Transthoracic echocardiography versus transesophageal echocardiography in detecting cardiac sources of embolism

Although the yield of potential cardiac sources of embolism by echocardiography in patients with stroke and arterial embolism has been low, with the advent of transesophageal echocardiography, a renewed enthusiasm for echocardiography in these patients has developed. This article reviews the six major studies comparing transthoracic to transesophageal echocardiography in the search for potential cardiac sources of embolism. The overall yield of transesophageal echocardiography in these studies for potential cardiac sources of embolism is 43% compared to 14% by transthoracic echocardiography in a total of 367 patients. In patients without clinical cardiac disease, the yield is lower but still substantially higher by transesophageal echocardiography (24% compared to 7% by transthoracic echocardiography). For left atrial thrombus, left atrial spontaneous contrast, patent foreman ovale, and atrial septal aneurysm (ASA), transesophageal echocardiography is clearly superior than transthoracic echocardiography. Data on the detection of mitral valve prolapse and left ventricular thrombus are conflicting and neither method is clearly superior. In addition, transesophageal echocardiography identifies certain abnormalities including debris in the aorta and prosthetic strands that transthoracic echocardiography is incapable of identifying. Although transthoracic echocardiography should continue to be the initial screening modality for stroke patients, transesophageal echocardiography should be performed when surface findings are negative or equivocal in patients with likely cardioembolic stroke.     

Postoperative Atrial Fibrillation or Flutter Following Transcatheter or Surgical Aortic Valve Replacement: PARTNER 3 Trial

ObjectivesThe aim of this study was to assess the incidence and prognostic impact of early and late postoperative atrial fibrillation or flutter (POAF) in patients with severe aortic stenosis (AS) treated with transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR).BackgroundThere is an ongoing controversy regarding the incidence, recurrence rate, and prognostic impact of early (in-hospital) POAF and late (postdischarge) POAF in patients with AS undergoing TAVR or SAVR.MethodsIn the PARTNER (Placement of Aortic Transcatheter Valve) 3 trial, patients with severe AS at low surgical risk were randomized to TAVR or SAVR. Analyses were performed in the as-treated population excluding patients with preexistent atrial fibrillation or flutter.ResultsAmong 781 patients included in the analysis, early POAF occurred in 152 (19.5%) (18 of 415 [4.3%] and 134 of 366 [36.6%] following TAVR and SAVR, respectively). Following discharge, 58 new or recurrent late POAF events occurred within 1 year following the index procedure in 55 of 781 patients (7.0%). Early POAF was not an independent predictor of late POAF following discharge (odds ratio: 1.04; 95% CI: 0.52-2.08; P = 0.90). Following adjustment, early POAF was not an independent predictor of the composite outcome of death, stroke, or rehospitalization (hazard ratio: 1.10; 95% CI: 0.64-1.92; P = 0.72), whereas late POAF was associated with an increased adjusted risk for the composite outcome (hazard ratio: 8.90; 95% CI: 5.02-15.74; P < 0.0001), irrespective of treatment modality.ConclusionsIn the PARTNER 3 trial, early POAF was more frequent following SAVR compared with TAVR. Late POAF, but not early POAF, was significantly associated with worse outcomes at 2 years, irrespective of treatment modality.     

Immune evasion in HPV− head and neck precancer–cancer transition is driven by an aneuploid switch involving chromosome 9p loss

An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV⁻) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3⁺ and CD8⁺ T cell microenvironments in precancer (mostly CD3⁺, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in TP53 mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and JAK2-PD-L1 codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV⁻ HNSC after anti–PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.

The genetic bases for predisposition, and neoplastic transformation, to cancer have been increasingly well described. However, it remains less clear how early, precancer cells employ these genetic alterations to acquire the characteristic features and properties (1) of malignant disease. For example, studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent, metastatic head and neck squamous cell carcinoma (HNSC) therapy (2–4). This underscores the importance of immune modulation in these tumors, despite a still suboptimal overall response rate of less than 20% in advanced cancers. Immune response within tumors has been observed to be strongest at the earliest neoplastic stages, as reported recently in lung adenocarcinoma precursors (5). As such, new, immune-based strategies could be developed to reduce the high global burden of HNSC, by intercepting the most common precursor of the most common HNSC presentation: HPV⁻ oral squamous cell carcinomas (6–8).Studies of chromosome somatic copy-number (CN) alteration (SCNA) profiles have reported the impact of 3p14, 9p21, or 17p13 loss in molecular models of HNSC progression (9) and risk (10–15). Early studies reported that patients with oral precancers harboring 9p21 and/or 3p14 loss were at significantly greater cancer risk than those with retention at these loci (10, 16). A comprehensive, prospective validation study examined the relative contribution of six candidate chromosome-arm regions. 9p21 loss had the greatest influence on cancer risk (13). The mechanism underlying the association between CN and malignant transformation of precancers, however, is unclear (17–20). Studies of CN-altered neoplastic cells have shown that SCNAs can trigger a cytotoxic response in experimental precancer systems (21, 22) but, paradoxically, were associated with immune evasion (23) and suppression (24) in computational studies of naturally occurring human cancers. The latter, in melanoma, found that nonresponders to PD-1 and CTLA-4 blockade had higher CN alteration and loss burdens, which correlated with immunologically cold tumors, characterized by cytotoxic-cell, marker, and metric reductions, and suppressive microenvironment cell, network, and signal increases (23–26). This SCNA-cold association was particularly strong in our previous, pan-The Cancer Genome Atlas (TCGA) computational study in HNSC (23). These data point to a putative in vivo switch from immune hot-to-cold in the precancer–cancer transition, and raise the hypothesis that SCNAs in precursor lesions contribute to malignant transformation through genomic events and mechanisms that enable the acquisition of immune-suppressive, evasive properties. To test this hypothesis, we evaluated CN influence on immune profiles and outcomes in a large prospective oral precancer patient cohort, and HPV⁻ HNSC (tissue specimens and cell lines) and anti–PD-1–treated recurrent-disease cohorts.     

Protruding atherosclerotic aortic plaques and dyslipidaemia: correlation to subtypes of ischaemic stroke.

AIMS: To evaluate whether thoracic aortic plaques together with dyslipidaemia are related to ischaemic stroke, and if so, to which of the subtypes of stroke. METHODS AND RESULTS: We performed transoesophageal echocardiography in 50 patients with acute ischaemic stroke and in 401 controls. The aorta was divided into two segments: (1) the proximal, proximal to the left subclavian artery, and (2) the distal aorta. Protruding plaques (Intima > or =4 mm in thickness) in the proximal aorta were detected in 14 of the 50 patients (28%) with stroke, and in 53 of the 401 controls (13%) (P<0.01). Plaque score in the proximal aorta (2.1 +/- 1.8 vs 0.9 +/- 0.7; P<0.05), low-density lipoprotein cholesterol level (3.60 +/- 0.85 vs 2.87 +/- 0.72 mmol/l; P<0.05), and apolipoprotein B/A-I ratio (0.98 +/-0.17 vs 0.73 +/- 0.16; P<0.005) were higher in patients with athero-thrombotic than in cardioembolic stroke. The score in the proximal aorta correlated with low-density lipoprotein cholesterol level (r=0.44, P<0.005) and apolipoprotein B/A-I ratio (r=0.40, P<0.01). CONCLUSION: Severe plaques in the proximal aorta together with dyslipidaemia are seen more frequently in patients with atherothrombotic stroke. Lipid analysis may contribute to the prediction and the treatment of the patients who are at high risk for atherothrombotic stroke.     

Hyperacute Management of Ischemic Strokes: JACC Focus Seminar

Acute ischemic stroke is the leading cause of disability and among the leading causes of mortality worldwide. Intravenous tissue plasminogen activator has been a cornerstone for treatment of acute ischemic stroke for more than 20 years; however, its use is limited due to a narrow therapeutic window, several contraindications, and low efficacy to recanalize the artery in large vessel occlusion. Recently, the addition of endovascular mechanical thrombectomy of large artery occlusion has revolutionized the stroke treatment for most disabling strokes. The paper reviews updates to the thrombolytic treatment as well as catheter-based treatment, and results from recent trials in the selection of patients in an extended time window using perfusion imaging.     

The Change in Body Composition After Bilateral Lung Volume Reduction Surgery for Underweight Patients with Severe Emphysema

The aim of this study was to examine the short-term effect of lung volume reduction surgery (LVRS) on body composition and other nutritional indicators in 28 patients with emphysema underwent thoracoscopic LVRS. Functional tests, body weight (BW), and body composition were measured before and 6 months after surgery. Mean daily caloric intake (CI) was estimated by 3-day dietary record as well. Fat-free mass (FFM) and fat mass (FM) were assessed by bioelectrical impedance analysis (BIA). FEV_1.0 and Vo _2max have improved after LVRS by 35.2% and 23.8%, respectively. Preoperatively, 75% of patients were underweight (% ideal body weight (%IBW) <90) with the mean %IBW at 84.5%. BW, CI, and FFM increased significantly after LVRS, whereas FM was unchanged. The change in BW correlated significantly with the change in FEV_1.0, MVV, and Vo _2max (p < 0.01) but not with CI. Bilateral LVRS results in an increase in FFM and functional improvement for underweight patients with severe emphysema, and it may contribute to the improvement in maximal exercise capacity. Accepted for publication: 12 December 2000     

An overview of robotic/mechanical devices for post-stroke thumb rehabilitation

Purpose: This article aims to clarify the current state-of-the-art of robotic/mechanical devices for post-stroke thumb rehabilitation as well as the anatomical characteristics and motions of the thumb that are crucial for the development of any device that aims to support its motion.

Methods: A systematic literature search was conducted to identify robotic/mechanical devices for post-stroke thumb rehabilitation. Specific electronic databases and well-defined search terms and inclusion/exclusion criteria were used for such purpose. A reasoning model was devised to support the structured abstraction of relevant data from the literature of interest.

Results: Following the main search and after removing duplicated and other non-relevant studies, 68 articles (corresponding to 32 devices) were left for further examination. These articles were analyzed to extract data relative to (i) the motions assisted/permitted – either actively or passively – by the device per anatomical joint of the thumb and (ii) mechanical-related aspects (i.e., architecture, connections to thumb, other fingers supported, adjustability to different hand sizes, actuators – type, quantity, location, power transmission and motion trajectory).

Conclusions: Most articles describe preliminary design and testing of prototypes, rather than the thorough evaluation of commercially ready devices. Defining appropriate kinematic models of the thumb upon which to design such devices still remains a challenging and unresolved task. Further research is needed before these devices can actually be implemented in clinical environments to serve their intended purpose of complementing the labour of therapists by facilitating intensive treatment with precise and repeatable exercises.

• Implications for Rehabilitation

• Post-stroke functional disability of the hand, and particularly of the thumb, significantly affects the capability to perform activities of daily living, threatening the independence and quality of life of the stroke survivors. The latest studies show that a high-dose intensive therapy (in terms of frequency, duration and intensity/effort) is the key to effectively modify neural organization and recover the motor skills that were lost after a stroke. Conventional therapy based on manual interaction with physical therapists makes the procedure labour intensive and increases the costs.

• Robotic/mechanical devices hold promise for complementing conventional post-stroke therapy. Specifically, these devices can provide reliable and accurate therapy for long periods of time without the associated fatigue. Also, they can be used as a means to assess patients? performance and progress in an objective and consistent manner.

• The full potential of robot-assisted therapy is still to be unveiled. Further exploration will surely lead to devices that can be well accepted equally by therapists and patients and that can be useful both in clinical and home-based rehabilitation practice such that motor recovery of the hand becomes a common outcome in stroke survivors.

• This overview provides the reader, possibly a designer of such a device, with a complete overview of the state-of-the-art of robotic/mechanical devices consisting of or including features for the rehabilitation of the thumb. Also, we clarify the anatomical characteristics and motions of the thumb that are crucial for the development of any device that aims to support its motion.

• Hopefully, this?combined with the outlined opportunities for further research?leads to the improvement of current devices and the development of new technology and knowledge in the field.

     

An exploration of physiotherapists’ experiences of robotic therapy in upper limb rehabilitation within a stroke rehabilitation centre

Purpose: Strokes are the world’s leading cause of adult disability, with movement impairment being more common in the upper limb (UL). Robotic therapy (RT) is identified as an effective adjunct to promote movement but with limited effect on functional capabilities. There is currently limited research in user experience of RT, specifically that of physiotherapists. This study sought to explore physiotherapists’ experience of using RT in rehabilitation of the UL, within a stroke rehabilitation centre in the north of England.

Method: Physiotherapists (n?=?6) shared their experiences of working with the InMotion2 robot through semi-structured interviews. Thematic analysis was employed to interpret data, identify emergent themes and interdependent relationships between them.

Findings: Five interdependent themes were identified focused around individualized care, influenced by evidence for practice, human relationships, skill mix, and resources and resource management. All physiotherapists valued the use of RT as an adjunct to conventional therapy, although barriers to successful implementation seemed to dominate the views of some.

Conclusions: RT was perceived positively by physiotherapists, regarded as an adjunct to conventional therapy. A framework to summarize the relationships of participants’ views and experiences is proposed in an attempt to understand the influences on the clinical use of RT.

• Implications for Rehabilitation

• Robotic therapy (RT) is valued as an adjunct to (conventional) person-centred rehabilitation.

• Resource management and skill mix are viewed as two key challenges to the successful implementation of RT.

• The production of evidence-based guidelines would be a useful development in the advancement.

     

Early versus late‐applied constraint‐induced movement therapy: A multisite,randomized controlled trial with a 12‐month follow‐up

Background and Purpose

A direct comparison between the effects of constraint‐induced movement therapy (CIMT) applied early after stroke and that of CIMT applied in the chronic phase has not been conducted. This study aimed to compare the long‐term effects of CIMT applied 6 months after stroke with the results of CIMT applied within 28 days post‐stroke.

Methods

This study was a single‐blinded, multicentre, randomized controlled trial with a crossover design. Forty‐seven patients received CIMT either early (within 28 days) or 6 months after stroke. Both groups received standard rehabilitation and were tested at 5 time points. The primary outcome measure was Wolf Motor Function Test (WMFT); the secondary measures were Nine‐Hole Peg Test (NHPT), the Fugl‐Meyer Assessment (FMA) of the upper extremity, Stroke Impact Scale, and Modified Rankin Scale (MRS).

Results

Compared with baseline data, both groups showed significant improvements in the primary and secondary outcome measures after 12 months. No significant differences between the 2 treatment groups were found before and after the delayed intervention group received CIMT at 6 months and during the 12‐month follow‐up. Both groups recovered considerably and showed only minor impairment (median FMA score of 64) after 6 months. The early intervention group showed an initially faster recovery curve of WMFT, NHPT, and MRS scores.

Discussion

In contrast to most CIMT studies, our study could not find an effect of CIMT applied 6 months after stroke. Our results indicate that commencing CIMT early is as good as delayed intervention in the long term, specifically in this group of patients who might have reached a ceiling effect during the first 6 months after stroke. Nevertheless, the early CIMT intervention group showed a faster recovery curve than the delayed intervention group, which can be a clinically important finding for patients in the acute phase.