Comparative analysis of traction forces in normal and glaucomatous trabecular meshwork cells within a 3D, active fluid-structure interaction culture environment.

This study presents a 3D in vitro cell culture model, meticulously 3D printed to replicate the conventional aqueous outflow pathway anatomical structure, facilitating the study of trabecular meshwork (TM) cellular responses under glaucomatous conditions. Glaucoma affects TM cell functionality, leading to extracellular matrix (ECM) stiffening, enhanced cell-ECM adhesion, and obstructed aqueous humor outflow. Our model, reconstructed from polyacrylamide gel with elastic moduli of 1.5 and 21.7 kPa, is based on serial block-face scanning electron microscopy images of the outflow pathway. It allows for quantifying 3D, depth-dependent, dynamic traction forces exerted by both normal and glaucomatous TM cells within an active fluid-structure interaction (FSI) environment. In our experimental design, we designed two scenarios: a control group with TM cells observed over 20 hours without flow (static setting), focusing on intrinsic cellular contractile forces, and a second scenario incorporating active FSI to evaluate its impact on traction forces (dynamic setting). Our observations revealed that active FSI results in higher traction forces (normal: 1.83-fold and glaucoma: 2.24-fold) and shear strains (normal: 1.81-fold and glaucoma: 2.41-fold), with stiffer substrates amplifying this effect. Glaucomatous cells consistently exhibited larger forces than normal cells. Increasing gel stiffness led to enhanced stress fiber formation in TM cells, particularly in glaucomatous cells. Exposure to active FSI dramatically altered actin organization in both normal and glaucomatous TM cells, particularly affecting cortical actin stress fiber arrangement. This model while preliminary offers a new method in understanding TM cell biomechanics and ECM stiffening in glaucoma, highlighting the importance of FSI in these processes. STATEMENT OF SIGNIFICANCE: This pioneering project presents an advanced 3D in vitro model, meticulously replicating the human trabecular meshwork's anatomy for glaucoma research. It enables precise quantification of cellular forces in a dynamic fluid-structure interaction, a leap forward from existing 2D models. This advancement promises significant insights into trabecular meshwork cell biomechanics and the stiffening of the extracellular matrix in glaucoma, offering potential pathways for innovative treatments. This research is positioned at the forefront of ocular disease study, with implications that extend to broader biomedical applications.

Design of a randomized clinical trial of brief couple therapy for PTSD augmented with intranasal oxytocin.

BACKGROUND: Leveraging military veterans' intimate relationships during treatment has the potential to concurrently improve posttraumatic stress disorder (PTSD) symptoms and relationship quality. Cognitive-Behavioral Conjoint Therapy (CBCT) and an 8-session Brief Cognitive-Behavioral Conjoint Therapy (bCBCT) are manualized treatments designed to simultaneously improve PTSD and relationship functioning for couples in which one partner has PTSD. Although efficacious in improving PTSD, the effects of CBCT on relationship satisfaction are small, especially among veterans. Intranasal oxytocin, which targets mechanisms of PTSD and relationship quality, may enhance the efficacy of bCBCT. METHOD/DESIGN: The purpose of this 4-year clinical trial is to compare the outcomes of bCBCT augmented with intranasal oxytocin versus bCBCT plus placebo. We will also explore potential mechanisms of action: self-reported communication skills, empathy, and trust. We will recruit 120 dyads (i.e., veteran with PTSD and their intimate partner) from the VA San Diego Healthcare System. Veterans will be administered 40 international units of oxytocin (n = 60) or placebo (n = 60) 30 min before each of 8 bCBCT sessions delivered via telehealth. Clinical and functioning outcomes will be assessed at five timepoints (baseline, mid-treatment, post-treatment, and 3- and 6-month follow-up). CONCLUSION: Study findings will reveal the efficacy of oxytocin-assisted brief couple therapy for PTSD, which could serve as highly scalable option for couples coping with PTSD, as well as provide preliminary evidence of interpersonal mechanisms of change. CLINICALTRIALS: govIdentifier:NCT06194851.

A single ALS center experience with clinical use of sodium phenylbutyrate-taurursodiol.

INTRODUCTION/AIMS: The aim of this study was to examine clinical utilization and discontinuation rates of sodium phenylbutyrate-taurursodiol (PB-TURSO) in a single Amyotrophic Lateral Sclerosis (ALS) center. PB-TURSO was approved by the United States Food and Drug Administration (FDA) in September 2022. Prior experience has been limited to clinical trials or expanded access protocols. In this manuscript, we discuss insurance approval rates, patient uptake, and discontinuation of PB-TURSO in a large academic center. METHODS: Records of patients seen for clinical visits between January 2022 and May 2023 were reviewed. Demographic and clinical characteristics of our clinic population and those initiating PB-TURSO were obtained from our clinical database. RESULTS: A total of 228 patients were seen during the observation period and 122 requested PB-TURSO prescriptions. 77% (94) were approved by insurance. 66% (65) of those who were approved or received free drug chose to start medication. 51% (34) of those who initiated PB-TURSO continued to take it through the end of the observation period. Four patients discontinued due to death during the observation period. Of the 29 patients who survived and discontinued, the main reasons for discontinuation were GI symptoms (17, 58.6%) and taste (8, 29.6%). DISCUSSION: PB-TURSO was approved by insurance for most patients. The discontinuation rate was high and was driven largely by GI side effects and taste. Future considerations would include deeper examination of demographic trends, patient costs, side effects, and potential benefits in clinical practice.

Segmental biomechanics of the normal and glaucomatous human aqueous outflow pathway.

The conventional aqueous outflow pathway, encompassing the trabecular meshwork (TM), juxtacanalicular connective tissue (JCT), and inner wall endothelium of Schlemm's canal (SC), governs intraocular pressure (IOP) regulation. This study targets the biomechanics of low-flow (LF) and high-flow (HF) regions within the aqueous humor outflow pathway in normal and glaucomatous human donor eyes, using a combined experimental and computational approach. LF and HF TM/JCT/SC complex tissues from normal and glaucomatous eyes underwent uniaxial tensile testing. Dynamic motion of the TM/JCT/SC complex was recorded using customized green-light optical coherence tomography during SC pressurization in cannulated anterior segment wedges. A hyperviscoelastic model quantified TM/JCT/SC complex properties. A fluid-structure interaction model simulated tissue-aqueous humor interaction. FluoSpheres were introduced into the pathway via negative pressure in the SC, with their motion tracked using two-photon excitation microscopy. Tensile test results revealed that the elastic moduli of the LF and HF regions in glaucomatous eyes are 3.5- and 1.5-fold stiffer than the normal eyes, respectively. The FE results also showed significantly larger shear moduli in the TM, JCT, and SC of the glaucomatous eyes compared to the normal subjects. The LF regions in normal eyes demonstrated larger elastic moduli compared to the HF regions in glaucomatous eyes. The resultant strain in the outflow tissues and velocity of the aqueous humor in the FSI models were in good agreement with the digital volume correlation and 3D particle image velocimetry data, respectively. This study uncovers stiffer biomechanical responses in glaucomatous eyes, with LF regions stiffer than HF regions in both normal and glaucomatous eyes. STATEMENT OF SIGNIFICANCE: This study delves into the biomechanics of the conventional aqueous outflow pathway, a crucial regulator of intraocular pressure and ocular health. By analyzing mechanical differences in low-flow and high-flow regions of normal and glaucomatous eyes, this research unveils the stiffer response in glaucomatous eyes. The distinction between regions' properties offers insights into aqueous humor outflow regulation, while the integration of experimental and computational methods enhances credibility. These findings have potential implications for disease management and present a vital step toward innovative ophthalmic interventions. This study advances our understanding of glaucoma's biomechanical basis and its broader impact on ocular health.

Dynamic traction force in trabecular meshwork cells: A 2D culture model for normal and glaucomatous states.

Glaucoma, which is associated with intraocular pressure (IOP) elevation, results in trabecular meshwork (TM) cellular dysfunction, leading to increased rigidity of the extracellular matrix (ECM), larger adhesion forces between the TM cells and ECM, and higher resistance to aqueous humor drainage. TM cells sense the mechanical forces due to IOP dynamic and apply multidimensional forces on the ECM. Recognizing the importance of cellular forces in modulating various cellular activities and development, this study is aimed to develop a 2D in vitro cell culture model to calculate the 3D, depth-dependent, dynamic traction forces, tensile/compressive/shear strain of the normal and glaucomatous human TM cells within a deformable polyacrylamide (PAM) gel substrate. Normal and glaucomatous human TM cells were isolated, cultured, and seeded on top of the PAM gel substrate with embedded FluoSpheres, spanning elastic moduli of 1.5 to 80 kPa. Sixteen-hour post-seeding live confocal microscopy in an incubator was conducted to Z-stack image the 3D displacement map of the FluoSpheres within the PAM gels. Combined with the known PAM gel stiffness, we ascertained the 3D traction forces in the gel. Our results revealed meaningfully larger traction forces in the glaucomatous TM cells compared to the normal TM cells, reaching depths greater than 10-µm in the PAM gel substrate. Stress fibers in TM cells increased with gel rigidity, but diminished when stiffness rose from 20 to 80 kPa. The developed 2D cell culture model aids in understanding how altered mechanical properties in glaucoma impact TM cell behavior and aqueous humor outflow resistance. STATEMENT OF SIGNIFICANCE: Glaucoma, a leading cause of irreversible blindness, is intricately linked to elevated intraocular pressures and their subsequent cellular effects. The trabecular meshwork plays a pivotal role in this mechanism, particularly its interaction with the extracellular matrix. This research unveils an advanced 2D in vitro cell culture model that intricately maps the complex 3D forces exerted by trabecular meshwork cells on the extracellular matrix, offering unparalleled insights into the cellular biomechanics at play in both healthy and glaucomatous eyes. By discerning the changes in these forces across varying substrate stiffness levels, we bridge the gap in understanding between cellular mechanobiology and the onset of glaucoma. The findings stand as a beacon for potential therapeutic avenues, emphasizing the gravity of cellular/extracellular matrix interactions in glaucoma's pathogenesis and setting the stage for targeted interventions in its early stages.

Implementing new computational methods for the study of JCT and SC inner wall basement membrane biomechanics and hydrodynamics.

PURPOSE: The conventional aqueous outflow pathway, which includes the trabecular meshwork (TM), juxtacanalicular tissue (JCT), and the inner wall endothelium of Schlemm's canal (SC), regulates intraocular pressure (IOP) by controlling the aqueous humor outflow resistance. Despite its importance, our understanding of the biomechanics and hydrodynamics within this region remains limited. Fluid-structure interaction (FSI) offers a way to estimate the biomechanical properties of the JCT and SC under various loading and boundary conditions, providing valuable insights that are beyond the reach of current imaging techniques. METHODS: In this study, a normal human eye was fixed at a pressure of 7 mm Hg, and two radial wedges of the TM tissues, which included the SC inner wall basement membrane and JCT, were dissected, processed, and imaged using 3D serial block-face scanning electron microscopy (SBF-SEM). Four different sets of images were used to create 3D finite element (FE) models of the JCT and inner wall endothelial cells of SC with their basement membrane. The outer JCT portion was carefully removed as the outflow resistance is not in that region, leaving only the SCE inner wall and a few µm of the tissue, which does contain the resistance. An inverse iterative FE algorithm was then utilized to calculate the unloaded geometry of the JCT/SC complex at an aqueous humor pressure of 0 mm Hg. Then in the model, the intertrabecular spaces, pores, and giant vacuole contents were replaced by aqueous humor, and FSI was employed to pressurize the JCT/SC complex from 0 to 15 mm Hg. RESULTS: In the JCT/SC complex, the shear stress of the aqueous humor is not evenly distributed. Areas proximal to the inner wall of SC experience larger stresses, reaching up to 10 Pa, while those closer to the JCT undergo lower stresses, approximately 4 Pa. Within this complex, giant vacuoles with or without I-pore behave differently. Those without I-pores experience a more significant strain, around 14%, compared to those with I-pores, where the strain is roughly 9%. CONCLUSIONS: The distribution of aqueous humor wall shear stress is not uniform within the JCT/SC complex, which may contribute to our understanding of the underlying selective mechanisms in the pathway.

Clinical characteristics of Long COVID patients presenting to a dedicated academic post-COVID-19 clinic in Central Texas.

Post-acute sequelae SARS-CoV-2 (PASC), also known as Long COVID, is a complex and widely recognized illness with estimates ranging from 5 to 30% of all COVID-19 cases. We performed a retrospective chart review of patients who presented to a dedicated Post-COVID-19 clinic between June 2021 and May 2022. The median patient age was 44.5 years, 63.5% patients were female, and patients presented at a median of 10.4 months from acute COVD-19 infection. 78% self-identified their race as white, and 21% identified as Latino ethnicity. During the acute COVID-19 infection, 50% of patients experienced moderate disease severity and 10.5% were hospitalized. The top three co-morbid conditions prior to SARS-CoV-2 infection included mental health conditions, hypertension and asthma. Patients reported a median of 18 new symptoms following COVID-19 illness, the most common were fatigue (89%), forgetfulness or "brain fog" (89%), and difficulty concentrating (77%). MoCA (Montreal Cognitive Assessment) assessment demonstrated that 46% had mild cognitive dysfunction. PHQ-9 (Patient Health Questionnaire) testing revealed 42% had moderate to severe depression, and 38% had moderate to severe anxiety on the GAD-7 (Generalized Anxiety Disorder) assessment. Symptom burden was similar across gender, age, and initial disease severity. PASC patients presenting to an academic Post-COVID-19 clinic experienced numerous multisystem symptoms and functional impairment, independent of the initial COVID-19 disease severity.

Growth differentiation factor 15 (GDF15) elevation in children with newly diagnosed cancer.

Background: Growth differentiation factor 15 (GDF15), an inflammatory marker and mediator of adult cancer cachexia, remains largely unexplored in children. GDF15 increases nausea, vomiting, and anorexia in cancer and contributes to malnutrition, with the potential to be a cachexia therapeutic target. No studies have examined GDF15 in children with newly diagnosed cancer. Our pilot study compares GDF15 in children with newly diagnosed cancer to age- and sex-matched controls and correlates levels with anthropometric measurements and quality of life (QOL). Methods: Children with newly diagnosed cancer aged 2-21 years were enrolled with serum GDF15 ELISA, anthropometric measures [height, weight, and mid-upper arm circumference (MUAC)], and QOL assessments (using PedsQL™ Core and Gastrointestinal Modules), which were collected at baseline and repeated 3 months later. Serum GDF15 levels were obtained from age- and sex-matched controls for comparison. Results: A total of 57 participants enrolled (N=30, cancer group; N=27, control group) with a median age of 8.8 years (IQR 5.6-15.9 years). The participants were primarily male (54.4%), white (82.5%), and non-Hispanic (82.5%). Cancer diagnoses included acute lymphoblastic leukemia (N=8), lymphoma (N=8), neuroblastoma (N=5), soft tissue tumors (N=4), acute myeloid leukemia (N=2), and single participants with brain, kidney, and bone tumors. Baseline GDF15 was higher in the cancer cohort compared to the control cohort (median=614.6pg/mL and 320.5pg/mL, respectively; p<0.001). When examining participants with evaluable baseline and 3-month follow-up GDF15 levels (N=18), GDF15 was not statistically different (median=657.1pg/mL and 675.3pg/mL, respectively; p=0.702). A total of 13 of the 30 participants and 21 caregivers completed the PedsQL™ Core and Gastrointestinal symptom modules. QOL scores did not differ significantly at 3-month follow-up compared to baseline, but diarrhea worsened (p=0.017). Median participant response for diarrhea at baseline was 92.9 (IQR=92.9-96.4; N=13), which was significantly better than the follow-up (median=78.6; IQR= 71.4-92.9; p=0.017). There were no correlations between change in height, weight, or MUAC and change in GDF15 levels (p=0.351, 0.920, and 0.269 respectively). Conclusion: GDF15 was elevated in children with cancer at diagnosis compared to controls but did not correlate with anthropometric measurements or QOL. This pilot study will inform future prospective studies to better describe the natural history of GDF15 and its role in cachexia and as a potential therapeutic target.

Unlocking Drug Resistance in Multiple Myeloma: Adipocytes as Modulators of Treatment Response.

Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of malignant plasma cells. Despite the development of a diverse array of targeted drug therapies over the last decade, patients often relapse and develop refractory disease due to multidrug resistance. Obesity is a growing public health threat and a risk factor for multiple myeloma, although the mechanisms by which obesity contributes to MM growth and progression have not been fully elucidated. In the present study, we evaluated whether crosstalk between adipocytes and MM cells promoted drug resistance and whether this was amplified by obesity. Human adipose-derived stem cells (ASCs) from nineteen normal (BMI = 20-25 kg/m2), overweight (25-30 kg/m2), or obese (30-35 kg/m2) patients undergoing elective liposuction were utilized. Cells were differentiated into adipocytes, co-cultured with RPMI 8226 or U266B1 multiple myeloma cell lines, and treated with standard MM therapies, including bortezomib or a triple combination of bortezomib, dexamethasone, and lenalidomide. We found that adipocytes from overweight and obese individuals increased cell adhesion-mediated drug resistance (CAM-DR) survival signals in MM cells, and P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) drug transporter expression. Further, co-culture enhanced in vitro angiogenesis, MMP-2 activity, and protected MM cells from drug-induced decreases in viability. In summary, we provide an underlying mechanism by which obesity can impair the drug response to MM and allow for recurrence and/or disease progression.

Biomechanics of the JCT and SC Inner Wall Endothelial Cells with Their Basement Membrane Using 3D Serial Block-Face Scanning Electron Microscopy.

BACKGROUND: More than ~70% of the aqueous humor exits the eye through the conventional aqueous outflow pathway that is comprised of the trabecular meshwork (TM), juxtacanalicular tissue (JCT), the inner wall endothelium of Schlemm's canal (SC). The flow resistance in the JCT and SC inner wall basement membrane is thought to play an important role in the regulation of the intraocular pressure (IOP) in the eye, but current imaging techniques do not provide enough information about the mechanics of these tissues or the aqueous humor in this area. METHODS: A normal human eye was perfusion-fixed and a radial wedge of the TM tissue from a high-flow region was dissected. The tissues were then sliced and imaged using serial block-face scanning electron microscopy. Slices from these images were selected and segmented to create a 3D finite element model of the JCT and SC cells with an inner wall basement membrane. The aqueous humor was used to replace the intertrabecular spaces, pores, and giant vacuoles, and fluid-structure interaction was employed to couple the motion of the tissues with the aqueous humor. RESULTS: Higher tensile stresses (0.8-kPa) and strains (25%) were observed in the basement membrane beneath giant vacuoles with open pores. The volumetric average wall shear stress was higher in SC than in JCT/SC. As the aqueous humor approached the inner wall basement membrane of SC, the velocity of the flow decreased, resulting in the formation of small eddies immediately after the flow left the inner wall. CONCLUSIONS: Improved modeling of SC and JCT can enhance our understanding of outflow resistance and funneling. Serial block-face scanning electron microscopy with fluid-structure interaction can achieve this, and the observed micro-segmental flow patterns in ex vivo perfused human eyes suggest a hypothetical mechanism.

Developing a compassionate community: a Canadian conceptual model for community capacity development.

The purpose of this article is to share a Canadian model called Developing a Compassionate Community (DCC) in which aging, dying, caregiving, and grieving are everyone's responsibility. The model provides a research-informed practice guide for people who choose to adopt a community capacity development approach to developing a compassioante community. Based on 30 years of Canadian research by the author in rural, urban, First Nations communities, and long-term care homes, the DCC model offers a practice theory and practical tool. The model incorporates the principles of community capacity development which are as follows: change is incremental and in phases, but nonlinear and dynamic; the change process takes time; development is essentially about developing people; development builds on existing resources (assets); development cannot be imposed from the outside; and development is ongoing (never-ending). Community capacity development starts with citizens who want to make positive changes in their lives and their community. They become empowered by gaining the knowledge, skills, and resources they need. The community mobilizes around finding solutions rather than discussing problems. Passion propels their action and commitment drives the process. The strategy for change is engaging, empowering, and educating community members to act on their own behalf. It requires mobilizing networks of families, friends, and neighbors across the community, wherever people live, work, or play. Community networks are encouraged to prepare for later life, and for giving and getting help among themselves. This Canadian model offers communities one approach to developing a compassionate community and is a resource for implementing a public health approach to end-of-life care in Canada. The model is also available to be evaluated for its applicability beyond Canada and is designed to be adapted to new contexts if desired.

Morphological and biomechanical analyses of the human healthy and glaucomatous aqueous outflow pathway: Imaging-to-modeling.

BACKGROUND AND OBJECTIVE: Intraocular pressure (IOP) is maintained via a dynamic balance between the production of aqueous humor and its drainage through the trabecular meshwork (TM), juxtacanalicular connective tissue (JCT), and Schlemm's canal (SC) endothelium of the conventional outflow pathway. Primary open angle glaucoma (POAG) is often associated with IOP elevation that occurs due to an abnormally high outflow resistance across the outflow pathway. Outflow tissues are viscoelastic and actively interact with aqueous humor dynamics through a two-way fluid-structure interaction coupling. While glaucoma affects the morphology and stiffness of the outflow tissues, their biomechanics and hydrodynamics in glaucoma eyes remain largely unknown. This research aims to develop an image-to-model method allowing the biomechanics and hydrodynamics of the conventional aqueous outflow pathway to be studied. METHODS: We used a combination of X-ray computed tomography and scanning electron microscopy to reconstruct high-fidelity, eye-specific, 3D microstructural finite element models of the healthy and glaucoma outflow tissues in cellularized and decellularized conditions. The viscoelastic TM/JCT/SC complex finite element models with embedded viscoelastic beam elements were subjected to a physiological IOP load boundary; the stresses/strains and the flow state were calculated using fluid-structure interaction and computational fluid dynamics. RESULTS: Based on the resultant hydrodynamics parameters across the outflow pathway, the primary site of outflow resistance in healthy eyes was in the JCT and immediate vicinity of the SC inner wall, while the majority of the outflow resistance in the glaucoma eyes occurred in the TM. The TM and JCT in the glaucoma eyes showed 1.32-fold and 1.13-fold larger beam thickness and smaller trabecular space size (2.24-fold and 1.50-fold) compared to the healthy eyes. CONCLUSIONS: Characterizing the accurate morphology of the outflow tissues may significantly contribute to constructing more accurate, robust, and reliable models, that can eventually help to better understand the dynamic IOP regulation, hydrodynamics of the aqueous humor, and outflow resistance dynamic in the human eyes. This model demonstrates proof of concept for determining changes to outflow resistance in healthy and glaucomatous tissues and thus may be utilized in larger cohorts of donor tissues where disease specificity, race, age, and gender of the eye donors may be accounted for.

Efficacy and Safety of Sublingual Cyclobenzaprine for the Treatment of Fibromyalgia: Results From a Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To evaluate the efficacy and safety of TNX-102 SL, a once-nightly sublingual formulation of cyclobenzaprine, in reducing pain in patients with fibromyalgia (FM). METHODS: RELIEF was a double-blind, randomized, placebo-controlled trial. Overall, 503 patients received TNX-102 SL 2.8 mg for 2 weeks, followed by 5.6 mg for 12 weeks (248 patients), or matching placebo (255 patients). The primary end point was change from baseline at week 14 in the weekly average of daily pain scores. Secondary end points included Patient Global Impression of Change (PGIC) scores, Fibromyalgia Impact Questionnaire Revised (FIQR) scores, Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance and Fatigue scores, and daily sleep quality. Safety was assessed by adverse event (AE) reporting. RESULTS: Reduction in daily pain from baseline at week 14 was significantly greater with TNX-102 SL (least squares [LS] mean change -1.9 [95% confidence interval (95% CI) -2.1, -1.7]) versus placebo (LS mean change -1.5 [95% CI -1.7, -1.3]; P = 0.01). TNX-102 SL was not associated with significant improvement in PGIC at week 14 but was associated with improvements in FIQR scores, PROMIS scores, and daily sleep quality. Overall, 59.7% of patients receiving TNX-102 SL and 46.3% receiving placebo reported treatment-emergent AEs; the most common were oral hypoesthesia (17.3% with TNX-102 SL versus 0.4% with placebo), oral paresthesia (5.6% versus 0.4%, respectively), and product taste abnormal (4.4% versus 0.4%, respectively). CONCLUSION: In this phase III, randomized, controlled trial of patients with FM, treatment with TNX-102 SL was associated with significant reductions in daily pain and was safe and well tolerated.

Developing an experimental-computational workflow to study the biomechanics of the human conventional aqueous outflow pathway.

The aqueous humor actively interacts with the trabecular meshwork (TM), juxtacanalicular tissue (JCT), and Schlemm's canal (SC) through a dynamic fluid-structure interaction (FSI) coupling. Despite the fact that intraocular pressure (IOP) undergoes significant fluctuations, our understanding of the hyperviscoelastic biomechanical properties of the aqueous outflow tissues is limited. In this study, a quadrant of the anterior segment from a normal human donor eye was dynamically pressurized in the SC lumen, and imaged using a customized optical coherence tomography (OCT). The TM/JCT/SC complex finite element (FE) with embedded collagen fibrils was reconstructed based on the segmented boundary nodes in the OCT images. The hyperviscoelastic mechanical properties of the outflow tissues' extracellular matrix with embedded viscoelastic collagen fibrils were calculated using an inverse FE-optimization method. Thereafter, the 3D microstructural FE model of the TM, with adjacent JCT and SC inner wall, from the same donor eye was constructed using optical coherence microscopy and subjected to a flow load-boundary from the SC lumen. The resultant deformation/strain in the outflow tissues was calculated using the FSI method, and compared to the digital volume correlation (DVC) data. TM showed larger shear modulus (0.92 MPa) compared to the JCT (0.47 MPa) and SC inner wall (0.85 MPa). Shear modulus (viscoelastic) was larger in the SC inner wall (97.65 MPa) compared to the TM (84.38 MPa) and JCT (56.30 MPa). The conventional aqueous outflow pathway is subjected to a rate-dependent IOP load-boundary with large fluctuations. This necessitates addressing the biomechanics of the outflow tissues using hyperviscoelastic material-model. STATEMENT OF SIGNIFICANCE: While the human conventional aqueous outflow pathway is subjected to a large-deformation and time-dependent IOP load-boundary, we are not aware of any studies that have calculated the hyperviscoelastic mechanical properties of the outflow tissues with embedded viscoelastic collagen fibrils. A quadrant of the anterior segment of a normal humor donor eye was dynamically pressurized from the SC lumen with relatively large fluctuations. The TM/JCT/SC complex were OCT imaged and the mechanical properties of the tissues with embedded collagen fibrils were calculated using the inverse FE-optimization algorithm. The resultant displacement/strain in the FSI outflow model was validated versus the DVC data. The proposed experimental-computational workflow may significantly contribute to understanding of the effects of different drugs on the biomechanics of the conventional aqueous outflow pathway.

Examining Influences on Problem Recognition and Help-Seeking for Child Externalizing Behaviors Among African American Mothers.

Childhood behavior problems are one of the most common clinical referrals. If left untreated, these behaviors can result in detrimental consequences to the child's development (Wehmeier et al., 2010; Scholtens et al., 2012). Behavior parent training has been identified as first-line treatment for oppositional behavior; however, many racial minority families fail to enroll in behavior parent training. The current study examines maternal help-seeking for children displaying oppositional behavior in hopes to delineate variables that might influence parent training enrollment among African American families. Participants were 112 African American mothers who were provided child behavior vignettes and completed measures assessing factors related to problem recognition, parental attributions, child rearing values, mental health stigmatization, racial identity, and treatment utilization. Results found that when presented with a child displaying clinically significant externalizing child behaviors, slightly more than half of African American mothers recognized clinically significant child behavior problems. Mothers were more likely to engage in behavioral parent training if problematic behavior was recognized. Additionally, mothers' attributions of child behavior, cultural values, and mental health stigmatization were influential to help seeking. This study supports the importance of considering cultural variables that impact problem recognition and subsequent treatment utilization among African American families.

Opening Doors to Recovery: A Randomized Controlled Trial of a Recovery-Oriented Community Navigation Service for Individuals With Serious Mental Illnesses and Repeated Hospitalizations.

Objective: Opening Doors to Recovery (ODR) is a community navigation and recovery support model created in southeast Georgia by diverse, collaborative stakeholders. Following promising results from a quasi-experimental study, this randomized controlled trial hypothesized that, among patients with serious mental illnesses being discharged from inpatient psychiatric settings, compared to those randomized to traditional case management (CM) services, those randomized to ODR would have (1) lower likelihood of hospitalization, fewer hospitalizations, and fewer inpatient days; (2) lower likelihood of arrest, fewer arrests, and longer time to arrest; and, secondarily, (3) greater housing satisfaction and housing stability; and (4) higher scores on several scales measuring recovery-related constructs.Methods: 240 individuals with Structured Clinical Interview for DSM-5 Disorders-based psychotic or mood disorders, functional impairment, and repeated hospitalizations were randomized (December 2014 to June 2018) to ODR or CM. Hospitalization and arrest data were collected from State agencies after 12 months, and housing- and recovery-related measures were collected in person, longitudinally at 4, 8, and 12 months. Intention-to-treat analyses were conducted. Effects of dropout were accounted for, and sensitivity analyses were run.Results: ODR was associated with fewer days hospitalized (RR = 0.86, P = .001), a lower incidence of arrests (OR = 0.35, P < .0005), and longer time to arrest (HR = 0.42, P = .001). In addition, measures of housing satisfaction (Cohen d = 0.45) and recovery (Cohen d = 0.33) were significantly more improved in ODR patients compared to CM patients.Conclusions: The ODR model appears to have advantages over more traditional CM services and could fill a gap in the service array. Studying the mediators of success, cost benefit, dissemination, fidelity, and financing of the model is warranted.Trial Registration: ClinicalTrials.gov identifier: NCT04612777.

Building Palliative Care Capacity for Generalist Providers in the Community: Results From the Capaciti Pilot Education Program.

Objective: Primary care providers play an important role in providing early palliative care, however they often lack practical supports to operationalize this approach in practice. CAPACITI is a virtual training program aimed at providing practical tips, strategies, and action plans to help primary care providers offer an early palliative approach to care. The CAPACITI pilot program consisted of 10 facilitated, monthly training sessions, covering identification and assessment, communication, and engaging caregivers and specialists. We present the findings of an evaluation of the pilot program. Method: We conducted a single cohort study of primary care providers who participated in CAPACITI. Study outcomes were the change in the percentage of caseload reported as requiring palliative care and improved confidence in competencies measured on a 20-item, study-created survey. Pre and post survey data were analyzed using paired t-tests. Results: Twenty-two teams representing 127 care providers (including 36 physicians and 28 Nurse Practitioners) completed CAPACITI. Paired comparisons showed a moderate improvement in confidence across the competencies covered (.6 to 1.3 mean improvement across items using seven-point scales, all P < .05). Pre-CAPACITI, clinician prescribers (N = 32) identified a mean of 1.2% of their caseload requiring a palliative approach to care, which increased to 1.6% post-program (P = .02). Said differently, the total group of paired clinician prescribers identified 338 patients as requiring palliative care in their caseloads at baseline vs 482 patients following the intervention, for an overall increase of 144 patients in their collective caseloads. Conclusion: CAPACITI improved self-assessed palliative care identification and provider confidence in core competencies. The program demonstrated potential for building palliative care capacity in primary care teams.

Young Adult Routines Inventory (YARI): Development and Initial Validation.

Young adulthood is characterized by important life transitions (e.g., college, employment, relocation, marriage), where time management skills and routines help promote positive adjustment. Routines are observable, repetitive behavior that are context specific and automate aspects of daily life (e.g., personal hygiene, health, occupational, academic). Although measures of routines exist for children, adolescents, and older adults, similar measures assessing young adult routines are lacking. The purpose of this study was to develop and initially validate The Young Adult Routines Inventory (YARI). Analyses revealed a four-factor measure reflecting daily routines, social routines, time management, and procrastination. The YARI demonstrates good internal consistency, construct, and convergent validity, and was positively correlated with measures of emotional well-being and perceived life satisfaction. The YARI was negatively correlated with self-reported symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) and successfully distinguished individuals with and without ADHD symptomatology. Preliminary evidence suggests the YARI is a promising measure of young adult routines.

Modeling the Endothelial Glycocalyx Layer in the Human Conventional Aqueous Outflow Pathway.

A layer of proteoglycans and glycoproteins known as glycocalyx covers the surface of the trabecular meshwork (TM), juxtacanalicular tissue (JCT), and Schlemm's canal (SC) inner wall of the conventional aqueous outflow pathway in the eye. This has been shown to play a role in the mechanotransduction of fluid shear stress and in the regulation of the outflow resistance. The outflow resistance in the conventional outflow pathway is the main determinant of the intraocular pressure (IOP) through an active, two-way, fluid-structure interaction coupling between the outflow tissues and aqueous humor. A 3D microstructural finite element (FE) model of a healthy human eye TM/JCT/SC complex with interspersed aqueous humor was constructed. A very thin charged double layer that represents the endothelial glycocalyx layer covered the surface of the elastic outflow tissues. The aqueous humor was modeled as electroosmotic flow that is charged when it is in contact with the outflow tissues. The electrical-fluid-structure interaction (EFSI) method was used to couple the charged double layer (glycocalyx), fluid (aqueous humor), and solid (outflow tissues). When the IOP was elevated to 15 mmHg, the maximum aqueous humor velocity in the EFSI model was decreased by 2.35 mm/s (9%) compared to the fluid-structure interaction (FSI) model. The charge or electricity in the living human conventional outflow pathway generated by the charged endothelial glycocalyx layer plays a minor biomechanical role in the resultant stresses and strains as well as the hydrodynamics of the aqueous humor.

The Effect of Intraocular Pressure Load Boundary on the Biomechanics of the Human Conventional Aqueous Outflow Pathway.

BACKGROUND: Aqueous humor outflow resistance in the trabecular meshwork (TM), juxtacanalicular connective tissue (JCT), and Schlemm's canal (SC) endothelium of the conventional outflow pathway actively contribute to intraocular pressure (IOP) regulation. Outflow resistance is actively affected by the dynamic outflow pressure gradient across the TM, JCT, and SC inner wall tissues. The resistance effect implies the presence of a fluid-structure interaction (FSI) coupling between the outflow tissues and the aqueous humor. However, the biomechanical interactions between viscoelastic outflow tissues and aqueous humor dynamics are largely unknown. METHODS: A 3D microstructural finite element (FE) model of a healthy human eye TM/JCT/SC complex was constructed with elastic and viscoelastic material properties for the bulk extracellular matrix and embedded elastic cable elements. The FE models were subjected to both idealized and a physiologic IOP load boundary using the FSI method. RESULTS: The elastic material model for both the idealized and physiologic IOP load boundary at equal IOPs showed similar stresses and strains in the outflow tissues as well as pressure in the aqueous humor. However, outflow tissues with viscoelastic material properties were sensitive to the IOP load rate, resulting in different mechanical and hydrodynamic responses in the tissues and aqueous humor. CONCLUSIONS: Transient IOP fluctuations may cause a relatively large IOP difference of ~20 mmHg in a very short time frame of ~0.1 s, resulting in a rate stiffening in the outflow tissues. Rate stiffening reduces strains and causes a rate-dependent pressure gradient across the outflow tissues. Thus, the results suggest it is necessary to use a viscoelastic material model in outflow tissues that includes the important role of IOP load rate.