Mechanisms of adaptive hypertrophic cardiac remodeling in a large animal model of premature ventricular contraction-induced cardiomyopathy.

Frequent premature ventricular contractions (PVCs) promoted eccentric cardiac hypertrophy and reduced ejection fraction (EF) in a large animal model of PVC-induced cardiomyopathy (PVC-CM), but the molecular mechanisms and markers of this hypertrophic remodeling remain unexplored. Healthy mongrel canines were implanted with pacemakers to deliver bigeminal PVCs (50% burden with 200-220 ms coupling interval). After 12 weeks, left ventricular (LV) free wall samples were studied from PVC-CM and Sham groups. In addition to reduced LV ejection fraction (LVEF), the PVC-CM group showed larger cardiac myocytes without evident ultrastructural alterations compared to the Sham group. Biochemical markers of pathological hypertrophy, such as store-operated Ca2+ entry, calcineurin/NFAT pathway, ß-myosin heavy chain, and skeletal type α-actin were unaltered in the PVC-CM group. In contrast, pro-hypertrophic and antiapoptotic pathways including ERK1/2 and AKT/mTOR were activated and/or overexpressed in the PVC-CM group, which appeared counterbalanced by an overexpression of protein phosphatase 1 and a borderline elevation of the anti-hypertrophic factor atrial natriuretic peptide. Moreover, the potent angiogenic and pro-hypertrophic factor VEGF-A and its receptor VEGFR2 were significantly elevated in the PVC-CM group. In conclusion, a molecular program is in place to keep this structural remodeling associated with frequent PVCs as an adaptive pathological hypertrophy.

Alterations of sarcoplasmic reticulum-mediated Ca2+ uptake in a model of premature ventricular contraction (PVC)-induced cardiomyopathy.

Premature ventricular contractions (PVCs) are the most frequent ventricular arrhythmias in the overall population. PVCs are known to acutely enhance contractility by the post-extrasystolic potentiation phenomenon, but over time persistent PVCs promote PVC-induced cardiomyopathy (PVC-CM), characterized by a reduction of the left ventricular (LV) ejection fraction. Ca2+ cycling in myocytes commands muscle contraction and in this process, SERCA2 leads the Ca2+ reuptake into the sarcoplasmic reticulum (SR) shaping cytosolic Ca2+ signal decay and muscle relaxation. Altered Ca2+ reuptake can contribute to the contractile dysfunction observed in PVC-CM. To better understand Ca2+ handling using our PVC-CM model (canines with 50% PVC burden for 12 weeks), SR-Ca2+ reuptake was investigated by measuring Ca2+ dynamics and analyzing protein expression. Kinetic analysis of Ca2+ reuptake in electrically paced myocytes showed a ~ 21 ms delay in PVC-CM compared to Sham in intact isolated myocytes, along with a ~ 13% reduction in SERCA2 activity assessed in permeabilized myocytes. Although these trends were not statistically significant between groups using hierarchical statistics, relaxation of myocytes following contraction was significantly slower in PVC-CM vs Sham myocytes. Western blot analyses indicate a 22% reduction in SERCA2 expression, a 23% increase in phospholamban (PLN) expression, and a 50% reduction in PLN phosphorylation in PVC-CM samples vs Sham. Computational analysis simulating a 20% decrease in SR-Ca2+ reuptake resulted in a ~ 22 ms delay in Ca2+ signal decay, consistent with the experimental result described above. In conclusion, SERCA2 and PLB alterations described above have a modest contribution to functional adaptations observed in PVC-CM.

Variation in outcome reporting in studies of fertility-sparing surgery for cervical cancer: A systematic review.

BACKGROUND: Cervical cancer affects 3197 women in the UK, and 604 000 women worldwide annually, with peak incidence seen in women between 30 and 34 years of age. For many, fertility-sparing surgery is an appealing option where possible. However, absence of large-scale data, along with a notable variation in reported outcomes in relevant studies, may undermine future efforts for consistent evidence synthesis. OBJECTIVES: To systematically review the reported outcomes measured in studies that include women who underwent fertility-sparing surgery for cervical cancer and identify whether variation exists. SEARCH STRATEGY: We searched MEDLINE, EMBASE and CENTRAL from inception to February 2019. SELECTION CRITERIA: Randomised controlled trials, cohort and observational studies, and case studies of more than ten participants from January 1990 to date. DATA COLLECTION AND ANALYSIS: Study characteristics and all reported treatment outcomes. MAIN RESULTS: A total of 104 studies with a sum of 9535 participants were identified. Most studies reported on oncological outcomes (97/104), followed by fertility and pregnancy (86/104), postoperative complications (74/104), intra-operative complications (72/104) and quality of life (5/104). There was huge variation and heterogeneity in reported outcomes, with only 12% being good quality and 87% being of poor quality. CONCLUSIONS: There is significant heterogeneity in the reported outcomes. An agreed Core Outcome Set is necessary for future studies to effectively harmonise reported outcomes that are measurable and relevant to patients, clinicians and researchers. This systematic review sets the groundwork for the development of a Core Outcome Set for fertility-sparing surgery in cervical cancer.

Standardising outcome reporting for clinical trials of interventions for heavy menstrual bleeding: Development of a core outcome set.

OBJECTIVE: To develop a core outcome set for heavy menstrual bleeding (HMB). DESIGN: Core outcome set (COS) development methodology described by the COMET initiative. SETTING: University hospital gynaecology department, online international survey and web-based international consensus meetings. POPULATION OR SAMPLE: An international collaboration of stakeholders (clinicians, patients, academics, guideline developers) from 20 countries and 6 continents. METHODS: Phase 1: Systematic review of previously reported outcomes to identify potential core outcomes. Phase 2: Qualitative studies with patients to identify outcomes most important to them. Phase 3: Online two-round Delphi survey to achieve consensus about which outcomes are most important. Phase 4: A consensus meeting to finalise the COS. MAIN OUTCOME MEASURES: Outcome importance was assessed in the Delphi survey on a 9-point scale. RESULTS: From the 'long list' of 114, 10 outcomes were included in the final COS: subjective blood loss; flooding; menstrual cycle metrics; severity of dysmenorrhoea; number of days with dysmenorrhoea; quality of life; adverse events; patient satisfaction; number of patients going on to have further treatment for HMB and haemoglobin level. CONCLUSIONS: The final COS includes variables that are feasible for use in clinical trials in all resource settings and apply to all known underlying causes of the symptom of HMB. These outcomes should be reported in all future trials of interventions, their systematic reviews, and clinical guidelines to underpin policy.

Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception.

BACKGROUND: Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes. METHODS: We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 µg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation. RESULTS: The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, -0.4 percentage points; 95% CI, -6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14). CONCLUSIONS: The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.).

Sentinel lymph node biopsy alone in the management of early cervical carcinoma.

OBJECTIVE: Sentinel lymph node (SLN) biopsy aims to assess lymph node status with reduced surgical morbidity. The aim of the study was to determine the accuracy and safety of SLN biopsy in the management of early cervical carcinoma using a double technique (technetium-99m (Tc-99m) nanocolloid and methylene blue dye injection). METHODS: This was a 10-year study from January 2009 to January 2019 that recruited 103 consecutive women undergoing surgery for early cervical carcinoma, FIGO 2009 stage IA1 (grade 3, and grade 2 with lymphovascular space invasion) to IB1 (<2 cm), at the West Kent Gynaecological Oncology Centre, Maidstone, UK. All patients were given the choice of pelvic node dissection and SLN mapping or SLN only. All patients elected to undergo SLN only. In total 97 patients had SLN mapping performed laparoscopically. We used the combined method (Tc-99m nanocolloid and/or methylene blue dye). All SLN routinely underwent ultrastaging. RESULTS: At least one SLN was detected in all 103 patients, using at least one of the combined methods (Tc-99m nanocolloid or blue dye). Bilaterally SLN were removed in 85/103 women with an 83% bilateral detection rate. The median SLN count was 2.3 (range 1-6) nodes. Of 103 patients, 7 (6.7%) patients had lymph node involvement. There were no pelvic or para-aortic lymph node recurrences with a median follow-up of 53 (range 8-120) months. The specificity and negative predictive value of a negative SLN was 100%. None of our 103 patients reported lower extremity lymphedema. CONCLUSION: In carefully selected patients with early cervical carcinoma, SLN biopsy alone appears to be a safe method for lymph node assessment of women undergoing surgical staging. Ultrastaging is an essential part of histologic examination of SLN.

Proarrhythmic effect of automatic threshold testing algorithm in dual chamber devices.

BACKGROUND: Operation of auto-threshold testing (ATT) algorithm in current dual chamber cardiac devices require temporary shortening of atrio-ventricular (AV) delay to accurately measure evoked potential (capture) after a pacing pulse. Near simultaneous AV pacing causes atrial pressure elevation and may be associated with atrial arrhythmias. OBJECTIVE: We evaluated the prevalence of atrial arrhythmias induced by ATT in Abbott devices. METHODS: Device clinic records were reviewed at a single center for patients with dual chamber Abbott pacemaker/ICD. ATT-induced atrial fibrillation (AF) cases were defined as new appropriate mode switch episodes while the ATT was operating. The auto-capture test trends were defined as unstable if there were deviations >1 V in capture threshold trend events that did not correlate with routine in-office testing. RESULTS: One hundred and seventy patients were programmed in dual chamber pacing mode. The ventricular ATT was active in 118 patients and of these 78 had true mode switch episodes. Six patients developed AF during ventricular ATT. Three patients had most recorded atrial arrhythmias in close association with ATT (63%, 66%, 100% vs 2%,9%, 33% in other patients with known prior AF). An unstable auto-capture trend curve was seen in 33 patients (6 showing ATT-induced AF) versus 85 patients with stable auto-capture curve and no ATT-induced AF (P = .0001, the χ2 test). CONCLUSION: Ventricular auto-capture algorithm use is associated with induction of AF in dual chamber Abbott devices with a prevalence of over 5%. AF occur more frequently (18%) in patients with erratic ventricular ATT trend results.

Post-extrasystolic potentiation as a predictor of premature ventricular contraction-cardiomyopathy in an animal model.

AIMS: High premature ventricular contractions (PVCs) burden does not always predict the development of PVC-cardiomyopathy (CM). We sought to evaluate post-extrasystolic potentiation (PESP) of left ventricular ejection fraction (LVEF) to predict the severity of PVC-CM in an animal model. METHODS AND RESULTS: Right ventricular apical bigeminal PVCs were introduced for 12 weeks in 11 canines to induce PVC-CM. Echocardiograms were performed to obtain LVEF without ectopy (Echo-1) and during PVCs (200 and 350 ms coupling intervals, Echo-2, and Echo-3, respectively), and premature atrial contractions (PACs) (Echo-4) at baseline and after 12 weeks of bigeminal PVCs. PESP was calculated as delta-LVEF between the sinus beat post-ectopy LVEF (Echo-2, -3, and -4, respectively) and LVEF without PVC (Echo-1) at baseline and 12 weeks of high PVC burden. A hyperdynamic LV function (LVEF > 70%) was noted in all animals only with early-coupled PVCs (LVEF at 200 ms: 74.4 ± 6%) at baseline. While PVC PESP at 200 ms had a strong significant correlation with the final 12-week LVEF (R = 0.8, P = 0.003), PVC PESP at 350 ms and PAC PESP had a positive but non-significant correlation (R = 0.53, P = 0.09, and R = 0.29, P = 0.34, respectively). Premature ventricular contraction PESP at 350 ms was significantly higher after PVC-CM had developed (delta-LVEF baseline 2.7 ± 2.9% vs. 12 weeks 18.6 ± 12.3% P < 0.001). CONCLUSION: Bigeminal early-coupled PVCs cause hyperdynamic left ventricular function in the structurally normal canine heart due to PESP. The degree of PESP at baseline is inversely proportional to the PVC-CM severity at 12 weeks and maybe a predictor of PVC-CM as it may assess the myocardial adaptation reserve to PVCs.

Fluoroscopy reduction during device implantation by using three-dimensional navigation. A single-center experience.

BACKGROUND AND OBJECTIVES: The use of nonfluoroscopic three-dimensional electroanatomic mapping (3DM) systems reduces radiation exposure during ablation procedures. In this study, we sought to determine the value of 3DM during routine device implant procedures. METHODS: Seventy nonselected patients underwent implantation of a single chamber, dual chamber, or biventricular device guided by Ensite (Abbott Laboratories) to limit fluoroscopy use and compared with 70 consecutive patients, who underwent matching procedures with standard fluoroscopy use (FL) in the period immediately preceding the use of 3DM. The venous anatomy, right atrium, and ventricle and coronary sinus were mapped with 0.035 inch J-wire, quadripolar catheter, and/or angioplasty wire. The leads were advanced under real-time visualization in Ensite. RESULTS: 3DM reduced both fluoroscopy time and dose. Median fluoroscopy time for FL vs 3DM was 5.5 minutes (interquartile range [IQR]: 3.8-8.1) vs 0.9 minutes (IQR: 0.6-1.9) (P < .001) for single chamber devices, 6.3 minutes (IQR: 5.1-7.9) vs 3.3 minutes (IQR: 1.9-4) (P < .001) for dual-chamber devices, and 28.6 minutes (IQR: 19.6-36.2) to 14.7 minutes (IQR: 10.4-22.3) (P = .009) for biventricular devices, respectively. The median air kerma for FL vs 3DM was 15.4 mGy (IQR: 8.1-30.2) vs 4 mGy (IQR: 1.8-8) (P < .001) for single chamber devices, 16 mGy (IQR: 12-18.5) to 9.4 mGy (IQR: 7.5-11.3) (P = .001) for dual-chamber devices, and 324 mGy (IQR: 143-668.7) to 115 mGy (IQR:77-204) (P = .014) for biventricular devices, respectively. There were no procedural complications. At 3-month follow-up, there was no difference in voltage threshold measurements between the groups. CONCLUSION: The use of 3DM leads to significantly reduced fluoroscopy time and fluoroscopy dose during routine device implantation.

Consequences of chronic frequent premature atrial contractions: Association with cardiac arrhythmias and cardiac structural changes.

INTRODUCTION: Frequent premature ventricular contractions (PVCs) can cause cardiomyopathy (CM). Postextrasystolic potentiation (PESP) and irregularity have been in implicated as triggers of PVC-CM. Because both phenomena can also be found in premature atrial contractions (PACs), it is speculated that frequent PACs have similar consequences. METHODS AND RESULTS: A single-center, retrospective study included all consecutive patients undergoing a 14-day Holter monitors (November 2014 to October 2016). Patients were divided into four groups by ectopy burden group 1 (<1%) and remaining by tertiles (group 2-4). Echocardiographic and arrhythmic data were compared between PAC and PVC burdens. In addition, a translational PAC animal model was used to assess the chronic effects of frequent PACs. A total 846 patients were reviewed. In contrast to PVCs, we found no difference in left ventricular ejection fraction (LVEF), end-systolic and end-diastolic dimensions and presence of CM (LVEF <50%) between different PAC groups. Multivariate regression analysis demonstrated that only PVC burden predicted low EF (odds ratio, 1.1; confidence interval, 1.03-1.13; P = .001). While there was a weak correlation between PAC burden and supraventricular tachycardia (SVT) episodes and atrial fibrillation (AF) burden (r = 0.19; P < .001), there was no correlation between PAC burden and LVEF or CM. Finally, atrial bigeminy in our animal model did not significantly decrease LVEF after 3 months. CONCLUSION: PAC burden is associated with increased AF and SVT episodes. In contrast to a high PVC burden, a high PAC burden is not associated with CM. Our findings suggest that heart rate irregularity and/or PESP may play a minimal role in the pathophysiology of PVC-CM.

Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma.

OBJECTIVE: The nature of the tumour-infiltrating leucocytes (TILs) is known to impact clinical outcome in carcinomas, including hepatocellular carcinoma (HCC). However, the role of tumour-infiltrating B cells (TIBs) remains controversial. Here, we investigate the impact of TIBs and their interaction with T cells on HCC patient prognosis. DESIGN: Tissue samples were obtained from 112 patients with HCC from Singapore, Hong Kong and Zurich and analysed using immunohistochemistry and immunofluorescence. RNA expression of CD19, CD8A, IFNG was analysed using quantitative PCR. The phenotype of freshly isolated TILs was analysed using flow cytometry. A mouse model depleted of mature B cells was used for functional study. RESULTS: Tumour-infiltrating T cells and B cells were observed in close contact with each other and their densities are correlated with superior survival in patients with HCC. Furthermore, the density of TIBs was correlated with an enhanced expression of granzyme B and IFN-γ, as well as with reduced tumour viability defined by low expression of Ki-67, and an enhanced expression of activated caspase-3 on tumour cells. CD27 and CD40 costimulatory molecules and TILs expressing activation marker CD38 in the tumour were also correlated with patient survival. Mice depleted of mature B cells and transplanted with murine hepatoma cells showed reduced tumour control and decreased local T cell activation, further indicating the important role of B cells. CONCLUSIONS: The close proximity of tumour-infiltrating T cells and B cells indicates a functional interaction between them that is linked to an enhanced local immune activation and contributes to better prognosis for patients with HCC.

Interlead heterogeneity of R- and T-wave morphology in standard 12-lead ECGs predicts sustained ventricular tachycardia/fibrillation and arrhythmic death in patients with cardiomyopathy.

INTRODUCTION: Nonuniformities in depolarization and repolarization morphology are critical factors in ventricular arrhythmogenesis. METHODS AND RESULTS: We assessed interlead R-wave heterogeneity (RWH) and T-wave heterogeneity (TWH) in standard 12-lead electrocardiograms (ECGs) using second central moment analysis. This technique quantifies variance about the mean morphology of beats in adjoining precordial leads, V4 , V5 , and V6 in this study. The study was conducted in 120 consecutive patients without an apparent reversible trigger for ventricular tachycardia (VT), recent myocardial infarction, or active ischemia, who presented for electrophysiologic study, implantable cardioverter defibrillator (ICD) placement, or generator change at our institution from 2008 to 2011. Primary outcome was sustained VT/ventricular fibrillation (VF) or appropriate ICD therapies. Secondary outcome was arrhythmic death or resuscitated cardiac arrest. Cutpoints for elevated RWH (>160 µV) and TWH (>80 µV) identified 67% of primary outcome cases and 85% of secondary outcome cases. Cardiomyopathy patients who met the primary outcome (n = 42) had significantly higher TWH than those who did not (n = 28) (TWH: 95 ± 11 µV vs. 44 ± 9 µV, P < 0.002). Likewise, cardiomyopathy patients who met secondary outcome (N = 13) had VT/VF during follow-up and also had significantly higher TWH than survivors (N = 57) (TWH: 105 ± 24 µV vs. 67 ± 8 µV, P < 0.002). Kaplan-Meier analysis revealed significant differences in arrhythmia-free survival (P = 0.012) and total survival (P = 0.011) among cardiomyopathy patients with (n = 37) compared to without (n = 33) elevated RWH and/or TWH independent of age, sex, and left ventricular ejection fraction (LVEF). CONCLUSION: Interlead RWH and TWH in 12-lead ECGs predict sustained ventricular arrhythmia, appropriate ICD therapies, and arrhythmic death or cardiac arrest in cardiomyopathy patients independent of LVEF and other standard variables.

Mechanisms of Undersensing by a Noise Detection Algorithm That Utilizes Far-Field Electrograms With Near-Field Bandpass Filtering.

BACKGROUND: Implantable cardioverter defibrillators (ICDs) must establish a balance between delivering appropriate shocks for ventricular tachyarrhythmias and withholding inappropriate shocks for lead-related oversensing ("noise"). To improve the specificity of ICD therapy, manufacturers have developed proprietary algorithms that detect lead noise. The SecureSenseTM RV Lead Noise discrimination (St. Jude Medical, St. Paul, MN, USA) algorithm is designed to differentiate oversensing due to lead failure from ventricular tachyarrhythmias and withhold therapies in the presence of sustained lead-related oversensing. METHODS AND RESULTS: We report 5 patients in whom appropriate ICD therapy was withheld due to the operation of the SecureSense algorithm and explain the mechanism for inhibition of therapy in each case. Limitations of algorithms designed to increase ICD therapy specificity, especially for the SecureSense algorithm, are analyzed. CONCLUSION: The SecureSense algorithm can withhold appropriate therapies for ventricular arrhythmias due to design and programming limitations. Electrophysiologists should have a thorough understanding of the SecureSense algorithm before routinely programming it and understand the implications for ventricular arrhythmia misclassification.

Recessive mutations in SLC38A8 cause foveal hypoplasia and optic nerve misrouting without albinism.

Foveal hypoplasia and optic nerve misrouting are developmental defects of the visual pathway and only co-occur in connection with albinism; to date, they have only been associated with defects in the melanin-biosynthesis pathway. Here, we report that these defects can occur independently of albinism in people with recessive mutations in the putative glutamine transporter gene SLC38A8. Nine different mutations were identified in seven Asian and European families. Using morpholino-mediated ablation of Slc38a8 in medaka fish, we confirmed that pigmentation is unaffected by loss of SLC38A8. Furthermore, by undertaking an association study with SNPs at the SLC38A8 locus, we showed that common variants within this gene modestly affect foveal thickness in the general population. This study reveals a melanin-independent component underpinning the development of the visual pathway that requires a functional role for SLC38A8.

Pterygium and conjunctival ultraviolet autofluorescence in young Australian adults: the Raine study.

BACKGROUND: Sun exposure is associated with several ophthalmic diseases, including pterygium which may develop in adolescence. This study reports the prevalence of pterygium and its associations in a large cohort of young Australian adults. Conjunctival ultraviolet autofluorescence, a biomarker of ocular sun exposure, has recently been characterized in some Australian populations. DESIGN: Cross-sectional population-based study. PARTICIPANTS: One thousand three hundred forty-four subjects aged 18-22 years in the Western Australian Pregnancy Cohort (Raine) Study. METHODS: Standardized colour and ultraviolet autofluorescence photographs of the nasal and temporal conjunctiva were taken, and assessed for presence of pterygium and area of autofluorescence. Sun exposure and protective factors were assessed by structured questionnaire. MAIN OUTCOME MEASURES: Area of conjunctival ultraviolet autofluorescence in square millimetre (mm(2)) and presence of pterygium. RESULTS: Median total conjunctival autofluorescence was 44.2 mm(2) (interquartile range 20.2-69.8 mm(2)). Median conjunctival autofluorescence was higher in nasal than in temporal quadrants (23.8 mm(2) vs. 18.9 mm(2), P < 0.001), but did not differ according to age or gender. Higher body mass index was associated with lower levels of autofluorescence. Total autofluorescence increased with increasing time spent outdoors. Prevalence of pterygium was 1.2% (95% confidence interval 0.6-1.8%), and was associated with male gender (odds ratio 6.71, P = 0.012). Participants with pterygium had significantly more conjunctival autofluorescence than those without (median 73.4 mm(2) vs. 44.0 mm(2), P = 0.001). CONCLUSIONS: Conjunctival ultraviolet autofluorescence is associated with increased time spent outdoors, and increased prevalence of pterygium. The association of this biomarker with other ophthalmohelioses, including cataract, ocular surface squamous neoplasia and eyelid malignancy, has yet to be determined.

Circulating fibrosis biomarkers and risk of atrial fibrillation: The Cardiovascular Health Study (CHS).

BACKGROUND: Cardiac fibrosis is thought to play a central role in the pathogenesis of atrial fibrillation (AF). Retrospective studies have suggested that circulating fibrosis biomarkers are associated with AF, but prospective studies are limited. METHODS: We measured circulating levels of 2 fibrosis biomarkers, procollagen type III, N-terminal propeptide (PIIINP) and transforming growth factor ß1 among participants of the CHS, a population-based study of older Americans. We used Cox proportional hazards and competing risks models to examine adjusted risk of incident AF over a median follow-up of 8.8 years. RESULTS: Levels of PIIINP were assessed in 2,935 participants, of whom 767 developed AF. Compared with the median PIIINP level (4.45 µg/L), adjusted hazard ratios (95% CIs) were 0.85 (0.72-1.00) at the 10th percentile, 0.93 (0.88-0.99) at the 25th percentile, 1.04 (0.95-1.04) at the 75th percentile, and 1.07 (0.90-1.26) at the 90th. Transforming growth factor ß1 levels, assessed in 1,538 participants with 408 cases of incident AF, were not associated with AF risk. CONCLUSION: In older adults, PIIINP levels were associated with risk of incident AF in a complex manner, with an association that appeared to be positive up to median levels but with little relationship beyond that. Further studies are required to confirm and possibly delineate the mechanism for this relationship.

Improvement in male pelvis magnetic resonance image contouring following radiologist-delivered training.

INTRODUCTION: The magnetic resonance linear accelerator (MRL) combines both magnetic resonance imaging and a linear accelerator, allowing for daily treatment adaptation. This study aimed to assess the impact of radiologist-delivered training in magnetic resonance (MR) contouring of relevant structures within the male pelvis. METHODS: Two radiation oncologists, two radiation oncology registrars and seven radiation therapists completed contouring on 10 male pelvis MR datasets both pre- and post-training. A 2-hour MR anatomy training session was delivered by a radiologist, who also provided the 'gold standard' contours. The pre- and post-training contours were compared against the gold standard with Dice similarity coefficient (DSC) and Hausdorff distances calculated; and the pre- and post-confidence scores and timing were compared. RESULTS: The improvement in DSC were significant in prostate, rectum and seminal vesicles, with a post-training median DSC of 0.87 ± 0.06, 0.92 ± 0.04 and 0.80 ± 0.14, respectively. The median Hausdorff improved with a median of 1.46 ± 0.78 mm, 0.52 ± 0.32 mm and 1.11 ± 0.86 mm for prostate, rectum and seminal vesicles, respectively. Bladder concordance was high both pre- and post-training. Urethra contours improved post-training, however, remained difficult to contour with a median post-DSC of 0.51 ± 0.24. Overall, confidence scoring improved (P < 0.001) and timing decreased by an average of 4.4 ± 16.4 min post-training. CONCLUSION: Radiologist-delivered training improved concordance of male pelvis contouring on MR datasets. Further work is required in the identification of urethra on MRs. These findings are of importance in the MRL adaptive workflow.

Arrhythmia-Induced Cardiomyopathy: JACC State-of-the-Art Review.

Arrhythmias frequently accompany heart failure and left ventricular dysfunction. Tachycardias, atrial fibrillation, and premature ventricular contractions can induce a reversible form of dilated cardiomyopathy (CM) known as arrhythmia-induced CM (AiCM). The intriguing question is why certain individuals are more susceptible to AiCM, despite similar arrhythmia burdens. The primary challenge is determining the extent of arrhythmias' contribution to left ventricular systolic dysfunction. AiCM should be considered in patients with a mean heart rate of >100 beats/min, atrial fibrillation, or a PVC burden of >10%. Confirmation of AiCM occurs when CM reverses upon eliminating the responsible arrhythmia. Therapy choice depends on the specific arrhythmia, patient comorbidities, and preferences. After left ventricular function is restored, ongoing follow-up is essential if an abnormal myocardial substrate persists. Accurate diagnosis and treatment of AiCM have the potential to enhance patients' quality of life, improve clinical outcomes, and reduce hospital admissions and overall health care costs.

Influences of Social-Psychological Constructs in Predicting Taiwanese Pro-Environmental Behaviors.

A value-belief-norm (VBN) model for understanding the pro-environmental behaviors (PEB) of Taiwanese was developed. This formulated VBN model included personal values, openness to change, awareness of consequences, personal norms, social norms, and PEB. Ecological world view and ascription of responsibility were excluded to develop a tighter model. A total of 1079 completed questionnaires were collected and structural equation modelling was utilized, where standard estimates and coefficients of determination validated the formulated VBN model's effectiveness. Each construct served its role as the mediator between its distal variable and outcome variable, with a substantial level of predictive accuracy, and 74.3% of the variance in PEB was accounted for. Further findings found that mature individuals had a stronger tendency towards awareness of consequences due to personal values; the young had a stronger tendency towards personal norms due to awareness of consequences; men had a stronger tendency towards personal norms due to awareness of consequences; and women had a weaker tendency due to a greater emphasis on altruism. Future interventions, such as sharing of personal pro-environmental lifestyles verbally or through social media, periodically decluttering personal items and maintaining a minimalist lifestyle, where these personal norms are in line with collective social norms, could help to strengthen PEB.

Development of Prostate Bed Delineation Consensus Guidelines for Magnetic Resonance Image-Guided Radiotherapy and Assessment of Its Effect on Interobserver Variability.

PURPOSE: The use of magnetic resonance imaging (MRI) in radiotherapy planning is becoming more widespread, particularly with the emergence of MRI-guided radiotherapy systems. Existing guidelines for defining the prostate bed clinical target volume (CTV) show considerable heterogeneity. This study aimed to establish baseline interobserver variability (IOV) for prostate bed CTV contouring on MRI, develop international consensus guidelines, and evaluate its effect on IOV. METHODS AND MATERIALS: Participants delineated the CTV on 3 MRI scans, obtained from the Elekta Unity MR-Linac, as per their normal practice. Radiation oncologist contours were visually examined for discrepancies, and interobserver comparisons were evaluated against simultaneous truth and performance level estimation (STAPLE) contours using overlap metrics (Dice similarity coefficient and Cohen's kappa), distance metrics (mean distance to agreement and Hausdorff distance), and volume measurements. A literature review of postradical prostatectomy local recurrence patterns was performed and presented alongside IOV results to the participants. Consensus guidelines were collectively constructed, and IOV assessment was repeated using these guidelines. RESULTS: Sixteen radiation oncologists' contours were included in the final analysis. Visual evaluation demonstrated significant differences in the superior, inferior, and anterior borders. Baseline IOV assessment indicated moderate agreement for the overlap metrics while volume and distance metrics demonstrated greater variability. Consensus for optimal prostate bed CTV boundaries was established during a virtual meeting. After guideline development, a decrease in IOV was observed. The maximum volume ratio decreased from 4.7 to 3.1 and volume coefficient of variation reduced from 40% to 34%. The mean Dice similarity coefficient rose from 0.72 to 0.75 and the mean distance to agreement decreased from 3.63 to 2.95 mm. CONCLUSIONS: Interobserver variability in prostate bed contouring exists among international genitourinary experts, although this is lower than previously reported. Consensus guidelines for MRI-based prostate bed contouring have been developed, and this has resulted in an improvement in contouring concordance. However, IOV persists and strategies such as an education program, development of a contouring atlas, and further refinement of the guidelines may lead to additional improvements.