Citations

Abstract Aims An artificial intelligence-enabled electrocardiogram (AI-ECG) is a promising tool to detect patients with aortic stenosis (AS) before developing symptoms. However, functional, structural, or haemodynamic components reflected in AI-ECG responsible for its detection are unknown. Methods and results The AI-ECG model that was developed at Mayo Clinic using a convolutional neural network to identify patients with moderate–severe AS was applied. In patients used as the testing group, the correlation between the AI-ECG probability of AS and echocardiographic parameters was investigated. This study included 102 926 patients (63.0 ± 16.3 years, 52% male), and 28 464 (27.7%) were identified as AS positive by AI-ECG. Older age, atrial fibrillation, hypertension, diabetes, coronary artery disease, and heart failure were more common in the positive AI-ECG group than in the negative group (P < 0.001). The AI-ECG was correlated with aortic valve area (ρ = −0.48, R2 = 0.20), peak velocity (ρ = 0.22, R2 = 0.08), and mean pressure gradient (ρ = 0.35, R2 = 0.08). The AI-ECG also correlated with left ventricular (LV) mass index (ρ = 0.36, R2 = 0.13), E/e′ (ρ = 0.36, R2 = 0.12), and left atrium volume index (ρ = 0.42, R2 = 0.12). Neither LV ejection fraction nor stroke volume index had a significant correlation with the AI-ECG. Age correlated with the AI-ECG (ρ = 0.46, R2 = 0.22) and its correlation with echocardiography parameters was similar to that of the AI-ECG. Conclusion A combination of AS severity, diastolic dysfunction, and LV hypertrophy is reflected in the AI-ECG to detect AS. There seems to be a gradation of the cardiac anatomical/functional features in the model and its identification process of AS is multifactorial.

BACKGROUND: Surgical management of splenic flexure carcinoma remains controversial. OBJECTIVE: This study aimed to establish an expert international consensus on splenic flexure carcinoma management. DESIGN: A 3-round online-based Delphi study was conducted between September 2020 and April 2021. SETTING: The first round included 18 experts from 12 different countries. For the second and third rounds, each expert in the first round was asked to invite 2 more colorectal surgeons (n = 47). Out of 47 invited experts, 89% (n = 42) participated in the second and third rounds of the consensus. INTERVENTIONS: A total of 35 questions were created and sent via the online questionnaire tool. MAIN OUTCOME MEASURES: Levels of recommendation based on voting concordance were graded as follows: more than 75% agreement was defined as strong, between 50% and 75% as moderate, and below 50% as weak. RESULTS: There was moderate consensus on the definition of splenic flexure (55%) as 10 cm from either side where the distal transverse colon turns into the proximal descending colon. Also, experts recommended an abdominopelvic CT scan plus intraoperative exploration (moderate consensus, 72%) for tumor localization and cancer registry. Segmental colectomy was the preferred technique for the management of splenic flexure carcinoma in the elective setting (72%). Moderate consensus was achieved on the technique of complete mesocolic excision and central vascular ligation principles for splenic flexure carcinoma (74%). Only strong consensus was achieved on the surgical approach for minimally invasive surgery (88%). LIMITATIONS: Subjective decisions are based on individual expert clinical experience and not evidence based. CONCLUSIONS: This is the first internationally conducted Delphi consensus study regarding splenic flexure carcinoma. The definition of splenic flexure remains ambiguous. To more effectively compare oncologic outcomes among different cancer registries, guidelines need to be developed to standardize each domain and avoid arbitrary definitions. See Video Abstract at http://links.lww.com/DCR/C143. ESTANDARIZACIÓN DE LA DEFINICIÓN Y MANEJO QUIRÚRGICO DEL CARCINOMA DE ÁNGULO ESPLÉNICO ESTABLECIDO POR UN CONSENSO INTERNACIONAL DE EXPERTOS UTILIZANDO LA TÉCNICA DELPHI: ¿ESPACIO PARA MEJORAR? ANTECEDENTES: El tratamiento quirúrgico del cáncer de ángulo esplénico sigue siendo controvertido. OBJETIVO: Establecer un consenso internacional de expertos sobre el manejo del cáncer del ángulo esplénico. DISEÑO: Se condujo un estudio Delphi en línea de 3 rondas entre septiembre de 2020 y febrero de 2021. ESCENARIO: La primera ronda incluyó a 18 expertos de 12 países distintos. Para la segunda y tercera rondas, a cada experto de la primera ronda se le pidió que invitara a 2 cirujanos colorrectales más de su región (n = 47). De los 47 expertos invitados, el 89% (n = 42) participó en la segunda y tercera ronda del consenso. INTERVENCIONES: Se crearon y enviaron un total de 35 preguntas a través de la herramienta de cuestionario en línea. PRINCIPALES MEDIDAS DE RESULTADO: Los niveles de recomendación basados en la concordancia de votos fueron jerarquizados de la siguiente manera: más del 75% de acuerdo se definió como fuerte, entre 50 y 75% como moderado y por debajo del 50% como débil. RESULTADOS: Hubo un consenso moderado sobre la definición de ángulo esplénico (55%) como 10 cm desde cualquier lado donde el colon transverso distal se convierte en el colon descendente proximal. Así también, los expertos recomendaron la tomografía computarizada abdominopélvica más la exploración intraoperatoria (consenso moderado, 72%) para la localización del tumor y el registro del ángulo esplénico. La colectomía segmentaria fue la técnica preferida para el tratamiento del cáncer de ángulo esplénico en el caso de ser electivo (72%). Se logró un consenso moderado sobre la técnica de escisión completa del mesocolon y los principios de ligadura vascular a nivel central para el cáncer de ángulo esplénico (74%). Solo se logró un fuerte consenso sobre el abordaje quirúrgico para la cirugía mínimamente invasiva (88%). LIMITACIONES: Decisiones subjetivas basadas en la experiencia clínica de expertos individuales y no basadas en evidencia. CONCLUSIONES: Este es el primer estudio internacional de consenso Delphi realizado sobre el cáncer de ángulo esplénico. Si bien encontramos un consenso moderado sobre las modalidades de diagnóstico preoperatorio y el manejo quirúrgico, la definición de ángulo esplénico sigue siendo ambigua. Para comparar de manera más efectiva los resultados oncológicos entre diferentes registros de cáncer, se deben desarrollar pautas para estandarizar cada dominio y evitar definiciones arbitrarias. Consulte Video Resumen en http://links.lww.com/DCR/C143. (Traducción—Dr. Osvaldo Gauto )

ImportanceThe frequency and clinical importance of structural valve deterioration (SVD) in patients undergoing self-expanding transcatheter aortic valve implantation (TAVI) or surgery is poorly understood.ObjectiveTo evaluate the 5-year incidence, clinical outcomes, and predictors of hemodynamic SVD in patients undergoing self-expanding TAVI or surgery.Design, Setting, and ParticipantsThis post hoc analysis pooled data from the CoreValve US High Risk Pivotal (n = 615) and SURTAVI (n = 1484) randomized clinical trials (RCTs); it was supplemented by the CoreValve Extreme Risk Pivotal trial (n = 485) and CoreValve Continued Access Study (n = 2178). Patients with severe aortic valve stenosis deemed to be at intermediate or increased risk of 30-day surgical mortality were included. Data were collected from December 2010 to June 2016, and data were analyzed from December 2021 to October 2022.InterventionsPatients were randomized to self-expanding TAVI or surgery in the RCTs or underwent self-expanding TAVI for clinical indications in the nonrandomized studies.Main Outcomes and MeasuresThe primary end point was the incidence of SVD through 5 years (from the RCTs). Factors associated with SVD and its association with clinical outcomes were evaluated for the pooled RCT and non-RCT population. SVD was defined as (1) an increase in mean gradient of 10 mm Hg or greater from discharge or at 30 days to last echocardiography with a final mean gradient of 20 mm Hg or greater or (2) new-onset moderate or severe intraprosthetic aortic regurgitation or an increase of 1 grade or more.ResultsOf 4762 included patients, 2605 (54.7%) were male, and the mean (SD) age was 82.1 (7.4) years. A total of 2099 RCT patients, including 1128 who received TAVI and 971 who received surgery, and 2663 non-RCT patients who received TAVI were included. The cumulative incidence of SVD treating death as a competing risk was lower in patients undergoing TAVI than surgery (TAVI, 2.20%; surgery, 4.38%; hazard ratio [HR], 0.46; 95% CI, 0.27-0.78; P = .004). This lower risk was most pronounced in patients with smaller annuli (23 mm diameter or smaller; TAVI, 1.32%; surgery, 5.84%; HR, 0.21; 95% CI, 0.06-0.73; P = .02). SVD was associated with increased 5-year all-cause mortality (HR, 2.03; 95% CI, 1.46-2.82; P < .001), cardiovascular mortality (HR, 1.86; 95% CI, 1.20-2.90; P = .006), and valve disease or worsening heart failure hospitalizations (HR, 2.17; 95% CI, 1.23-3.84; P = .008). Predictors of SVD were developed from multivariate analysis.Conclusions and RelevanceThis study found a lower rate of SVD in patients undergoing self-expanding TAVI vs surgery at 5 years. Doppler echocardiography was a valuable tool to detect SVD, which was associated with worse clinical outcomes.Trial RegistrationClinicalTrials.gov Identifiers: NCT01240902, NCT01586910, and NCT01531374

AbstractObjectiveTo investigate the effect of CRYSVITA® (burosumab‐twza) on FGF23 measurements in an intact and a C‐terminal immunoassay.MethodsAn intact serum FGF23 (MedFrontier) and a C‐terminal plasma FGF23 assay (Immutopics) were used. Serum/plasma pools were spiked to span the burosumab therapeutic range (1.4–11.3 μg/ml) and FGF23 recovery was assessed. Patient serum and plasma samples obtained pre and post‐burosumab treatment were evaluated on both assays and compared with corresponding phosphorus measurementsResultsSpiking burosumab (1.4–11.3 μg/ml) into sample pools resulted in a dose‐dependent negative analytical interference on intact FGF23 measurements and no significant interference for C‐terminal FGF23 measurements. However, more than a 500‐fold median increase (post‐ vs. pre‐burosumab administration) in in vivo FGF23 concentrations were observed by both assays.ConclusionsTherapeutic concentrations of burosumab result in a negative analytical interference of the intact, but not the C‐terminal FGF23 immunoassay. Despite this in vitro analytical interference in the intact assay, relatively large elevations of both intact FGF23 and C‐terminal FGF23 measurements were observed in vivo following burosumab administration. Following burosumab administration, FGF23 measurements must be interpreted within the clinical context of the patient and other relevant biomarker results.SummaryThis article describes a negative analytical interference by burosumab in an intact FGF23 immunoassay. The recovery of C‐terminal FGF23 is not significantly affected by the presence of burosumab. In vivo, both assays demonstrate extreme FGF23 elevations in the presence of the drug. Furthermore, the measurement of FGF23 blocked by burosumab is not clinically useful regarding hypophosphataemia.

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Background Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. Objectives We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. Design This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. Setting Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. Participants Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m2 or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis. Interventions Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician. Primary outcome The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. Results The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016). Conclusions Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections. Future work A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis. Limitations This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study. Trial registration This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.

Abstract Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep disruption enhances pain, but the underlying mechanisms remain unknown. Chronic pain engages brain stress circuits and increases secretion of dynorphin, an endogenous ligand of the kappa opioid receptor (KOR). We therefore hypothesized that hypothalamic dynorphin/KOR signalling may be a previously unknown mechanism that is recruited in pathological conditions requiring increased vigilance. We investigated the role of KOR in wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in freely moving naïve mice and in mice with neuropathic pain induced by partial sciatic nerve ligation using EEG/EMG recordings. Systemic continuous administration of U69,593, a KOR agonist, over 5 days through an osmotic minipump decreased the amount of NREM and REM sleep and increased sleep fragmentation in naïve mice throughout the light-dark sleep cycle. We used KORcre mice to selectively express a Gi-coupled designer receptor activated by designer drugs (Gi-DREADD) in KORcre neurons of the hypothalamic paraventricular nucleus, a key node of the hypothalamic-pituitary-adrenal stress response. Sustained activation of Gi-DREADD with clozapine-N-oxide delivered in drinking water over 4 days, disrupted sleep in these mice in a similar way as systemic U69,593. Mice with chronic neuropathic pain also showed disrupted NREM and total sleep that was normalized by systemic administration of two structurally different KOR antagonists, norbinaltorphimine and NMRA-140, currently in phase II clinical development, or by CRISPR/Cas9 editing of paraventricular nucleus KOR, consistent with endogenous KOR activation disrupting sleep in chronic pain. Unexpectedly, REM sleep was diminished by either systemic KOR antagonist or by CRISPR/Cas9 editing of paraventricular nucleus KOR in sham-operated mice. Our findings reveal previously unknown physiological and pathophysiological roles of dynorphin/KOR in eliciting arousal. Physiologically, dynorphin/KOR signalling affects transitions between sleep stages that promote REM sleep. Furthermore, while KOR antagonists do not promote somnolence in the absence of pain, they normalized disrupted sleep in chronic pain, revealing a pathophysiological role of KOR signalling that is selectively recruited to promote vigilance, increasing chances of survival. Notably, while this mechanism is likely beneficial in the short-term, disruption of the homeostatic need for sleep over longer periods may become maladaptive resulting in sustained pain chronicity. A novel approach for treatment of chronic pain may thus result from normalization of chronic pain-related sleep disruption by KOR antagonism.

Abstract Aims To evaluate the benefit of speckle tracking radial strain imaging (STRSI)-guided left ventricular (LV) lead (LVL) positioning in cardiac resynchronization therapy (CRT) in patients (pts) with ischaemic cardiomyopathy with CRT indication. Methods and results We conducted a prospective randomized controlled trial. Patients were enrolled in nine centres with 2:1 randomization into two groups (guided vs. control). Patients underwent STRSI to identify the optimal LV position from six LV segments at midventricular level. Implantation via STRSI was attempted for recommended segment in the guided group only. Follow-up included echocardiography (6 months) and clinical evaluation (6 and 12 months). The primary endpoint was comparison % reduction in LV end-systolic volume at 6 months with baseline. Secondary endpoints included hospitalizations for heart failure and death, and improvement in additional echocardiographic measurements and quality of life score. A total of 172 patients (115 guided vs. 57 control) were enrolled. In the guided group, 60% of the implanted LV leads were adjudicated to be successfully located at the recommended segment, whereas in the control group 44% reached the best STRSI determined segment. There was no difference between the groups in any of the primary or secondary endpoints at 6 and 12 months. Conclusion Our findings suggest that echo-guided implantation of an LV lead using STRSI does not improve the clinical or echocardiographic response compared with conventional implantation.