Surgical ablation for atrial fibrillation (AF) can be performed without additional risk of operative mortality or major morbidity, and is recommended at the time of concomitant mitral operations to restore sinus rhythm. (Class I, Level A) Surgical ablation for AF can be performed without additional operative risk of mortality or major morbidity, and is recommended at the time of concomitant isolated aortic valve replacement, isolated coronary artery bypass graft surgery, and aortic valve replacement plus coronary artery bypass graft operations to restore sinus rhythm. (Class I, Level B nonrandomized) Surgical ablation for symptomatic AF in the absence of structural heart disease that is refractory to class I/III antiarrhythmic drugs or catheter-based therapy or both is reasonable as a primary stand-alone procedure, to restore sinus rhythm. (Class IIA, Level B randomized) Surgical ablation for symptomatic persistent or longstanding persistent AF in the absence of structural heart disease is reasonable, as a stand-alone procedure using the Cox-Maze III/IV lesion set compared with pulmonary vein isolation alone. (Class IIA, Level B nonrandomized) Surgical ablation for symptomatic AF in the setting of left atrial enlargement (≥4.5 cm) or more than moderate mitral regurgitation by pulmonary vein isolation alone is not recommended. (Class III no benefit, Level C expert opinion) It is reasonable to perform left atrial appendage excision or exclusion in conjunction with surgical ablation for AF for longitudinal thromboembolic morbidity prevention. (Class IIA, Level C limited data) At the time of concomitant cardiac operations in patients with AF, it is reasonable to surgically manage the left atrial appendage for longitudinal thromboembolic morbidity prevention. (Class IIA, Level C expert opinion) In the treatment of AF, multidisciplinary heart team assessment, treatment planning, and long-term follow-up can be useful and beneficial to optimize patient outcomes. (Class I, Level C expert opinion).

Post-translational control of PERIOD stability by Casein Kinase 1δ and ε (CK1) plays a key regulatory role in metazoan circadian rhythms. Despite the deep evolutionary conservation of CK1 in eukaryotes, little is known about its regulation and the factors that influence substrate selectivity on functionally antagonistic sites in PERIOD that directly control circadian period. Here we describe a molecular switch involving a highly conserved anion binding site in CK1. This switch controls conformation of the kinase activation loop and determines which sites on mammalian PER2 are preferentially phosphorylated, thereby directly regulating PER2 stability. Integrated experimental and computational studies shed light on the allosteric linkage between two anion binding sites that dynamically regulate kinase activity. We show that period-altering kinase mutations from humans to Drosophila differentially modulate this activation loop switch to elicit predictable changes in PER2 stability, providing a foundation to understand and further manipulate CK1 regulation of circadian rhythms.

No abstract

The NHS Cancer Plan sets out targets for the diagnosis and treatment of cancer. Ideally, there should be a maximum of a 2-week wait from a referral for suspected cancer to an outpatient appointment. A fast track referral system has been established nationally, with general practitioners given guidelines as to appropriate referrals. In the South Essex region, we audited all such referrals using this system for a 12-month period and also all new patients diagnosed with head and neck cancer during the same period. We found that 71% of patients diagnosed with cancer were not referred using the fast track system and that only 15% of patients who were referred by the fast track system were subsequently found to have cancer. For patients with cancer who were referred using standard letters, the time from referral to initial consultation was generally much longer than the recommended period of 2 weeks. We conclude that improvements in utilizing the fast track system need to be made if it is to bring about an improvement in early diagnosis of head and neck cancer. As things stand, it may actually be detrimental for most cancer patients.