Cholinergic suppression: A postsynaptic mechanism of long-term associative learning

Food avoidance learning in the mollusc Pleurobranchaea entails reduction in the responsiveness of key brain interneurons in the feeding neural circuitry, the paracerebral feeding command interneurons (PCNs), to the neurotransmitter acetylcholine (AcCho). Food stimuli applied to the oral veil of an untrained animal depolarize the PCNs and induce the feeding motor program (FMP). Atropine (a muscarinic cholinergic antagonist) reversibly blocks the food-induced depolarization of the PCNs, implicating AcCho as the neurotransmitter mediating food detection. AcCho applied directly to PCN somata depolarizes them, indicating that the PCN soma membrane contains AcCho receptors and induces the FMP in the isolated central nervous system preparation. The AcCho response of the PCNs is mediated by muscariniclike receptors, since comparable depolarization is induced by muscarinic agonists (acetyl-ß -methylcholine, oxotremorine, pilocarpine), but not nicotine, and blocked by muscarinic antagonists (atropine, trifluoperazine). The nicotinic antagonist hexamethonium, however, blocked the AcCho response in four of six cases. When specimens are trained to suppress feeding behavior using a conventional food-avoidance learning paradigm (conditionally paired food and shock), AcCho applied to PCNs in the same concentration as in untrained animals causes little or no depolarization and does not initiate the FMP. Increasing the concentration of AcCho 10-100 times, however, induces weak PCN depolarization in trained specimens, indicating that learning diminishes but does not fully abolish AcCho responsiveness of the PCNs. This study proposes a cellular mechanism of long-term associative learning -- namely, postsynaptic modulation of neurotransmitter responsiveness in central neurons that could apply also to mammalian species

Can Interventional Cardiologists Help Deliver the UK Mechanical Thrombectomy Interventional Programme for Patients with Acute Ischaemic Stroke? A Discussion Paper from the British Cardiovascular Interventional Society Stroke Thrombectomy Focus Group

There is a willingness among UK interventional cardiologists to contribute to provision of a 24/7 mechanical thrombectomy (MT) service for all suitable stroke patients if given the appropriate training. This highly effective intervention remains unavailable to the majority of patients who might benefit, partly because there is a limited number of trained specialists. As demonstrated in other countries, interdisciplinary working can be the solution and an opportunity to achieve this is outlined in this article

Long-Term Outcomes After Transcatheter Aortic Valve Implantation in High-Risk Patients With Severe Aortic Stenosis The U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry

ObjectivesThe objective was to define the characteristics of a real-world patient population treated with transcatheter aortic valve implantation (TAVI), regardless of technology or access route, and to evaluate their clinical outcome over the mid to long term.BackgroundAlthough a substantial body of data exists in relation to early clinical outcomes after TAVI, there are few data on outcomes beyond 1 year in any notable number of patients.MethodsThe U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry was established to report outcomes of all TAVI procedures performed within the United Kingdom. Data were collected prospectively on 870 patients undergoing 877 TAVI procedures up until December 31, 2009. Mortality tracking was achieved in 100% of patients with mortality status reported as of December 2010.ResultsSurvival at 30 days was 92.9%, and it was 78.6% and 73.7% at 1 year and 2 years, respectively. There was a marked attrition in survival between 30 days and 1 year. In a univariate model, survival was significantly adversely affected by renal dysfunction, the presence of coronary artery disease, and a nontransfemoral approach; whereas left ventricular function (ejection fraction <30%), the presence of moderate/severe aortic regurgitation, and chronic obstructive pulmonary disease remained the only independent predictors of mortality in the multivariate model.ConclusionsMidterm to long-term survival after TAVI was encouraging in this high-risk patient population, although a substantial proportion of patients died within the first year

Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Dissociative seizures are paroxysmal events resembling epilepsy or syncope with characteristic features that allow them to be distinguished from other medical conditions. We aimed to compare the effectiveness of cognitive behavioural therapy (CBT) plus standardised medical care with standardised medical care alone for the reduction of dissociative seizure frequency. METHODS: In this pragmatic, parallel-arm, multicentre randomised controlled trial, we initially recruited participants at 27 neurology or epilepsy services in England, Scotland, and Wales. Adults (≥18 years) who had dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous 12 months were subsequently randomly assigned (1:1) from 17 liaison or neuropsychiatry services following psychiatric assessment, to receive standardised medical care or CBT plus standardised medical care, using a web-based system. Randomisation was stratified by neuropsychiatry or liaison psychiatry recruitment site. The trial manager, chief investigator, all treating clinicians, and patients were aware of treatment allocation, but outcome data collectors and trial statisticians were unaware of treatment allocation. Patients were followed up 6 months and 12 months after randomisation. The primary outcome was monthly dissociative seizure frequency (ie, frequency in the previous 4 weeks) assessed at 12 months. Secondary outcomes assessed at 12 months were: seizure severity (intensity) and bothersomeness; longest period of seizure freedom in the previous 6 months; complete seizure freedom in the previous 3 months; a greater than 50% reduction in seizure frequency relative to baseline; changes in dissociative seizures (rated by others); health-related quality of life; psychosocial functioning; psychiatric symptoms, psychological distress, and somatic symptom burden; and clinical impression of improvement and satisfaction. p values and statistical significance for outcomes were reported without correction for multiple comparisons as per our protocol. Primary and secondary outcomes were assessed in the intention-to-treat population with multiple imputation for missing observations. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN05681227, and ClinicalTrials.gov, NCT02325544. FINDINGS: Between Jan 16, 2015, and May 31, 2017, we randomly assigned 368 patients to receive CBT plus standardised medical care (n=186) or standardised medical care alone (n=182); of whom 313 had primary outcome data at 12 months (156 [84%] of 186 patients in the CBT plus standardised medical care group and 157 [86%] of 182 patients in the standardised medical care group). At 12 months, no significant difference in monthly dissociative seizure frequency was identified between the groups (median 4 seizures [IQR 0-20] in the CBT plus standardised medical care group vs 7 seizures [1-35] in the standardised medical care group; estimated incidence rate ratio [IRR] 0·78 [95% CI 0·56-1·09]; p=0·144). Dissociative seizures were rated as less bothersome in the CBT plus standardised medical care group than the standardised medical care group (estimated mean difference -0·53 [95% CI -0·97 to -0·08]; p=0·020). The CBT plus standardised medical care group had a longer period of dissociative seizure freedom in the previous 6 months (estimated IRR 1·64 [95% CI 1·22 to 2·20]; p=0·001), reported better health-related quality of life on the EuroQoL-5 Dimensions-5 Level Health Today visual analogue scale (estimated mean difference 6·16 [95% CI 1·48 to 10·84]; p=0·010), less impairment in psychosocial functioning on the Work and Social Adjustment Scale (estimated mean difference -4·12 [95% CI -6·35 to -1·89]; p<0·001), less overall psychological distress than the standardised medical care group on the Clinical Outcomes in Routine Evaluation-10 scale (estimated mean difference -1·65 [95% CI -2·96 to -0·35]; p=0·013), and fewer somatic symptoms on the modified Patient Health Questionnaire-15 scale (estimated mean difference -1·67 [95% CI -2·90 to -0·44]; p=0·008). Clinical improvement at 12 months was greater in the CBT plus standardised medical care group than the standardised medical care alone group as reported by patients (estimated mean difference 0·66 [95% CI 0·26 to 1·04]; p=0·001) and by clinicians (estimated mean difference 0·47 [95% CI 0·21 to 0·73]; p<0·001), and the CBT plus standardised medical care group had greater satisfaction with treatment than did the standardised medical care group (estimated mean difference 0·90 [95% CI 0·48 to 1·31]; p<0·001). No significant differences in patient-reported seizure severity (estimated mean difference -0·11 [95% CI -0·50 to 0·29]; p=0·593) or seizure freedom in the last 3 months of the study (estimated odds ratio [OR] 1·77 [95% CI 0·93 to 3·37]; p=0·083) were identified between the groups. Furthermore, no significant differences were identified in the proportion of patients who had a more than 50% reduction in dissociative seizure frequency compared with baseline (OR 1·27 [95% CI 0·80 to 2·02]; p=0·313). Additionally, the 12-item Short Form survey-version 2 scores (estimated mean difference for the Physical Component Summary score 1·78 [95% CI -0·37 to 3·92]; p=0·105; estimated mean difference for the Mental Component Summary score 2·22 [95% CI -0·30 to 4·75]; p=0·084), the Generalised Anxiety Disorder-7 scale score (estimated mean difference -1·09 [95% CI -2·27 to 0·09]; p=0·069), and the Patient Health Questionnaire-9 scale depression score (estimated mean difference -1·10 [95% CI -2·41 to 0·21]; p=0·099) did not differ significantly between groups. Changes in dissociative seizures (rated by others) could not be assessed due to insufficient data. During the 12-month period, the number of adverse events was similar between the groups: 57 (31%) of 186 participants in the CBT plus standardised medical care group reported 97 adverse events and 53 (29%) of 182 participants in the standardised medical care group reported 79 adverse events. INTERPRETATION: CBT plus standardised medical care had no statistically significant advantage compared with standardised medical care alone for the reduction of monthly seizures. However, improvements were observed in a number of clinically relevant secondary outcomes following CBT plus standardised medical care when compared with standardised medical care alone. Thus, adults with dissociative seizures might benefit from the addition of dissociative seizure-specific CBT to specialist care from neurologists and psychiatrists. Future work is needed to identify patients who would benefit most from a dissociative seizure-specific CBT approach. FUNDING: National Institute for Health Research, Health Technology Assessment programme

Winter Survival of Individual Honey Bees and Honey Bee Colonies Depends on Level of Varroa destructor Infestation

Background: Recent elevated winter loss of honey bee colonies is a major concern. The presence of the mite Varroa destructor in colonies places an important pressure on bee health. V. destructor shortens the lifespan of individual bees, while long lifespan during winter is a primary requirement to survive until the next spring. We investigated in two subsequent years the effects of different levels of V. destructor infestation during the transition from short-lived summer bees to long-lived winter bees on the lifespan of individual bees and the survival of bee colonies during winter. Colonies treated earlier in the season to reduce V. destructor infestation during the development of winter bees were expected to have longer bee lifespan and higher colony survival after winter. Methodology/Principal Findings: Mite infestation was reduced using acaricide treatments during different months (July, August, September, or not treated). We found that the number of capped brood cells decreased drastically between August and November, while at the same time, the lifespan of the bees (marked cohorts) increased indicating the transition to winter bees. Low V. destructor infestation levels before and during the transition to winter bees resulted in an increase in lifespan of bees and higher colony survival compared to colonies that were not treated and that had higher infestation levels. A variety of stress-related factors could have contributed to the variation in longevity and winter survival that we found between years. Conclusions/Significance: This study contributes to theory about the multiple causes for the recent elevated colony losses in honey bees. Our study shows the correlation between long lifespan of winter bees and colony loss in spring. Moreover, we show that colonies treated earlier in the season had reduced V. destructor infestation during the development of winter bees resulting in longer bee lifespan and higher colony survival after winter

Receiver development for BICEP Array, a next-generation CMB polarimeter at the South Pole

A detection of curl-type (B-mode) polarization of the primary CMB would be direct evidence for the inflationary paradigm of the origin of the Universe. The Bicep/Keck Array (BK) program targets the degree angular scales, where the power from primordial B-mode polarization is expected to peak, with ever-increasing sensitivity and has published the most stringent constraints on inflation to date. Bicep Array (BA) is the Stage-3 instrument of the BK program and will comprise four Bicep3-class receivers observing at 30/40, 95, 150 and 220/270 GHz with a combined 32,000+ detectors; such wide frequency coverage is necessary for control of the Galactic foregrounds, which also produce degree-scale B-mode signal. The 30/40 GHz receiver is designed to constrain the synchrotron foreground and has begun observing at the South Pole in early 2020. By the end of a 3-year observing campaign, the full Bicep Array instrument is projected to reach σr between 0.002 and 0.004, depending on foreground complexity and degree of removal of B-modes due to gravitational lensing (delensing). This paper presents an overview of the design, measured on-sky performance and calibration of the first BA receiver. We also give a preview of the added complexity in the time-domain multiplexed readout of the 7,776-detector 150 GHz receiver

Observing low elevation sky and the CMB Cold Spot with BICEP3 at the South Pole

BICEP3 is a 520 mm aperture on-axis refracting telescope at the South Pole, which observes the polarization of the cosmic microwave background (CMB) at 95 GHz to search for the B-mode signal from inflationary gravitational waves. In addition to this main target, we have developed a low-elevation observation strategy to extend coverage of the Southern sky at the South Pole, where BICEP3 can quickly achieve degree-scale E-mode measurements over a large area. An interesting E-mode measurement is probing a potential polarization anomaly around the CMB Cold Spot. During the austral summer seasons of 2018-19 and 2019-20, BICEP3 observed the sky with a flat mirror to redirect the beams to various low elevation ranges. The preliminary data analysis shows degree-scale E-modes measured with high signal-to-noise ratio

Polarization calibration of the BICEP3 CMB polarimeter at the South Pole

The BICEP3 CMB Polarimeter is a small-aperture refracting telescope located at the South Pole and is specifically designed to search for the possible signature of inflationary gravitational waves in the Cosmic Microwave Background (CMB). The experiment measures polarization on the sky by differencing the signal of co-located, orthogonally polarized antennas coupled to Transition Edge Sensor (TES) detectors. We present precise measurements of the absolute polarization response angles and polarization efficiencies for nearly all of BICEP3's ~800 functioning polarization-sensitive detector pairs from calibration data taken in January 2018. Using a Rotating Polarized Source (RPS), we mapped polarization response for each detector over a full 360 degrees of source rotation and at multiple telescope boresight rotations from which per-pair polarization properties were estimated. In future work, these results will be used to constrain signals predicted by exotic physical models such as Cosmic Birefringence

Observing low elevation sky and the CMB Cold Spot with BICEP3 at the South Pole

BICEP3 is a 520 mm aperture on-axis refracting telescope at the South Pole, which observes the polarization of the cosmic microwave background (CMB) at 95 GHz to search for the B-mode signal from inflationary gravitational waves. In addition to this main target, we have developed a low-elevation observation strategy to extend coverage of the Southern sky at the South Pole, where BICEP3 can quickly achieve degree-scale E-mode measurements over a large area. An interesting E-mode measurement is probing a potential polarization anomaly around the CMB Cold Spot. During the austral summer seasons of 2018-19 and 2019-20, BICEP3 observed the sky with a flat mirror to redirect the beams to various low elevation ranges. The preliminary data analysis shows degree-scale E-modes measured with high signal-to-noise ratio

Microwave multiplexing on the Keck Array

We describe an on-sky demonstration of a microwave-multiplexing readout system in one of the receivers of the Keck Array, a polarimetry experiment observing the cosmic microwave background at the South Pole. During the austral summer of 2018-2019, we replaced the time-division multiplexing readout system with microwave-multiplexing components including superconducting microwave resonators coupled to radio-frequency superconducting quantum interference devices at the sub-Kelvin focal plane, coaxial-cable plumbing and amplification between room temperature and the cold stages, and a SLAC Microresonator Radio Frequency system for the warm electronics. In the range 5-6 GHz, a single coaxial cable reads out 528 channels. The readout system is coupled to transition-edge sensors, which are in turn coupled to 150-GHz slot-dipole phased-array antennas. Observations began in April 2019, and we report here on an initial characterization of the system performance.Comment: 9 pages, 11 figures, Accepted by the Journal of Low Temperature Physics (Proceedings of the 18th International Workshop on Low Temperature Detectors