Surface Engineering of the Mechanical Properties of Molecular Crystals via an Atomistic Model for Computing the Facet Stress Response of Solids.

Dynamic molecular crystals are an emerging class of crystalline materials that can respond to mechanical stress by dissipating internal strain in a number of ways. Given the serendipitous nature of the discovery of such crystals, progress in the field requires advances in computational methods for the accurate and high-throughput computation of the nanomechanical properties of crystals on specific facets which are exposed to mechanical stress. Here, we develop and apply a new atomistic model for computing the surface elastic moduli of crystals on any set of facets of interest using dispersion-corrected density functional theory (DFT-D) methods. The model was benchmarked against a total of 24 reported nanoindentation measurements from a diverse set of molecular crystals and was found to be generally reliable. Using only the experimental crystal structure of the dietary supplement, L-aspartic acid, the model was subsequently applied under blind test conditions, to correctly predict the growth morphology, facet and nanomechanical properties of L-aspartic acid to within the accuracy of the measured elastic stiffness of the crystal, 24.53±0.56 GPa. This work paves the way for the computational design and experimental realization of other functional molecular crystals with tailor-made mechanical properties.

Tracking Gut Motility in Organ and Cultures.

Gastrointestinal (GI) motility is a key component of digestive health, and it is complex, involving a multitude of cell types and mechanisms to drive both rhythmic and arrhythmic activity. Tracking GI motility in organ and tissue cultures across multiple temporal (seconds, minutes, hours, days) scales can provide valuable information regarding dysmotility and to evaluate treatment options. Here, the chapter describes a simple method to monitor GI motility in organotypic cultures, using a single video camera is placed perpendicularly to the surface of the tissue. A cross-correlational analysis is used to track the relative movements of tissues between subsequent frames and subsequent fitting procedures to fit finite element functions to the deformed tissue to calculate the strain fields. Additional motility index measures from the displacement information are used to further quantify the behaviors of the tissues that are maintained in organotypic culture over days. The protocols presented in this chapter can be adapted to study organotypic cultures from other organs.

A Systematic Review of Frailty Scores Used in Heart Failure Patients.

BACKGROUND: Frailty is a complex, multi-dimensional syndrome commonly observed in patients with heart failure (HF). The presence of frailty in patients living with HF is strongly associated with increased vulnerability to adverse events, including falls, hospitalisation, and increased mortality. Several scoring systems have been developed to assess the presence of frailty in patients with HF. These scoring systems vary in their complexity and applicability; however, they provide the physician with a more comprehensive understanding of the biological, functional, and psychosocial needs of these patients. OBJECTIVES: To assess the clinical applicability of frailty tools in HF patients and their prognostic value, specifically relating to outcomes such as mortality, readmissions, and clinical deterioration. METHODS: A literature search using six electronic databases (PubMed, Scopus, Embase, MEDLINE, Cochrane and Web of Science) was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Key search Medical Subject Headings (MeSH) terms combined "Frailty" AND "Heart failure". Studies were included if they assessed frailty using systematically defined criteria in a HF population. The PRISMA guidelines were used to include all relevant articles based on titles and abstracts. Full text articles were screened based on abstract relevance. A systematic narrative review of the literature was conducted on the final list of full text articles. RESULTS: An initial search yielded 8,066 articles. Following the removal of duplicates, title, and abstract searches, the remaining 154 articles underwent full text review, with 31 articles accepted for final qualitative synthesis. The two most utilised frailty scores were the Fried Frailty Phenotype (n=10) and the Barthel Index (n=8). The frailty scores provide prognostic data on multiple outcomes including mortality, increased hospitalisation, and functional decline. CONCLUSION: At the present time there is no universally applied frailty measure in a HF population. Choice of frailty score should be guided by physician experience and clinical setting, as well as tailored to a patient's functional, biological, and psychosocial circumstances. A push to adopt a single universal scoring system may help to ensure that frailty is assessed in all patients who live with HF.

Microplastics as vectors of radioiodine in the marine environment: A study on sorption and interaction mechanism.

Radioiodine is one of the long-lived fission products and also an important radionuclide released during nuclear accidents, which generates interest in its environmental fate. Its sorption has been studied in a wide range of materials, but no equivalent study exists for microplastics, an emerging environmental vector. Weathering and biofilm formation on microplastics can enhance radioiodine sorption. For the first time, we're reporting how radioiodine interacts with different types of polyethylene derived microplastics (pristine, irradiated, and biofilm developed microplastics). This study revealed that exposure to radiation and the marine environment significantly alters the physico-chemical properties of microplastics. In particular, in marine-exposed samples, a signature of biofilm development was detected. Speciation study indicates that iodine exists in the iodide form in the studied marine environment. The study revealed that, iodide ions attach to biofilm-developed microplastics via electrostatic, ion-dipole, pore filling, and van der Waals interactions. Pore filling, ion-dipole, and van der Waals interactions may cause iodide binding to irradiated microplastics, whereas pore-filling and van der Waals interactions cause iodide binding to pristine microplastics. The distribution coefficient (Kd) of iodine on microplastics is positively correlated with biofilm biomass, which signifies the role of biofilm in radioiodine uptake. The Kd indicates microplastics are potential iodide accumulators and could be a possible vector in the marine system.

Syringol isolated from Eleusine coracana (L.) Gaertn bran suppresses inflammatory response through the down-regulation of cPLA2, COX-2, IκBα, p38 and MPO signaling in sPLA2 induced mice paw oedema.

Eleusine coracana (L.) Gaertn (E. coracana) is one of the highest consuming food crops in Asia and Africa. E. coracana is a plant with several medicinal values including anti-ulcerative, anti-diabetic, anti-viral and anti-cancer properties. However, the anti-inflammatory property of E. coracana remains to be elucidated. Therefore, the objective of present study was to investigate the potential in isolated molecule from E. coracana via a combination of in vitro, in vivo and in silico methods. In this study, we have isolated, purified and characterized an anti-inflammatory molecule from E. coracana bran extract known as syringol. Purification of syringol was accomplished by combination of GC-MS and RP-HPLC techniques. Syringol significantly inhibited the enzymes activity of sPLA2 (IC50 = 3.00 µg) and 5-LOX (IC50 = 0.325 µg) in vitro. The inhibition is independent of substrate concentration, calcium ion concentration and was irreversible. Syringol interacts with purified sPLA2 enzymes as evidenced by fluorescence and molecular docking studies. Further, the syringol molecule dose dependently inhibited the development of sPLA2 and λ-carrageenan induced edema. Furthermore, syringol decreases the expression of cPLA2, COX-2, IκBα, p38 and MPO in edematous tissues as demonstrated by western blots. These studies revealed that syringol isolated from E. coracana bran may develop as a potent anti-inflammatory molecule.

Biorelevant dissolution testing and physiologically based absorption modeling to predict in vivo performance of supersaturating drug delivery systems.

Supersaturating drug delivery systems (SDDS) enhance the oral absorption of poorly water-soluble drugs by achieving a supersaturated state in the gastrointestinal tract. The maintenance of a supersaturated state is decided by the complex interplay among inherent properties of drug, excipients and physiological conditions of gastrointestinal tract. The biopharmaceutical advantage through SDDS can be mechanistically investigated by coupling biopredictive dissolution testing with physiologically based absorption modeling (PBAM). However, the development of biopredictive dissolution methods possess challenges due to concurrent dissolution, supersaturation, precipitation, and possible redissolution of precipitates during gastrointestinal transit of SDDS. In this comprehensive review, our effort is to critically assess the current state-of-knowledge and provide future directions for PBAM of SDDS. The review outlines various methods used to retrieve physiologically relevant values for input parameters like solubility, dissolution, precipitation, lipid-digestion and permeability of SDDS. SDDS-specific parameterization includes solubility values corresponding to apparent physical form, dissolution in physiologically relevant volumes with biorelevant media, and transfer experiments to incorporate precipitation kinetics. Interestingly, the lack of experimental permeability values and modification of absorption flux through SDDS possess the additional challenge for its PBAM. Supersaturation triggered permeability modifications are reported to fit the observed plasma concentration-time profile. Hence, the experimental insights on good fitting with modified permeability can be potential area of future research for the development of in vitro methods to reliably predict oral absorption of SDDS.

Insights into co-amorphous systems in therapeutic drug delivery.

Co-amorphous (CAM) systems are promising drug-delivery systems in the arena of therapeutic drug delivery, addressing the poor aqueous solubility of drugs by enhancing solubility and thereby improving the oral bioavailability and therapeutic effect of the drug. A CAM system is a single-phase homogeneous blend of two or more low molecular weight molecules that can be drug-drug or drug-co-former, stabilized via intermolecular interactions, adding the benefit of thermodynamic stability. This review covers the fundamentals of CAM systems and recent advances in formulation development. In particular, we strive to address the theoretical, molecular, technical and biopharmaceutical aspects, advantages over polymeric amorphous solid dispersions, mechanisms of stabilization of amorphous forms, insights into unexplored in silico tools in excipient selection and regulatory viewpoints.

Mechanotransduction in gastrointestinal smooth muscle cells: role of mechanosensitive ion channels.

Mechanosensation, the ability to properly sense mechanical stimuli and transduce them into physiologic responses, is an essential determinant of gastrointestinal (GI) function. Abnormalities in this process result in highly prevalent GI functional and motility disorders. In the GI tract, several cell types sense mechanical forces and transduce them into electrical signals, which elicit specific cellular responses. Some mechanosensitive cells like sensory neurons act as specialized mechanosensitive cells that detect forces and transduce signals into tissue-level physiological reactions. Nonspecialized mechanosensitive cells like smooth muscle cells (SMCs) adjust their function in response to forces. Mechanosensitive cells use various mechanoreceptors and mechanotransducers. Mechanoreceptors detect and convert force into electrical and biochemical signals, and mechanotransducers amplify and direct mechanoreceptor responses. Mechanoreceptors and mechanotransducers include ion channels, specialized cytoskeletal proteins, cell junction molecules, and G protein-coupled receptors. SMCs are particularly important due to their role as final effectors for motor function. Myogenic reflex-the ability of smooth muscle to contract in response to stretch rapidly-is a critical smooth muscle function. Such rapid mechanotransduction responses rely on mechano-gated and mechanosensitive ion channels, which alter their ion pores' opening in response to force, allowing fast electrical and Ca2+ responses. Although GI SMCs express a variety of such ion channels, their identities remain unknown. Recent advancements in electrophysiological, genetic, in vivo imaging, and multi-omic technologies broaden our understanding of how SMC mechano-gated and mechanosensitive ion channels regulate GI functions. This review discusses GI SMC mechanosensitivity's current developments with a particular emphasis on mechano-gated and mechanosensitive ion channels.

Postnatal Ethanol Exposure Activates HDAC-Mediated Histone Deacetylation, Impairs Synaptic Plasticity Gene Expression and Behavior in Mice.

BACKGROUND: Alcohol consumption during pregnancy is widespread and contributes to pediatric neurological defects, including hippocampal and neocortex dysfunction, causing cognitive deficits termed fetal alcohol spectrum disorders. However, the critical mechanisms underlying these brain abnormalities remain poorly described. METHODS: Using a postnatal ethanol exposure (PEE) animal model and pharmacological, epigenetic, synaptic plasticity-related and behavioral approaches, we discovered a novel persistent epigenetic mechanism of neurodegeneration in neonatal hippocampus and neocortex brain regions and of cognitive decline in adult animals. RESULTS: PEE, which activates caspase-3 (CC3, a neurodegeneration marker), enhanced histone deacetylase (HDAC1-HDAC3) levels and reduced histone 3 (H3) and 4 (H4) acetylation (ac) in mature neurons. PEE repressed the expression of several synaptic plasticity genes, such as brain-derived neurotrophic factor, C-Fos, early growth response 1 (Egr1), and activity-regulated cytoskeleton-associated protein (Arc). Detailed studies on Egr1 and Arc expression revealed HDAC enrichment at their promoter regions. HDAC inhibition with trichostatin A (TSA) before PEE rescued H3ac/H4ac levels and prevented CC3 formation. Antagonism/null mutation of cannabinoid receptor type-1 (CB1R) before PEE to inhibit CC3 production prevented Egr1 and Arc loss via epigenetic events. TSA administration before PEE prevented postnatal ethanol-induced loss of Egr1 and Arc expression and neurobehavioral defects in adult mice via epigenetic remodeling. In adult mice, 3-day TSA administration attenuated PEE-induced behavioral defects. CONCLUSIONS: These findings demonstrate that CB1R/HDAC-mediated epigenetic remodeling disrupts gene expression and is a critical step in fetal alcohol spectrum disorder-associated cognitive decline but is reversed by restoration of histone acetylation in the brain.

microRNA overexpression in slow transit constipation leads to reduced NaV1.5 current and altered smooth muscle contractility.

OBJECTIVE: This study was designed to evaluate the roles of microRNAs (miRNAs) in slow transit constipation (STC). DESIGN: All human tissue samples were from the muscularis externa of the colon. Expression of 372 miRNAs was examined in a discovery cohort of four patients with STC versus three age/sex-matched controls by a quantitative PCR array. Upregulated miRNAs were examined by quantitative reverse transcription qPCR (RT-qPCR) in a validation cohort of seven patients with STC and age/sex-matched controls. The effect of a highly differentially expressed miRNA on a custom human smooth muscle cell line was examined in vitro by RT-qPCR, electrophysiology, traction force microscopy, and ex vivo by lentiviral transduction in rat muscularis externa organotypic cultures. RESULTS: The expression of 13 miRNAs was increased in STC samples. Of those miRNAs, four were predicted to target SCN5A, the gene that encodes the Na+ channel NaV1.5. The expression of SCN5A mRNA was decreased in STC samples. Let-7f significantly decreased Na+ current density in vitro in human smooth muscle cells. In rat muscularis externa organotypic cultures, overexpression of let-7f resulted in reduced frequency and amplitude of contraction. CONCLUSIONS: A small group of miRNAs is upregulated in STC, and many of these miRNAs target the SCN5A-encoded Na+ channel NaV1.5. Within this set, a novel NaV1.5 regulator, let-7f, resulted in decreased NaV1.5 expression, current density and reduced motility of GI smooth muscle. These results suggest NaV1.5 and miRNAs as novel diagnostic and potential therapeutic targets in STC.

Immunity to Vaccine-preventable Viral Infections in Australians Being Evaluated for Liver Transplantation.

BACKGROUND: Vaccine-preventable viral infections are associated with increased risk of morbidity and mortality in immunocompromised patients. Current guidelines recommend routine screening and vaccination of all patients before solid organ transplantation. We studied rates of immunity against vaccine-preventable viruses in liver transplantation (LT) recipients. METHODS: We retrospectively studied consecutive adult patients who underwent first deceased donor LT at a single center between August 2008 and October 2017. Viruses studied were hepatitis A (HAV), hepatitis B (HBV), varicella zoster virus (VZV), measles, and mumps. Hepatitis B surface antibody (anti-HBs) <10 IU/mL in HBV surface antigen-negative patients and negative IgG to other viruses was regarded as absent immunity. RESULTS: Five hundred and fifty-five patients underwent LT (72.4% male; median age, 55.0 y). Percentages of patients who lacked immunity to vaccine-preventable infections were HAV (31.8%), HBV (63.8%), measles (1.4%), mumps (6.6%), and VZV (3.8%). Age was positively associated with immunity (from either past exposure or vaccination) against most viruses, including HAV, measles, mumps, and VZV (P < 0.05 for all). In contrast, older age was marginally associated with anti-HBs <10 IU/mL (P = 0.046). No significant changes in immunity rates were observed during the study period. CONCLUSIONS: A substantial number of patients undergoing LT are not immune to vaccine-preventable viruses at the time of assessment. This presents an opportunity for pre-LT vaccination and in particular younger patients may need to be targeted.

Distinct functions of endogenous cannabinoid system in alcohol abuse disorders.

Δ9 -tetrahydrocannabinol, the principal active component in Cannabis sativa extracts such as marijuana, participates in cell signalling by binding to cannabinoid CB1 and CB2 receptors on the cell surface. The CB1 receptors are present in both inhibitory and excitatory presynaptic terminals and the CB2 receptors are found in neuronal subpopulations in addition to microglial cells and astrocytes and are present in both presynaptic and postsynaptic terminals. Subsequent to the discovery of the endocannabinoid (eCB) system, studies have suggested that alcohol alters the eCB system and that this system plays a major role in the motivation to abuse alcohol. Preclinical studies have provided evidence that chronic alcohol consumption modulates eCBs and expression of CB1 receptors in brain addiction circuits. In addition, studies have further established the distinct function of the eCB system in the development of fetal alcohol spectrum disorders. This review provides a recent and comprehensive assessment of the literature related to the function of the eCB system in alcohol abuse disorders.

CB1R regulates CDK5 signaling and epigenetically controls Rac1 expression contributing to neurobehavioral abnormalities in mice postnatally exposed to ethanol.

Fetal alcohol spectrum disorders (FASD) represent a wide array of defects that arise from ethanol exposure during development. However, the underlying molecular mechanisms are limited. In the current report, we aimed to further evaluate the cannabinoid receptor type 1 (CB1R)-mediated mechanisms in a postnatal ethanol-exposed animal model. We report that the exposure of postnatal day 7 (P7) mice to ethanol generates p25, a CDK5-activating peptide, in a time- and CB1R-dependent manner in the hippocampus and neocortex brain regions. Pharmacological inhibition of CDK5 activity before ethanol exposure prevented accumulation of cleaved caspase-3 (CC3) and hyperphosphorylated tau (PHF1) (a marker for neurodegeneration) in neonatal mice and reversed cAMP response element-binding protein (CREB) activation and activity-regulated cytoskeleton-associated protein (Arc) expression. We also found that postnatal ethanol exposure caused a loss of RhoGTPase-related, Rac1, gene expression in a CB1R and CDK5 activity-dependent manner, which persisted to adulthood. Our epigenetic analysis of the Rac1 gene promoter suggested that persistent suppression of Rac1 expression is mediated by enhanced histone H3 lysine 9 dimethylation (H3K9me2), a repressive chromatin state, via G9a recruitment. The inhibition of CDK5/p25 activity before postnatal ethanol exposure rescued CREB activation, Arc, chromatin remodeling and Rac1 expression, spatial memory, and long-term potentiation (LTP) abnormalities in adult mice. Together, these findings propose that the postnatal ethanol-induced CB1R-mediated activation of CDK5 suppresses Arc and Rac1 expression in the mouse brain and is responsible for persistent synaptic plasticity and learning and memory defects in adult mice. This CB1R-mediated activation of CDK5 signaling during active synaptic development may slow down the maturation of synaptic circuits and may cause neurobehavioral defects, as found in this FASD animal model.

Activity-dependent Signaling and Epigenetic Abnormalities in Mice Exposed to Postnatal Ethanol.

Postnatal ethanol exposure has been shown to cause persistent defects in hippocampal synaptic plasticity and disrupt learning and memory processes. However, the mechanisms responsible for these abnormalities are less well studied. We evaluated the influence of postnatal ethanol exposure on several signaling and epigenetic changes and on expression of the activity-regulated cytoskeletal (Arc) protein in the hippocampus of adult offspring under baseline conditions and after a Y-maze spatial memory (SP) behavior (activity). Postnatal ethanol treatment impaired pCaMKIV and pCREB in naïve mice without affecting H4K8ac, H3K14ac and H3K9me2 levels. The Y-maze increased pCaMKIV, pCREB, H4K8ac and H3K14ac levels in saline-treated mice but not in ethanol-treated mice; while H3K9me2 levels were enhanced in ethanol-exposed animals compared to saline groups. Like previous observations, ethanol not only reduced Arc expression in naïve mice but also behaviorally induced Arc expression. ChIP results suggested that reduced H3K14ac and H4K8ac in the Arc gene promoter is because of impaired CBP, and increased H3K9me2 is due to the enhanced recruitment of G9a. The CB1R antagonist and a G9a/GLP inhibitor, which were shown to rescue postnatal ethanol-triggered synaptic plasticity and learning and memory deficits, were able to prevent the negative effects of ethanol on activity-dependent signaling, epigenetics and Arc expression. Together, these findings provide a molecular mechanism involving signaling and epigenetic cascades that collectively are responsible for the neurobehavioral deficits associated with an animal model of fetal alcohol spectrum disorders (FASD).

CB1R-Mediated Activation of Caspase-3 Causes Epigenetic and Neurobehavioral Abnormalities in Postnatal Ethanol-Exposed Mice.

Alcohol exposure can affect brain development, leading to long-lasting behavioral problems, including cognitive impairment, which together is defined as fetal alcohol spectrum disorder (FASD). However, the fundamental mechanisms through which this occurs are largely unknown. In this study, we report that the exposure of postnatal day 7 (P7) mice to ethanol activates caspase-3 via cannabinoid receptor type-1 (CB1R) in neonatal mice and causes a reduction in methylated DNA binding protein (MeCP2) levels. The developmental expression of MeCP2 in mice is closely correlated with synaptogenesis and neuronal maturation. It was shown that ethanol treatment of P7 mice enhanced Mecp2 mRNA levels but reduced protein levels. The genetic deletion of CB1R prevented, and administration of a CB1R antagonist before ethanol treatment of P7 mice inhibited caspase-3 activation. Additionally, it reversed the loss of MeCP2 protein, cAMP response element binding protein (CREB) activation, and activity-regulated cytoskeleton-associated protein (Arc) expression. The inhibition of caspase-3 activity prior to ethanol administration prevented ethanol-induced loss of MeCP2, CREB activation, epigenetic regulation of Arc expression, long-term potentiation (LTP), spatial memory deficits and activity-dependent impairment of several signaling molecules, including MeCP2, in adult mice. Collectively, these results reveal that the ethanol-induced CB1R-mediated activation of caspase-3 degrades the MeCP2 protein in the P7 mouse brain and causes long-lasting neurobehavioral deficits in adult mice. This CB1R-mediated instability of MeCP2 during active synaptic maturation may disrupt synaptic circuit maturation and lead to neurobehavioral abnormalities, as observed in this animal model of FASD.

Purification and characterization of an anti-hemorrhagic protein from Naja naja (Indian cobra) venom.

Snake venom Kunitz-type proteins are well known to inhibit serine proteases but a few studies have also shown matrix metalloproteases (MMPs) inhibition. In view of the fact that MMPs and snake venom metalloproteases (SVMPs) have similar catalytic site, inhibition of SVMP activity by Kunitz-type proteins remains to be studied. Recent proteomic studies of Naja naja (N. naja) venom revealed the abundance of Kunitz-type proteins. In this regard, present study aimed at purification of a protease inhibitor from N. naja venom that inhibits the toxicity of SVMPs rich Echis carinatus (E. carinatus) venom. N. naja venom effectively inhibited E. carinatus venom-induced hemorrhage. Purification of the active principle responsible for anti-hemorrhagic effect was achieved by fractionation of N. naja venom in three successive chromatographic steps. SDS-PAGE revealed that purified anti-hemorrhagic protein (NNAh) has an apparent molecular mass of ∼44 kDa and single peak in RP-HPLC demonstrated its homogeneity. NNAh also inhibited myonecrosis induced by E. carinatus venom and reduced activity of creatine kinase in NNAh treated animal sera substantiated the anti-myonecrotic effect. Hemorrhage and myonecrosis inhibitory effects of NNAh were further supported by inhibition of E. carinatus venom-mediated gelatinolysis and collagenolysis. NNAh falls into the category of Kunitz-type serine protease inhibitor as determined by peptide mass fingerprinting and shown to be a strong inhibitor of chymotrypsin. Collectively our data signify that NNAh is a Kunitz-type chymotrypsin inhibitor which also inhibited metalloprotease activities of E. carinatus venom. In future, complete sequence of NNAh and peptide region(s) responsible for inhibition will assist to deduce the mechanism of action.

Endocannabinoid system in neurodegenerative disorders.

Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well-defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs.

Predictors of success for double balloon-assisted endoscopic retrograde cholangiopancreatography in patients with Roux-en-Y anastomosis.

BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) in patients with roux-en-Y anastomosis (REYA) is challenging. Use of double balloon enteroscope-assisted ERCP (DBE-ERCP) has been successful. We aim to determine predictors of successful biliary cannulation with DBE-ERCP in patients with REYA. METHODS: We retrospectively studied patients with REYA who had DBE-ERCP between 2009 and 2015. RESULTS: 86 DBE-ERCP were done on 52 patients. Patients had REYA for liver transplant (n = 26), gastrojejunostomy (n = 9), previous bile duct injury (n = 9), biliary atresia (n = 2) and other (n = 6). The biliary-enteric anastomosis was reached in 76% and cholangiogram was successful in 70%. Highest success rates were in patients with previous bile duct injury (94%) or gastrojejunostomy (89%). Post-transplant patients had intermediate success (64%). Patients with redo surgery (46%) and childhood surgery (38%), especially Kasai procedure (20%), had low success. Patients with previous bile duct injury were more likely to succeed (94% vs 63%, P = 0.010). Those more likely to fail were patients with childhood surgery (38% vs 73%, P = 0.037), biliary atresia (20% vs 73%, P = 0.013) and second operation post-transplant (25% vs 70%, P = 0.046). CONCLUSION: Indication for REYA impacts on successful biliary cannulation in patients undergoing DBE-ERCP. The procedure is most successful in non-liver transplant adult surgery and post-transplant patients without a second operation. It is least successful in patients with surgically corrected biliary atresia and post-transplant patients with second operation. Alternative methods of biliary access should be considered in these patients.

Validating a proxy for disease progression in metastatic cancer patients using prescribing and dispensing data.

BACKGROUND: Routine data collections are used increasingly to examine outcomes of real-world cancer drug use. These datasets lack clinical details about important endpoints such as disease progression. AIM: To validate a proxy for disease progression in metastatic cancer patients using prescribing and dispensing claims. METHODS: We used data from a cohort study of patients undergoing chemotherapy who provided informed consent to the collection of cancer-treatment data from medical records and linkage to pharmaceutical claims. We derived proxy decision rules based on changes to drug treatment in prescription histories (n = 36 patients) and validated the proxy in prescribing data (n = 62 patients). We adapted the decision rules and validated the proxy in dispensing data (n = 109). Our gold standard was disease progression ascertained in patient medical records. Individual progression episodes were the unit of analysis for sensitivity and Positive Predictive Value (PPV) calculations and specificity and Negative Predictive Value (NPV) were calculated at the patient level. RESULTS: The sensitivity of our proxy in prescribing data was 74.3% (95% Confidence Interval (CI), 55.6-86.6%) and PPV 61.2% (95% CI, 45.0-75.3%); specificity and NPV were 87.8% (95% CI, 73.8-95.9%) and 100% (95% CI, 90.3-100%), respectively. In dispensing data, the sensitivity of our proxy was 64% (95% CI, 55.0-77.0%) and PPV 56.0% (95% CI, 43.0-69.0%); specificity and NPV were 81% (95% CI, 70.05-89.0%) and 91.0% (95% CI, 82.0-97.0%), respectively. CONCLUSION: Our proxy overestimated episodes of disease progression. The proxy's performance is likely to improve if the date of prescribing is used instead of date of dispensing in claims data and by incorporating medical service claims (such as imaging prior to drug changes) in the algorithm. Our proxy is not sufficiently robust for use in real world comparative effectiveness research for cancer medicines.