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Background: Digitally accessible prescription claims have potential utility in timely identification and active follow up interventions for unsupervised medication discontinuation in consumers with schizophrenia and bipolar disorder, that may prevent relapse and other adverse outcomes. We conducted a systematic review in order to identify and understand definitions of non-adherence from prescription claims records to serve as decision points for interventions. Methods: Electronic searches were conducted using Ovid MEDLINE, PubMed, the Cochrane Central Register of Controlled Trials and PsycINFO on 12 January 2020 to identify studies published in English. Data extraction was done by two reviewers independently. A narrative synthesis and tabulation of outcomes was performed. PROSPERO (CRD42020201708). Results: Thirty-one studies were eligible for analysis. Three common computing parameters were used to calculate non-adherence over 12 months, the Medication Possession Ratio (MPR) was used most frequently (21 studies - 68%) with a non-adherence threshold Discussion: Computing non-adherence from prescription claim records is a potential decision point for interventions. Better utilisation of this widely available data should be used to improve clinical practice and ensure targeted access to services. Conclusion: While there was variation in methods used to compute non-adherence parameters from prescription claims records, all approaches demonstrated that non-adherence was associated with adverse outcomes, the foremost of which was rehospitalisation and increased costs of care. Prospero Registration: PROSPERO CRD42020201708

Metabolic and ionic changes during ischaemia predispose the heart to the damaging effects of reperfusion. Such changes and the resulting injury differ between immature and adult hearts. Therefore, cardioprotective strategies for adults must be tested in immature hearts. We have recently shown that the simultaneous activation of protein kinase A (PKA) and exchange protein activated by cAMP (Epac) confers marked cardioprotection in adult hearts. The aim of this study is to investigate the efficacy of this intervention in immature hearts and determine whether the mitochondrial permeability transition pore (MPTP) is involved. Isolated perfused Langendorff hearts from both adult and immature rats were exposed to global ischaemia and reperfusion injury (I/R) following control perfusion or perfusion after an equilibration period with activators of PKA and/or Epac. Functional outcome and reperfusion injury were measured and in parallel, mitochondria were isolated following 5 min of reperfusion to determine whether cardioprotective interventions involved changes in MPTP opening behaviour. Perfusion for 5 min preceding ischaemia of injury-matched adult and immature hearts with 5 µM 8-Br (8-Br-cAMP-AM), an activator of both PKA and Epac, led to significant reduction in post-reperfusion CK release and infarct size. Perfusion with this agent also led to a reduction in MPTP opening propensity in both adult and immature hearts. These data show that immature hearts are innately more resistant to I/R injury than adults, and that this is due to a reduced tendency of MPTP opening following reperfusion. Furthermore, simultaneous stimulation of PKA and Epac causes cardioprotection, which is additive to the innate resistance.

Primary central nervous system lymphoma (PCNSL) has variable imaging appearances, which overlap with those of glioblastoma (GBM), thereby necessitating invasive tissue diagnosis. We aimed to investigate whether a rapid filtration histogram analysis of clinical MRI data supports the distinction of PCNSL from GBM. Ninety tumours (PCNSL n = 48, GBM n = 42) were analysed using pre-treatment MRI sequences (T1-weighted contrast-enhanced (T1CE), T2-weighted (T2), and apparent diffusion coefficient maps (ADC)). The segmentations were completed with proprietary texture analysis software (TexRAD version 3.3). Filtered (five filter sizes SSF = 2–6 mm) and unfiltered (SSF = 0) histogram parameters were compared using Mann-Whitney U non-parametric testing, with receiver operating characteristic (ROC) derived area under the curve (AUC) analysis for significant results. Across all (n = 90) tumours, the optimal algorithm performance was achieved using an unfiltered ADC mean and the mean of positive pixels (MPP), with a sensitivity of 83.8%, specificity of 8.9%, and AUC of 0.88. For subgroup analysis with &gt, 1/3 necrosis masses, ADC permitted the identification of PCNSL with a sensitivity of 96.9% and specificity of 100%. For T1CE-derived regions, the distinction was less accurate, with a sensitivity of 71.4%, specificity of 77.1%, and AUC of 0.779. A role may exist for cross-sectional texture analysis without complex machine learning models to differentiate PCNSL from GBM. ADC appears the most suitable sequence, especially for necrotic lesion distinction.

Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure-activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of 59, a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound 59 was evaluated in mice for the inhibition of μ2 phosphorylation. Studies conducted with 59 in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain.

Daniel F. Doeppers. Madison, WI: University of Wisconsin Press, 2016. xvii and 443 pp., maps, photos, diagrams, illustrations, notes, glossary, index. $79.95 cloth (ISBN 978-0-299-30510-9).Feeding ...

Cartographic Humanism is an ambitious work, seeking to elucidate nothing less than the Making of Early Modern Europe. The transformation of Europe ‘from a derivative of Asia to the sovereign of the...

Receptor-interacting protein kinase 3 (RIP3) is a convergence point of multiple signalling pathways, including necroptosis, inflammation and oxidative stress, however, it is completely unknown whether it underlies acute myocardial ischemia/reperfusion (I/R) injury. Langendorff-perfused rat hearts subjected to 30 min ischemia followed by 10 min reperfusion exhibited compromised cardiac function which was not abrogated by pharmacological intervention of RIP3 inhibition. An immunoblotting analysis revealed that the detrimental effects of I/R were unlikely mediated by necroptotic cell death, since neither the canonical RIP3–MLKL pathway (mixed lineage kinase-like pseudokinase) nor the proposed non-canonical molecular axes involving CaMKIIδ–mPTP (calcium/calmodulin-dependent protein kinase IIδ–mitochondrial permeability transition pore), PGAM5–Drp1 (phosphoglycerate mutase 5–dynamin-related protein 1) and JNK–BNIP3 (c-Jun N-terminal kinase–BCL2-interacting protein 3) were activated. Similarly, we found no evidence of the involvement of NLRP3 inflammasome signalling (NOD-, LRR- and pyrin domain-containing protein 3) in such injury. RIP3 inhibition prevented the plasma membrane rupture and delayed mPTP opening which was associated with the modulation of xanthin oxidase (XO) and manganese superoxide dismutase (MnSOD). Taken together, this is the first study indicating that RIP3 regulates early reperfusion injury via oxidative stress- and mitochondrial activity-related effects, rather than cell loss due to necroptosis.

To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor-induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.

There is significant scientific interest in the potential of liposomes to provide targeted delivery of drugs to damaged areas of the myocardium after myocardial infarction. This interest stems from the substantial contribution of cardiovascular diseases (CVD) to morbidity and mortality and the consequent need to derive novel treatment strategies.1 Contemporaneously, there has been remarkable success in the development of targeted drug delivery using liposomes for the treatment of oncologic pathology.2 Accumulated information and technological advances in the development of different types of liposomes, the possibility of incorporation of different biologically active compounds in these particles, and their high transport ability opens new horizons in the creation of novel highly effective pharmacological interventions for the treatment of CVD. A wide variety of biologically active compounds, such as cytokine inhibitors, hormones, enzymes, signaling molecules, and antioxidants among others, have been found to have potential therapeutic value in the management of CVD. However, new pharmacokinetic approaches are necessary for these compounds to produce a beneficial effect. This may include ensuring drug delivery to a therapeutic target, protection of these medicines against biodegradation, and prolonged retention in the circulation.3–5 Various nanoparticles are being investigated in the search for a means of targeted drug delivery. Liposomes are probably one of the most promising particles in this respect. Once incorporated in liposomes, drugs can easily penetrate cellular membranes and enter the target cells.6 However, the transport capability of liposomes depends on their characteristics, such as the lipid composition of the liposomal membranes, their size, charge, various modifications of the liposomal surface, and inclusion of target molecules. Any modification of the liposomes modulates their properties, their interaction with cells, and efficacy of drug delivery.7,8 Importantly, pores can be formed in the capillaries located in the area of inflammation that can be caused by different pathological processes, including myocardial ischemia. These pores may become large enough allowing nanoparticles to penetrate the vascular barrier and accumulate in the affected area. This phenomenon is called the passive targeting of nanoparticles.9 The liposomes should be small enough to be able to implement this effect in the area of inflammation. It has been found that, to accumulate in the ischemic area, the nanoparticles should not exceed 200 nm.8,10 However, reducing the size of the liposomes may impair their ability to accommodate drugs that need to be delivered to the affected area. Consequently, the choice of the size of nanoparticles as a means of transport is of critical importance. Therefore, in this work, we studied the ability of liposomes of different sizes to accumulate in the myocardium during ischemia to identify the optimal size of these particles for targeting the damaged area of the heart. A number of agents have been found to be cardioprotective when applied before ischemia. However, it is worth mentioning that the clinical relevance of this kind of intervention is currently restricted to cardiac surgery with cardio-pulmonary bypass as the onset of ischemia is predictable in advance. Clearly, salvation of the myocardium during perfusion in patients in whom acute myocardial ischemia has already taken place has a broader clinical relevance.11 Furthermore, the passive targeting may contribute to a greater efficiency of liposome-assisted drug delivery before reperfusion rather than before ischemia. Consequently, in the present work, we assessed the accumulation of liposomes of different sizes in the myocardium and evaluated their effect on ischemia/reperfusion (I/R) injury.

Small molecule modulators of GPR88 activity (agonists, antagonists, or modulators) are of interest as potential agents for the treatment of a variety of psychiatric disorders including schizophrenia. A series of phenylglycinol and phenylamine analogs have been prepared and evaluated for their GPR88 agonist activity and pharmacokinetic (PK) properties.

A 30-year-old man with clinical and laboratory features of thrombotic thrombocytopenic purpura (ITP) underwent exchange transfusion with 9 units of whole blood over a 24-h period. Then, the neurological, renal, and haematological manifestations resolved and the patient recovered completely. Serial plasma samples were obtained before and at 8 h intervals during the exchange transfusion. A convalescent plasma sample was obtained 14 and 80 d later. Immune complexes were demonstrated in the pre-exchange transfusion plasma, by polyethylene glycol (PEG) gradient sedimentation, separated by electrophoresis and analysed immunochemically. There were shown to be light, medium and high molecular weight sedimentation zones in the PEG gradients. The medium zone consisted of immune complexes containing platelet membrane asrociated antigens and IgG antibody; the heavy and light zones only showed the presence of IgG. There was progressive clearance of these zones by the exchange transfusion with the convalescent specimens showing a marked decrease in all zones, especially those of the middle molecular weight (which on analysis represent true immune complexes). The clearance of these immune complexes from the circulation by exchange transfusion could explain the clinical response seen in the patient.

N-Benzylic-substituted glycine sulfonamides that reversibly inhibit diacylglycerol (DAG) lipases are reported. Detailed herein are the structure activity relationships, profiling characteristics and physico-chemical properties for the first reported series of DAG lipase (DAGL) inhibitors that function without covalent attachment to the enzyme. Highly potent examples are presented that represent valuable tool compounds for studying DAGL inhibition and constitute important leads for future medicinal chemistry efforts.

Over the past decade, a group of prolific and innovative evolutionary biologists has sought to reinvent historical linguistics through the use of phylogenetic and phylogeographical analysis, treating cognates like genes and conceptualizing the spread of languages in terms of the diffusion of viruses. Using these techniques, researchers claim to have located the origin of the Indo-European language family in Neolithic Anatolia, challenging the near-consensus view that it emerged in the grasslands north of the Black Sea thousands of years later. But despite its widespread celebration in the global media, this new approach fails to withstand scrutiny. As languages do not evolve like biological species and do not spread like viruses, the model produces incoherent results, contradicted by the empirical record at every turn. This book asserts that the origin and spread of languages must be examined primarily through the time-tested techniques of linguistic analysis, rather than those of evolutionary biology.