Explicit Theory-Informed Clinical Reasoning Curriculum in a Hybrid Learning Physical Therapy Program.

Despite agreement among educators that clinical reasoning (CR) is an essential skill for health care professionals, use of explicit, theory-informed CR strategies and tools are lacking in Doctor of Physical Therapy (DPT) educational programs. The purpose of this commentary is to describe a four-step process whereby CR is implemented as an explicit curricular component in an accelerated, hybrid DPT program. Our process utilized four steps: 1) Identifying relevant literature and theories that informed our current understanding of CR, 2) Creating a programmatic definition of CR, 3) Delineating educational principles and curricular components that operationalize the teaching and assessment of CR, and 4) Developing the faculty to implement CR in the curriculum. A DPT program that explicitly implemented CR into its curriculum received state and regional approval, and Candidate for Accreditation status and admitted its first cohort in 2022. Programmatic outcomes will be reported in two years. The curriculum was purposefully constructed with the goal to make proficiency in CR a required outcome. Robust teaching, learning, and assessment strategies were developed to cultivate and make explicit the essential behaviors and skills of CR. Setting high expectations for adaptive learners will add to the culture that supports excellence in PT education.

Effective chimeric antigen receptor T cells against SARS-CoV-2.

Current therapies to treat coronavirus disease 2019 (COVID-19) involve vaccines against the spike protein S1 of SARS-CoV-2. Here, we outline an alternative approach involving chimeric antigen receptors (CARs) in T cells (CAR-Ts). CAR-T recognition of the SARS-CoV-2 receptor-binding domain (RBD) peptide induced ribosomal protein S6 phosphorylation, the increased expression of activation antigen, CD69 and effectors, interferon-γ, granzyme B, perforin, and Fas-ligand on overlapping subsets of CAR-Ts. CAR-Ts further showed potent in vitro killing of target cells loaded with RBD, S1 peptide, or expressing the S1 protein. The efficacy of killing varied with different sized hinge regions, whereas time-lapse microscopy showed CAR-T cluster formation around RBD-expressing targets. Cytolysis of targets was mediated primarily by the GZMB/perforin pathway. Lastly, we showed in vivo killing of S1-expressing cells by our SARS-CoV-2 CAR-Ts in mice. The successful generation of SARS-CoV-2 CAR-Ts represents a living vaccine approach for the treatment of COVID-19.

Severity, Irritability, Nature, Stage, and Stability (SINSS): A clinical perspective.

Clinical reasoning errors in health-care can be mitigated with the use of systematic strategies and tools. One of these strategies is the SINSS construct, an acronym for Severity, Irritability, Nature, Stage, and Stability. The construct of SINSS appears in several textbooks and peer-reviewed articles. However, it has been inconsistently defined and applied in clinical practice. In this clinical perspective, the terms of the SINSS construct are defined in detail and their application to clinical practice is discussed. Current research showing the application of SINSS as a whole in clinical practice and educational settings is also presented. Recommendations for future application of SINSS are provided to advance the study of clinical reasoning and help minimize diagnostic, prognostic, and interventional clinical errors. The systematic use of SINSS allows the clinician to gain a thorough understanding of the patient's condition and symptoms, which can lead to a well-tolerated and appropriately tailored physical examination and intervention. Additionally, the proper use of this construct can result in more optimal patient outcomes, as well as provide a structure for the mentor and learner in helping uncover errors in the learner's clinical reasoning process.

Reliability and accuracy of an expert physical therapist as a reference standard for a manual therapy joint mobilization trial.

Objective: Previous studies on learning joint mobilization techniques have used expert practitioners as the reference standard as there is no current evidence on what ideal forces would be for effective mobilizations. However, none of these trials have documented the reliability or accuracy of the reference standard. Therefore, the purpose of this study was to report both the reliability and accuracy of an expert physical therapist (PT) acting as a reference standard for a manual therapy joint mobilization trial.Methods: A secondary analysis was performed using data from a published randomized, controlled, crossover study. The mobilization technique studied was the central posterior to anterior (PA) joint mobilization of the L3 vertebra. Reliability and accuracy data for the reference standard were collected over four time periods spanning 16 weeks.Results: Intrarater reliability of the expert PT for R1 and R2 joint forces was excellent (R1 Force ICC3,3 0.95, 95%CI 0.76-0.99 and R2 Force ICC3,3 0.90, 95%CI 0.49-0.99). Additionally, the expert PT was 92.3% accurate (mean % error±SD, 7.7 ± 5.5) when finding Grade III mean peak mobilization force and 85.1% accurate (mean % error±SD, 14.9 ± 8.3) when finding Grade IV mean peak mobilization force. Finally, correlations between actual applied forces and computed ideal forces were excellent (Pearson r 0.79-0.92, n = 24, P < 0.01 for all correlations).Discussion: The expert PT in this manual therapy joint mobilization trial showed excellent reliability and accuracy as the reference standard. The study supports the use of implementing quantitative feedback devices into the teaching of joint mobilization when a reliable and accurate reference standard has been identified.Level of Evidence: 2b.

Structural basis for STAT2 suppression by flavivirus NS5.

Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy that viruses use to establish infections, yet the detailed mechanism remains elusive, owing to a lack of structural information about the viral-cellular complex involved. Here, we report the cryo-EM and crystal structures of human STAT2 (hSTAT2) in complex with the non-structural protein 5 (NS5) of Zika virus (ZIKV) and dengue virus (DENV), revealing two-pronged interactions between NS5 and hSTAT2. First, the NS5 methyltransferase and RNA-dependent RNA polymerase (RdRP) domains form a conserved interdomain cleft harboring the coiled-coil domain of hSTAT2, thus preventing association of hSTAT2 with interferon regulatory factor 9. Second, the NS5 RdRP domain also binds the amino-terminal domain of hSTAT2. Disruption of these ZIKV NS5-hSTAT2 interactions compromised NS5-mediated hSTAT2 degradation and interferon suppression, and viral infection under interferon-competent conditions. Taken together, these results clarify the mechanism underlying the functional antagonism of STAT2 by both ZIKV and DENV.

The effect of real-time feedback on learning lumbar spine joint mobilization by entry-level doctor of physical therapy students: a randomized, controlled, crossover trial.

OBJECTIVE: To examine the effects of real-time, objective feedback on learning lumbar spine joint mobilization techniques by entry-level Doctor of Physical Therapy (DPT) students. METHODS: A randomized, controlled, crossover design was used. Twenty-four 1st Year DPT students were randomized into two groups. Group 1 (n = 12) practiced with the real-time feedback device first and then without it, while Group 2 (n = 12) practiced without the device first and then with it. Both practice periods with and without the device were 4 weeks long. Data were collected at Baseline, 5 weeks, 11 weeks, and 16 weeks. The crossover period was 5 weeks long, during which neither group practiced with or without the device. Eight force parameters were measured: R1 force; R2 force; Grade III and Grade IV mean peak force, frequency, and amplitude. RESULTS: When students practiced with the real-time feedback device, they more closely matched the reference standard for two outcomes: 1) the mean difference in R2 force between student and reference standard was better with device (38.0 ± 26.7 N) than without it (51.0 ± 38.5 N); P = .013; and 2) the mean difference in Grade III peak to peak amplitude force was also better with device (8.9 ± 9.3 N) than without it (11.8 ± 11.0); P = .026. All other force parameters improved when students practiced with the real-time feedback device, however, the differences between when they practiced without the device were not statistically significant. DISCUSSION: Real-time, objective feedback using a direct force measurement device improved learning for some aspects of lumbar spine joint mobilization by entry-level physical therapy students. LEVEL OF EVIDENCE: 2b.

Protein profiling and pseudo-parallel reaction monitoring to monitor a fusion-associated conformational change in hemagglutinin.

Influenza infection requires viral escape from early endosomes into the cytosol, which is enabled by an acid-induced irreversible conformational transformation in the viral protein hemagglutinin. Despite the direct relationship between this conformational change and infectivity, label-free methods for characterizing this and other protein conformational changes in biological mixtures are limited. While the chemical reactivity of the protein backbone and side-chain residues is a proxy for protein conformation, coupling this reactivity to quantitative mass spectrometry is a challenge in complex environments. Herein, we evaluate whether electrophilic amidination coupled with pseudo-parallel reaction monitoring is an effective label-free approach to detect the fusion-associated conformational transformation in recombinant hemagglutinin (rHA). We identified rHA peptides that are differentially amidinated between the pre- and post-fusion states, and validated that this difference relies upon the fusion-associated conformational switch. We further demonstrate that we can distinguish the fusion profile in a matrix of digested cellular lysate. This fusion assay can be used to evaluate fusion competence for modified HA. Graphical abstract.

Suppression of Type I Interferon Signaling by Flavivirus NS5.

Type I interferon (IFN-I) is the first line of mammalian host defense against viral infection. To counteract this, the flaviviruses, like other viruses, have encoded a variety of antagonists, and use a multi-layered molecular defense strategy to establish their infections. Among the most potent antagonists is non-structural protein 5 (NS5), which has been shown for all disease-causing flaviviruses to target different steps and players of the type I IFN signaling pathway. Here, we summarize the type I IFN antagonist mechanisms used by flaviviruses with a focus on the role of NS5 in regulating one key regulator of type I IFN, signal transducer and activator of transcription 2 (STAT2).

Structure and function of Zika virus NS5 protein: perspectives for drug design.

Zika virus (ZIKV) belongs to the positive-sense single-stranded RNA-containing Flaviviridae family. Its recent outbreak and association with human diseases (e.g. neurological disorders) have raised global health concerns, and an urgency to develop a therapeutic strategy against ZIKV infection. However, there is no currently approved antiviral against ZIKV. Here we present a comprehensive overview on recent progress in structure-function investigation of ZIKV NS5 protein, the largest non-structural protein of ZIKV, which is responsible for replication of the viral genome, RNA capping and suppression of host interferon responses. Structural comparison of the N-terminal methyltransferase domain and C-terminal RNA-dependent RNA polymerase domain of ZIKV NS5 with their counterparts from related viruses provides mechanistic insights into ZIKV NS5-mediated RNA replication, and identifies residues critical for its enzymatic activities. Finally, a collection of recently identified small molecule inhibitors against ZIKV NS5 or its closely related flavivirus homologues are also discussed.

Differential Diagnosis in a Patient Presenting With Both Systemic and Neuromusculoskeletal Pathology: Resident's Case Problem.

Study Design Resident's case problem. Background Patients presenting with multiple symptomatic areas pose a diagnostic challenge for the physical therapist. Though musculoskeletal and nonmusculoskeletal symptoms typically present separately, they can occur simultaneously and mimic each other. Consequently, the ability to differentiate between musculoskeletal and nonmusculoskeletal symptoms is an important skill for physical therapists. The purpose of this resident's case problem was to describe the clinical-reasoning process leading to medical and physical therapy management of a patient presenting with upper and lower back pain, bilateral radiating arm and leg pain, and abdominal pain. Diagnosis The patient was a 30-year-old woman referred to physical therapy for upper and lower back pain. A detailed history and thorough examination revealed that the patient had signs and symptoms consistent with a possible abdominal aortic aneurysm. She was referred for medical management and was diagnosed with symptomatic cholelithiasis. She subsequently had a cholecystectomy, which ultimately resolved her abdominal pain and reduced her pain in other areas significantly. Although many of her symptoms resolved postoperatively, her pain in other areas remained and was potentially musculoskeletal in origin. Following re-evaluation and 3 physical therapy treatments over a 2-month period, she was relatively symptom free at discharge and had achieved all functional rehabilitation goals. Discussion This resident's case problem provides an opportunity to discuss the differential diagnosis, clinical reasoning, and outcome of a patient who presented with both systemic and neuromusculoskeletal pathology. Level of Evidence Differential diagnosis, level 5. J Orthop Sports Phys Ther 2018;48(6):496-503. Epub 6 Feb 2018. doi:10.2519/jospt.2018.7652.

Zika virus genome biology and molecular pathogenesis.

Zika virus (ZIKV) is an emerging RNA virus in the widespread Flavivirus genus. Recently, ZIKV has rapidly spread around the world and has been implicated in human disease, including neurological disorders, triggering public and scientific attention. Understanding how ZIKV causes disease is the highest priority, yet little is known about this virus. Here we examine the currently published data from ZIKV studies to provide the latest understanding of ZIKV genome biology and molecular pathogenesis. The ZIKV genome evolved rapidly from the Flavivirus genus and diverged from the members of this genus, even within the dengue virus cluster to which ZIKV belongs. Genome variations and divergences also exist among ZIKV strains/isolates. These genome divergences might account for the uniqueness of Zika disease. ZIKV infection activates not only the antiviral immune response but also the pro-inflammatory responses associated with disease symptoms. Strikingly, ZIKV activates protein complexes that are functionally associated with disease process, such as glial cell activation and proliferation (for example, Toll-like receptors), apoptosis and cell death, and inflammation. The activation of these complexes may critically contribute to Zika disease. The novel insights into ZIKV genome divergence and disease mechanisms summarized in this review will help accelerate the development of anti-ZIKV strategies.

The structure of Zika virus NS5 reveals a conserved domain conformation.

The recent outbreak of Zika virus (ZIKV) has imposed a serious threat to public health. Here we report the crystal structure of the ZIKV NS5 protein in complex with S-adenosyl-L-homocysteine, in which the tandem methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) domains stack into one of the two alternative conformations of flavivirus NS5 proteins. The activity of this NS5 protein is verified through a de novo RdRp assay on a subgenomic ZIKV RNA template. Importantly, our structural analysis leads to the identification of a potential drug-binding site of ZIKV NS5, which might facilitate the development of novel antivirals for ZIKV.

The effectiveness of Pilates on balance and falls in community dwelling older adults.

PURPOSE: The purpose of this study was to determine whether Pilates is more effective than traditional strength and balance exercises for improving balance measures, balance confidence and reducing falls in community dwelling older adults with fall risk. METHOD: Thirty-one participants with fall risk were randomly assigned to the Pilates group (PG) or the traditional exercise group (TG). Both groups participated in 12 weeks of exercise, 2 times/week for 1 h. RESULTS: There was significant improvement in the Fullerton Advanced Balance Scale for both the PG (mean difference = 6.31, p < .05) and the TG (mean difference = 7.45, p = .01). The PG also showed significant improvement in the Activities-Specific Balance Confidence Scale (mean difference = 10.57, p = .008). CONCLUSION: Both Pilates and traditional balance programs are effective at improving balance measures in community dwelling older adults with fall risk, with the Pilates group showing improved balance confidence.