Dual-Use Strain Sensors for Acoustic Emission and Quasi-Static Bending Measurements.

In this paper, a MEMS piezoresistive ultrathin silicon membrane-based strain sensor is presented. The sensor's ability to capture an acoustic emission signal is demonstrated using a Hsu-Nielsen source, and shows comparable frequency content to a commercial piezoceramic ultrasonic transducer. To the authors' knowledge, this makes the developed sensor the first known piezoresistive strain sensor which is capable of recording low-energy acoustic emissions. The improvements to the nondestructive evaluation and structural health monitoring arise from the sensor's low minimum detectable strain and wide-frequency bandwidth, which are generated from the improved fabrication process that permits crystalline semiconductor membranes and advanced polymers to be co-processed, thus enabling a dual-use application of both acoustic emission and static strain sensing. The sensor's ability to document quasi-static bending is also demonstrated and compared with an ultrasonic transducer, which provides no significant response. This dual-use application is proposed to effectively combine the uses of both strain and ultrasonic transducer sensor types within one sensor, making it a novel and useful method for nondestructive evaluations. The potential benefits include an enhanced sensitivity, a reduced sensor size, a lower cost, and a reduced instrumentation complexity.

Prospective Multicenter International Registry of Ultrasound-Facilitated Catheter-Directed Thrombolysis in Intermediate-High and High-Risk Pulmonary Embolism (KNOCOUT PE).

BACKGROUND: Prior clinical trials have demonstrated the efficacy of ultrasound-facilitated catheter-directed thrombolysis (USCDT) for the treatment of acute intermediate-risk pulmonary embolism (PE) using reduced thrombolytic doses and shorter infusion durations. However, utilization and safety of such strategies in broader PE populations remain unclear. The KNOCOUT PE (The EKoSoNic Registry of the Treatment and Clinical Outcomes of Patients With Pulmonary Embolism) registry is a multicenter international registry designed to study the treatment of acute PE with USCDT, with focus on safety outcomes. METHODS: The KNOCOUT PE prospective cohort included 489 patients (64 sites internationally) with acute intermediate-high or high-risk PE treated with USCDT between March 2018 and June 2020. Principal safety outcomes were independently adjudicated International Society on Thrombosis and Haemostasis major bleeding at 72 hours post-treatment and mortality within 12 months of treatment. Additional outcomes included change in right ventricular/left ventricular ratio and quality of life measures over 12 months. RESULTS: Mean alteplase (r-tPA [recombinant tissue-type plasminogen activator]) infusion duration was 10.5 hours. Mean total r-tPA dose was 18.1 mg, with 31.0% of patients receiving ≤12 mg. Major bleeding events within 72 hours occurred in 1.6% (8/489) of patients. One patient experienced worsening of a preexisting subdural hematoma after USCDT and therapeutic anticoagulation, which ultimately required surgery. All-cause mortality at 30 days was 1.0% (5/489). Improvement in PE quality of life score was observed with a 41.1% (243/489, 49.7%) and 44.2% (153/489, 31.3%) mean relative reduction by 3 and 12 months, respectively. CONCLUSIONS: In a prospective observational cohort study of patients with intermediate-high and high-risk PE undergoing USCDT, mean r-tPA dose was 18 mg, and the rates of major bleeding and mortality were low. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03426124.

Testing a Behavioral Activation Gaming App for Depression During Pregnancy: Multimethod Pilot Study.

BACKGROUND: Depression during pregnancy is increasingly recognized as a worldwide public health problem. If untreated, there can be detrimental outcomes for the mother and child. Anxiety is also often comorbid with depression. Although effective treatments exist, most women do not receive treatment. Technology is a mechanism to increase access to and engagement in mental health services. OBJECTIVE: The Guardians is a mobile app, grounded in behavioral activation principles, which seeks to leverage mobile game mechanics and in-game rewards to encourage user engagement. This study seeks to assess app satisfaction and engagement and to explore changes in clinical symptoms of depression and anxiety among a sample of pregnant women with elevated depressive symptoms. METHODS: This multimethod pilot test consisted of a single-arm, proof-of-concept trial to examine the feasibility and acceptability of The Guardians among a pregnant sample with depression (N=18). Participation included two web-based study visits: (1) a baseline assessment to collect demographic and obstetric information and to assess clinical symptoms and (2) an exit interview to administer follow-up measures and explore user experience. Participants completed biweekly questionnaires (ie, Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7) during the trial to assess depression and anxiety symptom severity. App satisfaction was measured using 2 self-report scales (ie, Mobile Application Rating Scale and Player Experience of Needs Satisfaction scale). Engagement with The Guardians was captured using game interaction metric data. We used backward-eliminated mixed effects longitudinal models to examine the effects of app engagement and satisfaction and length of time in the study on symptoms of depression and anxiety. Content analysis was conducted on qualitative data from exit interviews. RESULTS: The 15-day and 30-day overall app retention rates were 26.6% and 15.1%, respectively. Mixed effects models found significant negative main effects of week in study (ß=-.35; t61=-3.05; P=.003), number of activities completed (ß=-.12; t61=-2.05; P=.04), days played (ß=-.12; t58=-2.9; P=.005), and satisfaction, according to the Mobile Application Rating Scale (ß=-3.05; t45=-2.19; P=.03) on depressive symptoms. We have reported about similar analyses for anxiety. There is preliminary evidence suggesting harder activities are associated with greater mood improvement than easier activities. Qualitative content analysis resulted in feedback falling under the following themes: activities, app design, engagement, fit of the app with lifestyle, perceived impact of the app on mood, and suggestions for app modifications. CONCLUSIONS: Preliminary results from this multimethod study of The Guardians indicate feasibility and acceptability among pregnant women with depression. Retention and engagement levels were more than double those of previous public mental health apps, and use of the app was associated with significant decrease in depressive symptom scores over the 10-week trial. The Guardians shows promise as an effective and scalable digital intervention to support women experiencing depression.

Effects of immune checkpoint blockade on antigen-specific CD8+ T cells for use in adoptive cellular therapy.

Adoptive T-cell therapies have been successfully used as prophylaxis or treatment for immunocompromised patients at risk of viral infections or advanced cancers. Unfortunately, for some refractory cancers, they have failed. To overcome this, checkpoint inhibitors are used to rescue immune antitumor responses. We hypothesized that in vitro checkpoint blockade during T-cell stimulation and expansion with messenger RNA (mRNA)-pulsed DCs may enhance the activity of antigen-specific T cells and improve the efficacy of adoptive cellular therapy platforms. Human peripheral blood mononuclear cells were isolated from cytomegalovirus (CMV)-seropositive donors to generate DCs. These were pulsed with CMV matrix phosphoprotein 65 (CMVpp65)-mRNA to educate T cells in coculture for 15 days. Three checkpoint blockade conditions were evaluated (anti-PD1, anti-Tim3, and anti-PD1 + Tim3). IL-2 and antibodies blockades were added every 3 days. Immunophenotyping was performed on Day 0 and Day 15. Polyfunctional antigen-specific responses were evaluated upon rechallenge with CMVpp65 peptides. CMVpp65-activated CD8+ T cells upregulate Lag3 and Tim3 (P ≤ 0.0001). Tim3 antibody blockade alone or in combination led to a significant upregulation of Lag3 expression on CD8+ pp65Tetramer+ central memory, effector memory, and terminal effector memory cells re-expressing RA (TEMRA) T cells. This latter T-cell subset uniquely maintains double-positive Tim3/Lag3 expression after checkpoint blockade. By contrast, PD1 blockade had minimal effects on Tim3 or Lag3 expression. In addition, IFN-γ secretion was reduced in T cells treated with Tim3 blockade in a dose-dependent manner (P = 0.004). In this study, we have identified a potential activating component of Tim3 and linkage between Tim3 and Lag3 signaling upon blocking the Tim3 axis during T-cell-antigen-presenting cell interactions that should be considered when targeting immune checkpoints for clinical use.

The impact of pulmonary hypertension on outcomes of transcatheter mitral valve replacement in mitral annular calcification.

OBJECTIVES: To assess the impact of pulmonary hypertension (PH) on outcomes of patients with severe mitral annular calcification (MAC) undergoing transcatheter mitral valve replacement (TMVR). BACKGROUND: PH is associated with poor outcomes after mitral valve surgery. Whether the presence of PH in patients with MAC undergoing (TMVR) is associated with poor outcomes, is unknown. METHODS: Retrospective evaluation of 116 patients from 51 centers in 11 countries who underwent TMVR with valve in mitral annular calcification (ViMAC) using balloon-expandable aortic transcatheter valves (THVs) from September 2012 to March 2017. Pulmonary artery systolic blood pressure (PASP) by echocardiogram was available in 90 patients. The subjects were stratified based on PASP: No PH = PASP ≤35 mmHg (n = 11); mild to moderate PH = PASP 36-49 mmHg (n = 21) and severe PH = PASP ≥50 mmHg (n = 58). Clinical, procedural, and echocardiographic outcomes were assessed. RESULTS: Mean age was 72.7 (±12.8) years, 59 (65.6%) were female, Society of Thoracic Surgeons score was 15.8 + 11.8% and 90.0% where in New York Heart Association (NYHA) class III-IV. There was no significant difference in all-cause mortality at 30 days (no PH = 27.3%, mild-moderate PH = 19.0%, severe PH = 31.6%; p = 0.55) or at 1 year (no PH = 54.5%, mild-moderate PH = 38.1%, severe PH = 56.1%; p = 0.36). No difference in adverse events, NYHA class or amount of residual mitral regurgitation at 1 year were observed between the groups. CONCLUSION: This study suggests that the presence of PH in patients with predominantly mitral stenosis with MAC undergoing TMVR does not impact mortality or adverse events. Further studies are needed to fully understand the effect of PH in this group of patients.

A Randomized Trial of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Intermediate-Risk Pulmonary Embolism: The OPTALYSE PE Trial.

OBJECTIVES: The aim of this study was to determine the lowest optimal tissue plasminogen activator (tPA) dose and delivery duration using ultrasound-facilitated catheter-directed thrombolysis (USCDT) for the treatment of acute intermediate-risk (submassive) pulmonary embolism. BACKGROUND: Previous trials of USCDT used tPA over 12 to 24 h at doses of 20 to 24 mg for acute pulmonary embolism. METHODS: Hemodynamically stable adults with acute intermediate-risk pulmonary embolism documented by computed tomographic angiography were randomized into this prospective multicenter, parallel-group trial. Patients received treatment with 1 of 4 USCDT regimens. The tPA dose ranged from 4 to 12 mg per lung and infusion duration from 2 to 6 h. The primary efficacy endpoint was reduction in right ventricular-to-left ventricular diameter ratio by computed tomographic angiography. A major secondary endpoint was embolic burden by refined modified Miller score, measured on computed tomographic angiography 48 h after initiation of USCDT. RESULTS: One hundred one patients were randomized, and improvements in right ventricular-to-left ventricular diameter ratio were as follows: arm 1 (4 mg/lung/2 h), 0.40 (24%; p = 0.0001); arm 2 (4 mg/lung/4 h), 0.35 (22.6%; p = 0.0001); arm 3 (6 mg/lung/6 h), 0.42 (26.3%; p = 0.0001); and arm 4 (12 mg/lung/6 h), 0.48 (25.5%; p = 0.0001). Improvement in refined modified Miller score was also seen in all groups. Four patients experienced major bleeding (4%). Of 2 intracranial hemorrhage events, 1 was attributed to tPA delivered by USCDT. CONCLUSIONS: Treatment with USCDT using a shorter delivery duration and lower-dose tPA was associated with improved right ventricular function and reduced clot burden compared with baseline. The major bleeding rate was low, but 1 intracranial hemorrhage event due to tPA delivered by USCDT did occur.

1-Year Outcomes of Transcatheter Mitral Valve Replacement in Patients With Severe Mitral Annular Calcification.

BACKGROUND: The risk of surgical mitral valve replacement in patients with severe mitral annular calcification (MAC) is high. Several patients worldwide with severe MAC have been treated successfully with transcatheter mitral valve replacement (TMVR) using balloon-expandable aortic transcatheter valves. The TMVR in MAC Global Registry is a multicenter registry that collects data on outcomes of these procedures. OBJECTIVES: The goal of this study was to evaluate 1-year outcomes in this registry. METHODS: This study was a multicenter retrospective review of clinical outcomes. RESULTS: A total of 116 extreme surgical risk patients with severe MAC underwent TMVR; 106 had a procedure date >1 year before data-lock and were included in the analysis. Their mean age was 73 ± 12 years, and 68% were female. The mean Society of Thoracic Surgeons score was 15.3 ± 11.6%, and 90% were in New York Heart Association functional class III or IV. Thirty-day and 1-year all-cause mortality was 25% and 53.7%, respectively. Most patients who survived 30 days were alive at 1 year (49 of 77 [63.6%]), and the majority (71.8%) were in New York Heart Association functional class I or II. Echocardiography data at 1 year were available in 34 patients. Mean left ventricular ejection fraction was 58.6 ± 11.2%, mean mitral valve area was 1.9 ± 0.5 cm2, mean mitral gradient was 5.8 ± 2.2 mm Hg, and 75% had zero or trace mitral regurgitation. CONCLUSIONS: TMVR with balloon-expandable aortic valves in extreme surgical risk patients with severe MAC is feasible but associated with high 30-day and 1-year mortality. Most patients who survive the 30-day post-procedural period are alive at 1 year and have sustained improvement of symptoms and transcatheter valve performance. The role of TMVR in patients with MAC requires further evaluation in clinical trials.

Impact of Pre-Existing Prosthesis-Patient Mismatch on Survival Following Aortic Valve-in-Valve Procedures.

OBJECTIVES: The aim of this study was to determine whether the association of small label size of the surgical valve with increased mortality after transcatheter valve-in-valve (ViV) implantation is, at least in part, related to pre-existing prosthesis-patient mismatch (PPM) (i.e., a bioprosthesis that is too small in relation to body size). BACKGROUND: Transcatheter ViV implantation is an alternative for the treatment of patients with degenerated bioprostheses. Small label size of the surgical valve has been associated with increased mortality after ViV implantation. METHODS: Data from 1,168 patients included in the VIVID (Valve-in-Valve International Data) registry were analyzed. Pre-existing PPM of the surgical valve was determined using a reference value of effective orifice area for each given model and size of implanted prosthetic valve indexed for body surface area. Severe PPM was defined according to the criteria proposed by the Valve Academic Research Consortium 2: indexed effective orifice area <0.65 cm2/m2 if body mass index is <30 kg/m2 and <0.6 cm2/m2 if BMI is ≥30 kg/m2. The primary study endpoint was 1-year mortality. RESULTS: Among the 1,168 patients included in the registry, 89 (7.6%) had pre-existing severe PPM. Patients with severe PPM had higher 30-day (10.3%, p = 0.01) and 1-year (unadjusted: 28.6%, p < 0.001; adjusted: 19.3%, p = 0.03) mortality rates compared with patients with no severe PPM (4.3%, 11.9%, and 10.9%, respectively). After adjusting for surgical valve label size, Society of Thoracic Surgeons score, renal failure, diabetes, and stentless surgical valves, presence of pre-existing severe PPM was associated with increased risk for 1-year mortality (odds ratio: 1.88; 95% confidence interval: 1.07 to 3.28; p = 0.03). Patients with severe PPM also more frequently harbored high post-procedural gradients (mean gradient ≥20 mm Hg). CONCLUSIONS: Pre-existing PPM of the failed surgical valve is strongly and independently associated with increased risk for mortality following ViV implantation.

Gene Therapy-Induced Antigen-Specific Tregs Inhibit Neuro-inflammation and Reverse Disease in a Mouse Model of Multiple Sclerosis.

The devastating neurodegenerative disease multiple sclerosis (MS) could substantially benefit from an adeno-associated virus (AAV) immunotherapy designed to restore a robust and durable antigen-specific tolerance. However, developing a sufficiently potent and lasting immune-regulatory therapy that can intervene in ongoing disease is a major challenge and has thus been elusive. We addressed this problem by developing a highly effective and robust tolerance-inducing in vivo gene therapy. Using a pre-clinical animal model, we designed a liver-targeting gene transfer vector that expresses full-length myelin oligodendrocyte glycoprotein (MOG) in hepatocytes. We show that by harnessing the tolerogenic nature of the liver, this powerful gene immunotherapy restores immune tolerance by inducing functional MOG-specific regulatory T cells (Tregs) in vivo, independent of major histocompatibility complex (MHC) restrictions. We demonstrate that mice treated prophylactically are protected from developing disease and neurological deficits. More importantly, we demonstrate that when given to mice with preexisting disease, ranging from mild neurological deficits to severe paralysis, the gene immunotherapy abrogated CNS inflammation and significantly reversed clinical symptoms of disease. This specialized approach for inducing antigen-specific immune tolerance has significant therapeutic potential for treating MS and other autoimmune disorders.

Low cost delivery of proteins bioencapsulated in plant cells to human non-immune or immune modulatory cells.

Targeted oral delivery of GFP fused with a GM1 receptor binding protein (CTB) or human cell penetrating peptide (PTD) or dendritic cell peptide (DCpep) was investigated. Presence of GFP(+) intact plant cells between villi of ileum confirm their protection in the digestive system from acids/enzymes. Efficient delivery of GFP to gut-epithelial cells by PTD or CTB and to M cells by all these fusion tags confirm uptake of GFP in the small intestine. PTD fusion delivered GFP more efficiently to most tissues or organs than the other two tags. GFP was efficiently delivered to the liver by all fusion tags, likely through the gut-liver axis. In confocal imaging studies of human cell lines using purified GFP fused with different tags, GFP signal of DCpep-GFP was only detected within dendritic cells. PTD-GFP was only detected within kidney or pancreatic cells but not in immune modulatory cells (macrophages, dendritic, T, B, or mast cells). In contrast, CTB-GFP was detected in all tested cell types, confirming ubiquitous presence of GM1 receptors. Such low-cost oral delivery of protein drugs to sera, immune system or non-immune cells should dramatically lower their cost by elimination of prohibitively expensive fermentation, protein purification cold storage/transportation and increase patient compliance.

A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study.

OBJECTIVES: This study conducted a prospective, single-arm, multicenter trial to evaluate the safety and efficacy of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis, using the EkoSonic Endovascular System (EKOS, Bothell, Washington). BACKGROUND: Systemic fibrinolysis for acute pulmonary embolism (PE) reduces cardiovascular collapse but causes hemorrhagic stroke at a rate exceeding 2%. METHODS: Eligible patients had a proximal PE and a right ventricular (RV)-to-left ventricular (LV) diameter ratio ≥0.9 on chest computed tomography (CT). We included 150 patients with acute massive (n = 31) or submassive (n = 119) PE. We used 24 mg of tissue-plasminogen activator (t-PA) administered either as 1 mg/h for 24 h with a unilateral catheter or 1 mg/h/catheter for 12 h with bilateral catheters. The primary safety outcome was major bleeding within 72 h of procedure initiation. The primary efficacy outcome was the change in the chest CT-measured RV/LV diameter ratio within 48 h of procedure initiation. RESULTS: Mean RV/LV diameter ratio decreased from baseline to 48 h post-procedure (1.55 vs. 1.13; mean difference, -0.42; p < 0.0001). Mean pulmonary artery systolic pressure (51.4 mm Hg vs. 36.9 mm Hg; p < 0.0001) and modified Miller Index score (22.5 vs. 15.8; p < 0.0001) also decreased post-procedure. One GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries)-defined severe bleed (groin hematoma with transient hypotension) and 16 GUSTO-defined moderate bleeding events occurred in 15 patients (10%). No patient experienced intracranial hemorrhage. CONCLUSIONS: Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis decreased RV dilation, reduced pulmonary hypertension, decreased anatomic thrombus burden, and minimized intracranial hemorrhage in patients with acute massive and submassive PE. (A Prospective, Single-arm, Multi-center Trial of EkoSonic® Endovascular System and Activase for Treatment of Acute Pulmonary Embolism (PE) [SEATTLE II]; NCT01513759).

Usefulness of translesional pressure gradient and pharmacological provocation for the assessment of intermediate renal artery disease.

OBJECTIVE: We sought to determine the hemodynamic significance of intermediate RAS by measuring translesional systolic pressure gradients (TSPG), using a pressure-sensing guidewire at baseline and after acetylcholine (ACh) induced hyperemia, following selective renal artery angiography. BACKGROUND: Renal artery stenosis (RAS) is a cause of reversible hypertension and nephropathy. Stenting effectively relieves RAS, however improvement in blood pressure control or renal function is variable and unpredictable. Hemodynamic significance is usually present with RAS when diameter stenosis is >75%, but is less predictable in intermediate (30%-75%) RAS. METHODS: Twenty-two patients (26 renal arteries) with uncontrolled hypertension underwent invasive hemodynamic assessment because of intermediate RAS, defined as radiocontrast angiographic diameter stenosis (DS) between 30% and 75% (quantitative DS was measured prospectively). Translesional pressure gradients were measured using a 0.014" pressure-sensing wire. Hyperemia was induced by administration of intrarenal ACh. RESULTS: Visual and measured angiographic lesion severity did not correlate with TSPG either at baseline (visual DS, R(2) = 0.091, P = 0.13; measured DS, R(2) = 0.124, P = 0.07) or with hyperemia (visual DS, R(2) = 0.057, P = 0.24; measured DS, R(2) = 0.101, P = 0.12). Baseline and maximal hyperemic gradient did correlate (R(2) = 0.567; P < 0.05). Pharmacological provocation produced a significant increase in TSPG (mean; baseline, 18 +/- 21 vs. hyperemia, 34 +/- 41 mm Hg; P < 0.05). A hemodynamically significant lesion (TSPG > 20 mm Hg) was found in 14/26 (54%) arteries (13 patients); 13 (60%) patients subsequently underwent renal artery stenting for hemodynamically significant RAS. At follow-up (at least 30 days), there was a significant decrease in systolic blood pressure (mean; 167 +/- 24 vs. 134 +/- 19 mm Hg; P < 0.001). CONCLUSIONS: Intrarenal administration of ACh induces hyperemia and can be used to unmask resistive renal artery lesions. Gradient measurement and induced hyperemia may be warranted in the invasive assessment of intermediate renal artery stenoses, rather than relying on stenosis severity alone. Further study is needed to determine whether translesional pressure gradients and pharmacological provocation predict clinical benefit after renal artery stenting.

Characteristics of centenarians admitted to a community teaching hospital.

BACKGROUND: The "oldest old" are the most rapidly growing segment of society, and clinicians will increasingly encounter this age group in this century. METHODS: To describe the characteristics of a special subgroup of the oldest old, the centenarians, we conducted a retrospective case series analysis of all patients 100 years of age and above admitted to a large community teaching hospital. RESULTS: Thirty-nine patients with a mean age of 101.3 years were admitted a total of 57 times during the 5-year study period. The main reasons for admission were hip fracture, stroke, and urinary tract infection. Patients admitted from nursing facilities were taking more medications than community dwelling patients, and patients who were confused on admission were more likely to be readmitted. Only 2 patients died. CONCLUSIONS: Polypharmacy is common in centenarians, especially in institutionalized patients, and confusion may be a useful predictor of subsequent readmission. In-hospital mortality, however, is low in this population.