of the CMC joint for incorporation into future models of hand function. From a clinical perspective, our findings provide a basis for evaluating CMC pathology, especially the mechanically mediated aspects of osteoarthritis (OA), and should be used to inform artificial joint design, where accurate replication of kinematics is essential for long-term success.

Subject-Specific Carpal Ligament Elongation in Extreme Positions, Grip, and the Dart Thrower's Motion.

This study examined whether the radiocarpal and dorsal capsular ligaments limit end-range wrist motion or remain strained during midrange wrist motion. Fibers of these ligaments were modeled in the wrists of 12 subjects over multiple wrist positions that reflect high demand tasks and the dart thrower's motion. We found that many of the volar and dorsal ligaments were within 5% of their maximum length throughout the range of wrist motion. Our finding of wrist ligament recruitment during midrange and end-range wrist motion helps to explain the complex but remarkably similar intersubject patterns of carpal motion.

In Vivo kinematics of the trapeziometacarpal joint during thumb extension-flexion and abduction-adduction.

PURPOSE: The primary aim of this study was to determine whether the in vivo kinematics of the trapeziometacarpal (TMC) joint differ as a function of age and sex during thumb extension-flexion (Ex-Fl) and abduction-adduction (Ab-Ad) motions. METHODS: The hands and wrists of 44 subjects (10 men and 11 women with ages 18-35 y and 10 men and 13 women with ages 40-75 y) with no symptoms or signs of TMC joint pathology were imaged with computed tomography during thumb extension, flexion, abduction, and adduction. The kinematics of the TMC joint were computed and compared across direction, age, and sex. RESULTS: We found no significant effects of age or sex, after normalizing for size, in any of the kinematic parameters. The Ex-Fl and Ab-Ad rotation axes did not intersect, and both were oriented obliquely to the saddle-shaped anatomy of the TMC articulation. The Ex-Fl axis was located in the trapezium and the Ab-Ad axis was located in the metacarpal. Metacarpal translation and internal rotation occurred primarily during Ex-Fl. CONCLUSIONS: Our findings indicate that normal TMC joint kinematics are similar in males and females, regardless of age, and that the primary rotation axes are nonorthogonal and nonintersecting. In contrast to previous studies, we found Ex-Fl and Ab-Ad to be coupled with internal-external rotation and translation. Specifically, internal rotation and ulnar translation were coupled with flexion, indicating a potential stabilizing screw-home mechanism. CLINICAL RELEVANCE: The treatment of TMC pathology and arthroplasty design require a detailed and accurate understanding of TMC function. This study confirms the complexity of TMC kinematics and describes metacarpal translation coupled with internal rotation during Ex-Fl, which may explain some of the limitations of current treatment strategies and should help improve implant designs.

Polar histograms of curvature for quantifying skeletal joint shape and congruence.

The effect of articular joint shape and congruence on kinematics, contact stress, and the natural progression of joint disease continue to be a topic of interest in the orthopedic biomechanics literature. Currently, the most widely used metrics of assessing skeletal joint shape and congruence are based on average principal curvatures across the articular surfaces. Here we propose a method for comparing articular joint shape and quantifying joint congruence based on three-dimensional (3D) histograms of curvature--shape descriptors that preserve spatial information. Illustrated by experimental results from the trapeziometacarpal joint, this method could help unveil the interrelations between joint shape and function and provide much needed insight for the high incidence of osteoarthritis (OA)--a mechanically mediated disease whose onset has been hypothesized to be precipitated by joint incongruity.

In vivo kinematics of the thumb carpometacarpal joint during three isometric functional tasks.

BACKGROUND: The thumb carpometacarpal (CMC) joint is often affected by osteoarthritis--a mechanically mediated disease. Pathomechanics of the CMC joint, however, are not thoroughly understood due to a paucity of in vivo data. QUESTIONS/PURPOSES: We documented normal, in vivo CMC joint kinematics during isometric functional tasks. We hypothesized there would be motion of the CMC joint during these tasks and that this motion would differ with sex and age group. We also sought to determine whether the rotations at the CMC joint were coupled and whether the trapezium moved with respect to the third metacarpal. METHODS: Forty-six asymptomatic subjects were CT-scanned in a neutral position and during three functional tasks (key pinch, jar grasp, jar twist), in an unloaded and a loaded position. Kinematics of the first metacarpal, third metacarpal, and the trapezium were then computed. RESULTS: Significant motion was identified in the CMC joint during all tasks. Sex did not have an effect on CMC joint kinematics. Motion patterns differed with age group, but these differences were not systematic across the tasks. Rotation at the CMC joint was generally coupled and posture of the trapezium relative to the third metacarpal changed significantly with thumb position. CONCLUSIONS: The healthy CMC joint is relatively stable during key pinch, jar grasp, and jar twist tasks, despite sex and age group. CLINICAL RELEVANCE: Our findings indicate that directionally coupled motion patterns in the CMC joint, which lead to a specific loading profile, are similar in men and women. These patterns, in addition to other, nonkinematic influences, especially in the female population, may contribute to the pathomechanics of the osteoarthritic joint.