Association of QRS narrowing with response to cardiac resynchronization therapy-a systematic review and meta-analysis of observational studies.

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.

Toxicity outcome of endorectal brachytherapy boost in medically inoperable patients.

AIM: This communication reviews results and toxicity of image-guided high-dose-rate endorectal brachytherapy (HDREBT) boost after external beam radiotherapy (ERT) in medically inoperable patients with rectal cancer. MATERIALS AND METHODS: A total of 18 patients with rectal cancer and clinical stage T2-4N0­2 treated with HDREBT boost after ERT were retrospectively reviewed. RESULTS: Following treatment with a median total dose (EQD2, α/ß = 10) of 66 Gy (range 48-92 Gy), the incidence of early and late rectal grade 3 toxicity was 11% and 19%, respectively. There was no correlation between the occurrence of acute and late toxicity. CONCLUSION: With proper technique, a combined approach using EBRT and HDREBT was associated with acceptable toxicity in medically inoperable rectal cancer patients.

Lyme carditis presenting as sick sinus syndrome.

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.

Value of electrocardiography in coronavirus disease 2019 (COVID-19).

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.

Combined stereotactic body radiotherapy and trans-arterial chemoembolization as initial treatment in BCLC stage B-C hepatocellular carcinoma.

PURPOSE: We retrospectively evaluated the efficacy and safety of stereotactic body radiotherapy (SBRT) combined with trans-arterial chemoembolization (TACE) as initial therapy in Barcelona Clinic Liver Cancer (BCLC) system stage B-C hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Seventy-two patients received a single dose of TACE followed by SBRT 4 weeks later. All patients had tumor sizes ≥5 cm, at least 700 ml of disease-free liver, Child-Pugh (CP) score ≤ B7 and tumor nodules ≤5. SBRT dose, ranging from 6â€¯× 5-8 Gy or 5-10â€¯× 4 Gy, was individualized according to normal tissue constraints. No subsequent scheduled treatment was delivered unless disease progression was observed. Local control (LC), overall survival (OS), progression-free survival (PFS), response rate (RR), and toxicity were evaluated. RESULTS: The patients' characteristics were: median age 60 years (range 28-87 years); CP score A/B (n = 68/4); BCLC stage B/C (n = 51/21); solitary/multifocal (n = 37/35); portal vein invasion (n = 18). The median tumor size and GTV were 11.2 cm (range 5.0-23.6 cm) and 751 cm3 (range 41-4009 cm3), respectively. The median equivalent dose in 2 Gy per fraction (EQD2, α/ß = 10) was 37.3 Gy2 (range, 28-72 Gy2). The median follow-up time was 16.8 months (range, 3-96 months). The objective RR was 68% and the 1­year LC rate was 93.6% (95% CI, 87.6-100%). The median OS was 19.8 months (95% CI, 11.6-30.6 months). SBRT-related grade 3 or higher adverse gastrointestinal events and treatment-related death occurred in three (2.8%) and one patient (1.4%) respectively. No patient developed classical radiation-induced liver injury. CONCLUSION: Our experience suggests that combined TACE and SBRT can be a safe and effective initial therapy for BCLC stage B-C HCC with appropriate patient selection. Further prospective trials are warranted.

Atrial fibrillation in patients with inherited cardiomyopathies.

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.

New electrocardiographic score for the prediction of atrial fibrillation: The MVP ECG risk score (morphology-voltage-P-wave duration).

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and has significant morbidity. A score composed of easily measured electrocardiographic variables to identify patients at risk of AF would be of great value in order to stratify patients for increased monitoring and surveillance. The purpose of this study was to develop an electrocardiographic risk score for new-onset AF. METHODS: A total of 676 patients without previous AF undergoing coronary angiography were retrospectively studied. Points were allocated based on P-wave morphology in inferior leads, voltage in lead 1, and P-wave duration (MVP). Patients were divided into three risk groups and followed until development of AF or last available clinical appointment. RESULTS: Mean age was 65 years, and 68% were male. The high- and intermediate-risk groups were more likely to develop AF than the low-risk group (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.3-4.4; p = 0.006 and OR 2.1, 95% CI 1.4-3.27; p = 0.009, respectively). The high-risk group had a significantly shorter mean time to development of AF (258 weeks; 95% CI 205-310 weeks) compared to the intermediate- (278 weeks; 95% CI 252-303 weeks) and low-risk groups (322 weeks 95% CI 307-338 weeks), p = 0.005. CONCLUSIONS: A simple risk score composed of easy-to-measure electrocardiographic variables can help to predict new-onset AF. Further validation studies will be needed to assess the ability of this risk score to predict AF in other populations.

Ambulatory ECG predictors of atrial fibrillation are ineffective in severe sleep apnea.

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.

Comparison of knot-tying proficiency and knot characteristics for square and reversing half hitch alternating-post surgical knots in a simulated deep body cavity among notice medical students.

BACKGROUND: 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. METHODS: 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. RESULTS: 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], p < 0.01), and RHAP knots were significantly tighter than square knots (46.8 mm [SD 0.4 mm] v. 49.3 mm [SD 0.7 mm], p < 0.05). There were no differences between RHAP and square knots in correct knot configuration, breaking strength or mechanism of failure. Reverse half hitch alternating-post knots were easier to tie within a deep-body cavity, whereas square knots were easier to learn. CONCLUSION: 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.

CONTEXTE: 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. MÉTHODES: 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. RÉSULTATS: 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], p < 0,01), et les nœuds demi-clé inversée alternée étaient significativement plus serrés que les nœuds plats (46,8 mm [É.T. : 0,4 mm] contre 49,3 mm [É.T. : 0,7 mm], p < 0,05). Aucune différence n'a été observée entre les 2 types de nœuds quant à la configuration, à la résistance à la traction et au mécanisme de défaillance. Les nœuds de type demi-clé inversée alternée étaient plus faciles à nouer dans une cavité profonde, mais la technique des nœuds plats était plus simple à apprendre. CONCLUSION: 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.

Whole-body vibration of mice induces progressive degeneration of intervertebral discs associated with increased expression of Il-1ß and multiple matrix degrading enzymes.

OBJECTIVE: Whole-body vibration (WBV) is a popular fitness trend based on claims of increased muscle mass, weight loss and reduced joint pain. Following its original implementation as a treatment to increase bone mass in patients with osteoporosis, WBV has been incorporated into clinical practice for musculoskeletal disorders, including back pain. However, our recent studies revealed damaging effects of WBV on joint health in a murine model. In this report, we examined potential mechanisms underlying disc degeneration following exposure of mice to WBV. METHODS: Ten-week-old male mice were exposed to WBV (45 Hz, 0.3 g peak acceleration, 30 min/day, 5 days/week) for 4 weeks, 8 weeks, or 4 weeks WBV followed by 4 weeks recovery. Micro-computed tomography (micro-CT), histological, and gene expression analyses were used to assess the effects of WBV on spinal tissues. RESULTS: Exposure of mice to 4 or 8 weeks of WBV did not alter total body composition or induce significant changes in vertebral bone density. On the other hand, WBV-induced intervertebral disc (IVD) degeneration, associated with decreased disc height and degenerative changes in the annulus fibrosus (AF) that did not recover within 4 weeks after cessation of WBV. Gene expression analysis showed that WBV for 8 weeks induced expression of Mmp3, Mmp13, and Adamts5 in IVD tissues, changes preceded by increased expression of Il-1ß. CONCLUSIONS: Progressive IVD degeneration induced by WBV was associated with increased expression of Il-1ß within the IVD that preceded Mmp and Adamts gene induction. Moreover, WBV-induced IVD degeneration is not reversed following cessation of vibration.

Survival Outcome Analysis of Stereotactic Body Radiotherapy and Immunotherapy (SBRT-IO) versus SBRT-Alone in Unresectable Hepatocellular Carcinoma.

Introduction: While combination of stereotactic body radiotherapy (SBRT) and immunotherapy are promising, their efficacy and safety have not been compared with SBRT-alone in patients with unresectable hepatocellular carcinoma (HCC). Methods: This retrospective study included 100 patients with nonmetastatic, unresectable HCC in two hospitals. Eligible patients had tumor nodules ≤3 and Child-Pugh liver function score of A5 to B7. Seventy patients received SBRT-alone, and 30 patients underwent combined SBRT and immunotherapy (SBRT-IO). Overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicity were analyzed. We adjusted for the potential confounding factors using propensity score matching. Results: The median tumor size was 7.3 cm (range, 2.6-18 cm). Twenty-five (25%) of patients had vascular invasion. Before propensity score matching, the 1-year and 3-year OS rate was 89.9% and 59.8% in the SBRT-IO group and 75.7% and 42.3% in SBRT-alone group (p = 0.039). After propensity score matching (1:2), 25 and 50 patients were selected from the SBRT-IO and SBRT-alone group. The 1-year and 3-year OS was 92.0% and 63.9% in the SBRT-IO group versus 74.0% and 43.3% in the SBRT-alone group (p = 0.034). The 1-year and 3-year TTP was better in SBRT-IO group (1-year: 68.9% vs. 58.9% and 3-year: 61.3% vs. 32.5%, p = 0.057). The ORR of 88% (complete response [CR]: 56%, partial response [PR]: 22%) in SBRT-IO arm was significantly better than 50% (CR: 20%, PR: 30%) in the SBRT-alone arm (p = 0.006). Three patients (12%) developed ≥grade 3 immune-related treatment adverse events (n = 2 hepatitis, n = 1 dermatitis) leading to permanent treatment discontinuation. Conclusion: Adding immunotherapy to SBRT resulted in better survival with manageable toxicities. Prospective randomized trial is warranted.

Survivals following discontinuation of PD-1 inhibitor treatment in advanced melanoma patients.

The aim of this study was to evaluate overall survival post-treatment discontinuation survival (OS PTD ) in advanced melanoma patients started on immunotherapy. This retrospective study included all unresectable advanced or metastatic melanoma patients who had permanent treatment discontinuation after receiving at least one cycle of palliative-intent programmed death-1 ± cytotoxic T-lymphocyte associated protein-4 inhibitor treatment from 2014 to 2019. Indications of permanent treatment discontinuation included treatment completion, toxicity or progression. OS PTD was defined as a time of permanent treatment discontinuation to the time of death. Our study ( N = 96) had 27, 12 and 57 patients who discontinued PD-1 inhibitor treatment due to treatment completion, toxicity and progression, respectively. Median treatment durations received for the treatment completion, toxicity and progression groups were 24, 6 and 3 months, respectively. As expected those patients who had disease progression on immunotherapy had very poor survival compared to those that completed treatment or stopped due to toxicity. A multivariable Cox model excluding the patients who progressed indicated no significant OS PTD differences between the toxicity and treatment completion group (HR, 0.894; 95% CI, 0.232-3.449; P = 0.871) who received single or dual immunotherapy. Our real-world study highlighted similar, durable survival at PD-1 inhibitor discontinuation due to either toxicity or treatment completion, despite longer treatment duration received in the completion group than toxicity group. Patients with progression on PD-1 inhibitor treatment have very poor survival. Our findings must be interpreted with caution due to its retrospective nature and small sample size.

Antithymocyte globulin for aplastic anemia secondary to pembrolizumab: a case report and review of literature.

Aplastic anemia is a rare but potentially serious complication of immune checkpoint inhibitor therapy. The authors present a case of pembrolizumab-induced aplastic anemia that was refractory to steroids but had some hematologic response to modified-dosing antithymocyte globulin (ATG). This is the first reported case of hematological response to ATG for immune checkpoint inhibitor-induced aplastic anemia and the first reported case of modified ATG dosing for this indication. Cases of immune checkpoint inhibitor-induced aplastic anemia and management options are also summarized. Given the high morbidity and mortality associated with ICI-induced aplastic anemia, more data is necessary to guide evidence-based management recommendations.

Immune checkpoint inhibitors (ICIs) are a form of anticancer therapy that enlists the body's own immune system to fight cancer cells. Although remarkably effective against some types of cancer, ICIs can also cause the augmented immune system to attack noncancer cells, resulting in unwanted off-target side effects. One rare but potentially serious complication of ICIs is aplastic anemia, where the body stops producing enough new blood cells. There is little known about ICI-induced aplastic anemia. The authors present a case of ICI-induced aplastic anemia that did not improve with standard treatment but had some response to antithymocyte globulin, which has not been previously reported. Previously published cases of ICI-induced aplastic anemia and management options are also summarized.

Association of circadian timing of initial infusions of immune checkpoint inhibitors with survival in advanced melanoma.

Aims: Chronomodulation of immune checkpoint inhibitors (ICIs) is not well understood. The authors evaluated the circadian timing of initial ICI infusions. Patients & methods: A retrospective cohort study of patients with advanced melanoma (n = 121) was conducted. Results: Exclusive afternoon timing of the first four infusions was associated with worse overall survival (5.5 vs 24.9 months; p < 0.001) and progression-free survival (3.3 vs 7.6 months; p = 0.009) on Kaplan-Meier curves. In multivariable Cox analysis, the rate of overall survival was lower in patients who received all first four ICI infusions in the afternoon versus patients who received ≥1 of the first four infusions in the morning (hazard ratio: 2.4; p = 0.004). Conclusion: Deliberate morning scheduling for the first several ICI treatments may improve patient-centered outcomes.

Long-Term Toxicities of Immune Checkpoint Inhibitor (ICI) in Melanoma Patients.

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.

Improved overall survival in dual compared to single immune checkpoint inhibitors in BRAF V600-negative advanced melanoma.

Aim: To evaluate the efficacy of dual versus single immune checkpoint inhibitors (ICI) in BRAF wild-type advanced melanoma patients. Materials & methods: A retrospective study of all advanced BRAF wild-type melanoma patients on palliative-intent ICI between 2015 and 2020 (n = 67). Results: Dual ICI had better overall survival (OS) when compared with single ICI in BRAF wild-type patients (hazard ratio: 0.204; 95% CI: 0.064-0.649; p = 0.007), but lost its statistical significance (median OSl not reached vs 20.9 months; p = 0.213; adjusted hazard ratio: 0.475; 95% CI: 0.164-1.380; p = 0.171) when only including patients treated after 2018 when dual ICI was funded in our province. Dual ICI were significantly associated with more frequent (p = 0.005) and severe (p = 0.026) immune-related adverse events, and required more immune-related adverse events-indicated systemic corticosteroid use (p < 0.001) compared with single ICI. Conclusion: While limited by small sample size and retrospective nature, dual ICI may have non statistically significant trend toward better OS efficacy when compared with single ICI in BRAF V600 wild-type advanced melanoma patients.

A novel yeast model detects Nrf2 and Keap1 interactions with Hsp90.

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.