Recent data suggest that Alzheimer's disease (AD) neuropathological changes are present years before sypmtoms onset. The need to study these early events has driven the genesis of observational cohorts of healthy middle age participants. On the other hand, the implementation of biomarkers for identifying AD pathology has created an opportunity to intervene pharmacologically at earlier stages. The objective of this talk is presenting the design and emerging data of the ALFA (alzheimer & families) cohort and of the European Prevention of Alzheimer's dementia (EPAD) as an example of newly designed interventional programmes.

Regarding observational cohorts, the ALFA cohort is a longitudinal study of AD patients' adult children run at the BarcelonaBeta Brain Research Center. It is aiming to define the early physiopathological events of AD, to understand the factors that modify its risk and to characterize the markers that predict its progression. The ALFA+ study, nested in the ALFA parent cohort, consists of repeated 3-year visits in which the 45-65 years old participants undergo clinical examination, cognitive tests, neuroimaging (MRI ABPET), and samples collection (blood, CSF). On the other hand, EPAD is a response to the Innovative Medicines funding call aiming to deliver a perpetual adaptive trial for the secondary prevention of AD. The aims of EPAD are to develop the necessary infrastructure including: 1) identification of subjects from existing cohorts and registers and recruitment into the EPAD Cohort and then EPAD trial, 2) the development of the necessary data management infrastructure to support disease modeling and adaptive trial decisions and 3) the establishment of a network of EPAD Trial Delivery Centre (TDC's) within collaborating countries in order to deliver the trial. In this talk, we will present cross sectional results from the ALFA parent cohort, initial MRI and amyloid PET results from the ALFA+ study and the latest update on EPAD.

In summary, emerging cohorts are studying the earliest stages of preclinical AD, which will be useful to understand early pathophysiological changes together with modelling the preclinical stages in order to inform newly designed trials such as EPAD.

The pathologic hallmarks of Alzheimer's disease (AD) include abnormal deposits of extracellular beta amyloid plaques and aggregates of hyperphosphorylated tau neurofibrillary tangles (NFTs). Current evidence strongly supports the role of beta amyloid as a disease initiating event occurring years before symptom onset. NFT accumulation has been thought to follow beta amyloid by 5-10 years. While beta amyloid has been associated with cognitive decline, the relationship between cortical beta amyloid and clinical disease stage has not been consistently supported. In contrast, the accumulation of tau is more closely associated with the degree of cortical neuronal loss as well as with increasing cognitive deficits and declining functions of daily living. Autopsy findings have indicated stronger correlations between NFT number and pre-mortem cognitive performance than counts of beta amyloid plaques in those same individuals. Across a substantial body of literature tau pathology has also been shown to be more closely related to cognitive impairment, predominantly memory decline, than amyloid in postmortem studies.

The advent of molecular imaging agents providing quantitative measures of beta amyloid and tau have allowed researchers to explore these proteins in AD in vivo. Therapeutic trials now routinely employ molecular imaging to screen prospective subjects as a component of enrollment criteria and to monitor response to therapy occurring at the cellular level. The relationship between tau tracer PET signal and cognitive performance has also been explored, though results have varied across studies, with most studies reporting substantial and significant correlations between neocortical tau standard uptake value ratios and Mini-Mental State Examination. Based on the neuropathological literature and early PET studies, it appears that the spatial location and density of tau may be indicative of the degree of neurodegeneration, synaptic dysfunction, and the character of cognitive deficits. Thus we hypothesized that the density and distribution of pathological tau (measured by PET imaging of Flortaucipir F 18) would correlate with cognitive impairment across a range of domains in a regionally distinct manner. This preliminary work explores relationships between spatial distribution of flortaucipir and a range of cognitive functions as assessed by neuropsychological measures.

Deciphering the intricate and interactive relationship between the information encoded in the genome and the ongoing synaptic activity is critical for understanding the molecular and cellular signaling underlying long-term memory formation and maintenance of long-lasting changes within the brain. To systematically dissect this question, we investigated the molecular basis of the signaling from synapses to the nucleus and from the nucleus to the synapses, which crucially determines the persistence of synaptic plasticity. We thus uncovered an activity-dependent protein kinase cascade CaMKK-CaMKIV that critically controls the amplitude and time course of phosphorylation of a nuclear transcription factor CREB downstream of synaptic activity, thereby activating a plethora of adaptive transcriptional responses within an active neuronal circuit. We also identified a novel "inverse" synaptic tagging mechanism in which one of CREB's target gene, Arc, acts as a brake that helps weaken the non-potentiated synapses during the maintenance phase of synaptic plasticity. In genomic parlance, Arc's rapid induction following strong physiological stimuli is dictated by a potent synaptic activity-responsive element (SARE) present in its enhancer/promoter region, which strikingly harbors a unique cluster of binding sites for CREB, MEF2 and SRF/TCF. Based on this discovery, we created a synthetic promoter E-SARE which now allows to map, label, record and manipulate active neuronal ensembles in various areas of the brain in vivo. Recently, we designed a new set of genetically encoded Ca²⁺ indicators (GECIs), such as R-CaMP2, which are molecular spies of neuronal activity with most desirable properties such as fast speed and signal linearity. This was largely achieved by exchanging the M13 sequence of classical GECIs with a sensitive CaM-binding sequence engineered based on neuronal CaMKKs. These efforts collectively start to illuminate key molecular and cellular events that are essential in neuronal coding and information processing in active neuronal circuits and systems in vivo.

Electrical spiking is the internal language of the nervous system, but membrane voltage is very hard to measure. This difficulty has been a major obstacle to developing therapeutics that affect neural activity. We developed optogenetic tools for all-optical electrophysiology ('Optopatch')—simultaneous optogenetic stimulation and optical readout of membrane potential. In combination with advanced optical systems and specialized software, Optopatch tools permit high-speed characterization of neuronal function. We have applied Optopatch in primary neurons, in human stem cell-derived neurons, and in rodent brain in vivo. In neurons derived from human induced pluripotent stem cells (iPSCs), optical electrophysiology enables detailed functional characterization of many thousands of neurons in a screening-compatible format. Neurons derived from patients with genetically based diseases of the nervous system show characteristic firing anomalies, which in some cases can be reversed by appropriate pharmacological agents.

Optopatch measurements also permit targeted measurements of individual ion channels heterologously expressed in stable cell lines. In HEK cells that express a voltage-gated sodium channel and an inward rectifier potassium channel, optogenetic stimulation activates the sodium channel, which leads to a voltage spike. The spike can be detected by a fluorescent voltage indicator. Compounds that modulate the activity of the sodium channel affect the spike waveform. We have used this technique to screen for activity-dependent modulators of the channels NaV1.7 and NaV1.9, both implicated in pain.

To apply Optopatch in vivo we developed custom optics to compensate for light scattering and to highlight cells embedded within the three dimensional tissue. We studied the dynamics of hippocampal neurons in mice walking on a treadmill. Optopatch experiments revealed the first information about inter-cellular correlations in sub-threshold membrane potentials in the hippocampus, and how changes in brain state (corresponding to walking or resting) affected these correlations. We identified multiple independent subthreshold signals, shared to varying degrees among distinct subsets of neurons.

Our research group at Caltech develops and employs optogenetics, tissue clearing, and viral vectors to gain new insights on circuits underlying locomotion, reward, and sleep. We showed how bidirectional manipulation of mesopontine cholinergic cell bodies exerted opposing effects on locomotor behavior and reinforcement learning and how these effects were separable via limiting photostimulation to PPN cholinergic terminals in the ventral substantia nigra pars compacta or to the ventral tegmental area, respectively (Xiao et al, Neuron, 2016). In most recent work (Cho et al., Neuron, 2017), the group has delineated novel arousal-promoting dopaminergic circuits that might be at the root of sleep disturbances common to numerous neuropsychiatric disorders. Genetically encoded tools that can be used to visualize, monitor, and modulate mammalian neurons are revolutionizing neuroscience. However, use of genetic tools in non-transgenic animals is often hindered by the lack of vectors capable of safe, efficient, and specific delivery to the desired cellular targets. To begin to address these challenges, we have developed an in vivo Cre-based selection platform (CREATE) for identifying adeno-associated viruses (AAVs) that more efficiently transduce genetically defined cell populations (Deverman et al, Nature Biotechnology, 2016). As a first test of the CREATE platform, we selected for viruses that transduced the brain after intravascular delivery and found a novel vector, AAV-PHP.B, that transduces most neuronal types and glia across the brain. We also demonstrate how whole-body tissue clearing can facilitate transduction maps of systemically delivered genes (Yang et al, Cell, 2014; Treweek et al, Nature Protocols, 2016) and how non-invasive delivery vectors can be used to achieve dense to sparse labeling to enable morphology tracing in both the central and peripheral nervous systems (Chan et al, Nature Neuroscience, 2017). Since CNS disorders are notoriously challenging due to the restrictive nature of the blood brain barrier, the recombinant vectors engineered to overcome this barrier can enable potential future use of exciting advances in gene editing via the CRISPR-Cas, RNA interference and gene replacement strategies to restore diseased CNS circuits.

Hypertension is the leading cause of death and disability-adjusted life-years worldwide. Lowering systolic blood pressure by 10 mmHg reduces the relative risk of a major cardiovascular event by 20%, with those at highest risk gaining the most in absolute terms. New guidelines have lowered or are considering lowering the threshold for initiation of pharmacologic therapy and BP goals. The reclassification of hypertension is accompanied by new treatment recommendations, with a target blood pressure of 130/80 mmHg, and treatment at <140/90 mmHg for those at increased risk. Hypertension has multiple causes and limitations of current treatment guidelines are well recgonised - mainly an all-comers approach to treatment; wide inter-individual response to drug classes despite stratification by age/ethnicity; uncertainty in stratification of ethnic minorities other than those of African ancestry; uncertainty in stratification to combination treatment required in most patients. Recent trials like the PATHWAY programme of trials now offer answers contributing to our better understanding of more optimal treatment strategies for hypertensive patients. PATHWAY 1 provides substantial evidence that initial combination therapy achieves more rapid blood pressure reduction safely and with the vast majority of patients reaching target BP within a few weeks of onset of treatment. PATHWAY 2 clearly establishes the case for recommending spironolactone as the optimal fourth line drug in the treatment algorithm for patients with resistant hypertensive patients. PATHWAY 3 provides an important insight into the different metabolic effects of the diuretics commonly used in hypertension treatment strategies and evidence for the benefits of a thiazide/amiloride combination.

Chronic kidney disease (CKD) is common, affecting 6-11% of the population in the developed world. Hypertension is an independent risk factor for CKD progression, and is a frequent finding in patients with CKD. Its prevalence increases as CKD progresses, with over 75% of patients with a glomerular filtration rate &lt;30ml/min having a blood pressure (BP) &gt;140/90mmHg. Despite treatment with multiple antihypertensive agents the majority of CKD patients fail to reach target BP. Recent studies have supported lower BP targets in select groups of patients with CKD as well as avoiding use of dual renin-angiotensin system blockade in all of these patients. Here, we shall review the optimal method of BP assessment in CKD as well as recent insights into its optimal management.

Non-adherence to medication is common amongst hypertensive patients, with estimates ranging from 7-48%. Total or partial non-adherence is thought to account for between 12-66% of cases of apparent resistant hypertension. Measurement of patient adherence has historically been very challenging, and as a result, suboptimal adherence to a prescribed drug regimen often goes unrecognised in everyday clinical practice. Detecting non-adherence can be challenging and traditional methods such as direct questioning and pill counts are known to provide unreliable estimates of true medication adherence. Patients tend to underreport non-adherence and may take medication immediately before clinic appointments, so-called 'white coat adherence'. Conversely, clinical judgement alone is believed to overestimate the rate of non-adherence to antihypertensive medication.

The most commonly used approach in routine clinical practice is directly observed dosing. Blood pressure is measured before and after medication in a clinic setting with the patient observed as they take their tablets. Where a patient's blood pressure falls below 140/90mmHg following directly observed dosing, non-adherence to medication can be assumed. Electronic monitoring methods such as the medication event monitoring system (MEMS; AARDEX Group, Ltd, Sion, Switzerland) have been widely used to monitor adherence in clinical trials, because of their automaticity and precision of timing when patients take or omit doses.

The 'gold-standard' measure of medication adherence is to take a urine sample after the patient has taken their medications and examine the sample for relevant drug metabolites using high- performance liquid chromatography-mass spectrometry. This technique has been recently developed in the UK and Germany and has been shown to be effective at accurately detecting non-adherence to specific drugs types. It is increasingly being used in clinical practice in the UK although its availability is not yet widespread.

Hypertension is the most important risk factor for health globally, and a major factor underlying strokes, heart attacks and heart failure. We now have many medicines that are effective in treating high blood pressure (BP), and a wealth of evidence showing that even small BP reductions can substantially reduce cardiovascular risk. Although we have a large number of available medicines for the treatment of hypertension, these are not always well tolerated and there are real opportunities focused on endothelial dysfunction, arterial stiffness and renal injury (with proteinuria), and in high-risk patients, such as those with treatment-resistant hypertension (TRH) and diabetic kidney disease. These include endothelin antagonists, phosphodiesterase inhibitors and guanylate cyclase stimulators. In addition, with the recent evidence of benefits from spironolactone in TRH, and the many adverse effects of exposure to high levels of aldosterone, there may be grounds for more selective approaches to blocking its function. In addition, new drugs for lowering glucose in type-2 diabetes, seem to both lower BP and reduce cardiovascular risk, and might have wider value. One of the major problems with treatment of hypertension is poor adherence to treatment. This has helped to fuel the creation of devices that can control BP therapy independent of the patient, such as renal denervation and baroreceptor activation therapy, remodelling the carotid artery and the creation of arteriovenous shunts. Although initially very promising, and potentially attractive alternatives to medication, there are a number of reasons to think that these agents may have powerful placebo effects, and that to avoid misleading outcomes, clinical trials need to be randomised, blinded and use sham control procedures (see SYMPLICITY HTN-3). Currently, a number of studies are underway and the outcomes are awaited with interest. In summary, there are continued interesting developments in relation to new medicines and devices as effective and well tolerated therapeutic approaches to the treatment of hypertension. The challenges will be cost-effectiveness and added value beyond lowering of BP.

There has long been debate that the traditional, modifiable risk factors (hyperlipidemia, hypertension, diabetes and smoking), all established more than 50 years ago, are incompletely predictive of cardiovascular disease (CVD). Furthermore, we have a poor understanding of how aging, the major CVD risk factor, promotes disease progression. Somatic DNA mutations accumulate with age in many tissues, leading to genomic mosaicism. However, the causal role of genomic mosaicism in the diseases of the elderly other than cancer is relatively unexplored. Large exome sequencing studies in humans have shown that aging is associated with an increased frequency of somatic mutations in the hematopoietic system that provide a competitive growth advantage to the mutant cell and therefore allow its clonal expansion (i.e. clonal hematopoiesis). Unexpectedly, these somatic mutations have been found to be associated with greater risk of coronary heart disease and stroke, suggesting a previously unrecognized link between somatic mutations in the hematopoietic system and CVD. One of the genes that is frequently mutated in clonal hematopoiesis is the epigenetic regulator Tet2. Using Tet2 as a test case, we explored whether the expansion of mutant hematopoietic cells promotes atherosclerosis and heart failure in experimental models. The findings of these studies support the concept that clonal hematopoiesis, due to somatic mutations, represents a new mechanism of CVD that shares features with hematologic malignancy. Further research in the area of hematovascular biology could provide a mechanistic framework for the development of personalized medicines for CVD that are tailored for individuals that carry specific somatic mutations in their hematopoietic cells.

The degradation of damaged mitochondria by mitophagy, a mitochondria-specific form of autophagy, is essential for the maintenance of healthy mitochondrial function. Mitophagy is often downregulated during chronic cardiac stress, whereas rescue of mitophagy delays the development of cardiac dysfunction. However, the molecular mechanisms through which mitophagy is activated during stress remains poorly understood in the heart. Using electron microscopy and mitochondria-targeted-Keima, a fluorescent dye that indicates the pH environment in which it is located, it has been observed that glucose deprivation (GD) and hypoxia (HO), stresses known to impose energy stress, induce mitophagy in cardiomyocytes (CMs). Although downregulation of Atg7, an intervention that abrogates a non-selective form of autophagy (hereafter conventional autophagy), does not affect GD- or HO-induced mitophagy, downregulation of Ulk1, one of the two mammalian orthologs of Atg1, markedly attenuates mitophagy in CMs. Autophagosomes observed in this form of mitophagy are associated with Rab9 but not LC3. Thus, mitophagy in CMs during energy stress is likely to be mediated by a mechanism distinct from conventional autophagy. In response to energy stress, Ulk1 and Rab9 form a complex, recruit Rip1, a Drp1 kinase, and induce Ser616 phosphorylation of Drp1 and mitochondrial fission. Through this mechanism, damaged portions of mitochondria in CMs are segregated and sequestered in Rab9-positive autophagosomes. In summary, mitophagy during energy stress is mediated by a molecular mechanism distinct from conventional autophagy in CMs and Ulk1 mediates mitochondrial fission and mitophagy through the coordinated actions of Rab9, Rip1, and Drp1, thereby playing a central role in degrading damaged mitochondria during energy stress. In the lecture, I will also discuss the functional significance of mitophagy mediated through the Ulk1-Rab9-Rip1-Drp1-dependent mechanism during pressure overload and myocardial ischemia.

Cardiac plasticity, defined as structural remodeling of the heart in response to environmental demands, is an intrinsic compensatory mechanism to maintain hemodynamic workload. Both hypertrophied and atrophied myocardium exhibit reduced contractility due to decreased myocardial flexibility. Our laboratory studies on the common mechanism underlying reduction of myocardial flexibility due to hemodynamic loading and unloading, and aims to establish novel therapeutic strategies for realization of a &quot;society of health and longevity&quot;. We used doxorubicin (DOX), a highly effective anticancer agent but induces myocardial atrophy, for investigating molecular mechanism of myocardial atrophy. We found that transient receptor potential canonical 3 (TRPC3) channels participate in DOX-induced myocardial atrophy in mice. DOX increased production of reactive oxygen species (ROS) in rodent cardiomyocytes through hypoxic stress-mediated upregulation of NADPH oxidase 2 (Nox2), which formed a stable complex with TRPC3. Specific inhibition of TRPC3-Nox2 coupling suppressed DOX-induced myocardial atrophy and left ventricular (LV) dysfunction and its upregulation of Nox2 and oxidative stress, without reducing hypoxic stress. Downregulation of the TRPC3-Nox2 complex through voluntary exercise promoted volume load-induced LV compliance and flexibility with physiological hypertrophic growth of the myocardium. As the prevention of cellular toxicity by inhibition of TRPC3-Nox2 complex also seemed to be applicable to macrophage and skeletal muscle cells, these results illustrate the impact of TRPC3 on LV compliance and flexibility and, focusing on the TRPC3-Nox2 complex, provide a new strategy for maintaining cardiocirculatory homeostasis.

Improved reperfusion strategies have shortened ischemic times and enhanced myocardial salvage in most patients with acute myocardial infarction (MI). Despite these achievements, patients with extensive myocardial injury during the acute phase remain at risk of developing chronic heart failure. MI triggers an inflammatory response that replaces the necrotic area with vascularized granulation tissue and eventually a collagen-rich scar. The heart can undergo deleterious changes in left ventricular geometry and function during this vulnerable period before scar formation has stabilized the infarct area. Therapeutic modulation of infarct healing may therefore hold promise for preventing postinfarction heart failure. Intracoronary infusion of autologous bone marrow cells (BMCs) during this critical time window has been explored as an adjunctive therapeutic strategy to improve heart function after MI in patients. Transcriptome and proteome analyses indicate that various BMC populations release a broad repertoire of cytokines and growth factors that may enhance tissue repair in a paracrine manner, thus providing a conceptual framework for this approach. However, BMC therapy is limited by low cell retention rates after intracoronary or intramyocardial delivery and by interindividual variations in cell functionality. We believe that systemic application of specific BMC-derived secreted proteins will enable more targeted approaches to improving tissue repair and heart function after MI. We recently performed a bioinformatic secretome analysis in BMCs from patients with acute MI who were enrolled in the BOOST 2 cell therapy trial. From this analysis, we identified several poorly characterized angiogenic growth factors. The mode of action and therapeutic potential of these proteins will be discussed during my talk.

The transient receptor potential (TRP) channel TRPM3 is a calcium-permeable cation channel activated by heat and by the neurosteroid pregnenolone sulfate (PregS). TRPM3 is highly expressed in sensory neurons, where it plays a key role in heat sensing and inflammatory hyperalgesia. In comparison to other TRP channels involved in nociception, very little is known about the regulation of this channel and its pharmacology is poorly developed. We developed novel potent TRPM3 agonists and antagonists and a variety of combined knockout models to elucidate the in vivo roles of TRPM3 in acute and chronic pain, and establish its relative contribution to acute noxious heat sensing. Our results shed new light on the relative roles of TRPV1, TRPM3 and TRPA1 in various forms of nociception, and may form the basis for the development of novel TRPM3-targeting analgesic drugs.

Calcium signaling is a central mechanism involved in neuronal functions and pathological conditions, including chronic pain. Two important and widespread ion channels may contribute to calcium signaling in this context: the Calcium Release-Activated Calcium (CRAC) channels underlying store-operated calcium entry (SOCE) and the Transient Receptor Potential Melastatin 7 (TRPM7) chanzyme, which combines a calcium-permeable ion channel and a kinase domain with phosphotransferase activity. In addition to calcium signaling, both mechanisms may contribute to calcium store refilling. In this presentation, I will discuss how TRPM7 contributes to and interacts with store operated calcium entry (SOCE) and how this affects the store refilling process and the store content in B lymphocytes. We found that although TRPM7 itself is not a store-operated ion channel, its activity is acutely linked to SOCE and its facilitating modulatory effect is mediated the kinase domain of the protein. In addition, TRPM7 contributes to calcium homeostasis by maintaining the filling state of intracellular calcium stores in resting cells, and this effect is mediated by TRPM7's ion channel domain. We hypothesize that TRPM7 channel activity is required to maintain the cellular calcium store content and that TRPM7 kinase phosphorylates and thereby modulates STIM proteins and/or other SOCE components. We conclude that the channel kinase TRPM7 and SOCE are synergistic mechanisms regulating intracellular calcium homeostasis.

TRPA1 channel is a nonselective cation channel sensitive to various 'pungent' substances including reactive oxygen species (ROS) and thought to be a nociceptor in the primary sensory neurons. Here we have clarified the physiological regulation of TRPA1 activity by prolyl hydroxylation in two animal models; one is hindlimb pain caused by ischemia/reperfusion and the other is oxaliplatin-induced cold hypersensitivity.

An transient ischemia/reperfusion of mouse hindlimb elicited spontaneous licking behavior peaked within 10 min. The licking was inhibited by ROS scavengers, a TRPA1 antagonist, or TRPA1 deficiency. In human TRPA1-expressing cells as well as cultured mouse dorsal root ganglion (DRG) neurons, ROS-evoked TRPA1 response was enhanced after hypoxia (80 mmHg) for 30 min. The hypoxia-induced sensitization to ROS was inhibited in cells expressing a proline-substituted, prolyl hydroxylase (PHD)-resistant TRPA1 mutant (TRPA1-P394A) or by coexpressing an inactive mutant of PHD. Consistently, a PHD inhibitor increased the ROS-evoked licking through TRPA1 activation. Our results suggest that hindlimb ischemia/reperfusion-evoked spontaneous licking, i.e. painful dysesthesia, is caused by ROS-evoked activation of TRPA1 that have been sensitized under hypoxia via inhibition of PHD-mediated prolyl hydroxylation of TRPA1.

Clinically, a platinum-based anticancer agent, oxaliplatin, induces a peculiar cold-triggered peripheral neuropathy within hours after infusion. In mice, a rapid-onset cold hypersensitivity was observed after injection of oxaliplatin, which was ameliorated by blockade or deficiency of TRPA1. The cold hypersensitivity was mimicked by an oxaliplatin metabolite, oxalate, structurally resembling PHD inhibitors. Accordingly, systemic PHD inhibitor induced cold hypersensitivity through TRPA1 sensitization. In human TRPA1-expressing cells, a cold-evoked TRPA1 response was observed in the presence of PHD inhibitor, or in cells expressing TRPA1-P394A mutant, both of which were reduced by ROS scavengers. Taken together, our findings provide evidence that PHD inhibition uncovers TRPA1 sensitization to ROS, which enables TRPA1 to convert ROS signaling into cold sensitivity.

Cannabis sativa preparations have probably been used since millennia for pain relief and are still an important part of our analgesic pharmacopeia. This presentation will summarize our current understanding about the analgesic mechanism of cannabinoids, from molecular mechanisms to the physiological effects. The psychoactive ingredient of C. sativa, &#61508;9-tetrahydrocannabinol (THC) activates two different G protein-coupled cannabinoid receptors, CB1 and CB2, both of which mediate different aspects of cannabinoid analgesic effects. CB2 receptors are mostly localized on immune cells and activated microglia. The analgesic effects of CB2 activation are mainly due to anti-inflammatory mechanisms, but probably also through the modulation of algogenic mediators. CB1 is prominently expressed in the central nervous system and is well-known as an important mediator of synaptic plasticity. Activation of CB1 on neurons modulates pain responses at different level, including the processing of nociceptive stimuli and the regulation of descending pain control systems. I will also show evidence that endocannabinoid signaling is involved in the modulation of the affective component of pain.

Since the discovery that LPA receptor signaling initiates neuropathic pain (Nature Medicine 2004), we have studied to probe that this finding is generalized in various chronic pain diseases. Current studies revealed that LPA1 signaling is involved in the development of chronic pain diseases. We have obtained findings that LPA1 receptor KO mice lose the chronic pain in partial sciatic nerve ligation-induced neuropathic (NeuP), paclitaxel treatments-induced NeuP, diabetic NeuP, central post stroke pain, spinal cord injury-induced NeuP, repeated acid saline-induced and intermittent psychological (empathy) or cold stress-induced fibromyalgia-like pain models. In some animal models, we also obtained the evidence that LPA1 signaling is also involved in the maintenance of chronic pain, since LPA1 antagonists reversed the established pain. Throughout the pharmacotherapeutical studies, we found that peripheral pain memory is maintained or feed-forwarded by LPA signaling in the spinal cord, and supra-spinal pain memory is additionally reinforced by arising pain itself, since repeated and complete medicinal treatments could completely cure the pain diseases even after the cessation of treatments. I will present key findings underlying my hypothesis and expect fruitful discussion.

Abstract not yet available.

Prescribing medicines is a core activity for all healthcare systems, both in hospitals and primary care. In the UK, an average of around 20 prescriptions are written for every member of the population each year. Prescribing is a challenging task for any healthcare professional. Prescribers have to select the correct medicine, dosage, route, and frequency of administration, sometimes in the face of diagnostic uncertainty, taking into account potential individual variability in pharmacokinetics and response as a consequence of co-morbidity, genetics, and interacting drugs. Given that individual patients have different ideas and expectations, and the outcome of any prescription is uncertain, the prescriber also needs to be able to counsel the patient and plan an appropriate strategy for monitoring and follow-up for evidence of benefit and/or harms. Given these complexities, it is perhaps not surprising that poor prescribing is common: around 5 to 10% of UK prescriptions contain an error. These errors result from a combination of poor performance of individual prescribers and the increasing demands of a pressurised healthcare system. In these circumstances it is important that undergraduate and continuing education provides the training to ensure that all prescribers meet minimum standards of prescribing competency. In response to these concerns, the British Pharmacological Society and UK Medical Schools have developed the Prescribing Safety Assessment (PSA) as a summative assessment of knowledge, judgement and skills related to prescribing and supervising the use of medicines in a modern healthcare system. The PSA is intended to enable final-year medical students at the end of their undergraduate training to demonstrate that they have achieved the necessary competence to prescribe, and supervise the use of, medicines in a modern healthcare system. This presentation will describe the development of the assessment items, the online system used to deliver of the PSA, the performance of the UK candidates and medical schools, and the basic psychometric properties of the assessment. It will go on to describe the various international collaborations that have developed and the opportunities that exist to create global standards of prescribing practice.

Background

In Sweden, five and a half years of medical studies lead to graduation, whereas another one and a half year of supervised internship, organized under the National Board of Health and Welfare, is needed for a license to practice and the right to freely prescribe medicines. Most medical schools in Sweden today apply an integrated theme based curriculum with no separate courses in pharmacology or pharmacotherapy and, more importantly, no separate examination of prescribing skills. A final, national exam after internship covers general practice, internal medicine, surgery and psychiatry. Again, knowledge in clinical pharmacology or rational prescribing is not assessed separately. Furthermore, final year medical students state that their training in rational prescribing is to limited and that they do not feel confident in prescribing drugs.

Poor quality of the drug treatment in elderly patients has been highlighted in recent years, with the use of medicines unsuitable for the elderly, polypharmacy with an increased risk of unwanted drug interactions, and the lack of clear indications for long term treatment with eg proton pump inhibitors on the one hand, and too little treatment with eg anticoagulants in atrial fibrillation on the other hand.

Aim

With the aim to improve drug treatment of the elderly, the National Board of Health and Welfare, in close collaboration with clinical pharmacology experts at Swedish universities, has developed a national web-based, problem oriented course on pharmacotherapy for the elderly for newly graduated, but not yet licensed, physicians.

Results and discussion

The scope and outline of the course will be presented, together with data on participation and student evaluations and satisfaction of this course, as well as their evaluation of their Clinical pharmacology training at medicinal school. Attempts to evaluate the actual outcome in terms of quality of prescribing will be discussed. Also, the possibilities to integrate this type of course as part of a national examination of prescribing skills will be discussed, in the context of a planned change into six years of medical school with no internship in Sweden.

The concept of the neurovascular unit is now relatively well accepted. The neurovascular unit emphasizes that cell-cell interaction between neuronal, glial, and vascular elements is critical for brain function. Within the neurovascular unit in cerebral white matter, oligodendrocyte precursor cells (OPCs) may receive/provide trophic support from/to neighboring cells to maintain proper white matter function. During development or after white matter damage, OPCs proliferate and migrate to their target regions, where they differentiate into oligodendrocytes and form myelin sheaths. For OPC proliferation and differentiation, trophic support from neighboring cells, such as astrocytes and pericytes, would be needed. For example, astrocytes produce brain-derived neurotrophic factor that promotes oligodendrogenesis (i.e. OPC proliferation and differentiation) to ease white matter damage under pathological conditions. In addition, pericytes also secrete several soluble factors, at least partly through the function of intracellular A-kinase anchor protein 12 (AKAP12). When AKAP12 is knocked down, AKAP12-deficient pericytes no longer support OPC proliferation and differentiation. On the contrary, OPCs may also secrete soluble factors to regulate the microenvironment within the neurovascular unit. Under physiological conditions, OPCs are an important source of transforming growth factor-β1 that supports blood-brain barrier integrity. But after white matter injury, OPCs can rapidly respond to the stress and produce matrix metalloproteinase-9 that leads to BBB leakage and triggers secondary cascades of cerebrovascular injury and demyelination. Because white matter damage is one of the major hallmarks of several cerebrovascular diseases and because OPCs are an important cell type for white matter function, understanding and dissecting these OPC-related non-cell autonomous mechanisms in the neurovascular unit may lead to novel opportunities for white matter protection and white matter recovery.

EPCs are bone-marrow derived cells capable of differentiating ex vivo into endothelial-like cells becoming a model for endothelial generation and vascular repair. It is also accepted that EPCs can be incorporated into neovessels and their restorative actions on vascular remodeling have been widely reported in vivo in stroke models or traumatic brain injury.

At the same time, several nourishing factors have been reported to modulate EPCs function (such as VEGF or HMGB1), whereas other studies have demonstrated the benefit of factors secreted by EPCs (such as VEGF or HGF). In this regard, EPCs secretome mediates multiple cell-cell interactions playing a pivotal role to achieve brain remodeling including angiogenesis, neurogenesis or oligodendrogenesis in a whole neurorepair niche, in which other types of cells such as neurons, astrocytes, endothelial cells, pericytes and neural progenitor cells are comprised. More specifically the secretome of EPCs is known to stimulate endothelial cell migration, growth and function, to protect from axonal degeneration in cultured cortical neurons exposed to oxygen-glucose deprivation or promote tissue revascularization and recovery in ischemic tissues.

In the context of white matter remodeling, an endogenous pool of oligodendrocyte precursor cells (OPCs) is widely distributed in the adult brain for physiological myelin renewal and for repair under pathological conditions. In demyelinating disorders, residual OPCs tend to proliferate and differentiate into oligodendrocytes to alleviate white matter damage, however, the regeneration of oligodendrocytes and myelin sheaths might fail. One therapeutic strategy to boost this oligovascular remodeling are cell-based therapies, including EPCs secretome. In this regard we have identified the presence of several trophic, proteolytic and signaling factors in the EPC-CM that support the therapeutic effects on white matter remodeling. By using a combination of in vitro culture systems and an in vivo mouse model of chronic cerebral hypoperfusion targeting white matter degeneration we asked whether EPC secretome could enhance oligovascular proliferation, maturation and repair in damaged white matter. Our results demonstrate that the treatment with the EPC secretome preserves cognitive function and enhances oligo-angiogenesis in the injured white matter.

Carbon monoxide (CO) is a gaseous molecule produced from heme by heme oxygenase (HO). CO production at low concentrations is thought to have several useful biological roles in pathophysiological conditions. In mammals, a proper neurovascular unit comprising endothelial cells, pericytes, oligodendrocytes, astrocytes, microglia, and neurons is essential for the homeostasis and survival of the central nervous system (CNS). In addition, the repair of neurovascular systems after CNS diseases such as traumatic brain injury may be responsible for functional recovery. CO/HO may enhance cellular networks in neurovascular unit. The cellular mechanisms and interactions by which CO/HO are exploited for therapeutic application in traumatic brain injury. Our current study is focused on the possible role of CO/HO in the neurovascular unit in terms of neurogenesis, oligodendrocytes, angiogenesis, and synaptic plasticity, ultimately leading to behavioral changes in traumatic brain injury.

Central nervous system (CNS) inflammation involving various types of immune cells is a potential therapeutic target for CNS diseases. In recent years, a number of studies have focused on the pathophysiological roles of microglia, the most abundant CNS resident immune cells, and CNS-infiltrating macrophages, both of which can migrate toward sites of CNS tissue damage with inflammation. Whereas their roles in CNS inflammation are still under debate, their contribution to CNS diseases could be more manifested in CNS demyelinating diseases, in which focal inflammatory white matter injury are observed. Here we discuss the evidence that regulation of transient receptor potential (TRP) channels, a nonselective Ca2+-permeable cation channels that serve as cellular sensors for mechanical, thermal, and chemical stimuli, in microglia/macrophages can modulate CNS inflammation and subsequent white matter injury in CNS diseases. In particular, we focus on the pathophysiological role of TRPM2, a redox-sensitive cation channel. At first, we demonstrate that TRPM2 in CNS-infiltrating macrophages plays a crucial role in development of experimental autoimmune encephalomyelitis (EAE), the most commonly used experimental model for the common demyelinating disease multiple sclerosis. EAE progression was suppressed by gene knockout or pharmacological inhibition of TRPM2; this was attributed to a reduction in CXCL2 chemokine production by CNS-infiltrating macrophages in TRPM2-knockout mice, resulting in suppression of neutrophil infiltration into the CNS. These results reveal an important role of TRPM2 in the pathogenesis of EAE. Next, we used a chronic cerebral hypoperfusion mouse model to investigate the role of TRPM2, and found that TRPM2-mediated activation of microglia, not macrophages, specifically contributes to inflammatory responses, demyelination and cognitive impairment. Taken together, these findings shed light on the understanding of the mechanisms of CNS inflammation, and are expected to provide a novel therapeutic molecule in microglia/macrophages for CNS demyelinating diseases.

Pharmacology has been the science at the heart of many of the advances in healthcare that we now take for granted. Those advances have depended on expertise in all areas from basic pharmacology through translational research to prescribing and monitoring the use of medicines by patients. Each step has required the contribution of individuals with a clear grasp of the fundamental principles of pharmacology and clinical pharmacology supported by knowledge of the actions of specific drugs. The purpose of the IUPHAR Pharmacology Education Project (PEP) is to support the development of this expertise by promoting learning in pharmacology and clinical pharmacology to a worldwide audience.

The specific aims of the project are: (i) to produce a simple, attractive easily searchable resource that will support the education students of the pharmacological and other biomedical sciences, as well as health professions students including medicine, nursing, pharmacy and others, (ii) to make helpful resources available to pharmacology educators who are responsible for delivering education, and (iii) to service the needs of students and teachers in resource-poor countries or where pharmacology is less well developed.

The initial development of the project is led by an international Editorial Board that brings together individuals with demonstrable commitment to pharmacology education. The delivery platform is based in Drupal software that enables the Editors and senior curator to add and edit contributions.

The content of the project is divided into four 'sections': Pharmacology, Clinical pharmacology, Drugs and Therapeutics, Each section is divided into 'modules', each of which will have associated with it between 4 and 10 'topics'. Each topic will have a summary text of up to 500 words that will highlight the most important aspects of this topic. This summary text will have other learning resources attached (e.g. web-links, articles, video and audio files, PowerPoint).

The editors welcome the input of colleagues from around the world as we help learners to make links with existing resources and gradually create new ones. The ultimate intention is to create an easily searchable website that signposts users to openly accessible resources that are relevant to the groups above.

The need for bringing pharmacological sciences education to a broader audience provided the stimulus for the creation of the Pharmacology Education Project (PEP) by IUPHAR as a companion website for the Guide to Pharmacology. In this presentation, the taxonomy and structure of the PEP website will be described. The material provided on the PEP website is organized in an intuitive, hierarchical structure divided into four general sections: Pharmacology, Clinical Pharmacology, Drugs and Therapeutics. An introductory text is included in each section emphasizing the relevance of the section to learners and explaining the content structure. Each section is divided into modules, for example, Pharmacodynamics under the section, Pharmacology. Every module includes descriptive text explaining the module content in clear and simple English broken up into easily read paragraphs including simple tables or diagrams. Each module houses reports on several topics, each of which has a summary text highlighting the most important aspects of the topic. For example, therapeutic index under the module Pharmacodynamics. The hallmark of the PEP website is the attachment of other learning resources (e.g. web-links, articles, video and audio files, PowerPoint files) each with its own short commentary to the summary text. These short commentaries provide enough information to help the viewer decide whether the attached learning resources are appropriate for their needs without having to examine the resource. The commentary includes a summary of the linked content, the relation of the linked content to the topic, potential use of the linked content in learning, and prerequisite topics. A user-friendly online submission tool helps authors navigate through the sections, modules, and topics in submitting content. Content submitted by the international pharmacology community is vetted by members of the PEP Editorial Board. The PEP website is a simple, attractive, easily searchable resource that supports students of the biomedical sciences, medicine, nursing and pharmacy as well as those who teach them.

The impact of evidence-based pharmacotherapy has been limited, especially in emerging economies. This is due to the multidisciplinary character of drug prescribing decisions, to the paucity of qualified teachers, and to the notorious complexity of treatment guidelines. To address this problem, we are developing the PharmaFrog app. The app contains everything that is needed for an informed pharmacotherapy decision, from the physiology of drug targets, through basic and clinical pharmacology, to prescribing situations encountered upon treatment of diseases that cause the majority of the worldwide mortality and morbidity. PharmaFrog integrates these various medical curricular elements by establishing causal relationships among short, non-redundant knowledge elements. Users may look up a certain drug, beginning with its mechanism and ending with its applications. Alternatively, they may start with the treatment of a particular condition and, if needed, access drug mechanism information. PharmaFrog is smartphone-based (currently Android and iOS) and fully functional offline. The app has been inspired by medical students of the Kilimanjaro Christian Medical University College in Moshi, Tanzania. It is developed by an informal group of students and experts in physiology, basic and clinical pharmacology, eLearning and informatics from Africa, Asia, Europe, and North America, with the financial support of the University Medical Center Mainz and of the German Federal Ministry of Economic Cooperation and Development. Within the first 5 weeks after its launch in Novemeber 2017 the demo version of the app was downloaded in 47 countries and received top ratings, despite its limited scope. The scope is currently being expanded to the planned 70 diseases. The modular structure of the knowledge database enables the implementation of further functionalities, such as interactive learning, knowledge assessment, and prescribing decision support training (www.PharmaFrog.org). PharmaFrog targets students and practitioners of professions involved in drug prescribing and drug administration. We believe that once completed, it can significantly improve the quality of drug prescribing.

University teaching has, for the last couple of decades, been in a state of change. While there have been many drivers for this, it has in part been in response to reports that the passive learning encouraged by the traditional didactic approach to content delivery, is associated with poorer outcomes in terms of student learning, than programs that encourage active learning. Current recommendations, therefore, are for courses to incorporate more opportunities for active learning. This has led to increase in use of models of content delivery in which students are introduced to content prior to face-to-face class time, with class time used for interactive learning activities. The push from Universities to change the way content is delivered has created some angst amongst those involved in the design and delivery of teaching programs. As educators, we are asked to provide more resources for students to use for self-directed learning (SDL), to develop online modules to deliver content and to create engaging, interactive activities for use in class. Many feel that they lack the expertise to develop their own resources, or the time to search for appropriate alternatives. The Pharmacology Education Project (PEP; https://www.pharmacologyeducation.org/) may help facilitate this.

In addition to being a general resource students can be referred to, the layout of the PEP into sections, modules and then topics can help with the identification of relevant resources that can be adapted for use as SDL activities, or to provide ideas for use in interactive face-to-face classes. Each module is broken up into topics, with the content presented in clear and simple language, highlighting the most important aspects. An important feature of the website is the links to other relevant online resources, which have been identified and suggested by content experts. Each of these links is accompanied by a short summary of the resource and categorised according to type (slide set, video, animation, podcast, simulation, etc) and suggested academic level it is suitable for (Beginner-Intermediate-Advanced). This presentation will discuss examples of how the PEP website can be used in the development of teaching materials for specific pharmacological topics.

INTRODUCTION

There is a global increase in the use of medication especially with the rapidly ageing populations. More than half of the admission to hospitals are often due to preventable pharmacological problems. Given the reported high rates of adverse events mostly related to medication errors, polypharmacy in the elderly patients, increase complexity of diseases and medications, there is an urgent need for teaching of clinical pharmacology to medical and health science students. The author presents the Pharmacology Education Project (PEP) and a THREE-STEP APPRAOCH technique in the teaching of clinical pharmacology.

METHODS

1. STEP 1: Activation of learners' prior knowledge. Students are encouraged to activate their prior knowledge of pharmacology with reference to PEP. The core topics for activation and preparation include adverse drug reactions, hypoglycemic agents, analgesics, antithrombotics, anticoagulants, drugs used in cardiovascular disorders and psychotropic drugs.

2. STEP 2: Contextualization of students' learning. Using common and clinically important case scenarios, the teachers, who have in-depth understanding of clinical pharmacology and geriatric patients, as well as the practical experience of prescribing, guide and assist the students to develop relevant conceptual frameworks in pharmaco-therapy. The students will be able to comprehend and contextualize the learned pharmacological content and the application in the clinical and geriatric patients.

3. STEP 3: Metacognition. Students reflect on their learning in pharmo-therapy and pharmacokinetics of clinical and geriatric patients, and articulate how they would apply the contextualized knowledge in the future. This leads to students' in depth understanding of pharmacology, as well as to future applications to practice. This will support the notion of training students in self-directed and lifelong learning.

CONCLUSIONS

Using the PEP Web content together with educational principles of activation of learners' prior knowledge, contextualized learners' needs and nurturing metacognition in the teaching of clinical and geriatric pharmacology have been rewarding in the promoting of self-directed and lifelong learning of medical and health science students.

Hypertension promotes the progressive damage to the kidney, heart and the vasculature. An inflammatory response involving T cells and macrophages plays a pivotal role in the pathogenesis of hypertensive organ damage, although mechanisms leading to such immune cell activation are insufficiently understood. The gut microbiota is a complex bacterial community with importance for host health. Importantly, the microbiota takes a bidirectional role in immune system development and maintenance meaning that shifts in microbiome composition and function may alter the function of certain immune cells and vice versa. The presentation will focus on the role of high salt on the microbiome and salt-sensitive hypertension. Further, it will focus on short-chain fatty acids (SCFA), which can be produced by gut bacteria from dietary fiber and their role host immune homeostasis and cardiovascular disease.

Lack of proper molecular definition of cell types responsible for specific homeostatic functions has been a key limitation in understanding kidney disease.

To fill this gap, we characterized 57,979 cells from healthy mouse kidneys using unbiased single-cell RNA sequencing. We showed that genetic mutations with similar phenotypes were mostly expressed by well known, single unique differentiated cell types. On the other hand, unexpected plasticity of epithelia in the terminal segment of the kidney (collecting duct) responsible for final composition of the urine generated cell types that explain a wide range of kidney diseases. Computational cell trajectory analysis and in vivo lineage tracing, showed that intercalated cells (that secrete protons or bicarbonate) and principal cells (that maintain salt, water and potassium balance) undergo a Notch mediated interconversions via a newly identified transitional cell type. In disease states, this transition is shifted towards the principal cell fate, which likely contributes to metabolic acidosis observed in kidney disease.

In summary, single cell analysis advanced a mechanistic description of kidney diseases by identifying defective homeostatic cell lineages.

Kidney is the organ that has one of the most complicated architecture in the body. The sophisticated architecture of nephron made its physiology difficult to unravel and the variety for experimental approach for renal (patho)physiology is limited so far. These factors prevent drug development and widening the pharmacological research. In vivo optical imaging is a long-time used powerful tool to for evaluating the renal physiology of small animals and has the potential to elucidate the unknown regulatory mechanisms of renal pathophysiology. The experimental approach using multiphoton laser microscopy expand what we can do by using intravital imaging and has revealed the heterogeneity of blood flow in each capillary in several experimental models of disease, glomerular sieving of several proteins, slowing of tubular flow in oliguric model, and the balance between the ischemic and normoxic capillary number correlates with renal function. Moreover, we recently found that ischemia/reperfusion-induced damage changed renal tubular glucose handling and that the inhibitor of sodium glucose cotransporter 2 induced remarkable pharmacological effects in this condition. At this symposium, I would like to discuss the recent progress in our understanding of renal (patho)physiology and pharmacology.

Chronic kidney disease (CKD) causes both medical and medicoeconomical problems worldwide. Regenerative medicine strategies using human pluripotent stem cells, such as human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), are expected as candidates to solve these problems. Cell replacement therapy, disease modeling and drug discovery with patient-derived stem cells should be applied for CKD. However, the methods to generate fully differentiated renal cells and tissues from hiPSCs/ESCs remain to be developed. The mechanisms of kidney morphogenesis and cell fate determination of renal lineage cells have been elucidated by experimental animal models. By mimicking in vivo kidney development, we are aiming to develop stepwise differentiation methods towards adult renal cells and tissues from hiPSCs/ESCs. The mammalian adult kidney, metanephros, develops by mutual interaction between two renal progenitor tissues, the ureteric bud (UB) and metanephric mesenchyme (MM) that are derived from early embryonic germ layers, anterior and posterior intermediate mesoderms (IMs), respectively. The UB gives rise to the collecting ducts and lower urinary tract from renal pelvis to a part of urinary bladder, while MM differentiates into nephrons and interstitium by developing embryonic progenitor cells, such as nephron progenitors (NPs). We have recently established highly efficient differentiation methods from hiPSCs/ESCs into Woffian duct epithelia and NPs through anterior and posterior IMs, respectively. Furthermore, we succeeded in the generation of nephron- and UB-like structures from the induced progenitor cells. We are currently establishing the recombination of these organoids in order to generate functional kidney tissues and to create the disease models from patient-derived hiPSCs. I would like to show our recent efforts towards the development of regenerative therapies and disease modeling for kidney diseases.

Around the year 2000, at a similar time to the creation of the National Institute for Clinical Excellence (NICE), other UK organisations were established to address health technology assessment (HTA) in Scotland and Wales, in each case led by a clinical pharmacologist (Sir Michael Rawlins, England, Prof David Lawson, Scotland; Prof Phil Routledge, Wales). Whereas NICE had a broad remit in HTA, guidelines development, quality standards and beyond, the key purpose of the Scottish Medicines Consortium (SMC; https://www.scottishmedicines.org.uk) has been to identify, and accept for use, those newly licensed medicines that clearly represent good value for money to the NHS in Scotland. Indeed, SMC has reviewed all newly licensed medicines, all new formulations of existing medicines and new indications for established products since 2002. SMC analyses information supplied by the medicine manufacturer on the health benefits of the medicine and the justification of its price. With limited resources, SMC works for the NHS to make sure that medicines representing good value for money are accepted for routine use as quickly as possible so they can benefit patients. The Consortium is made up of lead clinicians, pharmacists and health economists, together with NHS managers, the pharmaceutical industry and the public. Among the clinicians in the process, clinical pharmacologists have always played a central role, for their specialty focus on medicines, and their understanding of the drug development and medicines licensing process, clinical trials of efficacy, clinical-effectiveness, use of real world data, and, increasingly, making effective use of health economic data. As clinicians, clinical pharmacologist are relatively comfortable with making judgements in situations of incomplete information, and can act independent of field specialists in recognising when a new medicines produces an incremental benefit or is likely to be a 'breakthrough' product. Challenges to the system have been created by expensive drugs, often for cancer or orphan conditions, but the robust process at SMC allows for discussions on discounting in one form or another if a drug does not provide value for money. SMC is a cost-effective organisation, making medicines cost-effective in Scotland.

Wales is part of the UK; it has a devolved National Health Service serving a population of just over 3 million. Our overriding aim is to provide equity of access for patients to clinically and cost effective medicines in a timely fashion working in partnership with patients, clinicians and pharmaceutical industry, and informed by clinical need. Achieving this has involved embracing an evolutionary approach to the All Wales Medicines Strategy HTA process, conducting business in an open and transparent manner, and working with key stakeholders in the service.

Pharmacists are well placed with their clinical, business and managerial skills to play a pivotal role in HTA. From horizon scanning, linking with patient groups and clinician networks, critiquing the assessment through to monitoring and reporting on service uptake; the pharmacist working in a multidisciplinary team is a key stakeholder in improving patient access to positively appraised medicines.

Since establishment in 2002 developments include the introduction of processes to specifically consider:- Patient Access Schemes which have the scope to introduce medicines that would otherwise not be to be deemed cost-effective, processes to appraise orphan and ultra orphan and medicines, and monitoring of the implementation of mandatory advice on medicines availability. Information technology has been introduced to maximize and streamline data collection, delivery, use and analysis in a variety of key areas such as financial forecasting and uptake.

We recognize that HTA is not always appropriate, alternative routes for patient access to medicines which we have a central role in include a national interim commissioning process, Individual Patient Funding Requests (IPFRs), and Free of Charge supplies. Collectively these processes provide a potential route of timely access for patients. Pharmacists thus work closely with patients and carers, patient interest groups, clinicians and the pharmaceutical industry to facilitate medicines access according to the principles of prudent healthcare which underpin the activities of NHS Wales.

The evaluation of new medicines for their comparative clinical- and cost-effectiveness encompasses the processes of health technology assessment (HTA) and appraisal. HTA is the scientific process concerned with the generation, synthesis and critique of evidence; whereas appraisal is the function of policymakers in arriving at a decision to inform payers and providers of healthcare. Evidence generation and synthesis is normally performed by the marketing authorisation holder (MAH). In Wales, a country of 3.1m population with a public healthcare provider (the National Health Service), the assessment of evidence submitted by MAHs is conducted by the All Wales Therapeutics and Toxicology Centre, and appraised by the New Medicines Group (NMG) and the All Wales Medicines Strategy Group (AWMSG). Health economists contribute extensively to both processes. Their role in assessing submitted (and other relevant) evidence includes scrutinising the MAH submission for accuracy, assumptions in the economic modelling, plausible parameter estimates and clinical representativeness. Submitted models (usually developed in Excel) are tested to assess the relation between the reported incremental cost-effectiveness ratio (ICER), and changes in model inputs. The plausibility of resource use estimates, especially if based on expert opinion, and unit costs are considered in the context of the decision problem, the pathway of care, and expected patient contact with the health service. Utility values are compared with those of age-matched general public. Unusually high values for a severe disease might signal that the ICER is unreliable. Trial-based and extrapolated estimates of treatment effectiveness are assessed in view of the available data, the use of indirect treatment comparisons and correct application of parametric models. Health economist members of the NMG and AWMSG judge whether new medicines are cost-effective by comparing the most plausible ICER with the threshold range of £20,000 to £30,000 per quality-adjusted life-year (QALY). There is a degree of flexibility around the threshold for certain treatments (for rare diseases and those which extend life at the end of life). Judgements are made of the budget impact, the greater the impact, the more certainty is required in the ICER estimate. Deliberations by all members lead to a vote for final recommendation.

Abstract not yet available.

The clinical outcome of preterm and term neonates can be significantly improved with the use of safe and effective medicines appropriately investigated in this patient population. Neonates are not just little infants or children. They need a much more detailed approach in decisions about when to treat a disease or condition, with which medicine and most importantly with what kind of dosing regimen for that particular medicine. However, even in 2018, health care professionals involved in neonatal care are routinely prescribing drug formulations, and applying dosing regimens, that initially have been developed for use in adults. Furthermore, the medicines these professionals are using were developed with adult pathophysiology in mind, and are based on adult indications. The overall aim of administering a specific drug to a patient is to reach effective treatment for a given disease while avoiding disproportional side-effects. Neonatal clinical pharmacology aims to predict drug-specific (side)-effects based on its pharmacokinetics and pharmacodynamics. Pharmacokinetics (PK, absorption, distribution and elimination, through either metabolism or primary renal elimination, ADME) hereby estimates the relationship between a drug concentration at a specific site (e.g. plasma, cerebrospinal fluid) and time after its administration (what the body does to the drug). Pharmacodynamics (PD) aims at both the effects and side-effects of a given drug (what the drug does to the body). PK and PD display extensive variability with population specific characteristics because of the fast maturational changes in the neonatal period and early infancy, while side effects may be more difficult to detect, both in the short-term but especially in the long-term. This presentation will give practical examples of the most recent developments in the area of neonatal clinical pharmacology.

The general pharmacokinetic principles of disposition and elimination of exogenous compounds apply, irrespective of population specific characteristics. However, pregnancy and delivery warrant a focused approach because important alterations in physiology (e.g. renal, hepatic, metabolism, body composition) affect drug disposition up to the level of clinical relevance.

During pregnancy, there are changes in distribution volume due to changes in body composition, in metabolic activity affecting drug metabolism and in renal elimination (GFR, tubular) capacity. The link between pregnancy related changes in medical physiology and changes in drug disposition will be illustrated based on aspects of cefazolin, ketorolac and paracetamol dispositions during pregnancy and after delivery. Beyond these anecdotal observations, patterns related to medical physiology are unveiled. Moreover, pregnancy is not a dichotomous variable.

Pregnancy and postpartum can be considered as another special population, but physiology-based pharmacokinetic model development, the development of large and high quality epidemiological datasets are key issues. Finally, and similar to neonates or infants, drug development plans should also focus on specific pregnancy related diseases (pre-eclampsia, hyperemesis, preterm labor, fetal diseases) beyond generating information on already available drugs. Repurposing like for sildenafil to treat growth restriction or other fetal diseases is a nice illustration of a 'go' between approaches, redeveloping an already existing drug for another pregnancy related disease.

Perinatal period represents a continuous and dynamically changing state of growth and development. Marked differences in the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of many drugs are reported between newborns and adults due to the developmental changes in physiological parameters during perinatal period. The lack of clinical trial data directly results in the variation and uncertainty of drug therapy in clinical practice. There has been a growing interest in exploring innovative methodology to optimize drug therapy in this vulnerable population. In this context, PK-PD modeling presents a promising and valuable approach. PK-PD modeling is the science of quantitative pharmacology. In application to pediatrics, it involves primarily developmental PK and PD modeling and simulation, which can combine information from many diverse sources as drug characteristics, developmental clinical pharmacology, physiological changes during childhood, pediatric disease and statistics. This presentation will use cases studies to demonstrate how to apply PK-PD modeling in optimization of clinical trial design and personalized drug therapy in perinatal period.

The development of antiretroviral therapy formed the roadmap for the universal control and prevention of existing and new human immune deficiency virus (HIV) infections, respectively. Since the early 1990s administration of prophylactic antiretroviral therapy to pregnant women to assure prevention of the mother-to-child transmission has proven the most efficient and cost-effective way to achieve control of pediatric HIV infection. In the countries with consistent access to antiretroviral therapy and universal prevention of mother-to-child transmission the number of pediatric HIV infections has decreased to lees than 2%. In the last decade, specifically, much progress has been made in the universal antiretroviral treatment coverage of women during pregnancy and labor in resource-limited settings. Despite this progress, the rates of HIV infection among adolescent girls and young women in the areas most affected by HIV epidemic remain high, reflecting the continued mother-to-child transmission. With an estimated more than 2 million of children living with HIV infection, the delivery of effective well tolerated antiretroviral therapy to the world's pediatric population is of crucial importance. As with any other innovative therapeutic modality, however, the data guiding the dosing, efficacy and safety of antiretroviral drugs for pregnant and lactating women and children have lagged substantially behind as compared to the information available for adults. Given the high numbers of HIV-infected pregnant and lactating women and children with access to antiretroviral therapy globally, a better understanding of the therapeutic targets of antiretroviral drugs during pregnancy, lactation and for neonatal and pediatric HIV infection is needed. This lecture will provide an overview of the most recent approaches to using antiretroviral drugs to prevent mother-to-child transmission of HIV infection during pregnancy, delivery and throughout breastfeeding. The lecture will provide an update on the therapeutic management of HIV in newborns, infants, children and adolescents living with HIV. Special attention will be placed on the pharmacokinetics and pharmacodynamics of the antiretroviral drugs in pediatric populations with the focus on the role of therapeutic targets and therapeutic drug monitoring in improving the outcome of antiretroviral treatment in these vulnerable populations.

The process of drug development covers a wide range of activities from target identifications of drug discovery to clinical trials. The process requires specialized knowledge and highly developed skills. For many complex diseases the molecular mechanisms behind the disease are not well understood. In this environment the need for partnering of pharmaceutical companies with all other relevant stakeholders is getting more important. Pharmaceutical companies have developed a variety of partnering models. In this session, specifically focusing on the drug discovery, the various partnering models used by Bayer are to be discussed.

The business model of pharmaceutical industry is changing in response to the environmental changes around pharmaceutical industry. In the past, pharmaceutical companies largely relied on in-house research. However, they are now actively looking for outside collaborators and use of open innovation has become a critical success factor in drug discovery. The objective of this session is to look into the current trend and discuss how to realize productive open innovation now and in the future.

In the session, we will first looks at some factors that have made the pharmaceutical industry turn their focus from internal to external. One important factor is low success rate particularly in phase II trials testing concepts of drug candidates in humans. To address this challenge, pharmaceutical companies have tries to better understand disease mechanisms in collaboration with academic researchers.

Finding external partners is the first, but the most important step in open innovation. Some domestic pharmaceutical companies have launched initiatives to locate potential collaborators using their company websites. In parallel to this kind of effort, pharmaceutical companies need to think about how to design an environment from which innovative ideas and breakthroughs would come up. In this session, some collaboration such as Takeda's T-CiRA will be presented as a new style of collaboration with academia.

Drug discovery consists of many processes and research stages, suggesting that a successful drug discovery using open innovation require effective collaboration among multiple players such as academia, bioventure and pharmaceutical company, etc. As a foundation of successful open innovation, we need to create &quot;drug discovery ecosystem&quot; where those players could collaborate in a synergistic way with each other. In this session, we will focus on the domestic situation and discuss how to build &quot;drug discovery ecosystem&quot; in Japan.

While science and technology are now more innovative and successful than ever, their translation into novel treatments and therapeutics to address key health problems remains a challenge. Recognizing that to close the industry/academia divide, we created the SPARK AT Stanford program in which scientists from both sides work more closely together. SPARK, created twelve years ago, is a partnership between Stanford University and volunteers from the local biotechnology, pharmaceutical, and healthcare investment industries. SPARK's mission is three-fold: first, to help academic investigators overcome the obstacles intrinsic to moving research discoveries from bend to bedside; second, to educate faculty and trainees about the translational research process so that development of promising new discoveries becomes second nature, and so that trainees are better prepared for potential industry careers; and third, to promote efficient, cost-effective, and innovative approaches to discovery and development. So far, 60% of the ～100 projects have been licensed to companies and/or entered clinical trials. Through weekly meetings, SPARK's activities conducted on campus, provide a rich learning experience that is open to faculty, staff, students, and postdoctoral fellows; this ensures that the know-how remains here and that the out-of -the-box and risk-taking attitude of academia is maintained, while industry's real-life experience is implemented. We are 'exporting' SPARK to other academic institutions and formed a Global SPARK community to promote translational research in over three dozen academic institutions on five continents.

I will discuss how SPARK works with the barriers to translating our academic discoveries, what academia can do about them, and how my own experience in moving findings from my academic basic research lab to a startup and approved drug, has changed what I currently do.

P2X receptors are ligand-gated ion channels activated by extracellular ATP. There are seven P2X receptor subtypes in mammals (P2X1 to P2X7) that assemble to form functional homo or hetero trimeric cation-selective channels. P2X receptors contribute to many important physiological processes, including the modulation of neurotransmitter release, hearing protection, male fertility, the response to inflammation and pain sensation. They are also involved in severe disorders, such as neuropathic pain and are thus recognized as important therapeutic targets. Recent X-ray structures of P2X receptors solved in resting, open-channel, and desensitized states have greatly advanced our understanding of agonist binding and channel gating. However, despite these significant biophysical advances, there is still a lack of specific pharmacological tools targeting P2X receptors. Recent developments of optogenetics offer great opportunities for the optical control of channel activation, with exquisite temporal and spatial resolution. Inspired by these achievements, we have developed new and versatile approaches, called optogating and opto-tweezers, in which the gating machinery of the P2X2 receptor was reprogrammed to respond to light. We demonstrated photocontrol of neuronal activity by a light-gated P2X receptor, in which the natural sensitivity to ATP was genetically removed. We also uncovered part of the gating mechanism and ion permeation of P2X receptors using these optical actuators. Engineered light-gated purinergic receptors represent valuable tools for investigating P2X signaling in native tissues.

Photopharmacology (also known as optopharmacology) is a novel technique allowing manipulation of the biological activity of endogenous targets with accurate spatial and temporal resolution via the use of light and small, diffusible, drug-like, photo-regulated ligands as external triggers for receptor activation or inactivation. Herein, we used photopharmacology to study regulatory mechanisms involved in persistent and chronic pain. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors responsible of the neuromodulatory effect of glutamate, the major neurotransmitter involved in the transmission of pain throughout the central nervous system. Taking advantage of novel selective photoswitchable allosteric modulators that we recently developed, we took control of mGluRs by light in the brain of freely moving animals and studied the role of these receptors in chronic pain. We demonstrated that mGluRs expressed in the amygdala, a key brain region linking pain sensation with negative emotions, can rapidly and reversibly inhibit behavioral symptoms associated to chronic pain. These findings could help to define novel and more precise therapeutic interventions for chronic pain, and exemplify the potential of in vivo photopharmacology.

During brain development, neural stem cells change their competency, producing neurons first and glial cells later. It is therefore very important to maintain neural stem cells until the final stage of development to generate a full diversity of cell types. We previously found that fate determination factors such as Hes1 and Ascl1/Mash1 are expressed in an oscillatory manner in neural stem cells but exhibit sustained expression during cell differentiation. We also showed by optogenetic approach that sustained expression of Ascl1/Mash1 promotes neuronal differentiation, whereas oscillatory expression of Ascl1/Mash1 activates proliferation of neural stem cells. Furthermore, inactivation of Ascl1/Mash1 inhibits proliferation of neural stem cells, suggesting that Ascl1/Mash1 oscillations are important for proliferation of neural stem cells. In the adult brain, neural stem cells are mostly quiescent, and we found that Hes1 expression is sustained, while Ascl1/Mash1 expression is repressed in those cells. Furthermore, optogenetic induction of Ascl1/Mash1 oscillations activated quiescent neural stem cells to enter cell cycle. These results suggest that the oscillatory control of Ascl1/Mash1 may be important for the active state of neural stem cells.

We have developed &quot;synaptic optogenetic probes,&quot; such as AS-probes (Hayashi-Takagi et al., Nature 525, 2015), with which we can label enlarged spines after a learning task, and induce shrinkage of these spines to test their role in the learning. We think the probe labels enlarged spines in the following mechanisms. 1) Neuronal activity facilitates transcription of the probe DNA. 2) 3'UTR of the probe promotes transport of mRNA to the dendrite leaving little mRNA in the soma to suppress somatic translation of the probe. 3) Synaptic activity induces efficient translation of the probe around the activated and tagged synapses in dendrites. 4) Enlargement of spines efficiently captures newly synthesized probes. 5) Due to the PEST sequence of the probe, ubiquitin proteasomes degradate excess proteins to prevent labeling of non-stimulated spines. 6) Repetitive and selective activation of the synapses maintains the labeling over one day, suggesting the presence of a discrete learning circuit for each task. We are now improving the promoter, 3'UTR, photoactive peptide, and spine targeting signal to allow visualization of the learning circuits over various brain areas, including the nucleus accumbens, medial prefrontal, and posterior parietal cortices. During improvement of our probes, we found that axonal boutons opposing to the enlarged spines tended to display similar discrete labeling patterns when we chose proper targeting signal and 3'UTR for axonal boutons. We are now confirming the properties of these spine and axonal probes which help us to identify learning circuits at both regional and synaptic levels.