A multi-method exploration of a cardiac rehabilitation service delivered by registered Clinical Exercise Physiologists in the UK: key learnings for current and new services.

BACKGROUND: Cardiac rehabilitation has been identified as having the most homogenous clinical exercise service structure in the United Kingdom (UK), but inconsistencies are evident in staff roles and qualifications within and across services. The recognition of Clinical Exercise Physiologists (CEPs) as a registered health professional in 2021 in the UK, provides a potential solution to standardise the cardiac rehabilitation workforce. This case study examined, in a purposefully selected cardiac exercise service that employed registered CEPs, (i) how staff knowledge, skills and competencies contribute to the provision of the service, (ii) how these components assist in creating effective service teams, and (iii) the existing challenges from staff and patient perspectives. METHODS: A multi-method qualitative approach (inc., semi-structured interviews, observations, field notes and researcher reflections) was employed with the researcher immersed for 12-weeks within the service. The Consolidated Framework for Implementation Research was used as an overarching guide for data collection. Data derived from registered CEPs (n = 5), clinical nurse specialists (n = 2), dietitians (n = 1), service managers/leads (n = 2) and patients (n = 7) were thematically analysed. RESULTS: Registered CEPs delivered innovative exercise prescription based on their training, continued professional development (CPD), academic qualifications and involvement in research studies as part of the service. Exposure to a wide multidisciplinary team (MDT) allowed skill and competency transfer in areas such as clinical assessments. Developing an effective behaviour change strategy was challenging with delivery of lifestyle information more effective during less formal conversations compared to timetabled education sessions. CONCLUSIONS: Registered CEPs have the specialist knowledge and skills to undertake and implement the latest evidence-based exercise prescription in a cardiac rehabilitation setting. An MDT service structure enables a more effective team upskilling through shared peer experiences, observations and collaborative working between healthcare professionals.

A polygenic risk score for the QT interval is an independent predictor of drug-induced QT prolongation.

Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions. The possibility that genetic risk, in the form of polygenic risk scores (PGS), could be integrated into prediction of risk of diLQTS has great potential, although it is unknown how genetic risk is related to clinical risk factors as might be applied in clinical decision-making. In this study, we examined the PGS for QT interval in 2500 subjects exposed to a known QT-prolonging drug on prolongation of the QT interval over 500ms on subsequent ECG using electronic health record data. We found that the normalized QT PGS was higher in cases than controls (0.212±0.954 vs. -0.0270±1.003, P = 0.0002), with an unadjusted odds ratio of 1.34 (95%CI 1.17-1.53, P<0.001) for association with diLQTS. When included with age and clinical predictors of QT prolongation, we found that the PGS for QT interval provided independent risk prediction for diLQTS, in which the interaction for high-risk diagnosis or with certain high-risk medications (amiodarone, sotalol, and dofetilide) was not significant, indicating that genetic risk did not modify the effect of other risk factors on risk of diLQTS. We found that a high-risk cutoff (QT PGS ≥ 2 standard deviations above mean), but not a low-risk cutoff, was associated with risk of diLQTS after adjustment for clinical factors, and provided one method of integration based on the decision-tree framework. In conclusion, we found that PGS for QT interval is an independent predictor of diLQTS, but that in contrast to existing theories about repolarization reserve as a mechanism of increasing risk, the effect is independent of other clinical risk factors. More work is needed for external validation in clinical decision-making, as well as defining the mechanism through which genes that increase QT interval are associated with risk of diLQTS.

Life-long music and dance relationships inform impressions of music- and dance-based movement therapies in individuals with and without mild cognitive impairment.

Background: No effective therapies exist to prevent degeneration from Mild Cognitive Impairment (MCI) to Alzheimer's disease. Therapies integrating music and/or dance are promising as effective, non-pharmacological options to mitigate cognitive decline. Objective: To deepen our understanding of individuals' relationships (i.e., histories, experiences and attitudes) with music and dance that are not often incorporated into music- and dance-based therapeutic design, yet may affect therapeutic outcomes. Methods: Eleven older adults with MCI and five of their care partners/ spouses participated (4M/12F; Black: n=4, White: n=10, Hispanic/ Latino: n=2; Age: 71.4±9.6). We conducted focus groups and administered questionnaires that captured aspects of participants' music and dance relationships. We extracted emergent themes from four major topics, including: (1) experience and history, (2) enjoyment and preferences, (3) confidence and barriers, and (4) impressions of music and dance as therapeutic tools. Results: Thematic analysis revealed participants' positive impressions of music and dance as potential therapeutic tools, citing perceived neuropsychological, emotional, and physical benefits. Participants viewed music and dance as integral to their lives, histories, and identities within a culture, family, and/ or community. Participants also identified lifelong engagement barriers that, in conjunction with negative feedback, instilled persistent low self-efficacy regarding dancing and active music engagement. Questionnaires verified individuals' moderately-strong music and dance relationships, strongest in passive forms of music engagement (e.g., listening). Conclusions: Our findings support that individuals' music and dance relationships and the associated perceptions toward music and dance therapy may be valuable considerations in enhancing therapy efficacy, participant engagement and satisfaction for individuals with MCI.

Development and validation of the Atri-Risk Conduction Index risk score to predict risk of atrial fibrillation after typical atrial flutter ablation.

BACKGROUND: Identification of patients at risk for atrial fibrillation (AF) after typical atrial flutter (tAFL) ablation is important to guide monitoring and treatment. OBJECTIVE: The purpose of this study was to create and validate a risk score to predict AF after tAFL ablation METHODS: We identified patients who underwent tAFL ablation with no AF history between 2017 and 2022 and randomly allocated to derivation and validation cohorts. We collected clinical variables and measured conduction parameters in sinus rhythm on an electrophysiology recording system (CardioLab, GE Healthcare). Univariate and multivariate logistic regressions (LogR) were used to evaluate association with AF development. RESULTS: A total of 242 consecutive patients (81% male; mean age 66 ± 11 years) were divided into derivation (n =142) and validation (n = 100) cohorts. Forty-two percent developed AF over median follow-up of 330 days. In multivariate LogR (derivation cohort), proximal to distal coronary sinus time (pCS-dCS) ≥70 ms (odds ratio [OR] 16.7; 95% confidence interval [CI] 5.6-49), pCS time ≥36 ms (OR 4.5; 95% CI 1.5-13), and CHADS2-VASc score ≥3 (OR 4.3; 95% CI 1.6-11.8) were independently associated with new AF during follow-up. The Atri-Risk Conduction Index (ARCI) score was created with 0 as minimal and 4 as high-risk using pCS-dCS ≥70 ms = 2 points; pCS ≥36 ms = 1 point; and CHADS2-VASc score ≥3 = 1 point. In the validation cohort, 0% of patients with ARCI score = 0 developed AF, whereas 89% of patients with ARCI score = 4 developed AF. CONCLUSION: We developed and validated a risk score using atrial conduction parameters and clinical risk factors to predict AF after tAFL ablation. It stratifies low-, moderate-, and high-risk patients and may be helpful in individualizing approaches to AF monitoring and anticoagulation.

A systematic review of diagnostic and interventional techniques in non-occlusive hepatic artery hypoperfusion syndrome.

OBJECTIVE: This systematic review aims to elucidate the diagnostic capabilities of imaging techniques in identifying Non-Occlusive Hepatic Artery Hypoperfusion Syndrome (NOHAH) and to evaluate the efficacy and outcomes of splenic artery embolization (SAE), including the choice and placement of embolic agents. MATERIALS AND METHODS: A comprehensive literature search was conducted using PubMed, CINAHL, and Scopus databases, adhering to PRISMA guidelines. Fifteen studies encompassing 240 patients treated with embolization (using coils or Amplatzer Vascular Plugs (AVP)) were analyzed. Key metrics assessed included patient demographics, embolization techniques, embolic agents, technical success, radiologic findings pre- and post-embolization, and complication rates. RESULTS: Among the 240 patients studied, 177 (73.8%) were reported by gender, with a majority being male (127/177, 71.7%). Doppler ultrasonography (DUS) emerged as the primary initial screening tool in 80% of studies. The hepatic arterial resistive index (RI) was a critical parameter, with mean values significantly decreasing from 0.84 pre-embolization to 0.70 post-embolization (p < 0.001). All cases confirmed technical success via digital subtraction angiography, revealing delayed hepatic arterial filling without stenosis or thrombosis. Coils were the predominant embolic agent, used in 80.8% of patients, followed by AVP in 16.3%. The overall mortality rate was 4.58%, with 29 major and 3 minor complications noted. Notably, proximal placement of coils in the splenic artery was associated with lower mortality rates compared to distal placement and showed comparable complication rates to AVPs. CONCLUSION: DUS is a reliable screening modality for NOHAH, with post-SAE assessments showing significant improvements. The choice and location of embolization significantly impact patient outcomes, with proximal placement of coils emerging as a preferable strategy due to lower mortality rates and comparable complication profiles to alternative methods.

Gait signature changes with walking speed are similar among able-bodied young adults despite persistent individual-specific differences.

Understanding individuals' distinct movement patterns is crucial for health, rehabilitation, and sports. Recently, we developed a machine learning-based framework to show that "gait signatures" describing the neuromechanical dynamics governing able-bodied and post-stroke gait kinematics remain individual-specific across speeds. However, we only evaluated gait signatures within a limited speed range and number of participants, using only sagittal plane (i.e., 2D) joint angles. Here we characterized changes in gait signatures across a wide range of speeds, from very slow (0.3 m/s) to exceptionally fast (above the walk-to-run transition speed) in 17 able-bodied young adults. We further assessed whether 3D kinematic and/or kinetic (ground reaction forces, joint moments, and powers) data would improve the discrimination of gait signatures. Our study showed that gait signatures remained individual-specific across walking speeds: Notably, 3D kinematic signatures achieved exceptional accuracy (99.8%, confidence interval (CI): 99.1-100%) in classifying individuals, surpassing both 2D kinematics and 3D kinetics. Moreover, participants exhibited consistent, predictable linear changes in their gait signatures across the entire speed range. These changes were associated with participants' preferred walking speeds, balance ability, cadence, and step length. These findings support gait signatures as a tool to characterize individual differences in gait and predict speed-induced changes in gait dynamics.

Effects of urban-induced mutations on ecology, evolution and health.

Increasing evidence suggests that urbanization is associated with higher mutation rates, which can affect the health and evolution of organisms that inhabit cities. Elevated pollution levels in urban areas can induce DNA damage, leading to de novo mutations. Studies on mutations induced by urban pollution are most prevalent in humans and microorganisms, whereas studies of non-human eukaryotes are rare, even though increased mutation rates have the potential to affect organisms and their populations in contemporary time. Our Perspective explores how higher mutation rates in urban environments could impact the fitness, ecology and evolution of populations. Most mutations will be neutral or deleterious, and higher mutation rates associated with elevated pollution in urban populations can increase the risk of cancer in humans and potentially other species. We highlight the potential for urban-driven increased deleterious mutational loads in some organisms, which could lead to a decline in population growth of a wide diversity of organisms. Although beneficial mutations are expected to be rare, we argue that higher mutation rates in urban areas could influence adaptive evolution, especially in organisms with short generation times. Finally, we explore avenues for future research to better understand the effects of urban-induced mutations on the fitness, ecology and evolution of city-dwelling organisms.

Parents on the Concept of Physical Literacy: What Do They Know, What Do They Do, and What Do They Want?

Physical literacy development in early childhood, viewed by many as the foundation for lifelong physical activity engagement, is significantly influenced by parents. Our aim was to explore parents' understanding of physical literacy and gain insight into their perspectives on physical literacy promotion. We recruited 18 parents of children between 5 and 8 years old in Australia. Using semistructured interviews and thematic analysis, we identified several key issues regarding parents' understanding and implementation of physical literacy. Parents expressed interest in improving their implementation of physical literacy practices and had (often unintentionally) provided support for physical literacy subcomponents in the past. However, they described difficulties prioritizing physical literacy above other parental demands and expressed conflicting perceptions regarding where the responsibility should lie for developing their child's physical literacy (e.g., at home or at school). To ensure that the physical literacy "message" reaches parents, we encourage physical literacy promoters to consider the target (e.g., responsibility, priorities, and awareness) of their promotional strategies. Further investigation into the influence of sociocultural and economic factors on parents' understanding and application of physical literacy is warranted.

Insight into the adaptive role of arachnid genome-wide duplication through chromosome-level genome assembly of the Western black widow spider.

Although spiders are one of the most diverse groups of arthropods, the genetic architecture of their evolutionary adaptations is largely unknown. Specifically, ancient genome-wide duplication occurring during arachnid evolution ~450 mya resulted in a vast assembly of gene families, yet the extent to which selection has shaped this variation is understudied. To aid in comparative genome sequence analyses, we provide a chromosome-level genome of the Western black widow spider (Latrodectus hesperus)-a focus due to its silk properties, venom applications, and as a model for urban adaptation. We used long-read and Hi-C sequencing data, combined with transcriptomes, to assemble 14 chromosomes in a 1.46 Gb genome, with 38,393 genes annotated, and a BUSCO score of 95.3%. Our analyses identified high repetitive gene content and heterozygosity, consistent with other spider genomes, which has led to challenges in genome characterization. Our comparative evolutionary analyses of eight genomes available for species within the Araneoidea group (orb weavers and their descendants) identified 1,827 single-copy orthologs. Of these, 155 exhibit significant positive selection primarily associated with developmental genes, and with traits linked to sensory perception. These results support the hypothesis that several traits unique to spiders emerged from the adaptive evolution of ohnologs-or retained ancestrally duplicated genes-from ancient genome-wide duplication. These comparative spider genome analyses can serve as a model to understand how positive selection continually shapes ancestral duplications in generating novel traits today within and between diverse taxonomic groups.

Efficient DNA-based data storage using shortmer combinatorial encoding.

Data storage in DNA has recently emerged as a promising archival solution, offering space-efficient and long-lasting digital storage solutions. Recent studies suggest leveraging the inherent redundancy of synthesis and sequencing technologies by using composite DNA alphabets. A major challenge of this approach involves the noisy inference process, obstructing large composite alphabets. This paper introduces a novel approach for DNA-based data storage, offering, in some implementations, a 6.5-fold increase in logical density over standard DNA-based storage systems, with near-zero reconstruction error. Combinatorial DNA encoding uses a set of clearly distinguishable DNA shortmers to construct large combinatorial alphabets, where each letter consists of a subset of shortmers. We formally define various combinatorial encoding schemes and investigate their theoretical properties. These include information density and reconstruction probabilities, as well as required synthesis and sequencing multiplicities. We then propose an end-to-end design for a combinatorial DNA-based data storage system, including encoding schemes, two-dimensional (2D) error correction codes, and reconstruction algorithms, under different error regimes. We performed simulations and show, for example, that the use of 2D Reed-Solomon error correction has significantly improved reconstruction rates. We validated our approach by constructing two combinatorial sequences using Gibson assembly, imitating a 4-cycle combinatorial synthesis process. We confirmed the successful reconstruction, and established the robustness of our approach for different error types. Subsampling experiments supported the important role of sampling rate and its effect on the overall performance. Our work demonstrates the potential of combinatorial shortmer encoding for DNA-based data storage and describes some theoretical research questions and technical challenges. Combining combinatorial principles with error-correcting strategies, and investing in the development of DNA synthesis technologies that efficiently support combinatorial synthesis, can pave the way to efficient, error-resilient DNA-based storage solutions.

Developing and testing a web-based platform for antiretroviral therapy (ART) adherence support among adolescents and young adults (AYA) living with HIV.

Objective: Describe the development and testing of a web-based platform for antiretroviral treatment (ART) adherence support among HIV+ adolescents and young adults (AYA) in a randomized controlled trial (RCT). Methods: A seven-member multi-disciplinary team operationalized the flat, password protected, web-based platform. Manualized protocols guided the objectives and content for each of the eight web-based sessions. Team members evaluated usability and content validity. Client satisfaction and perceived ease of use was evaluated with the first ten HIV+ AYA participants. Results: The web-based platform was developed, evaluated, refined, implemented and pilot tested between September 2020 to April 2022. Usability was rated as high; the evaluation of content validity showed an excellent fit between session content and objectives. HIV+ AYA participants (mean age = 24.2 years) were satisfied with the quality, type, and amount of support/education received, and found the platform easy to use, operate, and navigate. Average time spent per session was 6.5 min. Conclusion: Findings support the usability, validity, acceptability, and feasibility of this web-based platform for ART adherence support among HIV+ AYA. Innovation: Our research and findings are responsive to research gaps and the need for transparency in the methodological development and testing of web-based control arms for ART adherence support among HIV+ AYA.

MetaWin 3: open-source software for meta-analysis.

The rise of research synthesis and systematic reviews over the last 25 years has been aided by a series of software packages providing simple and accessible GUI interfaces which are intuitively easy to use by novice analysts and users. Development of many of these packages has been abandoned over time due to a variety of factors, leaving a gap in the software infrastructure available for meta-analysis. To fulfill the continued demand for a GUI-based meta-analytic system, we have now released MetaWin 3 as free, open-source, multi-platform software. MetaWin3 is written in Python and developed from scratch relative to earlier versions. The codebase is available on Github, with pre-compiled executables for both Windows and macOS available from the MetaWin website. MetaWin includes standardized effect size calculations, exploratory and publication bias analyses, and allows for both simple and complex explanatory models of variation within a meta-analytic framework, including meta-regression, using traditional least-squares/moments estimation.

Associations between music and dance relationships, rhythmic proficiency, and spatiotemporal movement modulation ability in adults with and without mild cognitive impairment.

Background: Personalized dance-based movement therapies may improve cognitive and motor function in individuals with mild cognitive impairment (MCI), a precursor to Alzheimer's disease. While age- and MCI-related deficits reduce individuals' abilities to perform dance-like rhythmic movement sequences (RMS)-spatial and temporal modifications to movement-it remains unclear how individuals' relationships to dance and music affect their ability to perform RMS. Objective: Characterize associations between RMS performance and music or dance relationships, as well as the ability to perceive rhythm and meter (rhythmic proficiency) in adults with and without MCI. Methods: We used wearable inertial sensors to evaluate the ability of 12 young adults (YA; age=23.9±4.2 yrs; 9F), 26 older adults without MCI (OA; age=68.1±8.5 yrs; 16F), and 18 adults with MCI (MCI; age=70.8±6.2 yrs; 10F) to accurately perform spatial, temporal, and spatiotemporal RMS. To quantify self-reported music and dance relationships and rhythmic proficiency, we developed Music (MRQ) and Dance Relationship Questionnaires (DRQ), and a rhythm assessment (RA), respectively. We correlated MRQ, DRQ, and RA scores against RMS performance for each group separately. Results: The OA and YA groups exhibited better MRQ and RA scores than the MCI group (p<0.006). Better MRQ and RA scores were associated with better temporal RMS performance for only the YA and OA groups (r2=0.18-0.41; p<0.045). DRQ scores were not associated with RMS performance in any group. Conclusions: Cognitive deficits in adults with MCI likely limit the extent to which music relationships or rhythmic proficiency improve the ability to perform temporal aspects of movements performed during dance-based therapies.

Quantifying changes in individual-specific template-based representations of center-of-mass dynamics during walking with ankle exoskeletons using Hybrid-SINDy.

Ankle exoskeletons alter whole-body walking mechanics, energetics, and stability by altering center-of-mass (CoM) motion. Controlling the dynamics governing CoM motion is, therefore, critical for maintaining efficient and stable gait. However, how CoM dynamics change with ankle exoskeletons is unknown, and how to optimally model individual-specific CoM dynamics, especially in individuals with neurological injuries, remains a challenge. Here, we evaluated individual-specific changes in CoM dynamics in unimpaired adults and one individual with post-stroke hemiparesis while walking in shoes-only and with zero-stiffness and high-stiffness passive ankle exoskeletons. To identify optimal sets of physically interpretable mechanisms describing CoM dynamics, termed template signatures, we leveraged hybrid sparse identification of nonlinear dynamics (Hybrid-SINDy), an equation-free data-driven method for inferring sparse hybrid dynamics from a library of candidate functional forms. In unimpaired adults, Hybrid-SINDy automatically identified spring-loaded inverted pendulum-like template signatures, which did not change with exoskeletons (p > 0.16), except for small changes in leg resting length (p < 0.001). Conversely, post-stroke paretic-leg rotary stiffness mechanisms increased by 37-50% with zero-stiffness exoskeletons. While unimpaired CoM dynamics appear robust to passive ankle exoskeletons, how neurological injuries alter exoskeleton impacts on CoM dynamics merits further investigation. Our findings support Hybrid-SINDy's potential to discover mechanisms describing individual-specific CoM dynamics with assistive devices.

Evaluating the prescribing and monitoring of medications associated with QTc-prolongation in the ambulatory care setting.

RATIONALE: Little is known about the prescribing of medications with potential to cause QTc-prolongation in the ambulatory care settings. Understanding real-world prescribing of QTc-prolonging medications and actions taken to mitigate this risk will help guide strategies to optimize safety and appropriate prescribing among ambulatory patients. OBJECTIVE: To evaluate the frequency of clinician action taken to monitor and mitigate modifiable risk factors for QTc-prolongation when indicated. METHODS: This retrospective, cross-sectional study evaluated clinician action at the time of prescribing prespecified medications with potential to prolong QTc in adult patients in primary care. The index date was defined as the date the medication was ordered. Electronic health record (EHR) data were evaluated to assess patient, clinician and visit characteristics. Clinician action was determined if baseline or follow-up monitoring was ordered or if action was taken to mitigate modifiable risk factors (laboratory abnormalities or electrocardiogram [ECG] monitoring) within 48 h of prescribing a medication with QTc-prolonging risk. Descriptive statistics were used to describe current practice. RESULTS: A total of 399 prescriptions were prescribed to 386 patients, with a mean age of 51 ± 18 years, during March 2021 from a single-centre, multisite health system. Of these, 17 (4%) patients had a known history of QTc-prolongation, 170 (44%) did not have a documented history of QTc-prolongation and 199 (52%) had an unknown history (no ECG documented). Thirty-nine patients (10%) had at least one laboratory-related risk factor at the time of prescribing, specifically hypokalemia (16 patients), hypomagnesemia (8 patients) or hypocalcemia (19 patients). Of these 39 patients with laboratory risk factors, only 6 patients (15%) had their risk acknowledged or addressed by a clinician. Additionally, eight patients' most recent QTc was ≥500 ms and none had an ECG checked at the time the prescription was ordered. CONCLUSION: Despite national recommendations, medication monitoring and risk mitigation is infrequent when prescribing QTc-prolonging medications in the ambulatory care setting. These findings call for additional research to better understand this gap, including reasons for the gap and consequences on patient outcomes.

Trajectories of Loneliness During Adolescence Predict Subsequent Symptoms of Depression and Positive Wellbeing.

There is a need to identify the outcomes of changes in loneliness during adolescence, and to consider this within a multidimensional framework of loneliness. This study considered the effects of different trajectories of change in Isolation Loneliness and in Friendship Loneliness upon both positive wellbeing and symptoms of depression. To achieve this, 1782 (43% female; 12.92 years old at the start of the study, SD = 1.60) young people took part in a longitudinal study with four data points across 2 years. Four Isolation Loneliness trajectories and five Friendship Loneliness trajectories were identified. Youth who experienced low levels of Isolation Loneliness that subsequently increased appear to be at particular risk for poor outcomes. Similarly, initially high levels of Friendship Loneliness that decreased rapidly, or which began at a low level and only increased marginally, seem to also be a risk. Loneliness is a multi-dimensional construct and its development during adolescence impacts upon young people's depressive symptomatology and positive mental wellbeing.

A Discussion of the Contemporary Prediction Models for Atrial Fibrillation.

Atrial Fibrillation is a complex disease state with many environmental and genetic risk factors. While there are environmental factors that have been shown to increase an individual's risk of atrial fibrillation, it has become clear that atrial fibrillation has a genetic component that influences why some patients are at a higher risk of developing atrial fibrillation compared to others. This review will first discuss the clinical diagnosis of atrial fibrillation and the corresponding rhythm atrial flutter. We will then discuss how a patients' risk of stroke can be assessed by using other clinical co-morbidities. We will then review the clinical risk factors that can be used to help predict an individual patient's risk of atrial fibrillation. Many of the clinical risk factors have been used to create several different risk scoring methods that will be reviewed. We will then discuss how genetics can be used to identify individuals who are at higher risk for developing atrial fibrillation. We will discuss genome-wide association studies and other sequencing high-throughput sequencing studies. Finally, we will touch on how genetic variants derived from a genome-wide association studies can be used to calculate an individual's polygenic risk score for atrial fibrillation. An atrial fibrillation polygenic risk score can be used to identify patients at higher risk of developing atrial fibrillation and may allow for a reduction in some of the complications associated with atrial fibrillation such as cerebrovascular accidents and the development of heart failure. Finally, there is a brief discussion of how artificial intelligence models can be used to predict which patients will develop atrial fibrillation.

Nicotinamide-Expanded Allogeneic Natural Killer Cells with CD38 Deletion, Expressing an Enhanced CD38 Chimeric Antigen Receptor, Target Multiple Myeloma Cells.

Natural killer (NK) cells are a vital component of cancer immune surveillance. They provide a rapid and potent immune response, including direct cytotoxicity and mobilization of the immune system, without the need for antigen processing and presentation. NK cells may also be better tolerated than T cell therapy approaches and are susceptible to various gene manipulations. Therefore, NK cells have become the focus of extensive translational research. Gamida Cell's nicotinamide (NAM) platform for cultured NK cells provides an opportunity to enhance the therapeutic potential of NK cells. CD38 is an ectoenzyme ubiquitously expressed on the surface of various hematologic cells, including multiple myeloma (MM). It has been selected as a lead target for numerous monoclonal therapeutic antibodies against MM. Monoclonal antibodies target CD38, resulting in the lysis of MM plasma cells through various antibody-mediated mechanisms such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, significantly improving the outcomes of patients with relapsed or refractory MM. However, this therapeutic strategy has inherent limitations, such as the anti-CD38-induced depletion of CD38-expressing NK cells, thus hindering ADCC. We have developed genetically engineered NK cells tailored to treat MM, in which CD38 was knocked-out using CRISPR-Cas9 technology and an enhanced chimeric antigen receptor (CAR) targeting CD38 was introduced using mRNA electroporation. This combined genetic approach allows for an improved cytotoxic activity directed against CD38-expressing MM cells without self-inflicted NK-cell-mediated fratricide. Preliminary results show near-complete abolition of fratricide with a 24-fold reduction in self-lysis from 19% in mock-transfected and untreated NK cells to 0.8% of self-lysis in CD38 knock-out CAR NK cells. Furthermore, we have observed significant enhancements in CD38-mediated activity in vitro, resulting in increased lysis of MM target cell lines. CD38 knock-out CAR NK cells also demonstrated significantly higher levels of NK activation markers in co-cultures with both untreated and αCD38-treated MM cell lines. These NAM-cultured NK cells with the combined genetic approach of CD38 knockout and addition of CD38 CAR represent a promising immunotherapeutic tool to target MM.