Understanding Allosteric Modulation of G-Protein Coupled Receptors

G protein-coupled receptors (GPCRs) which are seven-transmembrane allosteric machine constitutes largest and diverse family of membrane proteins. GPCR participate in activating a diverse range of signaling pathways, in response to ligand perturbation which ranges from neurotransmitters, hormones to photons. The role of GPCRs in a wide range of key physiological processes and their ubiquity in mammalian genome makes them attractive pharmaceutical targets. Signal transduction in GPCR occur mainly, via G-proteins and leads to a cascade of signaling. In addition to the orthosteric site, GPCRs also possesses a topographically distinct allosteric site which contributes to allosteric modulation, i.e long distant ligand binding for activating G proteins and trigger GDP release. The mechanism that governs allosteric activation triggering GDP release is yet uncertain. Differential ligands bind to GPCR\u27s orthosteric sites and can modulate allosteric signaling. Ligands that increase or decrease the GPCR signaling are classified as agonists and antagonists respectively. Compared to orthosteric ligand allosteric modulator through electrostatic repulsion, steric hindrance or conformational stability can select subsets of signaling responses. We in this study are trying to understand the basis of ligand-biased signaling or functional selectivity that leads to long-distance signaling in a receptor. Using the information from crystal structures of the receptor, combined with molecular dynamics simulations, we performed a systematic analysis to identify the basis of conformational selectivity for allosteric bias in GPCRs. Our study explores the conformational landscape of GPCRs as a function of the activity of the receptor. Normal modes analysis (NMA) was used to identify low-frequency modes that describe conformational changes due to large-scale domain motions in the receptor. NMA characterized changes in correlated motions of residues in the rest six global modes and revealed conformation shift starting from the inactive structure. We used MD simulations coupled with network analysis to reveal correlated motion between G-protein Coupling site and ligand binding site. Changes in dynamically correlated residue motion in allosteric networks reveals the characteristic feature of receptor activity in GPCRs. Single point mutations studies were aimed to analyze the changes in the structural scaffold of GPCRs as a result of mutations. Mutational studies facilitated in determining the basis of functional selectivity and changes in the allosteric communication as a result of allosteric binding to the receptor. Single point mutations also revealed residues critical for functional activity of GPCRs. Inter residue contact network responsible for biased signaling using microsecond atomic level simulations reveals differential allosteric modulation. Finally, comparative analysis using mutual information in the internal coordinates of mutants and wild types helped to quantify the allosteric modulation and long-range cooperativity between binding sites in GPCRs

Admission Variables Predict Success in a Hybrid-online Physical Therapist Education Program

Purpose: Screening student applicants can be a valuable measure for hybrid-online Doctor of Physical Therapy (DPT) programs.Institutions embrace a wide variety of measurements that drive admissions decisions. However, uncertainties exist regarding the most accurate admission predictors of academic outcomes, especially among hybrid-online DPT programs. The purpose of this study was to examine predictive relationships between applicants’ admission variables and program grade point average and National Physical Therapy Examination (NPTE) performance in a cohort of entry-level hybrid-online DPT students. Methods: A retrospective cohort design and convenience sampling method was used across two entry-level hybrid-online DPT programs in the Southeastern US. Hybrid-online DPT programs utilized ≥51% online instructional delivery. Applicants’ undergraduate admissions records, DPT program academic records, and NPTE scores were collected. Multiple linear regression analyses tested the hypotheses. Cross-tabulations and McNemar’s test were used to identify cut-off scores for variables and odds-ratios of passing the NPTE. Results: N=377 were collected and analyzed from two hybrid-online DPT programs (N=143 [38%] Program A; N=234 [62%] Program B) between Fall of 2018 and Spring of 2020. Applicant undergraduate (uGPA) and trending (tGPA)(final 60 credits) predicted first-time NPTE pass rate (r2 = 0.30, p2 = 0.18, p2 = 0.26, p = 0.02), F(6, 370). Applicant uGPA and tGPA were associated with 3-fold and 2-fold increase odds of passing NPTE on the first attempt, respectively. Conclusions: This study suggests certain applicant variables may be more indicative of success and could be weighted more heavily during the application process. Cumulative and trending undergraduate GPA accurately predict academic performance in hybrid-online DPT education, and NPTE scores. Notably, GRE and undergraduate science GPA were unremarkable. Hybrid-online DPT program GPA strongly predicts outcomes in NPTE scores

Assessing Ground Reaction Forces and Degenerative Changes of Sound Limb in Unilateral Lower Extremity Amputees: A Systematic Review

Abstract Background: There is a rising number of individuals undergoing lower extremity amputation (LEA) and is associated with increased risk of comorbidities. Osteoarthritis (OA) and Degenerative Joint Disease (DJD) are conditions that cause reduction in an individual’s function, independence, and quality of life. Research Design: A search of multiple databases using terms associated with possible functional declines as evidenced by the International Classification of Functioning, Disability and Health (ICF), followed by assessment of evidence using the PEDro scoring method will be conducted. Multiple reviewers will screen, sort, rate and extract data from articles. Methods: A computer-aided literature search of PubMed, CINAHL, and Google Scholar was performed to identify studies published beginning in 2009 that investigated factors that contribute to degenerative changes in the contralateral limb of a unilateral LEA. Results: A total of 21 studies were selected from a total of 56 collected studies. Predictors of osteoarthritis (OA) following lower limb amputation include age, etiology, level of amputation, gender, Body Mass Index (BMI), comorbidity, pain, phantom pain, streng and OA. The impact of ground reaction forces on the sound limb varies between studies. In general, poor gait mechanics and resulting compensatory mechanisms are significant contributors to the occurrence of OA. Conclusion: There is a dearth of information relating to the prevention of degenerative changes in those with LEA and protocols for pain management and training pre- and post-joint replacement. The incidence of OA in the contralateral limb is still not fully understood. Further investigation into the biomechanics of compensatory mechanisms is necessary to fully understand the functional impact on the population. It is imperative to develop thorough physical therapy protocols for individuals in early onset of OA and those undergoing joint replacement due to degeneration

Creating Bridges of Interprofessional Education: Opportunities for Collaborating Across Multiple Disciplines and Campuses

Introduction and Purpose: The purpose of this special interest report is to discuss strategies used by to integrate simulation activities across multiple campuses and programs to foster inter- and intra-professional education. Inter-professional (IP) simulations were done between multiple campuses of a large scale, multi-state, health science university. These simulations utilized Doctor of Occupational Therapy (OTD), Doctor of Physical Therapy (DPT), and Master of Science Speech/Language Pathology (MS-SLP) students and faculty. IP simulations involved DPT students and faculty from the health sciences university in one state and physical therapist assistant (PTA) students and faculty from a different university in that same state. Summary of Use and Results: When IP learning opportunities are designed into health science curricula, it can enhance knowledge, skills, and attitudes to prepare future clinicians to work as part of a collaborative practice-ready workforce. Students participating in IP activities identified themselves having more competence and sense of salience with IP interactions. Valuable student learning occurs when students are armed with attitudes and knowledge of IP collaboration. Moving forward from these experiences, students can progress in IP activities that further translate into enhanced competencies and develop IP technical skills. Importance to Members: Integrating inter- and intra- professional education in clinical and academic settings has the potential to improve behaviors amongst team players promoting improved patient safety and patient outcomes. However, there continues to be a need for research demonstrating the efficacy of IPE and its impact on student and clinician learning and the effects on patient outcomes. IPE Simulation Opportunity 1: IP Collaboration of OT and PT Students: Within the first two weeks of beginning our OT and PT program, students are introduced to an interdisciplinary simulation experience to anchor emerging skills to basic concepts of patient care. The experience is simple and intimate, but organically creates open discussion much deeper than a lab activity involving students partnering with other students to practice learned therapeutic interventions and procedures. The experience is set up with a simulated patient prompted to ask the students questions such as “What is the difference between OT and PT?” Student observers watch as their fellow classmates in the simulation hot seat have to problem solve within a natural hospital environment. The experience brings to light the social components involved in the usually rehearsed informed consent, environmental barriers such as bed rails and tray tables, interprofessional communication with the other discipline with a patient present, and interpretation of vital assessments in patient friendly language. The class debriefs after the simulation to observations, perspectives, and insights. This initial simulation provides an initial experience bridging academia to real-world clinical practice. IPE Simulation Opportunity 2: Intgraprofessional Collaboration of PT and PTA Students Three short simulations were conducted with a group of DPT students and a group of PTA students. The first simulation was of PTA and DPT students reviewing a medical record together and planning for a treatment session on a complex neuro case with a recent history of seizures, traumatic brain injury (TBI), and craniotomy. They had a simulated Clinical Instructor (CI) to guide them. The second simulation involved mobilizing this patient in an EVA walker with multiple lines and tubes with the patient’s mother present with CI guidance as needed. The third simulation involved responding to the patient having a seizure with the mother present and then a debriefing with their CI on the session using the Clinical Performance Indicators (CPI) to guide the discussion. IPE Simulation Opportunity 3: Interprofessional Collaboration of OT, PT, and SLP During SLP program development, IPEC core competencies were mapped to the clinical curriculum and activities developed for OT, PT, and SLP students’ IPE experiences. The activities designed by an IPE faculty team included simulation case scenarios experienced by students each trimester. The case scenarios vary in complexity across IPEC competencies and sub-competencies. For each case scenario simulation, an SLP, PT, and OT student volunteer to act out the improvised scenario, with one or two other students acting as patients, caregivers, or other team members. The rest of the participants observe the scenario and upon completion, all students (actors and observers) participate in a debriefing, which includes reactions, observations, reflections, and discussion. The debrief sessions are structured using the General Interprofessional Debriefing Questions Facilitator Guide to ensure IPEC core competencies were addressed in the simulation. Student feedback is positive with general requests to offer additional experiences. Conclusions: It is important for future research to explore the validity, reliability, and efficacy of IP learning activities to develop best-practices in IPE. This will help clinicians and educators in customizing their needs to meet patient outcomes, accreditation standards, programmatic goals, and institutional goals in their respective programs and settings

COVID-19 vaccine-associated myocarditis: Analysis of the suspected cases reported to the EudraVigilance and a systematic review of the published literature

BACKGROUND: Myocarditis secondary to Coronavirus Disease 2019 (COVID-19) vaccination has been reported in the literature. OBJECTIVE: This study aimed to characterize the reported cases of myocarditis after COVID-19 vaccination based on age, gender, doses, and vaccine type from published literature and the EudraVigilance database. METHODS: We performed an analysis in the EudraVigilance database (until December 18, 2021) and a systematic review of published literature for reported cases of suspected myocarditis and pericarditis (until 30th June 2022) after the COVID-19 vaccination. RESULTS: EudraVigilance database analysis revealed 16,514 reported cases of myocarditis or pericarditis due to the vaccination with COVID-19 vaccines. The cases of myo- or pericarditis were reported predominantly in the age group of 18-64 (n = 12,214), and in males with a male-to-female (M: F) ratio of 1.7:1. The mortality among myocarditis patients was low, with 128 deaths (2 cases per 10.000.000 administered doses) being reported. For the systematic review, 72 studies with 1026 cases of myocarditis due to the vaccination with COVID-19 vaccines were included. The analysis of published cases has revealed that the male gender was primarily affected with myocarditis post-COVID-vaccination. The median (IQR) age of the myocarditis cases was 24.6 [19.5-34.6] years, according to the systematic review of the literature. Myocarditis cases were most frequently published after the vaccination with m-RNA vaccines and after the second vaccination dose. The overall mortality of published cases was low (n = 5). CONCLUSION: Myocarditis is a rare serious adverse event associated with a COVID-19 vaccination. With early recognition and management, the prognosis of COVID-19 vaccine-induced myocarditis is favorable

Survey of CT radiation doses and iodinated contrast medium administration: an international multicentric study

ObjectiveTo assess the relationship between intravenous iodinated contrast media (ICM) administration usage and radiation doses for contrast-enhanced (CE) CT of head, chest, and abdomen-pelvis (AP) in international, multicenter settings. MethodsOur international (n = 16 countries), multicenter (n = 43 sites), and cross-sectional (ConRad) study had two parts. Part 1: Redcap survey with questions on information related to CT and ICM manufacturer/brand and respective protocols. Part 2: Information on 3,258 patients (18-96 years; M:F 1654:1604) who underwent CECT for a routine head (n = 456), chest (n = 528), AP (n = 599), head CT angiography (n = 539), pulmonary embolism (n = 599), and liver CT examinations (n = 537) at 43 sites across five continents. The following information was recorded: hospital name, patient age, gender, body mass index [BMI], clinical indications, scan parameters (number of scan phases, kV), IV-contrast information (concentration, volume, flow rate, and delay), and dose indices (CTDIvol and DLP). ResultsMost routine chest (58.4%) and AP (68.7%) CECT exams were performed with 2-4 scan phases with fixed scan delay (chest 71.4%; AP 79.8%, liver CECT 50.7%) following ICM administration. Most sites did not change kV across different patients and scan phases; most CECT protocols were performed at 120-140 kV (83%, 1979/2685). There were no significant differences between radiation doses for non-contrast (CTDIvol 24 [16-30] mGy; DLP 633 [414-702] mGycm) and post-contrast phases (22 [19-27] mGy; 648 [392-694] mGycm) (p = 0.142). Sites that used bolus tracking for chest and AP CECT had lower CTDIvol than sites with fixed scan delays (p < 0.001). There was no correlation between BMI and CTDIvol (r2 <= - 0.1 to 0.1, p = 0.931). ConclusionOur study demonstrates up to ten-fold variability in ICM injection protocols and radiation doses across different CT protocols. The study emphasizes the need for optimizing CT scanning and contrast protocols to reduce unnecessary contrast and radiation exposure to patients. Clinical relevance statementThe wide variability and lack of standardization of ICM media and radiation doses in CT protocols suggest the need for education and optimization of contrast usage and scan factors for optimizing image quality in CECT

A Comparison of Gait Kinetics between Prosthetic Feet during Functional Activities - Symmetry in External Work Approach

Background: Unilateral transtibial amputees (TTAs) show subtle gait variations while using different prosthetic feet. These variations have not been detected consistently with previous experimental measures. In this research project a novel measure for quantifying kinetic gait differences among prosthetic feet, called Symmetry in External Work (SEW), was introduced. The reliability of the SEW measure was calculated and its correlation with selected clinical measures was determined. The SEW measure was then applied to determine gait differences among four categories of prosthetic feet during various functional activities. Methodology: The study was conducted in three phases. Phase I was a single subject Pilot study to determine the sensitivity of the SEW measure to different prosthetic feet and functional activities. In Phase II, test-retest reliability of the SEW measure was determined for 5 TTAs during the functional activities of level walking, incline walking, decline walking, ascending stairs, descending stairs, sit-to-stand and stand-to-sit. The agreement between SEW values obtained from F-scan and force plates was also calculated. In Phase III, 11 subjects underwent 6 testing sessions over a period of 10-12 weeks. In session 1 subjects were tested wearing their existing prostheses (Baseline session), were given specialized prosthetic training and were tested again after 2 weeks (Training session). For sessions 3 through session 6, subjects were tested with a study socket and one of four randomized test feet. The test feet were SACH, SAFE, Talux and Proprio foot, classified as K1_foot, K2_foot, K3_foot and MP_foot, based on Medicare Functional Classification Level. The Step Watch Activity Monitor (SAM) recorded their daily activities in the 10-14 day accommodation period between two sessions. At each testing session, subjects completed the Prosthesis Evaluation Questionnaire (PEQ-13) and Usability questionnaire, and were evaluated using the Amputee Mobility Predictor (AMP) and the 6-minute walk test (6MWT). Ground reaction forces were collected using F-scan in-sole sensors as subjects performed the above mentioned functional activities. SEW values between the intact limb and the prosthetic limb were computed by integrating vertical ground reaction forces. Intra-class Correlation Coefficients (ICCs) were calculated to determine test-retest reliability and a repeated measure ANOVA was used to establish differences between the prosthetic feet. Results: The ICC values for Test-Retest reliability ranged from 0.84-0.94 for the various functional activities. There was moderate agreement between the SEW values calculated with F-scan and force plates. The SEW values were significantly different between the K3_foot and other feet during level walking and decline walking. During stair ascent, the MP_foot had a significantly higher SEW value than the other feet. There were no differences between feet during incline walking and stair descent. Training resulted in a significant improvement in symmetry from the Baseline session during sit-to-stand, while for stand-to-sit there were no differences between sessions. The PEQ-13 score was not different between sessions, while the Usability scores were significantly different between the K3_foot/MP_foot and K1_foot/K2_foot. The AMP score had a significant increase following Training while the 6MWT score showed a significant increase in the distance walked with the K1_foot, K3_foot and MP_foot over Baseline. The output of SAM did not show any difference in the number of steps or activity level of subjects. There was good to excellent correlation between the SEW values for level walking and other clinical outcome measures. Discussion and Conclusion: The SEW measure had excellent test-retest reliability and the agreement between the F-scan and force plates values could not be established because of a small sample size. The variations in SEW values were the result of distinctive designs of prosthetic feet. The high SEW value of the K3_foot can be attributed to its heel-toe foot plate and J shaped ankle spring design, which allowed for greater late stance stability. The active dorsiflexion feature of the MP_foot caused a change in strategy, typically used during stair ascent, resulting in a greater inter-limb symmetry. The SEW measure is a viable method to detect kinetic gait differences among prosthetic feet and represents a resource-effective alternative to traditional gait laboratories. It has several advantages and with further development of in-sole sensor technology, the potential for clinical use due to its relatively low cost instrumentation and minimal subject intervention

Developing Self-Efficacy in Doctoral Students for Treating Patients with Hand Therapy

In the Doctor of Physical Therapy (DPT) program, the process of fabricating orthotics, including prescribing, and modifying orthotics is documented in the Physical Therapy Guide to PT Practice as an intervention that physical therapists perform with patients. However, not all DPT students are educated on the process of fabricating orthoses or know which orthosis should be recommended for a specific diagnosis. Many patients who are diagnosed with a wrist or hand condition require an orthosis as part of the appropriate treatment. The problem addressed in this study is if DPT students do not typically learn about orthotics related to patient conditions and learn the fabrication process, they have decreased self-efficacy of treating patients with wrist and hand conditions. DPT students may have a higher self-efficacy of treating patients with hand and wrist conditions if they are educated on fabricating orthoses and know which orthosis to recommend for a diagnosis. Self-efficacy involves how an individual perceives themselves succeeding in a task. Working successfully in a challenging clinical environment is dependent on a physical therapist’s self-efficacy. The purpose of this quasi-experimental pretest posttest study was to explore the benefits of educating DPT students on upper extremity orthotics and fabricating upper extremity orthotics on the affect their self-efficacy of treating patients with wrist and hand dysfunction. The research helped to answer questions related to physical therapy students’ experience of an orthotics fabrication lab and the relationship, if any, of their self-efficacy of treating patients. Data was collected using a web-based survey including the adapted Physiotherapy Self Efficacy questionnaire and a question regarding future interest in hand therapy to evaluate if a relationship exists between self-efficacy and receiving training on upper extremity orthotic fabrication. Approximately 130 participants were recruited for the study. Recommendations for implementing orthotics training for DPT students were suggested based on results. Results from this study identify strong rationale to support orthodics training; including upper extremity orthotic fabrication and training, in DPT curricula. Future DPTs can be more prepared to treat a wrist and hand caseload and have successful treatment outcomes. Keywords: Physical therapy education, hand therapy, student engagement, orthosis patients, Bandura’s self-efficacy. DOI: 10.7176/RHSS/14-4-02 Publication date: May 30th 202

Admission Variables Predict Success in a Hybrid-online Physical Therapist Education Program

Purpose: Screening student applicants can be a valuable measure for hybrid-online Doctor of Physical Therapy (DPT) programs.Institutions embrace a wide variety of measurements that drive admissions decisions. However, uncertainties exist regarding the most accurate admission predictors of academic outcomes, especially among hybrid-online DPT programs. The purpose of this study was to examine predictive relationships between applicants’ admission variables and program grade point average and National Physical Therapy Examination (NPTE) performance in a cohort of entry-level hybrid-online DPT students. Methods: A retrospective cohort design and convenience sampling method was used across two entry-level hybrid-online DPT programs in the Southeastern US. Hybrid-online DPT programs utilized ≥51% online instructional delivery. Applicants’ undergraduate admissions records, DPT program academic records, and NPTE scores were collected. Multiple linear regression analyses tested the hypotheses. Cross-tabulations and McNemar’s test were used to identify cut-off scores for variables and odds-ratios of passing the NPTE. Results: N=377 were collected and analyzed from two hybrid-online DPT programs (N=143 [38%] Program A; N=234 [62%] Program B) between Fall of 2018 and Spring of 2020. Applicant undergraduate (uGPA) and trending (tGPA)(final 60 credits) predicted first-time NPTE pass rate (r2 = 0.30, p2 = 0.18, p2 = 0.26, p = 0.02), F(6, 370). Applicant uGPA and tGPA were associated with 3-fold and 2-fold increase odds of passing NPTE on the first attempt, respectively. Conclusions: This study suggests certain applicant variables may be more indicative of success and could be weighted more heavily during the application process. Cumulative and trending undergraduate GPA accurately predict academic performance in hybrid-online DPT education, and NPTE scores. Notably, GRE and undergraduate science GPA were unremarkable. Hybrid-online DPT program GPA strongly predicts outcomes in NPTE scores