Use of variable online visual feedback to optimize sensorimotor coding and learning of a motor sequence.

The present study characterized the impact of reliable and/or unreliable online visual feedback and their order of presentation on the coding and learning of a motor sequence. Participants practiced a 12-element motor sequence 200 times. During this acquisition phase, two groups received a single type (i.e., either reliable or unreliable) of online visual feedback, two other groups encountered both types of feedback: either reliable first then unreliable, or unreliable first then reliable. Delayed retention tests and intermanual transfer tests (visuospatial and motor) were administered 24 hours later. Results showed that varying the reliability of online visual information during the acquisition phase allowed participants to use different task coding modalities without damaging their long-term sequence learning. Moreover, starting with reliable visual feedback, replaced halfway through with unreliable feedback promoted motor coding, which is seldom observed. This optimization of motor coding opens up interesting perspectives, as it is known to promote better learning of motor sequences.

Reliability of on-line visual feedback influences learning of continuous motor task of healthy young adults.

A continuous task was used to determine how the reliability of on-line visual feedback during acquisition impacts motor learning. Participants performed a right hand pointing task of a repeated sequence with a visual cursor that was either reliable, moderately unreliable, or largely unreliable. Delayed retention tests were administered 24 h later, as well as intermanual transfer tests (performed with the left hand). A visuospatial transfer test was performed with the same targets' sequence (same visuospatial configuration) while a motor transfer test was performed with the visual mirror of the targets' sequence (same motor patterns). Results showed that pointing was slower and long-term learning disrupted in the largely unreliable visual cursor condition, compared with the reliable and moderately unreliable conditions. Also, analysis of transfers revealed classically better performance on visuospatial transfer than on motor transfer for the reliable condition. However, here we first show that such difference disappears when the cursor was moderately or largely unreliable. Interestingly, these results indicated a difference in the type of sequence coding, depending on the reliability of the on-line visual feedback. This recourse to mixed coding opens up interesting perspectives, as it is known to promote better learning of motor sequences.

Metamemory mediates the protective effect of cognitive reserve on episodic memory during aging.

The present study investigated the impact of cognitive reserve on episodic memory and metamemory control during aging using a multidimensional index of cognitive reserve and a measure of metamemory control abilities. We tested the hypotheses that cognitive reserve may play a protective role against age-related differences in episodic memory and metamemory control and that metamemory control may mediate the effect of cognitive reserve on episodic memory during aging. Young and older adults carried out a readiness-recall task in which task difficulty was manipulated through a variation of the nature of the cue-target pair link (weak vs. strong semantic associates). Episodic memory was assessed through recall performance, and metamemory by a task difficulty index reflecting the ability to adjust study time to task difficulty. Results confirmed that older adults recall fewer words, indicating an age-related deficit in episodic memory, and that older adults adjust less to task difficulty, suggesting impaired metamemory control. Findings also showed that metamemory control moderates the age-related decline in episodic memory and that cognitive reserve plays a protective role against age-related deficits in episodic memory and metamemory control. In addition, metamemory abilities mediated the beneficial effect of cognitive reserve on episodic memory performance during aging. Hence, this study sheds new light on the mechanisms underlying the impact of cognitive reserve on cognitive aging, highlighting the role of metacognitive processes.

Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models.

Local immunotherapy ideally stimulates immune responses against tumors while avoiding toxicities associated with systemic administration. Current strategies for tumor-targeted, gene-based delivery, however, are limited by adverse effects such as off-targeting or antivector immunity. We investigated the intratumoral administration of saline-formulated messenger (m)RNA encoding four cytokines that were identified as mediators of tumor regression across different tumor models: interleukin-12 (IL-12) single chain, interferon-α (IFN-α), granulocyte-macrophage colony-stimulating factor, and IL-15 sushi. Effective antitumor activity of these cytokines relied on multiple immune cell populations and was accompanied by intratumoral IFN-γ induction, systemic antigen-specific T cell expansion, increased granzyme B+ T cell infiltration, and formation of immune memory. Antitumor activity extended beyond the treated lesions and inhibited growth of distant tumors and disseminated tumors. Combining the mRNAs with immunomodulatory antibodies enhanced antitumor responses in both injected and uninjected tumors, thus improving survival and tumor regression. Consequently, clinical testing of this cytokine-encoding mRNA mixture is now underway.

How the COVID-19 Pandemic Has Affected Cardiology Fellow Training.

With the advent of the COVID-19 pandemic in the United States, resources have been reallocated and elective cases have been deferred to minimize the spread of the disease, altering the workflow of cardiac catheterization laboratories across the country. This has in turn affected the training experience of cardiology fellows, including diminished procedure numbers and a narrow breadth of cases as they approach the end of their training before joining independent practice. It has also taken a toll on the emotional well-being of fellows as they see their colleagues, loved ones, patients or even themselves struggling with COVID-19, with some succumbing to it. The aim of this opinion piece is to focus attention on the impact of the COVID-19 pandemic on fellows and their training, challenges faced as they transition to practicing in the real world in the near future and share the lessons learned thus far. We believe that this is an important contribution and would be of interest not only to cardiology fellows-in-training and cardiologists but also trainees in other procedural specialties.

An experimental model of anti-PD-1 resistance exhibits activation of TGFß and Notch pathways and is sensitive to local mRNA immunotherapy.

Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. Several mechanisms of innate and acquired resistance to checkpoint blockade have been defined and include mutations of MHC I and IFNγ signaling pathways. However, such mutations occur in a low frequency of patients and additional mechanisms have yet to be elucidated. In an effort to better understand acquired resistance to checkpoint blockade, we generated a mouse tumor model exhibiting in vivo resistance to anti-PD-1 antibody treatment. MC38 tumors acquired resistance to PD-1 blockade following serial in vivo passaging. Lack of sensitivity to PD-1 blockade was not attributed to dysregulation of PD-L1 or ß2M expression, as both were expressed at similar levels in parental and resistant cells. Similarly, IFNγ signaling and antigen processing and presentation pathways were functional in both parental and resistant cell lines. Unbiased gene expression analysis was used to further characterize potential resistance mechanisms. RNA-sequencing revealed substantial differences in global gene expression, with tumors resistant to anti-PD-1 displaying a marked reduction in expression of immune-related genes relative to parental MC38 tumors. Indeed, resistant tumors exhibited reduced immune infiltration across multiple cell types, including T and NK cells. Pathway analysis revealed activation of TGFß and Notch signaling in anti-PD-1 resistant tumors, and activation of these pathways was associated with poorer survival in human cancer patients. While pharmacological inhibition of TGFß and Notch in combination with PD-1 blockade decelerated tumor growth, a local mRNA-based immunotherapy potently induced regression of resistant tumors, resulting in complete tumor remission, and resensitized tumors to treatment with anti-PD-1. Overall, this study describes a novel anti-PD-1 resistant mouse tumor model and underscores the role of two well-defined signaling pathways in response to immune checkpoint blockade. Furthermore, our data highlights the potential of intratumoral mRNA therapy in overcoming acquired resistance to PD-1 blockade.

Surgical Versus Transcatheter Aortic Valve Replacement in Patients With Malignancy.

BACKGROUND: Patients with aortic stenosis (AS) and malignancy experience poor clinical outcomes with challenging decisions regarding aortic valve replacement (AVR). We sought to compare the outcomes of transcatheter (TAVR) versus surgical (SAVR) AVR in patients with AS and malignancy. METHODS: Based on the Nationwide Readmission Database, we compared all patients with malignancy who underwent isolated SAVR vs. TAVR in 2016 for severe AS. We performed univariate and multivariate analyses for baseline characteristics and clinical outcomes. A total of 2566 patients were included, 1952 (76%) had TAVR and the remaining 614 (24%) had isolated SAVR. Patients who underwent TAVR were older (82 vs 72 years, p < .001), had more metastasis (19 vs 14%, p = .004), heart failure (72% vs 34%, p < .001), coronary artery disease (72% vs 52%, p < .001), anemia (28% vs 22%, p = .006), chronic lung (30% vs 22%, p < .001) and renal disease (35% vs 14%, p < .001), and shorter length of stay (3 vs 7 days, p < .001). RESULTS: In multivariate regression, TAVR and SAVR had similar in-patient mortality (HR = 1.08; 95%CI 0.61 ̶ 1.94) and 30-day readmission (HR = 1.26; 95%CI 0.95 ̶ 1.67). TAVR was associated with lower vascular complications (HR = 0.59; 95%CI 0.41 ̶ 0.86), acute deep venous thrombosis (HR = 0.25, 95%CI 0.1 ̶ 0.59), acute kidney injury (HR = 0.24, 95%CI 0.17 ̶ 0.33), blood transfusion (HR = 0.22, 95%CI 0.16 ̶ 0.3), cardiogenic shock (HR = 0.48, 95%CI 0.26 ̶ 0.89), and respiratory complications (HR = 0.26, 95%CI 0.2 ̶ 0.35). CONCLUSIONS: In patients with malignancy, TAVR is a viable and safe option compared to SAVR with better clinical outcomes, especially thromboembolic events.

Primary Thymic Signet Ring Cell Adenocarcinoma: A Currently Unrecognized Variant.

We describe the first case of primary thymic adenocarcinoma with signet ring cell features. The patient was a 39-year-old Filipino male who presented with a huge anterior mediastinal mass extending to the left supraclavicular fossa, which underwent an incisional biopsy. Extensive clinicoradiological work-up showed no evidence of any primary tumor in other organs, and radiological imaging confirmed a primary tumor location in the thymic area. He later developed bilateral pleural and pericardial effusions and eventually died of his tumor. The biopsy contained a neoplastic growth of solid nests made of cells with prominent signet ring features in sclerotic stroma. Immunohistochemically, the tumor cells were reactive for cytokeratin 7, carcinoembryonic antigen, and CD5 and negative for cytokeratin 20, TTF1, napsin A, α-fetoprotein, PAX-8, CD-117, CA19-9, CA-125, CDX2, p63, and CD99. No genetic alterations of ALK, RET, and ROS1 were found, nor was any ALK or ROS1 immunostaining detected, as known to occur in a fraction of primary pulmonary adenocarcinomas. Morphologically, this thymic tumor resembled signet ring cell adenocarcinomas of other locations, including, stomach, pancreas, and lung, but CD5 immunoreactivity strongly supported the clinical and radiological evidence of a primary thymic origin. In the English literature, only 58 cases of primary thymic adenocarcinoma are on record and this is the first report of a signet ring cell variant, which further broadens the morphological spectrum of thymic adenocarcinoma subtypes.

A Case of Type I and II Brugada Phenocopy Unmasked in a Patient with Normal Baseline Electrocardiogram (ECG).

BACKGROUND Brugada pattern on electrocardiogram (ECG) is seen when there are at least 2 mm J-point elevation and 1 mm ST-segment elevation in two or more of the right precordial leads, with right bundle-branch block (RBBB)-like morphology. Elevation of a coved-type shape in leads V1 and V2 is consistent with type I Brugada pattern, whereas elevation of a saddle-back configuration distinguishes type II Brugada. If accompanied by life-threatening arrhythmias or sudden cardiac death, Brugada syndrome (BrS) is diagnosed. The presence of Brugada ECG pattern in absence of the syndrome has come to be known as Brugada phenocopy (BrP). CASE REPORT We introduce a case of both Brugada type I and II patterns unmasked in a 28-year-old female with fever secondary to mastitis. Though fever-induced BrP is a universally known phenomenon, the presentation of both type I and II patterns presenting in a patient during a single hospitalization makes this case unique from others. The patient was brought to the emergency department after experiencing a syncopal episode that appeared classically vasovagal in nature. Once her fever resolved, her baseline ECG showed no abnormalities. CONCLUSIONS Though Brugada ECG pattern may be very alarming, especially after syncope, appropriate management in the case of a fever-induced event would consist of observation with cardiac monitoring, immediate treatment of fever with antipyretics, and antibiotics for suspected infection. Close follow-up by a cardiologist as an outpatient is imperative to further ascertain if the patient is at high risk of life-threatening arrhythmias, significant for BrS.

Atypical pituitary adenoma with neurocytic transformation.

Here, we report an example of an atypical prolactin-producing pituitary adenoma showing clear morphologic and immunohistochemical evidence of neurocytic transformation. Its features support the concept that neoplastic neuroendocrine cells, in this case adenohypophyseal cells, are capable of neuronal differentiation and broaden the morphologic spectrum of such rare tumors. Our findings have implications with respect to the nosology of neuronal tumors of the adenohypophysis.