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Pei-Pei Huang,1,&ast; Samantha Yun-Kai Poon,2,&ast; Shao-Hsuan Chang,3 Chien-Wen Kuo,4 Ming-Wen Chien,1 Chien-Chih Chen,5 Shao-Chin Chiang2,6 1Division of Outpatient Pharmacy, Department of Pharmacy, Cheng Hsin General Hospital, Taipei, Taiwan; 2Department of Pharmacy, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University (Yang Ming Campus), Taipei, Taiwan; 3Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL, USA; 4Department of Pharmacy, Cheng Hsin General Hospital, Taipei, Taiwan; 5Division of Colorectal Surgery, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan; 6Department of Pharmacy, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan&ast;These authors contributed equally to this workCorrespondence: Shao-Chin Chiang, Department of Pharmacy, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University (Yang Ming Campus), Taipei, Taiwan, Tel +886-983641216, Email scchiang316@nycu.edu.tw; scchiang@kfsyscc.orgPurpose: Medication reconciliation (MedRec) is a process to ensure complete and accurate communication of patient medication information throughout care transitions to prevent medication errors. Hospitals in Taiwan have stride to implement a universal protocol for MedRec. To establish a feasible protocol indigenously, the World Health Organization (WHO) protocol was incorporated with the Taiwan National Health Insurance (NHI) PharmaCloud patient medication profile. The efficiency and error detection capability of this modified protocol was evaluated in two hospitals.Methods: A prospective, non-randomized, unblinded, multicenter cohort study was conducted. Subjects were recruited among patients admitted for colorectal or orthopedic surgery with at least 4 or more chronic drugs. To obtain the best possible medication history (BPMH), the control group was conducted according to the WHO protocol, and the experimental group used the modified WHO protocol with the medication data from the PharmaCloud system. The time spent on the two protocols was recorded. Admission and discharge orders were reconciled against the BPMH to identify any discrepancies. Discrepancies were evaluated by appropriateness, prescribing intentions, and types of inappropriateness. The levels of potential harm were classified for inappropriate discrepancies.Results: The mean time to obtain BPMH in the control group was 34.3± 10.8 minutes and in the experimental group 27.5± 11.5 minutes (P = 0.01). The experimental group had more subjects with discrepancies (87.9%) than the control (58.3%) (p < 0.001). The discrepancies in both admission and discharge orders for the experimental group (84.5 and 67.2%) were higher than those of the control (47.9 and 37.5%). Many inappropriate discrepancies were classified as the potential harm of level 2 (77.8%).Conclusion: Through the establishment of BPMH with the medication data from the Taiwan NHI PharmaCloud, MedRec could be achieved with greater efficiency and error detection capability in both the admission and discharge order validation processes.Keywords: medication reconciliation, prescription discrepancy, PharmaCloud, best possible medication history, BPMH

S-palmitoylation is an essential lipid modification catalysed by zDHHC-palmitoyl acyltransferases that regulates the localisation and activity of substrates in every class of protein and tissue investigated to date. In the heart, S-palmitoylation regulates sodiumcalcium exchanger (NCX1) inactivation, phospholemman (PLM) inhibition of the Na+/K+ ATPase, Nav1.5 influence on membrane excitability and membrane localisation of heterotrimeric G-proteins. The cell surface localised enzyme zDHHC5 palmitoylates NCX1 and PLM and is implicated in injury during anoxia/reperfusion. Information is lacking about how palmitoylation remodels in cardiac diseases. We investigated expression of zDHHC5 in animal models of left ventricular hypertrophy (LVH) and heart failure (HF), along with HF tissue from humans. zDHHC5 expression was rapidly elevated during onset of LVH, whilst HF was associated with decreased zDHHC5 expression. Paradoxically, palmitoylation of the zDHHC5 substrate NCX1 was significantly reduced in LVH but increased in human HF. Overexpression of zDHHC5 in rabbit ventricular cardiomyocytes was not sufficient to drive changes in palmitoylation of zDHHC5 substrates or overall cardiomyocyte contractility, suggesting changes in zDHHC5 expression in disease may not be a primary driver of pathology. zDHHC5 itself is regulated by post-translational modifications, including palmitoylation in its Cterminal tail, and we found the palmitoylation of zDHHC5 may be increased in heart failure in the same manner as NCX1, suggesting additional regulatory mechanisms such as acyl-CoA availability may be involved. Importantly, this study provides the first evidence that palmitoylation of cardiac substrates is altered in the setting of HF, and that expression of zDHHC5 is dysregulated in both hypertrophy and HF.

The bifunctional cation channel/kinase TrpM7 is ubiquitously expressed and regulates embryonic development and pathogenesis of several common diseases. The TrpM7 integral membrane ion channel domain regulates transmembrane movement of divalent cations, and its kinase domain controls gene expression via histone phosphorylation. Mechanisms regulating TrpM7 are elusive. It exists in two populations in the cell: at the cell surface where it controls divalent cation fluxes, and in intracellular vesicles where it controls zinc uptake and release. Here we report that TrpM7 is palmitoylated at a cluster of cysteines at the C terminal end of its Trp domain. Palmitoylation controls the exit of TrpM7 from the endoplasmic reticulum and the distribution of TrpM7 between cell surface and intracellular pools. Using the Retention Using Selective Hooks (RUSH) system, we demonstrate that palmitoylated TrpM7 traffics from the Golgi to the surface membrane whereas non-palmitoylated TrpM7 is sequestered in intracellular vesicles. We identify the Golgi-resident enzyme zDHHC17 and surface membrane-resident enzyme zDHHC5 as responsible for palmitoylating TrpM7 and find that TrpM7-mediated transmembrane calcium uptake is significantly reduced when TrpM7 is not palmitoylated. The closely related channel/kinase TrpM6 is also palmitoylated on the C terminal side of its Trp domain. Our findings demonstrate that palmitoylation controls ion channel activity of TrpM7 and that TrpM7 trafficking is dependent on its palmitoylation. We define a new mechanism for post translational modification and regulation of TrpM7 and other Trps.

Graphical abstract, Highlights • The structural element that directs NCX1 palmitoylation interacts with zDHHC-PATs. • NCX2 and NCX3 are dually palmitoylated. • Arresting NCX1 within the Golgi or ER does not change its palmitoylation status. • APT1 but not APT2 governs the subcellular organization of NCX1. • APT1 catalyzes NCX1 depalmitoylation in the Golgi but not in the ER., Catalyzed by zDHHC-PAT enzymes and reversed by thioesterases, protein palmitoylation is the only post-translational modification recognized to regulate the sodium/calcium exchanger NCX1. NCX1 palmitoylation occurs at a single site at position 739 in its large regulatory intracellular loop. An amphipathic ɑ-helix between residues 740–756 is a critical for NCX1 palmitoylation. Given the rich background of the structural elements involving in NCX1 palmitoylation, the molecular basis of NCX1 palmitoylation is still relatively poorly understood. Here we found that (1) the identity of palmitoylation machinery of NCX1 controls its spatial organization within the cell, (2) the NCX1 amphipathic ɑ-helix directly interacts with zDHHC-PATs, (3) NCX1 is still palmitoylated when it is arrested in either Golgi or ER, indicating that NCX1 is a substrate for multiple zDHHC-PATs, (4) the thioesterase APT1 but not APT2 as a part of NCX1-depalmitoylation machinery governs subcellular organization of NCX1, (5) APT1 catalyzes NCX1 depalmitoylation in the Golgi but not in the ER. We also report that NCX2 and NCX3 are dually palmitoylated, with important implications for substrate recognition and enzyme catalysis by zDHHC-PATs. Our results could support new molecular or pharmacological strategies targeting the NCX1 palmitoylation and depalmitoylation machinery.

The electrogenic sodium/calcium exchanger (NCX) mediates bidirectional calcium transport controlled by the transmembrane sodium gradient. NCX inactivation occurs in the absence of phosphatidylinositol 4,5-bisphosphate and is facilitated by palmitoylation of a single cysteine at position 739 within the large intracellular loop of NCX. The aim of this investigation was to identify the structural determinants of NCX1 palmitoylation. Full-length NCX1 (FL-NCX1) and a YFP fusion protein of the NCX1 large intracellular loop (YFP-NCX1) were expressed in HEK cells. Single amino acid changes around Cys-739 in FL-NCX1 and deletions on the N-terminal side of Cys-739 in YFP-NCX1 did not affect NCX1 palmitoylation, with the exception of the rare human polymorphism S738F, which enhanced FL-NCX1 palmitoylation, and D741A, which modestly reduced it. In contrast, deletion of a 21-amino acid segment enriched in aromatic amino acids on the C-terminal side of Cys-739 abolished YFP-NCX1 palmitoylation. We hypothesized that this segment forms an amphipathic α-helix whose properties facilitate Cys-739 palmitoylation. Introduction of negatively charged amino acids to the hydrophobic face or of helix-breaking prolines impaired palmitoylation of both YFP-NCX1 and FL-NCX1. Alanine mutations on the hydrophilic face of the helix significantly reduced FL-NCX1 palmitoylation. Of note, when the helix-containing segment was introduced adjacent to cysteines that are not normally palmitoylated, they became palmitoylation sites. In conclusion, we have identified an amphipathic α-helix in the NCX1 large intracellular loop that controls NCX1 palmitoylation. NCX1 palmitoylation is governed by a distal secondary structure element rather than by local primary sequence.

Myocardial injury after aneurysmal subarachnoid hemorrhage (aSAH) is associated with poor outcomes. Delayed cerebral ischemia (DCI) is also a complication of aSAH. We sought to determine whether (1) DCI could be predicted by demographics, aSAH severity/aneurysm location, or aSAH-associated myocardial injury (SAHMI), and (2) DCI is associated with increased mortality after aSAH.Prospective longitudinal study of 149 aSAH subjects with definitive DCI evaluation, age 18-75 years, Hunt and Hess (HH) ≥ 3, and/or Fisher ≥ 2, and admitted to the Neurovascular ICU. DCI was defined by the presence of neurological deterioration accompanied by evidence of abnormal cerebral blood flow.Subjects were 48% DCI(+) and 52% DCI(-). DCI(+) subjects had more severe aSAH [HH (P = 0.002), Fisher (P = 0.004), admission Glasgow Coma Scale (P = 0.018)]. More DCI(+) subjects had pulmonary congestion than DCI(-) subjects (63 vs. 39%, P = 0.003). On echocardiogram, cardiac output (CO, liters per minute [LPM]) was significantly higher in DCI(+) than in DCI(-) subjects (6 ± 2 vs. 5 ± 1 LPM; P = 0.015). Multivariate analysis identified CO and Fisher grade as independent predictors of DCI (P = 0.02, 0.019). For each 1 LPM increase in CO, the odds of DCI increased by 1.5 (95% CI: 1.1-2.1). Fisher grade 4 increased the odds of DCI by 6.5 compared to Fisher grade 2 (95% CI: 1.6-25.8). After controlling for Fisher grade, CO remained an independent predictor of DCI (P = 0.02). Three-month mortality rate was not significantly different between DCI groups, P = 0.786.Elevated CO and Fisher grade are predictors of DCI after aSAH. However, prevention of DCI may not decrease mortality.

Transshipments refer to a variety of actions that can result in the sharing of inventory among locations, possibly at different levels of the supply chain. The implementation of transshipment can minimize the cost while maintaining a certain service. It is common for a distributor to use several retailers of different locations to transship its products throughout a region. Therefore, the selection of effective transshipment rules in multi-location inventory systems is important for a successful retail sector. Our research is motivated by observations from various industries such as apparel, fashion goods, and toys, particularly by those retailers with brick and click outlets. The objective of this study is to evaluate a variety of transshipment policies via simulation. A simulation model is used to evaluate the performance of various transshipment policies in corporation with two inventory control policies. According to the numerical experiment results, some managerial implications are suggested. The main findings of this study is that using lateral transshipment in corporation with (Q,R) and (R,s,S) policies inventory policies can result in lower cost and high service level. Furthermore, the (R,s,S)policy is more effective than (Q,R) policy when transshipment policy is applied for the set of circumstances under investigation. The same methodology and modeling approach used in this study could be applied to various supply chains of products with the similar characteristics.

In this paper, we summarize our development efforts for a top-coatless 193nm immersion positive tone development (PTD) contact hole (C/H) resist with improved litho and defect performances for logic application specifically with an advance node. The ultimate performance goal was to improve the depth of focus (DoF) margin, mask error enhancement factor (MEEF), critical dimension uniformity (CDU), contact edge roughness (CER), and defect performance. Also, the through pitch CD difference was supposed to be comparable to the previous control resist. Effects of polymer and PAG properties have been evaluated for this purpose. The material properties focused in the evaluation study were polymer activation energy (Ea), polymer solubility differentiated by polymerization process types, and diffusion length (DL) and acidity (pKa) of photoacid generator (PAG). Additionally, the impact of post exposure bake (PEB) temperature was investigated for process condition optimization. As a result of this study, a new resist formulation to satisfy all litho and defect performance was developed and production yield was further improved.

The consumption of Chinese herbal medicines (CHMs) is increasing exponentially. Many patients utilize CHMs concomitantly with prescription drugs in great frequency. Herb-drug interaction has hence become an important focus of study. Transporter-mediated herb-drug interactions have the potential to seriously influence drug efficacy and toxicity. Since organic anion transporter 1 (OAT1) is crucial in renal active secretion and drug-drug interactions, the possibility of modulation of OAT1-mediated drug transport should be seriously concerned. Sixty-three clinically used CHMs were evaluated in the study. An hOAT1-overexpressing cell line was used for thein vitroCHMs screening, and the effective candidates were administered to Wistar rats to access renal hemodynamics. The regulation of OAT1 mRNA expression was also examined for further evidence of CHMs affecting OAT1-mediated transport. Among all the 63 CHMs, formulae Gui Zhi Fu Ling Wan (GZ) and Chia Wei Hsiao Yao San (CW) exhibited significant inhibitions on hOAT1-mediated [3H]-PAH uptakein vitroand PAH clearance and net secretionin vivo. Moreover, GZ showed concentration-dependent manners bothin vitroandin vivo, and the decrease of rOAT1 mRNA expression indicated that GZ not only inhibited function of OAT1 but also suppressed expression of OAT1.

The first liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of p-aminohippuric acid and inulin, both typical biomarkers of kidney function. 5-(Hydroxymethyl)furfural, generated from inulin by acid and heat preparation, was used as an inulin substitute for the quantification. Acetaminophen was used as the internal standard. Solid-phase extraction was carried out with 5% methanol as the washing solution to optimize the retention of the analytes and to avoid obstruction of the orifice plate of the mass spectrometer caused by any unreacted inulin residue remaining from the sample preparation process. Chromatography separation was performed on a Symmetry C(18) column and a mobile phase composed of 2 mM ammonium formate and 0.1% formic acid in water (solvent A) and 2 mM ammonium formate and 0.1% formic acid in acetonitrile (solvent B) (30:70, v/v). Detection was performed with a triple-quadrupole tandem mass spectrometer using positive ion mode electrospray ionization in the multiple reaction monitoring mode. The selected transitions were m/z 195.2 → 120.2, 127.1 → 109.1, and 152.1 → 110.0 for p-aminohippuric acid, inulin [measured as 5-(hydroxymethyl)furfural], and acetaminophen, respectively. The linearity ranged from 10 to 140 μg/mL and from 100 to 1,400 μg/mL for p-aminohippurric acid and inulin (r 0.99), respectively. The precisions and accuracies were all within 12 and 11% for the lower limit of quantification and quality control samples, respectively. This application was proven to be reliable and accurate and was successfully applied to a renal function study.

Infection of human cells by Human T-cell leukaemia virus (HTLV-1) is mediated by the viral envelope glycoproteins. The gp46 surface glycoprotein binds to a cell surface receptors, including heparan sulphate proteoglycans, neuropilin-1, and Glut-1, allowing the transmembrane glycoprotein to initiate fusion of the viral and cellular membranes. The envelope glycoproteins are recognised by neutralising antibodies and cytotoxic T lymphocytes following a protective immune response, and therefore represent attractive components for an HTLV-1 vaccine. Here we begin to explore the immunological properties of recombinant SU as a potential subunit vaccine candidate. We have used a soluble recombinant gp46 fused to the Fc-region of human IgG (sRgp46-Fc) as an immunogen to vaccinate mice and generate monoclonal antibodies (mAbs) targeting SU. The recombinant SU protein is highly immunogenic, inducing high titre antibody responses to the immunogen and facilitating selection of hybridomas that secrete anti-SU mAbs. Many of these mAbs recognise envelope expressed by HTLV-1 infected cells and these antibodies strongly stimulate neutrophil-mediated cytotoxic responses. Moreover, several of the mAbs directly and robustly antagonise envelope-mediated fusion and neutralize pseudovirus infectivity. While antibodies targeting either the receptor-binding domain or C-terminal domain of SU exhibit anti-viral activity, the most potently neutralizing mAbs tend to recognise epitopes that cluster in the N-terminal receptor-binding domain of SU. Thus, our data demonstrate that recombinant forms of SU possess immunological features that are of direct utility to subunit vaccine design.