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ICI therapy has greatly improved patient outcomes in melanoma, but at the cost of immune-related adverse events (irAEs). Data on the chronicity of irAEs, especially in real-world settings, are currently limited. We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥ 6 months), transient (resolution over a period < 6 months), or no irAEs. A total of 283 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, fifteen (9.3%) experienced long-term irAEs as their longest-lasting toxicity, thirty-four (21.1%) developed transient irAEs only, and forty-six (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (36.0%) or skin-related (32.4%). Grade 3–4 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still requiring treatment for long-term or permanent irAEs 6 months or more following the completion of ICI therapy, including twenty-four patients on thyroid hormone replacement and twenty-two on oral steroids. ICI treatment was temporarily interrupted for 64 (22.6%) irAEs and permanently discontinued due to irAEs in 38 patients (13.6% of irAEs, 23.6% of patients); additionally, 4 (2.5%) patients died of irAEs. Our findings show that ICI treatment in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients, which should therefore be discussed when obtaining consent for treatment.

Immunotherapy has revolutionized treatment outcomes in numerous cancers. However, clinical trials have largely excluded patients with autoimmune diseases (ADs) due to the risk of AD flares or predilection for developing organ-specific inflammation. The objective of this study was to evaluate the safety and efficacy of immunotherapy in patients with cancer and preexisting ADs. A retrospective, single-center study of patients with cancer initiated on immune checkpoint inhibitors between 2012 and 2019 was conducted. The primary outcome was the development of immune-related adverse events (irAEs) with respect to the presence of AD at baseline. Associations were assessed using Kaplan-Meier curves, bivariate and multivariable analyses. Of the 417 patients included in this study, 63 patients (15%) had preexisting ADs. A total of 218 patients (53%) developed at least 1 irAE. There was no association between the presence of baseline AD on the development, grade, or number of irAEs; time to irAE or irAE recovery; systemic corticosteroid or additional immunosuppressant treatment for irAEs; permanent treatment discontinuation; or overall response rate. Two smaller cohorts were studied, melanoma and non-small cell lung cancer, and there was no effect of baseline AD on overall survival on either cohort. However, a greater proportion of patients with baseline ADs had full recovery from their irAE (P=0.037). Furthermore, age below 65, baseline steroid use, and single-agent immunotherapy regimens were protective in terms of the development of irAEs. Our study suggests that immune checkpoint inhibitors have similar safety and efficacy profiles in patients with preexisting ADs.

Chagas' disease and Lyme disease are two endemic, vector-borne zoonotic infectious diseases that impact multiple organ systems, including the heart. Chagas' cardiomyopathy is a progressive process that can evolve into a dilated cardiomyopathy and heart failure several decades after the acute infection; in contrast, although early-disseminated Lyme carditis has been relatively well characterized, the sequelae of Lyme disease on the heart are less well-defined. A century of research on Chagas' cardiomyopathy has generated compelling data for pathophysiological models, evaluated the efficacy of therapy in large randomized controlled trials, and explored the social determinants of health impacting preventative measures. Recognizing the commonalities between Chagas' disease and Lyme disease, we speculate on whether some of the lessons learned from Chagas' cardiomyopathy may be applicable to Lyme carditis.

Background: The impact of BMI on immune checkpoint inhibitor toxicity and efficacy has not been clearly characterized. Methods: The authors conducted a retrospective single-center study of patients with advanced unresectable/metastatic cancer initiated on immune checkpoint inhibitors. Results: Of the 409 patients included in the study, 115 (28%) had a BMI ≥30. There was no difference in the development of immune-related adverse events, treatment response or overall survival with respect to BMI

Aim: To evaluate overall survival in advanced cancer patients who achieved complete response (CR) with immune checkpoint inhibitor (ICI) therapy. Methods: This retrospective study included patients with advanced unresectable or metastatic cancer who received at least one cycle of palliative-intent ICI. Best overall response was used to define response groups. Results: 21 (7%) of 322 patients achieved CR. Multivariate analysis demonstrated that CR was independently associated with better overall survival compared with disease progression (hazard ratio: 0.012; 95% CI: 0.002–0.090) and stable disease (hazard ratio: 0.063; 95% CI: 0.009–0.464) as well as a nonsignificant trend toward better overall survival compared with partial response (hazard ratio: 0.169; 95% CI: 0.023–1.252) regardless of cancer type, ICI regimen or ICI line. Conclusion: Patients who achieved CR had longer survival compared with patients who did not achieve CR.

Nrf2 is the master transcriptional regulator of cellular responses against oxidative stress. It is chiefly regulated by Keap1, a substrate adaptor protein that mediates Nrf2 degradation. Nrf2 activity is also influenced by many other protein interactions that provide Keap1-independent regulation. To study Nrf2 regulation, we established and characterized yeast models expressing human Nrf2 (also known as NFE2L2), Keap1 and other proteins that interact with and regulate Nrf2. Yeast models have been well established as powerful tools to study protein function and genetic and physical protein-protein interactions. In this work, we recapitulate previously described Nrf2 interactions in yeast and discover that Nrf2 interacts with the molecular chaperone Hsp90. Our work establishes yeast as a useful tool to study Nrf2 interactions and provides new insight into the crosstalk between the antioxidant response and the heat shock response.

Asymptomatic bradyarrhythmias involving sinus node dysfunction and atrioventicular blocks are frequently noted in clinical practice. Its prevalence is expected to rise as devices that are developed for monitoring cardiac rhythm for longer duration become more widely available. Episodes of bradyarrhythmia that are asymptomatic are considered to have a benign course compared with those that cause symptoms and do not necessitate further treatment. However, in certain cases, they can be a harbinger of future symptoms or cardiac manifestations of systemic diseases. The evaluation and risk stratification of individuals presenting with asymptomatic bradyarrhythmias is important not only for preventing implantation of unnecessary permanent pacing devices but also for reducing significant morbidity by implementing proper treatment as required. In this article, we will review the current evidence on the pathophysiology, diagnosis, evaluation and management of patients with asymptomatic bradyarrhythmias.

In December 2019, reports of an unknown pneumonia not responsive to traditional treatments arose in Wuhan, China. The pathogen was subsequently identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known to be responsible for the coronavirus disease-2019 (COVID-19) illness, and public health emergency of international concern was declared by the World Health Organization. There is increasing awareness of the cardiovascular manifestations of COVID-19 disease, and the adverse impact of cardiovascular involvement on its prognosis. In this setting, the electrocardiogram (ECG) is one of the leading tools to assess the extent of cardiac involvement in COVID-19 patients, due to its wide disponibility, low cost, and the possibility of remote evaluation. In this article, we review the role of the ECG in the identification of cardiac involvement in COVID-19, highlighting relevant clinical implications.

Aim: To evaluate the correlation between venous thromboembolism events (VTEs) and immune checkpoint inhibitor (ICI)-based regimens. Methods: This is a retrospective study of 403 patients with advanced cancer on ICI-based regimens. Results: We report 8% VTE incidence post-ICI initiation over a median of 11.1 months of follow-up. Compared with single-agent ICI, dual-ICI was significantly correlated with higher incidence of VTE (odds ratio [OR]: 4.196, 95% CI: 1.527–11.529, p = 0.005), but chemotherapy–immuno-oncology combination was not (OR: 1.374, 95% CI: 0.285–6.632, p = 0.693). Subsequent systemic therapy post-ICI was also independently associated with higher VTE incidence (OR: 2.599, 95% CI: 1.169–5.777, p = 0.019). Conclusion: Our findings suggest potential underreporting of VTE incidence in ICI clinical trials. As dual-ICI is becoming more prevalent in cancer management, clinicians should maintain vigilance regarding VTE in patients with advanced cancer on ICI-based regimens.

Lyme disease is the most reported tick-borne illness in North America. Lyme carditis (LC) is an early-disseminated manifestation of Lyme disease, most commonly presenting as symptomatic high-degree atrioventricular block (AVB) which resolves with appropriate antibiotic therapy. However, long-term outcomes of treated LC have not previously been described. We present a series of 7 patients (median 28 years, 6 male) with serologically confirmed LC treated with a standard protocol developed at our center including antibiotics and pre-discharge stress test to assess AV node stability. At a mean follow-up of 20.8 months, all patients were asymptomatic, had resumed normal activities, and were free of conduction abnormalities. None required permanent pacing. Our study supports avoidance of permanent pacing for LC if conduction is stable at discharge.

PurposeStereotactic body radiation therapy (SBRT) is a novel local therapy for the treatment of hepatocellular carcinoma (HCC). While effective, there is currently noreliable radiological marker to guide patient selection. In this study, we investigated the prognostic value of capsule appearanceon contrast-enhanced computed tomography (CT) for patients undergoing SBRT. Materials and Methods Between 2006 and 2017, 156 consecutive patients with Child-Pugh score class A/B and HCC ≥5cm that underwent SBRT were retrospectively analysed. Baseline triple-phase CTs of the abdomen were reviewed for the presence of capsule appearances and correlated with objective response rate (ORR), overall survival (OS), and pattern of treatment failure. ResultsCapsule appearance on CT was present in 83 (53.2%) patients.It was associated with improved ORR by Response Evaluation Criteria in Solid Tumours (RECIST) (60.2% vs 24.7%; pConclusion Capsule appearance on CT could potentially be a non-invasive prognostic marker for selecting HCC patients undergoing SBRT. Larger cohort is warranted to validate our findings.

Lyme disease, a tickborne infection caused by Borrelia burgdorferi, can affect cardiac tissue causing Lyme carditis. Patients with Lyme carditis most commonly present with varying degrees of atrioventricular block and rarely with sick sinus syndrome. A previously healthy 22 year-old male presented with syncope. His 2 week Holter monitor showed sinus pauses of 6.5 and 6.8 s. Lyme serology, including Western blot, was positive. A stress test, completed after 8 days of intravenous antibiotics for Lyme carditis, revealed no conduction abnormalities. He was discharged on 3 weeks of oral antibiotics and had no conduction abnormalities on subsequent follow-up.

As cardiovascular implantable electronic devices (CIEDs) are increasingly indicated in older patients, and the burden of cancer is rising with the aging population, the management of patients with CIEDs who require radiotherapy (RT) is a timely concern. The objective of the study was to evaluate the management of, and malfunctions in, patients with CIEDs undergoing RT. A retrospective study of patients with CIEDs receiving RT at Kingston Health Sciences Center from March 2007–April 2018 was conducted. Data on demographics, RT, devices, and management were compared for the primary outcome of device malfunction. Of the 189 patients with CIEDs receiving a total of 297 courses of RT, 4 patients (2.1%) experienced device malfunctions. Higher beam energy was associated with a malfunction (p

Proficiency-based knot-tying curricula have been developed for square knots for medical students, but, to our knowledge, no such curriculum exists for the reverse half hitch alternating-post (RHAP) knot. We aimed to compare medical students' knot-tying proficiency, knot-tying self-confidence and final knot characteristics for RHAP and square knots in a simulated deep body cavity.We performed a within-subject prospective crossover study of novice medical students who received 30 minutes of training in tying both RHAP and square knots. Participant performance was assessed via a knot-tying checklist, and knot configuration, tensile strength, tightness (loop circumference) and mechanism of failure were also assessed. Participants' self-reported confidence in knot tying was captured.Twenty-one students participated in the study. Mean scores on the knot-tying checklist were significantly higher for RHAP knots than for square knots (6.9 [standard deviation (SD) 2.1] v. 5.2 [SD 2.3],Novice medical students were more proficient in tying RHAP knots than square knots in a simulated deep body cavity. Students were able to construct RHAP knots more securely and reported increased confidence in tying RHAP knots at depth compared to square knots.Des programmes d'enseignement fondés sur la compétence dans l'exécution de nœuds chirurgicaux par les étudiants en médecine ont été créés pour les nœuds plats, mais autant que nous sachions, un tel programme n'existe pas pour le nœud de type demi-clé inversée alternée. Nous avons comparé les aptitudes d'exécution de nœuds et la confiance des étudiants en médecine, ainsi que les caractéristiques des nœuds résultants, pour les nœuds de type demi-clé inversée alternée et les nœuds plats, dans une simulation de cavité profonde.Nous avons réalisé une étude croisée prospective intra-sujet portant sur des étudiants en médecine débutants, qui ont reçu une formation de 30 minutes sur l'exécution de nœuds de type demi-clé inversée alternée et de nœuds plats. Le travail des participants a été évalué à l'aide d'une liste de vérification d'exécution des nœuds; la configuration des nœuds, la résistance à la traction, le serrage (circonférence de la boucle) et le mécanisme de défaillance ont aussi été évalués. La confiance en soi rapportée par les participants quant à leurs aptitudes d'exécution de nœuds a aussi été examinée.Vingt-et-un étudiants ont pris part à cette étude. Les scores moyens de la liste de vérification d'exécution des nœuds étaient significativement plus élevés pour les nœuds de type demi-clé inversée alternée que pour les nœuds plats (6,9 [écart-type (É.T.) : 2,1] contre 5,2 [É.T. : 2,3],Les aptitudes des étudiants en médecine débutants pour l'exécution de nœuds de type demi-clé inversée alternée étaient supérieures à leurs aptitudes pour l'exécution de nœuds plats, lors d'une simulation de cavité profonde. Les étudiants ont pu réaliser des nœuds de type demi-clé inversée alternée plus solides et ont rapporté une confiance plus grande quant à l'exécution de ce type de nœuds que pour l'exécution de nœuds plats en profondeur.

Atrial fibrillation (AF) is a risk factor for ischemic stroke and reported to be associated with severe obstructive sleep apnea (OSA). The aim of this study was to determine the occurrence of newly detected AF in patients with severe OSA and no previous history of AF. Prospective observational study included patients with severe OSA (Apnea-Hypopnea Index [AHI] ≥ 30) and no history of AF. Primary outcome was detection of AF lasting ≥10 seconds. Patients were subjected to 2 24-hour Holter monitors, and if no AF was detected, implanted with a Medtronic Reveal XT implantable loop recorder. Follow-up was done every 6 months for a total of 3years. Implantable loop recorder was explanted if the primary outcome was detected (AF) or the battery was exhausted. Of the 31 patients enrolled, 6 withdrew participation in the study before implantation. Mean age was 57 ± 10years, mean body mass index was 35 ± 6; 52% male patients. Hypertension 56% and coronary artery disease 24%. Mean AHI was 55 ± 18. AF was detected in 5 patients (20%). AF mean duration was 4.8hours (range 20 seconds to 15.3 hours). Mean time to diagnosis was 11 ± 7 months. Male gender was predictive for AF detection (p = 0.04). Continuous positive airway pressure therapy was used by 96% of patients with 68% total adherence. Mean follow-up was 27 months. In conclusion, extended cardiac monitoring of patients with severe OSA may facilitate the identification of newly detected AF.

Lyme carditis (LC) is an early-disseminated manifestation of Lyme disease, most commonly presenting as a high-degree atrioventricular block (AVB). The degree of AVB can fluctuate rapidly within minutes, and progression to third-degree AVB is potentially fatal if not recognized and managed promptly. However, the AVB in LC is often transient and usually resolves with appropriate antibiotic therapy. LC should be on the differential diagnosis in young patients presenting with new high-degree AVB and factors that increase the index of suspicion for Lyme disease. The Suspicious Index in Lyme Carditis (SILC) score helps clinicians risk-stratify for LC. A systematic approach to the diagnosis and treatment of LC minimizes the unnecessary implantation of permanent pacemakers.

Prolonged QRS duration, which reflects a higher degree of mechanical dysynchrony, is a predictor of response to CRT. However, the association of QRS narrowing after biventricular pacing with CRT response rates is not clear. Our aim was to conduct a systematic review and meta-analysis on the association between QRS narrowing after cardiac resynchronization therapy (CRT) and clinical and echocardiographic response to CRT in patients with heart failure. Two independent investigators searched MedLine and EMBASE databases through July 2018 without any limitations. Studies providing estimates (continuous data) on the association of QRS shortening with either clinical (defined as New York Heart Association (NYHA) reduction ≥ 1) or echocardiographic (defined as left ventricular end-systolic volume (LVESV) reduction ≥ 15%) response to CRT were finally included in the quantitative synthesis. We included 32 studies (14 studies (1274 patients mean age 64 years old, males 79.3%) using clinical CRT response and 18 studies (1270 patients, mean age 64 years old, males 69.1%) using echocardiographic CRT response). A significant association between QRS narrowing and shorter attained QRS duration with clinical and echocardiographic CRT response was observed. The observed association was independent of the timing of QRS width measurement after CRT implantation. Acute and late improvement of electrical dysynchrony as depicted by QRS narrowing following biventricular pacing is associated with clinical and echocardiographic response to CRT. However, large prospective studies are needed to further examine our findings.

Background Obstructive sleep apnea (OSA) is strongly associated with atrial fibrillation (AF). Long-term ECG monitoring with implantable loop recorders facilitates the identification of undiagnosed AF in 20% of severe OSA cases. However, ambulatory ECG (AECG) monitoring is less resource intensive, and various parameters have been shown to predict AF. The aim of this study was to assess the efficacy of such AECG-based AF predictors in identifying patients with severe OSA most at risk. Methods Prospective observational study including patients with severe OSA and no history of AF. Patients had two 24-h AECG recordings, and if no AF was detected, implanted with a loop recorder (maximum 3 years). Results Of 25 patients implanted, AF ≥ 10 s was detected in 5 patients. None of the parameters from the AECG recordings were significantly different between patients who did and did not develop AF. Conclusions AECG-based parameters were not effective for the prediction of AF in this severe OSA cohort.

Background Atrial fibrillation (AF), which affects 1% to 4% of the general population, is an important risk factor for stroke. New technologies for AF screening are now available, but their real-world application in clinical settings has not yet been thoroughly investigated. The aim of this project was to describe the introduction and feasibility of a mobile electrocardiogram (ECG) device for AF screening in a large-scale, undifferentiated population. Methods A total of 184 Canadian primary care physicians were provided with a KardiaMobile ECG device (AliveCor) for 3 months. Physicians were asked to obtain a single 30-second ECG recording of all patients seen in their daily practice who were ≥65 years old and not previously diagnosed with AF. Evaluation of the Kardia device by physicians was measured using a Likert scale–based questionnaire. Results One hundred thirty-three physicians (72%) reported their findings and completed the survey. A total of 7585 patients were screened (42% of eligible patients). AF was detected in 471 patients (6.2%). Anticoagulation therapy was initiated in 270 patients (57%). Physicians generally reported a high perceived clinical value (94%) and ease of integration (89%) of the device. Conclusions Previously undiagnosed AF is common in older individuals attending primary care clinics. The KardiaMobile ECG device appears to be an effective screening tool for AF with high physician acceptability. More research on the feasibility of such novel technologies is warranted for future consideration of integration in population-based screening programs.

BACKGROUND: Lyme carditis (LC), an early manifestation of Lyme disease that most commonly presents as high‐degree atrioventricular block (AVB), usually resolves with antibiotic treatment. When LC is not identified as the cause of AVB, a permanent pacemaker may be inappropriately implanted in a reversible cardiac conduction disorder. HYPOTHESIS: The likelihood that a patient's high‐degree AVB is caused by LC can be evaluated by clinical characteristics incorporated into a risk stratification tool. METHODS: A systematic review of all published cases of LC with high‐degree AVB, and five cases from the authors' experience, was conducted. The results informed the development of a new risk stratification tool, the Suspicious Index in LC (SILC) score. The SILC score was then applied to each case included in the review. RESULTS: Of the 88 cases included, 51 (58%) were high‐risk, 31 (35.2%) intermediate‐risk, and 6 (6.8%) low‐risk for LC according to the SILC score (sensitivity 93.2%). For the subset of 32 cases that reported on all SILC variables, 24 (75%) cases were classified as high‐risk, 8 (25%) intermediate‐risk, and 0 low‐risk (sensitivity 100%). Specificity could not be assessed (no control group). Notably, 6 of the 11 patients who received permanent pacemakers had reversal of AVB with antibiotic treatment. CONCLUSION: The SILC risk score and COSTAR mnemonic (constitutional symptoms; outdoor activity; sex = male; tick bite; age

The incidence of Lyme disease, a tick-borne bacterial infection, is dramatically increasing in North America. The diagnosis of Lyme carditis (LC), an early disseminated manifestation of Lyme disease, has important implications for patient management and preventing further extracutaneous complications. High-degree atrioventricular block is the most common presentation of LC, and usually resolves with antibiotic therapy. A systematic approach to the diagnosis of LC in patients with high-degree atrioventricular block will facilitate the identification of this usually transient condition, thus preventing unnecessary implantation of permanent pacemakers in otherwise healthy young individuals.

See related articles at [[www.cmaj.ca/lookup/doi/10.1503/cmaj.191279][2]][2] and [[www.cmaj.ca/lookup/doi/10.1503/cmaj.191194][3]][3] A 56-year-old woman presented to the emergency department with a new well-defined erythematous patch on her right clavicular region ([Figure 1][3]), myalgia and

We read with interest the paper by Asghar et al. [(1)][1] on gender differences in authorship of cardiology literature. This paper highlights the value of mentorship in promoting gender equity and reported a significant increase in the proportion of female first and senior authors over time. The

Atrial fibrillation (AF) often complicates the course of inherited cardiomyopathies and, in some cases, may be the presenting feature. Each inherited cardiomyopathy has its own peculiar pathogenetic characteristics that can contribute to the development and maintenance of AF. Atrial fibrillation may occur as a consequence of disease-specific defects, non-specific cardiac chamber changes secondary to the primary illness, or a combination thereof. The presence of AF can denote a turning point in the progression of the disease, promoting clinical deterioration and increasing morbidity and mortality. Furthermore, the management of AF can be particularly challenging in patients with inherited cardiomyopathies. In this article, we review the current information on the prevalence, pathophysiology, risk factors, and treatment of AF in three different inherited cardiomyopathies: hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia/cardiomyopathy, familial dilated cardiomyopathy, and left ventricular non-compaction cardiomyopathy.

Because cardiovascular implantable electronic devices are increasingly indicated in older patients, and the burden of cancer is rising with the growth and aging of the world population, the management of patients with cardiac devices who require radiotherapy for cancer treatment is a timely concern. Device malfunctions might occur in as high as 3% of radiotherapy courses, posing a substantial issue in clinical practice. A nonsystematic comprehensive review was undertaken. We searched PubMed and the MEDLINE database for randomized controlled trials, meta-analyses, systematic reviews, observational studies, in vitro / in vivo studies, and case reports. Articles were selected by 2 independent reviewers, and emphasis was given to information of interest to a general medical readership. The pathophysiology and predictors of cardiovascular implantable electronic device malfunction due to radiotherapy are reviewed, recommendations for the management of patients with such devices undergoing radiotherapy are summarized, and the clinical significance and future directions of this field are discussed. Radiotherapy-induced device malfunctions are rare, but because of the potential complications, the development of evidence-based guidelines for the management of patients with cardiovascular implantable electronic devices undergoing radiotherapy is a timely concern.