Citations

Background: Myocarditis may predispose to dilated cardiomyopathy (DCM) and sudden cardiac death (SCD). Familial data indicate a potential genetic susceptibility shared with arrhythmogenic cardiomyopathy (ACM). We present the first large-scale genotype-phenotype study of adults with acute myocarditis. Methods: A cohort comprising 336 consecutive patients with acute myocarditis was enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterised cardiomyopathy-associated genes. The burden of rare protein altering variants (PAV) in ACM genes, DCM genes, and TTN specifically, were compared with local healthy controls sequenced on the same platform (n=1053). Case ascertainment was assessed against national hospital admission data. Results: We identified rare protein-altering variants in 23% of cases compared to 16% in controls (Δ+6.8%; p=0.021), with rare truncating variants (tv) in 6% of cases compared to <1% of controls ((Δ+5%; p=0.0097). In London (n=230; median left ventricular ejection fraction (LVEF) 63%), which was representative of national myocarditis admissions, 4.8% of cases carried rare tv, particularly within ACM genes (3% cases vs 0% controls; odds ratio 8.2; p=0.001). This was predominantly driven by desmoplakin (DSP)-tv in patients with normal LVEF. In Maastricht (n=106; median LVEF 30%), rare tv in DCM genes were enriched, particularly TTN-tv found in 7% (all with LVEF<50%) compared to 1% in controls (OR 3.6; p=0.0116). During a median follow-up of 1.9 years, all-cause mortality was greatest in those with a DCM variant (18% vs 4% with no variant; OR 5.0; p=0.004). Conclusion: We identified enrichment of cardiomyopathy gene variants in acute myocarditis patients, dominated by DSP-tv in those with normal LVEF and TTN-tv in those with reduced LVEF. Incorporation of genetic testing may be beneficial to identify such high-risk individuals and guide family screening in acute myocarditis patients.

AbstractBackgroundPosterior wall isolation (PWI) is an emerging approach in atrial fibrillation (AF) ablation, yet its efficacy remains controversial. This is the first meta‐analysis of randomized controlled trials (RCT) to evaluate the efficacy of PWI in AF ablation.ObjectiveTo assess the efficacy of PWI in reducing atrial arrhythmia recurrence following initial AF ablation at long‐term follow‐ups when compared to conventional methods.MethodsWe conducted a literature search from inception through September 2021 in EMBASE and MEDLINE databases. We included RCTs that compared outcomes in PWI and conventional approaches of AF ablation. Data from each study were combined using the random‐effects, generic inverse variance method of DerSimonian and Laird to calculate odds ratio (OR), and 95% confidence interval (CI).ResultsEight RCT from 2009 to 2020, including 1024 AF patients, were included. PWI did not decrease overall atrial arrhythmias recurrence (RR 0.96, 95% CI:0.88–1.05, I2 = 31.6%, p‐value 0.393). However, the pooled analysis showed a significant decrease in AF recurrence in PWI compared to controlled approaches (RR 0.88, 95% CI:0.81–0.96, I2 = 48.2%, p‐value .004). In the subgroup analysis, PWI significantly decreased AF recurrence in the studies that included only persistent AF (RR = 0.89, 95% CI:0.80–0.98, I2 = 65.2%, p‐value .014). PWI significantly decreased AF recurrence when compared to PVI with roof line (RR 0.84, 95% CI 0.74–0.95, I2 0.00%, p‐value .008).ConclusionOur study suggests that adding PWI significantly decreased AF recurrence in patients with persistent AF compared to controlled approaches. It highlights the importance of considering PWI during the initial procedure in this patient population.

Abstract Introduction: Advances in technology and internet capability have provided an opportunity for efficient collection of Patient Reported Outcomes (PRO) during medical treatment. Here we describe the development and implementation of a system for monitoring patient reported adverse events (AEs) and quality of life (QoL) using electronic PRO (ePRO) instruments for patients enrolled on the Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular analysis (I-SPY 2 TRIAL), a phase II adaptive platform clinical trial for locally advanced breast cancer. Methods: We designed an ePRO system to increase the accuracy of patient-reported QoL and AE data collection with the intent to act on symptoms in real time. Using the OpenClinica electronic data capture system, we developed rules-based logic to build automated ePRO surveys, customized to the I-SPY 2 treatment schedule. Weekly surveys contained a maximum of 126 validated, branching logic questions from the Patient Reported Outcomes Measurement Information System (PROMIS®) Health Measures and the National Cancer Institute’s Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE™) instruments. We piloted ePROs at the University of California, San Francisco (UCSF) to evaluate compatibility with a variety of I-SPY 2 patient scenarios (e.g., dose delays). We then staggered rollout of the ePRO system to 22 I-SPY 2 sites to ensure technological feasibility. In order to improve accuracy of data collection, we utilized real-time tracking and developed a Clinical Research Coordinator (CRC) training manual, which integrated workflow diagrams with technical solutions. CRCs were trained using remote video sessions. Results: The UCSF ePRO pilot began in September of 2020. Over 9-months, we accrued 43 I-SPY 2 patients (average age of 43.8 years), whose interactions with the ePRO system informed design improvements. Of the patients who received a baseline ePRO survey, the completion rate was 75.9% (average age of 44.2 years). This represents an increase from the 15-20% baseline completion rate for the 360 UCSF I-SPY 2 patients who received paper-based PRO surveys between May 2012 - January 2019. As of June 2021, the ePRO system was operational at all 22 I-SPY 2 sites. The UCSF pilot revealed that engagement with patients at critical timepoints improved survey completion. CRCs facilitated patient participation by sending instructional emails and communicating with patients weekly. We tracked data completeness using a Patient Tracking report, which displayed each patient’s survey completion history. This real-time tool enabled CRCs to identify patients who had not completed ePRO surveys prior to their visit, so they could be provided a tablet computer to complete the survey in the clinic. After introducing tablets into the workflow at UCSF, patient completion of the baseline survey increased from 75.9% to 80%. Conclusion: The transition from paper to electronic QOL and AE data collection improves the ability of patients to complete PRO surveys, but the process must also be optimized and integrated into clinical workflow and trial conduct. In the future, we will present additional results highlighting the feasibility of multilingual ePRO integration into I-SPY 2. ePRO also provides a new opportunity for data analysis, as well as the potential to reduce high grade toxicity through early intervention. It will allow us to assess QoL and AE data by drug regimen, site, provider, and study treatment. The creation of clinician-facing reports also enables access to patient responses in real-time. By implementing ePRO within I-SPY 2, we not only increase efficiency and accuracy of patient-reported data collection, but also improve quality of care and patient safety. Citation Format: Anna Northrop, Anika Christofferson, Michelle Melisko, Laura Sit, Ebunoluwa Olunuga, Ananya Mittal, Adi Goldman, Thelma Brown, Diane Heditsian, Bev Parker, Susie Brain, Carol Simmons, Alessandra Taboada, Kathryn J Ruddy, Tina Hieken, Mara Piltin, Kiri Cook, Carolina Salvador, Candace Mainor, Anosheh Afghahi, Sarah Tevis, Anne Blaes, Irene Kang, Susan Melin, Laura Esserman, Adam Asare, Dawn L Hershman, Amrita Basu. Improving patient-reported outcome data capture for clinical research: ePRO in ISPY 2, a phase 2 breast cancer study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-12-02.

Background: Prospective evaluation of clinical outcomes after posterior meniscal root repair utilizing a transtibial pullout technique is limited, and factors that may contribute to outcomes are unclear. Hypothesis: It was hypothesized that there would be an overall significant improvement in outcomes after root repair and that differences in clinical outcomes would correlate with age, body mass index (BMI), sex, and meniscal extrusion. Study Design: Case-control study; Level of evidence, 3. Methods: Consecutive patients undergoing transtibial medial or lateral meniscal root repair were enrolled prospectively at 2 orthopaedic centers between March 2017 and January 2019. Pre- and postoperative magnetic resonance imaging (MRI) were obtained to assess for meniscal healing, quantification of extrusion, articular cartilage grade, and subchondral bone changes. Patient-reported outcomes including International Knee Documentation Committee (IKDC) scores, Tegner activity scale, and visual analog scale (VAS) for pain were collected preoperatively and 2 years postoperatively. Patients were then subdivided by clinical and demographic characteristics to determine factors associated with clinical outcomes. Results: Included were 45 patients (29 female, 16 male; mean age, 42.3 ± 12.9 years; mean BMI, 31.6 kg/m 2 ) who underwent 47 meniscal root repairs (29 medial and 16 lateral; 2 had both). Significant improvements at 2-year follow-up were seen in IKDC score (41.1 vs 78.4; P < .001), Tegner activity level (3 vs 4; P < .001), and VAS pain (2.8 vs 0.7; P < .001). BMI, preoperative malalignment, cartilage status, and progressive meniscus extrusion (Δ = 0.7 mm) did not have a negative impact on IKDC and Tegner scores 2 years postoperatively. Age greater than or equal to 50 years and extrusion pre- and postoperatively were associated with decreased Tegner scores. Progressive meniscal extrusion was associated with a decreased overall improvement in Tegner scores. Conclusion: Transtibial root repair for medial and lateral posterior meniscal root tears demonstrated significantly improved clinical outcomes at 2 years postoperatively. Increased age, increased BMI, cartilage status, and meniscal extrusion did not have a negative impact on short-term functional outcomes (IKDC), but age greater than or equal to 50 years and extrusion negatively influenced patient activity level (Tegner). Registration: NCT03037242 ( ClinicalTrials.gov identifier).

OBJECTIVE Combinations of certain social risk factors of race, sex, education, socioeconomic status (SES), insurance, education, employment, and one’s housing situation have been associated with poorer pain and disability outcomes after lumbar spine surgery. To date, an exploration of such factors in patients with cervical spine surgery has not been conducted. The objective of the current work was to 1) define the social risk phenotypes of individuals who have undergone cervical spine surgery for myelopathy and 2) analyze their predictive capacity toward disability, pain, quality of life, and patient satisfaction–based outcomes. METHODS The Cervical Myelopathy Quality Outcomes Database was queried for the period from January 2016 to December 2018. Race/ethnicity, educational attainment, SES, insurance payer, and employment status were modeled into unique social phenotypes using latent class analyses. Proportions of social groups were analyzed for demonstrating a minimal clinically important difference (MCID) of 30% from baseline for disability, neck and arm pain, quality of life, and patient satisfaction at the 3-month and 1-year follow-ups. RESULTS A total of 730 individuals who had undergone cervical myelopathy surgery were included in the final cohort. Latent class analysis identified 2 subgroups: 1) high risk (non-White race and ethnicity, lower educational attainment, not working, poor insurance, and predominantly lower SES), n = 268, 36.7% (class 1); and 2) low risk (White, employed with good insurance, and higher education and SES), n = 462, 63.3% (class 2). For both 3-month and 1-year outcomes, the high-risk group (class 1) had decreased odds (all p < 0.05) of attaining an MCID score in disability, neck/arm pain, and health-related quality of life. Being in the low-risk group (class 2) resulted in an increased odds of attaining an MCID score in disability, neck/arm pain, and health-related quality of life. Neither group had increased or decreased odds of being satisfied with surgery. CONCLUSIONS Although 2 groups underwent similar surgical approaches, the social phenotype involving non-White race/ethnicity, poor insurance, lower SES, and poor employment did not meet MCIDs for a variety of outcome measures. This finding should prompt surgeons to proactively incorporate socially conscience care pathways within healthcare systems, as well as to optimize community-based resources to improve outcomes and personalize care for populations at social risk.

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to date been anecdotal. Here, we conducted a phase 1 clinical trial of systemic OV therapy and investigated the mechanisms of action in responding T-cell lymphoma (TCL) patients. A single IV dose of VSV-IFNβ-NIS was administered to patients with relapsed refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DL). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication and immune responses. Fifteen patients received VSV-IFNβ-NIS (7 multiple myeloma, 7 TCL, 1 acute myeloid leukemia); 3 patients were treated at each DL1 through DL3 (0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL4 (1.7 x 1011 TCID50). There were no dose limiting toxicities. 3 of 7 patients with TCL had RECIST responses: a 3-month PR at DL2, a 6-month PR and a durable CR ongoing at 20 months at DL4. Viremia peaked at the end of infusion and no infectious virus shedding was detected. Plasma interferon-β levels, a biomarker of VSV-IFNβ-NIS replication, peaked between 4h and 48h post infusion. The patient with CR had robust viral replication with increased ell free DNA in her plasma, a very high peak IFNβ level of 18,213 pg/ml, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. Further clinical testing is warranted. (This trial is registered at www.clinicaltrials.gov as NCT03017820).

Abstract Autoimmune polyglandular syndromes (APS) are rare disorders characterized by auto‐destruction of endocrine and non‐endocrine organs by organ‐specific antibody‐directed T‐lymphocytic infiltration. This case highlights a 29‐year‐old Caucasian man with vitiligo found to have significant neurological abnormalities in the setting of newly diagnosed pernicious anemia and thyroid autoimmune disease.

OBJECTIVE High-impact chronic pain (HICP) is a recently proposed metric that indicates the presence of a severe and troubling pain-related condition. Surgery for cervical spondylotic myelopathy (CSM) is designed to halt disease transition independent of chronic pain status. To date, the prevalence of HICP in individuals with CSM and their HICP transition from presurgery is unexplored. The authors sought to define HICP prevalence, transition, and outcomes in patients with CSM who underwent surgery and identify predictors of these HICP transition groups. METHODS CSM surgical recipients were categorized as HICP at presurgery and 3 months if they exhibited pain that lasted 6–12 months or longer with at least one major activity restriction. HICP transition groups were categorized and evaluated for outcomes. Multivariate multinomial modeling was used to predict HICP transition categorization. RESULTS A majority (56.1%) of individuals exhibited HICP preoperatively; this value declined to 15.9% at 3 months (71.6% reduction). The presence of HICP was also reflective of other self-reported outcomes at 3 and 12 months, as most demonstrated notable improvement. Higher severity in all categories of self-reported outcomes was related to a continued HICP condition at 3 months. Both social and biological factors predicted HICP translation, with social factors being predominant in transitioning to HICP (from none preoperatively). CONCLUSIONS Many individuals who received CSM surgery changed HICP status at 3 months. In a surgical population where decisions are based on disease progression, most of the changed status went from HICP preoperatively to none at 3 months. Both social and biological risk factors predicted HICP transition assignment.

Abstract Purpose Using electrocardiogram (ECG) interpretation as an example of a widely taught diagnostic skill, the authors conducted a systematic review and meta-analysis to demonstrate how research evidence on instruction in diagnosis can be synthesized to facilitate improvement of educational activities (instructional modalities, instructional methods, and interpretation approaches), guide the content and specificity of such activities, and provide direction for research. Method The authors searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, PsycInfo, CINAHL, ERIC, and Web of Science databases through February 21, 2020, for empirical investigations of ECG interpretation training enrolling medical students, residents, or practicing physicians. They appraised study quality with the Medical Education Research Study Quality Instrument and pooled standardized mean differences (SMDs) using random effects meta-analysis. Results Of 1,002 articles identified, 59 were included (enrolling 17,251 participants). Among 10 studies comparing instructional modalities, 8 compared computer-assisted and face-to-face instruction, with pooled SMD 0.23 (95% CI, 0.09, 0.36) indicating a small, statistically significant difference favoring computer-assisted instruction. Among 19 studies comparing instructional methods, 5 evaluated individual versus group training (pooled SMD −0.35 favoring group study [95% CI, −0.06, −0.63]), 4 evaluated peer-led versus faculty-led instruction (pooled SMD 0.38 favoring peer instruction [95% CI, 0.01, 0.74]), and 4 evaluated contrasting ECG features (e.g., QRS width) from 2 or more diagnostic categories versus routine examination of features within a single ECG or diagnosis (pooled SMD 0.23 not significantly favoring contrasting features [95% CI, −0.30, 0.76]). Eight studies compared ECG interpretation approaches, with pooled SMD 0.92 (95% CI, 0.48, 1.37) indicating a large, statistically significant effect favoring more systematic interpretation approaches. Conclusions Some instructional interventions appear to improve learning in ECG interpretation; however, many evidence-based instructional strategies are insufficiently investigated. The findings may have implications for future research and design of training to improve skills in ECG interpretation and other types of visual diagnosis.