Improvements on the Inhaler

Background: Inhalers are a commonplace in American health care and deliver crucial drugs to patients with COPD and asthma. Inhaler use has been shown to be unsatisfactory among patients resulting in ineffective medication delivery. The goal of this project was to improve the inhaler design for increased effectiveness and ease of use. Methods: Our team first interviewed a Pulmonologist regarding patient inhaler use. Dr. Harry Kane demonstrated the proper use of an inhaler as well and described errors in inhaler use are due to patient technique. A variety of inhalers currently available were examined and were compared for ease of use. Results: Interview with attending physician revealed numerous patient errors that impede effectiveness of inhaled medication. Two common mistakes were identified: patients inhaling too rapidly and patients dispensing the medication too late. Inhaling too rapidly decreases the fraction of drug that reaches the lungs, decreasing effectiveness. Dispensing the medication after a patient reaches total lung capacity (TLC) prevents the drug from reaching their lungs, decreasing effectiveness. Conclusions: We conclude that inhalers could be used more effectively by addressing patient education and feedback mechanisms. Possible solutions discuss audible feedback to help coordinate patient breath with optimal dispersal timing. Future work includes prototyping a design and eliciting patient feedback

Pleiotropic Phenotypes Associated With PKP2 Variants

Plakophilin-2 (PKP2) is a component of the desmosome complex and known for its role in cell-cell adhesion. Recently, alterations in the Pkp2 gene have been associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy (ACM or ARVC), Brugada syndrome (BrS), and idiopathic ventricular fibrillation to name the most relevant. However, the assessment of pathogenicity regarding the genetic variations associated with Pkp2 is still a challenging task: the gene has a positive Residual Variation Intolerance Score and the potential deleterious role of several of its variants has been disputed. Limitations in facilitating interpretation and annotations of these variants are seen in the lack of segregation and clinical data in the control population of reference. In this review, we will provide a summary of all the currently available genetic information related to the Pkp2 gene, including different phenotypes, ClinVar annotations and data from large control database. Our goal is to provide a literature review that could help clinicians and geneticists in interpreting the role of Pkp2 variants in the context of heritable sudden death syndromes. Limitations of current algorithms and data repositories will be discussed

Improving the Inhaler

Background: Inhalers used to dispense various pharmacological agents play an important role in the care of patients with pulmonary disease. These pharmacological agents can be very effective, however, many patients that use inhalers often deliver these drugs incorrectly or in a sub-optimal manner. Our project aims to improve the design of the inhaler in order to increase the effectiveness of drug delivery and also ease of patient use. Methods: We interviewed a critical care pulmonologist regarding patient inhaler use and compliance. This physician offered information about proper inhaler use and described common errors that patients encounter when attempting to dispense drugs via inhalers. Both steroidal and albuterol inhalers that are currently being prescribed were allocated for our examination and use to help develop a more user friendly model. Results: The pulmonologist illustrated several errors that patients will commonly make which can degrade the efficacy of the inhaled drug delivery. One frequently encountered error was that drug is dispensed by the patient once they had already reached their total lung capacity, or inhaled fully. This sort of error leads to the drug being dispensed into the throat and failure to reach the intended target, the lungs. Additionally, the physician noted that patients often forget to administer their inhaled drugs because the inhaler does not fit comfortably into the patient’s pocket and so it is not optimally portable. Conclusion: Our research suggests that inhaler design could be improved in order to increase the effectiveness of drug delivery and patient compliance. We are considering incorporating audible actuation clues that will alert the patient when to dispense the drug, and also provide electronic feedback to the patient’s mobile device. This would help educate the patient on how to coordinate their breathing with actuation of the device to dispense the medication

Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy:a translational study

AIMS: Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls. METHODS AND RESULTS: Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls. CONCLUSIONS: We speculate that exercise challenges a cardiomyocyte "desmosomal reserve" which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy

Modulation of heart rate by acute or chronic aerobic exercise. Potential effects on blood pressure control

It was initially assumed that heart rate and arterial blood pressure were modulated by normal respiration and muscle contraction. The arterial baroreflex, an inverse relationship between blood pressure and heart rate, was later reported. Nonetheless, it was then assumed that those responses involved vagal modulation. We summarize available evidence on the modulation of heart rate by acute or chronic aerobic exercise as well as its potential implications on BP control. Numerous studies have tried to clarify whether aerobic exercise modifies neurally-mediated vasoconstriction, but they report contradictory results. In view of these incongruities, the aim of this narrative review is to summarize available evidence on the modulation of heart rate by acute or chronic aerobic exercise as well as its potential implications on blood pressure control. We mainly focus on the effects of aerobic exercise in both heart rate and blood pressure. Heart rate and heart rate variability have been indistinctly considered similar metrics, but they have completely different meanings when properly used. Both are risk markers in cardiac disease, whereas heart rate variability is also an index of sympathovagal modulation of heart rate. On the other hand, heart rate recovery has been also used as an index for mirroring both cardiovascular fitness and autonomic function, and can be used as a measure of vagal reactivation. Importantly, it is now well-known that a reduced rate of heart rate recovery represents a powerful predictor of overall mortality. In this review, due to its complexity, we have included studies in which any of these three parameters have been analyzed

Blockade of the Adenosine 2A Receptor Mitigates the Cardiomyopathy Induced by Loss of Plakophilin-2 Expression

Background: Mutations in plakophilin-2 (PKP2) are the most common cause of familial Arrhythmogenic Right Ventricular Cardiomyopathy, a disease characterized by ventricular arrhythmias, sudden death, and progressive fibrofatty cardiomyopathy. The relation between loss of PKP2 expression and structural cardiomyopathy remains under study, though paracrine activation of pro-fibrotic intracellular signaling cascades is a likely event. Previous studies have indicated that ATP release into the intracellular space, and activation of adenosine receptors, can regulate fibrosis in various tissues. However, the role of this mechanism in the heart, and in the specific case of a PKP2-initiated cardiomyopathy, remains unexplored. Objectives: To investigate the role of ATP/adenosine in the progression of a PKP2-associated cardiomyopathy. Methods: HL1 cells were used to study PKP2- and Connexin43 (Cx43)-dependent ATP release. A cardiac-specific, tamoxifen-activated PKP2 knock-out murine model (PKP2cKO) was used to define the effect of adenosine receptor blockade on the progression of a PKP2-dependent cardiomyopathy. Results: HL1 cells silenced for PKP2 showed increased ATP release compared to control. Knockout of Cx43 in the same cells blunted the effect. PKP2cKO transcriptomic data revealed overexpression of genes involved in adenosine-receptor cascades. Istradefylline (an adenosine 2A receptor blocker) tempered the progression of fibrosis and mechanical failure observed in PKP2cKO mice. In contrast, PSB115, a blocker of the 2B adenosine receptor, showed opposite effects. Conclusion: Paracrine adenosine 2A receptor activation contributes to the progression of fibrosis and impaired cardiac function in animals deficient in PKP2. Given the limitations of the animal model, translation to the case of patients with PKP2 deficiency needs to be done with caution

Blockade of the Adenosine 2A Receptor Mitigates the Cardiomyopathy Induced by Loss of Plakophilin-2 Expression

Background: Mutations in plakophilin-2 (PKP2) are the most common cause of familial Arrhythmogenic Right Ventricular Cardiomyopathy, a disease characterized by ventricular arrhythmias, sudden death, and progressive fibrofatty cardiomyopathy. The relation between loss of PKP2 expression and structural cardiomyopathy remains under study, though paracrine activation of pro-fibrotic intracellular signaling cascades is a likely event. Previous studies have indicated that ATP release into the intracellular space, and activation of adenosine receptors, can regulate fibrosis in various tissues. However, the role of this mechanism in the heart, and in the specific case of a PKP2-initiated cardiomyopathy, remains unexplored. Objectives: To investigate the role of ATP/adenosine in the progression of a PKP2-associated cardiomyopathy. Methods: HL1 cells were used to study PKP2- and Connexin43 (Cx43)-dependent ATP release. A cardiac-specific, tamoxifen-activated PKP2 knock-out murine model (PKP2cKO) was used to define the effect of adenosine receptor blockade on the progression of a PKP2-dependent cardiomyopathy. Results: HL1 cells silenced for PKP2 showed increased ATP release compared to control. Knockout of Cx43 in the same cells blunted the effect. PKP2cKO transcriptomic data revealed overexpression of genes involved in adenosine-receptor cascades. Istradefylline (an adenosine 2A receptor blocker) tempered the progression of fibrosis and mechanical failure observed in PKP2cKO mice. In contrast, PSB115, a blocker of the 2B adenosine receptor, showed opposite effects. Conclusion: Paracrine adenosine 2A receptor activation contributes to the progression of fibrosis and impaired cardiac function in animals deficient in PKP2. Given the limitations of the animal model, translation to the case of patients with PKP2 deficiency needs to be done with caution

Surgical ventricular reconstruction for ischemic cardiomyopathy-a systematic review and meta-analysis of 7,685 patients

Background: Surgical ventricular reconstruction (SVR) has been used to control adverse ventricular remodeling and improve cardiac function in ischemic cardiomyopathy. The purpose of this systematic review and meta-analysis was to collect and analyze all available evidence on the utilization and efficacy of SVR. Methods: An electronic database search was performed to identify all retrospective and prospective studies on SVR for ischemic cardiomyopathy in the English literature from 2000 through 2020. A total of 92 articles with a collective 7,685 patients undergoing SVR were included in the final analysis. Results: The mean patient age was 61 years (95% CI: 59-63) and 80% (78-82%) were male. Congestive heart failure was present in 66% (54-78%) and angina in 58% (45-70%). Concomitant coronary artery bypass grafting was undertaken in 92% (90-93%) while 21% (18-24%) underwent mitral valve repair. Pre vs. post-SVR, significant improvement was seen in left ventricular ejection fraction (LVEF) [29.9% (28.8-31.2%) vs. 40.9% (39.4-42.4%), P\u3c0.01], left ventricular end-systolic (LVESD) and end-diastolic diameters (LVEDD) [LVESD: 49.9 mm (48.1-51.7) vs. 45 mm (42.8-47.3), P\u3c0.01, LVEDD: 63.8 mm (62-65.6) vs. 58.23 mm (56.6-60), P\u3c0.01], and left ventricular end-systolic (LVESVI) and end-diastolic volume indices (LVEDVI) [LVESVI: 83.9 mL/m2 (79.3-88.4) vs. 46.8 mL/m2 (43.5-50.1), P\u3c0.01; LVEDVI: 119.9 mL/m2 (112.1-127.6) vs. 79.6 mL/m2 (73.6-85.7), P\u3c0.01]. Mean New York Heart Association class improved from 3 (2.8-3.1) to 1.8 (1.5-2) (P\u3c0.01). The 30-day mortality was 4% (3-5%) while late mortality was 19% (9-34%) at a mean follow-up of 27.5 [21-34] months. Conclusions: In patients with ischemic cardiomyopathy, SVR reduces left ventricular volumes and improves systolic function leading to symptomatic improvement

Chromosome 3 and 8q Aberrations in Uveal Melanoma Show Greater Impact on Survival in Patients with Light Iris versus Dark Iris Color

Purpose: Individuals with gray, blue, or green eyes have a higher chance of developing uveal melanoma (UM) than those with brown eyes. We wondered whether iris pigmentation might be related not only to predisposition to UM but also to its behavior; therefore, we compared the clinical, histopathologic, and genetic characteristics of UM between eyes with different colors. Design: We determined iris color in a large cohort of patients enucleated for UM. Clinical and histopathologic tumor characteristics, chromosome status, and survival were compared among 3 groups on the basis of iris color. Participants: A total of 412 patients with choroidal/ciliary body UM, who had undergone primary enucleation at the Leiden University Medical Center, Leiden, The Netherlands, between 1993 and 2019, were divided into 3 groups based on iris color: gray/blue, green/hazel, and brown. The validation cohort included 934 patients with choroidal/ciliary body UM treated at Wills Eye Hospital (WEH). Methods: Comparison of clinical, histopathologic, and genetic characteristics of UM in patients with different iris colors. Main Outcome Measures: Melanoma-related survival in UM patients, divided over 3 iris color groups, in relation to the tumor's chromosome 3 and 8q status. Results: Moderate and heavy tumor pigmentations were especially seen in eyes with a brown iris (P < 0.001). Survival did not differ between patients with different iris colors (P = 0.27); however, in patients with a light iris, copy number changes in chromosome 3 and 8q had a greater influence on survival than in patients with a dark iris. Likewise, chromosome 3 and chromosome 8q status affected survival more among patients with lightly pigmented tumors than in patients with heavily pigmented tumors. The WEH cohort similarly showed a greater influence of chromosome aberrations in light-eyed individuals. Conclusions: Although iris color by itself did not relate to UM-related survival, chromosome 3 and 8q aberrations had a larger influence on survival in patients with a light iris than those with a brown iris. This suggests a synergistic effect of iris pigmentation and chromosome status in the regulation of oncogenic behavior of UM. Iris color should be taken into consideration when calculating a patient's risk for developing metastases

IUGR Is Associated With Marked Hyperphosphorylation of Decidual and Maternal Plasma IGFBP-1.

Context: The mechanisms underpinning intrauterine growth restriction (IUGR), as a result of placental insufficiency, remain poorly understood, no specific treatment is available, and clinically useful biomarkers for early detection are lacking. Objective: We hypothesized that human IUGR is associated with inhibition of mechanistic target of rapamycin (mTOR) and activation of amino acid response (AAR) signaling, increased protein kinase casein kinase-2 (CK2) activity, and increased insulin-like growth factor-binding protein 1 (IGFBP-1) expression and phosphorylation in decidua and that maternal plasma IGFBP-1 hyperphosphorylation in the first trimester predicts later development of IUGR. Design, Setting, and Participants: Decidua [n = 16 appropriate-for-gestational age (AGA); n = 16 IUGR] and maternal plasma (n = 13 AGA; n = 13 IUGR) were collected at delivery from two different cohorts. In addition, maternal plasma was obtained in the late first trimester from a third cohort of women (n = 7) who later delivered an AGA or IUGR infant. Main Outcome Measures: Total IGFBP-1 expression and phosphorylation (Ser101/Ser119/Ser169), mTOR, AAR, and CK2 activity in decidua and IGFBP-1 concentration and phosphorylation in maternal plasma. Results: We show that decidual IGFBP-1 expression and phosphorylation are increased, mTOR is markedly inhibited, and AAR and CK2 are activated in IUGR. Moreover, IGFBP-1 hyperphosphorylation in first-trimester maternal plasma is associated with the development of IUGR. Conclusions: These data are consistent with the possibility that the decidua functions as a nutrient sensor linking limited oxygen and nutrient availability to increased IGFBP-1 phosphorylation, possibly mediated by mTOR and AAR signaling. IGFBP-1 hyperphosphorylation in first-trimester maternal plasma may serve as a predictive IUGR biomarker, allowing early intervention