Research Spotlight

DiPasquale, J., Trammell, M., Clark, K., Fowler, H., Callender, L., Bennett, M. and Swank, C. (2021). “Intensity of usual care physical therapy during inpatient rehabilitation for people with neurologic diagnoses.” Pm r Feb 18. [Epub ahead of print].

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INTRODUCTION: Early, intense rehabilitation is essential to promote recovery after stroke, spinal cord injury (SCI), and traumatic brain injury (TBI). However, intensity of usual care rehabilitation interventions during inpatient rehabilitation are poorly characterized. OBJECTIVE: We described the intensity of usual care rehabilitation interventions completed during the subacute phase of recovery from neurologic injury. DESIGN: Observational. SETTING: Inpatient Rehabilitation Facility. INTERVENTIONS: 22 usual care physical therapy interventions were grouped into 6 categories: gait (4 activities), functional (2), strengthening (4), aerobic (6), balance (4), and wheelchair (2). PATIENTS: Patients admitted to inpatient rehabilitation with a primary diagnosis of stroke, SCI or TBI within 6 months of injury. MAIN OUTCOME MEASURE(S): Cardiovascular intensity (physiological and perceived) was recorded during rehabilitation activity sessions. Physiological intensity was assessed by heart rate response (HRR) via a Polar A370 Fitness Watch and characterized as very light (<30%), light (30%-39%), moderate (40%-59%), vigorous (60%-89%), and near maximal (≥90%). Perceived intensity was assessed using the Rate of Perceived Exertion scale (RPE). RESULTS: Patients [stroke n = 16 (number of activity sessions = 388 / average session duration = 15.1 minutes); SCI n = 15 (299 / 27.3 minutes); TBI n = 15 (340 / 13.4 minutes)] participated. For patients with stroke, moderate-to-vigorous HRR was attained between 42% (aerobic exercise) to 55% (wheelchair propulsion) of activity sessions. For patients with SCI, moderate-to-vigorous HRR was attained between 29% (strength training) to 46% (gait training) of activity sessions. For patients with TBI, moderate-to-vigorous HRR was attained between 29% (balance activities) to 47% (gait training) of activity sessions. Associations between HRR and RPE were very weak across stroke (r = 0.12), SCI (r = 0.18), and TBI (r = 0.27). CONCLUSIONS: Patients with stroke, SCI, and TBI undergoing inpatient rehabilitation achieve moderate-to-vigorous intensity during some usual care activities such as gait training. Patient perception of intensity was dissimilar to physiological response.

Strack, J.E., Torres, V.A., Pennington, M.L., Cardenas, M.N., Dupree, J., Meyer, E.C., Dolan, S., Kruse, M.I., Synett, S.J., Kimbrel, N.A. and Gulliver, S.B. (2021). “Psychological distress and line-of-duty head injuries in firefighters.” Occup Med (Lond) Feb 18;kqab013. [Epub ahead of print].

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BACKGROUND: Head injuries are common injury in the fire service; however, very little data exist on the risks this may pose to the development of post-traumatic stress disorder (PTSD) and depression in this high-risk population. AIMS: Our study aimed to compare levels of PTSD and depression symptoms in firefighters with a line-of-duty head injury, non-line-of-duty head injury and no head injury. METHODS: In this cross-sectional study, we assessed current PTSD and depression symptoms as well as retrospective head injuries. RESULTS: Seventy-six per cent of the total sample reported at least one head injury in their lifetime. Depression symptoms were significantly more severe among firefighters with a line-of-duty head injury compared to those with no head injury, but not compared to those who sustained a non-line-of-duty head injury. Depression symptoms did not differ between firefighters with a non-line-of-duty head injury and those with no head injury. PTSD symptoms were significantly more severe among firefighters with a line-of-duty head injury compared to both firefighters with no head injury and those with a non-line-of-duty head injury. CONCLUSIONS: We found that firefighters who reported at least one line-of-duty head injury had significantly higher levels of PTSD and depression symptoms than firefighters who reported no head injuries. Our findings also suggest head injuries sustained outside of fire service could have less of an impact on the firefighter’s PTSD symptom severity than head injuries that occur as a direct result of their job.

Nazif, T.M., Moses, J., Sharma, R., Dhoble, A., Rovin, J., Brown, D., Horwitz, P., Makkar, R., Stoler, R., Forrest, J., Messé, S., Dickerman, S., Brennan, J., Zivadinov, R., Dwyer, M.G. and Lansky, A.J. (2021). “Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Replacement: REFLECT II.” JACC Cardiovasc Interv 14(5): 515-527.

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OBJECTIVES: The REFLECT II (Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Implantation) trial was designed to investigate the safety and efficacy of the TriGUARD 3 (TG3) cerebral embolic protection in patients undergoing transcatheter aortic valve replacement. BACKGROUND: Cerebral embolization occurs frequently following transcatheter aortic valve replacement and procedure-related ischemic stroke occurs in 2% to 6% of patients at 30 days. Whether cerebral protection with TriGuard 3 is safe and effective in reducing procedure-related cerebral injury is not known. METHODS: This prospective, multicenter, single-blind, 2:1 randomized (TG3 vs. no TG3) study was designed to enroll up to 345 patients. The primary 30-day safety endpoint (Valve Academic Research Consortium-2 defined) was compared with a performance goal (PG). The primary hierarchical composite efficacy endpoint (including death or stroke at 30 days, National Institutes of Health Stroke Scale score worsening in hospital, and cerebral ischemic lesions on diffusion-weighted magnetic resonance imaging at 2 to 5 days) was compared using the Finkelstein-Schoenfeld method. RESULTS: REFLECT II enrolled 220 of the planned 345 patients (63.8%), including 41 roll-in and 179 randomized patients (121 TG3 and 58 control subjects) at 18 US sites. The sponsor closed the study early after the U.S. Food and Drug Administration recommended enrollment suspension for unblinded safety data review. The trial met its primary safety endpoint compared with the PG (15.9% vs. 34.4% (p < 0.0001). The primary hierarchal efficacy endpoint at 30 days was not met (mean scores [higher is better]: -8.58 TG3 vs. 8.08 control; p = 0.857). A post hoc diffusion-weighted magnetic resonance imaging analysis of per-patient total lesion volume above incremental thresholds showed numeric reductions in total lesion volume >500 mm(3) (-9.7%) and >1,000 mm(3) (-44.5%) in the TG3 group, which were more pronounced among patients with full TG3 coverage: -51.1% (>500 mm(3)) and -82.9% (>1,000 mm(3)). CONCLUSIONS: The REFLECT II trial demonstrated that the TG3 was safe compared with a historical PG but did not meet its pre-specified primary superiority efficacy endpoint.

Kirtane, A.J., Stoler, R., Feldman, R., Neumann, F.J., Boutis, L., Tahirkheli, N., Toelg, R., Othman, I., Stein, B., Choi, J.W., Windecker, S., Yeh, R.W., Dauerman, H.L., Price, M.J., Underwood, P., Allocco, D., Meredith, I. and Kereiakes, D.J. (2021). “Primary Results of the EVOLVE Short DAPT Study: Evaluation of 3-Month Dual Antiplatelet Therapy in High Bleeding Risk Patients Treated With a Bioabsorbable Polymer-Coated Everolimus-Eluting Stent.” Circ Cardiovasc Interv Mar 1;CIRCINTERVENTIONS120010144. [Epub ahead of print]. Circinterventions120010144.

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BACKGROUND: Prolonged dual antiplatelet therapy (DAPT) after percutaneous coronary intervention is associated with increased bleeding, despite a reduced incidence of ischemic events. The SYNERGY everolimus-eluting stent is a thin-strut platinum-chromium stent that elutes everolimus from a thin abluminal layer of bioabsorbable polymer. These design elements may facilitate rapid endothelialization and enable shorter-duration DAPT. METHODS: EVOLVE Short DAPT prospectively evaluated the safety of 3-month DAPT in high bleeding risk patients treated with the SYNERGY everolimus-eluting stent, enrolling 2009 patients at 110 global sites. Patients with acute myocardial infarction or complex lesions were excluded. After percutaneous coronary intervention, patients were required to take DAPT (aspirin+P2Y(12) inhibitor) for 3 months, except those on chronic anticoagulation in whom aspirin was optional. Patients free of events (stroke, myocardial infarction, revascularization, and stent thrombosis) who discontinued P2Y(12) inhibitor at 3 months, but continued aspirin, and had at least 1 year of follow-up or an end point event were included in the primary analysis. Two powered coprimary end points were (1) death/myocardial infarction compared with a historical control and (2) study stent-related definite/probable stent thrombosis compared to a performance goal. RESULTS: The analysis population consisted of 1487 patients. The adjusted rate of death/myocardial infarction between 3 and 15 months was 5.6% among patients receiving 3-month DAPT versus 5.7% patients in the 12-month DAPT control (propensity adjusted difference=-0.12%; 97.5% upper bound=1.63% which was less than the prespecified margin of 2.52; P(non-inferiority)=0.0016). The rate of study stent-related stent thrombosis between 3-15 months was 0.2% in the 3-month DAPT group (97.5% upper bound=0.63%; P=0.0005 for comparison to 1% performance goal). CONCLUSIONS: Favorable rates of ischemic outcomes were observed among selected high bleeding risk patients undergoing percutaneous coronary intervention with the SYNERGY everolimus-eluting stent who tolerated 3 months of P2Y(12) inhibitor and then discontinued it, supporting the safety of abbreviated DAPT with this stent platform. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02605447.

Odiase, E., Zhang, X., Chang, Y., Nelson, M., Balaji, U., Gu, J., Zhang, Q., Pan, Z., Spechler, S.J. and Souza, R.F. (2021). “In Esophageal Squamous Cells from Eosinophilic Esophagitis Patients, Th2 Cytokines Increase Eotaxin-3 Secretion through Effects on Intracellular Calcium and a Non-Gastric Proton Pump.” Gastroenterology Feb 10;S0016-5085(21)00403-0. [Epub ahead of print].

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BACKGROUND & AIMS: In upper airway cells, Th2 cytokines that signal through IL-4 receptor alpha (IL4Rα) have been shown to stimulate eotaxin-3 secretion via a non-gastric proton pump (ngH(+),K(+)ATPase). To seek novel targets for eosinophilic esophagitis (EoE) treatments, we evaluated ngH(+),K(+)ATPase expression in EoE squamous cells, and explored molecular pathways involved in eotaxin-3 secretion by IL4Rα signaling. METHODS: ngH(+),K(+)ATPase expression in EoE cells was evaluated by qPCR and western blotting. IL-4-stimulated eotaxin-3 secretion was measured by ELISA after treatment with omeprazole, SCH 28080 (potassium-competitive acid blocker), EGTA-AM (calcium chelator), 2-APB (inhibitor of endoplasmic reticulum calcium release), verapamil and diltiazem (L-type calcium channel inhibitors). Intracellular calcium transients were measured by Fluo-4 fluorescence. Key experiments were confirmed in EoE primary cells and in RNA sequencing datasets from mucosal biopsies of EoE patients and controls. RESULTS: EoE cells expressed ngH(+),K(+)ATPase mRNA and protein. Omeprazole and SCH 28080 decreased IL-4-stimulated eotaxin-3 secretion. IL-4 increased intracellular calcium transients, and IL-4-stimulated eotaxin-3 secretion was blocked by EGTA-AM, 2-APB, verapamil, and diltiazem. The combination of omeprazole and verapamil suppressed IL-4-stimulated eotaxin-3 secretion more than either agent alone. EoE biopsies expressed higher ngH+,K+ATPase and exhibited more calcium signaling than controls. CONCLUSIONS: EoE cells express a non-gastric proton pump that mediates Th2 cytokine-stimulated eotaxin-3 secretion. IL-4 induces calcium release from the endoplasmic reticulum and calcium entry via L-type calcium channels, increasing intracellular calcium that contributes to eotaxin-3 secretion by EoE cells. L-type calcium channel inhibitors block Th2 cytokine-stimulated eotaxin-3 secretion, suggesting a potential role for these agents in EoE treatment.