The suprachiasmatic nucleus (SCN) is a complex structure dependent upon multiple mechanisms to ensure rhythmic electrical activity that varies between day and night, to determine circadian adaptation and behaviours. SCN neurons are exposed to glutamate from multiple sources including from the retino-hypothalamic tract and from astrocytes. However, the mechanism preventing inappropriate post-synaptic glutamatergic effects is unexplored and unknown. Unexpectedly we discovered that TRESK, a calcium regulated two-pore potassium channel, plays a crucial role in this system. We propose that glutamate activates TRESK through NMDA and AMPA mediated calcium influx and calcineurin activation to then oppose further membrane depolarisation and rising intracellular calcium. Hence, in the absence of TRESK, glutamatergic activity is unregulated leading to membrane depolarisation, increased nocturnal SCN firing, inverted basal calcium levels and impaired sensitivity in light induced phase delays. Our data reveals TRESK plays an essential part in SCN regulatory mechanisms and light induced adaptive behaviours.

Background: Growing prevalence of atrial fibrillation (AF) in the ageing population, and its associated life-changing health and resource implications, have led to a need to improve its early detection. Primary care is an ideal place to screen for AF, however this is limited by shortages in general practitioner (GP) resources. Recent increases in the number of clinical pharmacists within primary care, makes them ideally placed to conduct AF screening. This study aimed to determine the feasibility of GP practice-based clinical pharmacists to screen the over 65s for AF, using digital technology and pulse palpation during the influenza vaccination season. Methods and Findings: Screening was conducted over two influenza vaccination seasons, 2017-2018 and 2018-2019 in four GP practices in Kent, UK. Pharmacists were trained by a cardiologist to pulse palpate, record and interpret a single-lead ECG (SLECG). Eligible persons aged ≥65 years, attending an influenza vaccination clinic were offered a free heart rhythm check. 604 participants were screened (median age 73 years, 42.7% male). Total prevalence of AF was 4.3%. All participants with AF qualified for anticoagulation and were more likely to be male (57.7%); older; have an increased BMI and have a CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥ 75, Diabetes, previous Stroke, Age 65-74 years, Sex category) score ≥ 3. The sensitivity and specificity of clinical pharmacists diagnosing AF using pulse palpation was 76.9% [95% CI: 56.4-91.0] and 92.2% [89.7-94.3], respectively. This rose to 88.5% (69.9-97.6) and 97.2% [95.5-98.4] with a SLECG. At follow-up, four participants (0.7%) were diagnosed with new AF and 3 (0.5%) were initiated on anticoagulation. Screening with SLECG also helped identify new non-AF cardiovascular diagnoses, such as left ventricular hypertrophy, in 28 participants (4.6%). The screening strategy was cost-effective in 71.8% and 64.3% of the estimates for SLECG or pulse palpation, respectively. Feedback from participants (422/604) was generally positive. Key limitations of the study were that the intervention did not reach individuals who did not attend the practice for an influenza vaccination and there was a limited representation of UK ethnic minority groups in the study cohort. Conclusions: This study demonstrates that AF screening performed by GP practice-based pharmacists was feasible, economically viable and positively endorsed by participants. Furthermore, diagnosis of AF by the clinical pharmacist using a SLECG was more sensitive and more specific than the use of pulse palpation alone. Future research should explore the key barriers preventing the adoption of national screening programmes.

Two-pore domain potassium (K2P) channels stabilize the resting membrane potential of both excitable and nonexcitable cells and, as such, are important regulators of cell activity. There are many conditions where pharmacological regulation of K2P channel activity would be of therapeutic benefit, including, but not limited to, atrial fibrillation, respiratory depression, pulmonary hypertension, neuropathic pain, migraine, depression, and some forms of cancer. Up until now, few if any selective pharmacological regulators of K2P channels have been available. However, recent publications of solved structures with small-molecule activators and inhibitors bound to TREK-1, TREK-2, and TASK-1 K2P channels have given insight into the pharmacophore requirements for compound binding to these sites. Together with the increasing availability of a number of novel, active, small-molecule compounds from K2P channel screening programs, these advances have opened up the possibility of rational activator and inhibitor design to selectively target K2P channels.

Background: Atrial fibrillation (AF) affects up to 10% of people aged ≥65 years, yet a third of all cases remain undetected. Practice-based pharmacists are in an ideal position to facilitate opportunistic AF screening, while increasing general practice capacity at a time of workforce crisis. Aim: To explore the perspectives of three stakeholder groups involved in the 'Pharmacists Detecting Atrial Fibrillation' (PDAF) study to elucidate the facilitators and barriers to pharmacist-led AF screening in general practice. Design & setting: A qualitative study took place, comprising homogeneous focus groups with stakeholders in Kent, UK. Method: The stakeholder groups — patients, general practice staff (GPS), and clinical pharmacists (CPs) — were recruited using convenience sampling. Audio-recordings were transcribed verbatim and analysed using a deductive Theoretical Domains Framework (TDF) approach. Results: Twenty-five patients, four pharmacists, and nine practice staff participated in six focus groups. Three main themes were identified: knowledge and awareness; prioritisation of resources; and environmental considerations. The public's lack of awareness of AF-related risks and pharmacist-led screening services was highlighted. Practice-based pharmacists were perceived as an underutilised educational resource which, together with novel electrocardiogram devices, enabled convenient access to screening while reducing GPs' workload. Participants agreed that AF screening should be incorporated into personalised health checks and at-risk groups should be prioritised, such as care home residents. Patients favoured the general practice environment over the community pharmacy where concerns of privacy, staffing, and commercialisation were raised. Conclusion: The findings of this study support the introduction of pharmacist-led AF screening programmes in general practice surgeries. Commissioners should consider the added value of utilising CPs and focus on the delivery of AF screening within an integrated service.