Assessment of Adherence to Clinical Guidelines in Patients with Chronic Hepatitis B.

Background and aims: Adherence to guidelines is associated with improved long-term outcomes in patients with chronic hepatitis B (CHB). We aimed to study the degree of adherence and determinants of non-adherence to management guidelines in a low endemic country. Methods: We reviewed the medical records of all CHB patients who visited our outpatient clinic in 2020. Adherence to guidelines was assessed based on predefined criteria based on the EASL guidance, and included the initiation of antiviral therapy when indicated, the optimal choice of antiviral therapy based on comorbidities, an assessment of HAV/HCV/HDV/HIV serostatus, renal function monitoring and enrolment in a HCC surveillance program if indicated. The adherence rates were compared across types of outpatient clinic (dedicated viral hepatitis clinic versus general hepatology clinic). Results: We enrolled 482 patients. Among the 276 patients with an indication for antiviral therapy, 268 (97.1%) received treatment. Among the patients with renal and/or bone disease, 26/29 (89.7%) received the optimal choice of antiviral agent. The assessment of HAV/HCV/HDV/HIV serostatus was performed in 86.1/91.7/94.4/78.4%. Among the 91 patients treated with tenofovir disoproxil, 57 (62.6%) underwent monitoring of renal function. Of the 241 patients with an indication for HCC surveillance, 212 (88.3%) were enrolled in a surveillance program. Clinics dedicated to viral hepatitis had superior adherence rates compared to general hepatology clinics (complete adherence rates 63.6% versus 37.2%, p < 0.001). Conclusions: Follow-up at a dedicated viral hepatitis clinic was associated with superior adherence to management guidelines.

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

Genetically predicted circulating protein biomarkers and ovarian cancer risk.

OBJECTIVE: Most women with epithelial ovarian cancer (EOC) are diagnosed after the disease has metastasized and survival in this group remains poor. Circulating proteins associated with the risk of developing EOC have the potential to serve as biomarkers for early detection and diagnosis. We integrated large-scale genomic and proteomic data to identify novel plasma proteins associated with EOC risk. METHODS: We used the germline genetic variants most strongly associated (P <1.5 × 10-11) with plasma levels of 1329 proteins in 3301 healthy individuals from the INTERVAL study to predict circulating levels of these proteins in 22,406 EOC cases and 40,941 controls from the Ovarian Cancer Association Consortium (OCAC). Association testing was performed by weighting the beta coefficients and standard errors for EOC risk from the OCAC study by the inverse of the beta coefficients from INTERVAL. RESULTS: We identified 26 proteins whose genetically predicted circulating levels were associated with EOC risk at false discovery rate < 0.05. The 26 proteins included MFAP2, SEMG2, DLK1, and NTNG1 and a group of 22 proteins whose plasma levels were predicted by variants at chromosome 9q34.2. All 26 protein association signals identified were driven by association with the high-grade serous histotype that comprised 58% of the EOC cases in OCAC. Regional genomic plots confirmed overlap of the genetic association signal underlying both plasma protein level and EOC risk for the 26 proteins. Pathway analysis identified enrichment of seven biological pathways among the 26 proteins (Padjusted <0.05), highlighting roles for Focal Adhesion-PI3K-Akt-mTOR and Notch signaling. CONCLUSION: The identified proteins further illuminate the etiology of EOC and represent promising new EOC biomarkers for targeted validation by studies involving direct measurement of plasma proteins in EOC patient cohorts.

Contemporary Psychodynamic Approaches to Treating Anxiety: Theory, Research, and Practice.

Psychodynamic theory is founded on the idea that much, if not most, of human behavior is influenced by forces and experiences that lie outside of conscious awareness. It posits that despite what we may or may not recognize about our lived experience, an essential connection exists between unconscious processes and everyday psychological functioning. By extension, psychodynamic theory presumes that unconscious conflicts are pathognomonic of anxiety disorders and anxiety symptoms more generally. At the same time, the term "psychodynamic" refers not only to that which occurs within one's mind but also what happens between people and within families, groups, and systems. A comprehensive psychodynamic treatment of anxiety attempts to take into account these multiple domains of experience and functioning (including biological and genetic considerations) and applies a specific therapeutic approach to working with patients based in part on clinical techniques first developed by Sigmund Freud 100 years ago.

Mechanism, selectivity promotion, and new ultraselective pathways in Ag-catalyzed heterogeneous epoxidation.

The selective oxidation of styrene on clean and modified Ag(100) surfaces has been studied by synchrotron fast XPS and temperature-programmed reaction spectroscopy. By following the time dependence of surface species, it is unequivocally demonstrated that the necessary and sufficient conditions for epoxide formation are oxygen adatoms and pi-adsorbed alkene molecules. Increased oxygen coverage and coadsorbed Cs have pronounced and opposite effects on epoxidation selectivity, consistent with the view that the valence charge density on O(a) is pivotal in determining this property. Submonolayer quantities of Cs nitrate generated in situ open a new, low-temperature ultraselective, epoxidation pathway thought to involve direct oxygen transfer from the oxyanion to the alkene.

Chemosensory Activation of an Antennular Grooming Behavior in the Spiny Lobster, Panulirus argus, Is Tuned Narrowly to L-Glutamate.

Antennular grooming behavior (AGB) is a stereotyped behavior in crustaceans in which the first pair of antennae, the major olfactory organs, are clasped and wiped repetitively by the third maxillipeds, which also serve as feeding appendages. AGB apparently functions to clear away accumulating debris on or between the antennular aesthetascs (olfactory sensilla). The purpose of this research was to determine whether AGB can be activated by chemicals commonly found in food odors. Lobsters were presented, via headset or handheld pipette, with 27 chemicals found in their food. One chemical, L-glutamate, evoked very high frequencies of wiping. Most chemicals tested were not stimulatory and only a few were weakly stimulatory (adenosine-5'-monophosphate, glycine, D-glutamate). This is surprising because previous studies have shown that other behaviors (antennular flick, search) can be evoked by a much broader array of chemicals found in food odorants. On the basis of these results, we propose that chemosensory neurons that specifically detect L-Glu activate AGB through a recently described non-olfactory pathway. Furthermore, we propose that the role of L-Glu in evoking AGB is based on its electrostatic properties. Because it has a high probability of electrostatic adherence to the antennular cuticle, L-Glu is a sensitive indicator of fouling by food-associated chemicals and thus an appropriate compound to stimulate antennular grooming.

Responses of olfactory receptor neurons in the spiny lobster to binary mixtures are predictable using a noncompetitive model that incorporates excitatory and inhibitory transduction pathways.

Coding of binary mixtures by a population of olfactory receptor neurons in the spiny lobster (Panulirus argus) was examined. Extracellular single-unit responses of 50 neurons to seven compounds and their binary mixtures were recorded. The ability of a noncompetitive model with correction for binding inhibition to predict responses to mixtures based on responses to their components was compared with the predictive abilities of other models. This model assumes that different compounds activate different transduction processes in the same neuron leading to excitation or inhibition, and it includes a term quantifying the degree to which binding of an odorant to its receptor sites is inhibited by other compounds. The model accurately predicted the absolute response magnitude of the population of neurons for 13 of 15 mixtures assessed, which is superior to the predictive power of any of the other models. The model also accurately predicted the across neuron patterns generated by the binary mixtures, as evaluated by multidimensional scaling analysis. The results suggest that there is no emergence of unique qualities for binary mixtures relative to components of these mixtures.

Non-reciprocal cross-adaptation of spiking responses of individual olfactory receptor neurons of spiny lobsters: evidence for two excitatory transduction pathways.

Single-unit spiking responses of 72 olfactory receptor neurons (ORNs) in the olfactory organ of the spiny lobster Panulirus argus were recorded extracellularly during presentation of a set of seven odorant stimuli (adenosine-5'-monophosphate, ammonium chloride, betaine, L-cysteine, L-glutamate, D,L-succinate and taurine) and analyzed in order to evaluate the response specificities of single ORNs and the independence of receptor sites. Individual ORNs often had narrow excitatory response spectra, but the most excitatory compound was different from neuron to neuron. These results suggest that these compounds can exert most of their excitatory effects through relatively independent receptor site types. To determine the relative independence of excitatory transduction processes in single ORNs for these stimuli, single-unit spiking responses of these neurons under conditions of self- and cross-adaptation were analyzed. The results demonstrate extensive cross-adaptation between pairs of the seven stimuli. When averaged across all neurons and all cross-adaptation conditions, cross-adaptation resulted in a mean reduction of 81% of the unadapted response. However, there were differences in the degree and pattern of adaptation for different pairs of compounds and for different neuron types (defined by most excitatory or 'best' chemical). For a given neuron type, there were significant levels of non-reciprocal cross-adaptation: neurons cross-adapted more when adapted to their best chemical than when adapted to their non-best chemicals. These results suggest the existence of two excitatory transduction pathways within an olfactory receptor neuron: one pathway activated exclusively by the best chemical and a second pathway activated by a broader spectrum of chemicals.

Responses of olfactory receptor cells of spiny lobsters to binary mixtures. I. Intensity mixture interactions.

1. Neural coding of chemical mixtures was studied with the use of the peripheral olfactory system of the spiny lobster. The occurrence of mixture interactions (i.e., where the observed response to a mixture deviates significantly from the expected response) in individual cells and the effect of such mixture interactions on the coding of odorant intensity by populations of cells were examined. 2. Extracellular recordings of spiking activity of 98 primary olfactory receptor cells in the antennules were measured in response to seven compounds [adenosine-5'-monophosphate (AMP), betaine (Bet), L-cysteine (Cys), L-glutamate (Glu), ammonium chloride (NH4), DL-succinate (Suc), and taurine (Tau)] and their binary mixtures. To identify mixture interactions, observed responses to a range of concentrations of a binary mixture were compared with the predicted responses based on three mathematical models: a single receptor model, which assumes that the two compounds of a mixture bind to the same receptor site; a multiple receptor model, which assumes that the two compounds bind to two independent receptor sites; and a mixed composition receptor model, which incorporates our current state of knowledge of transduction processes in olfactory receptor cells of spiny lobsters. 3. Mixture interactions in individual cells were common: statistically significant mixture interactions were observed in 25% of the possible cases (Fig. 5). Suppression was much more common than enhancement. 4. Mixture interactions had significant effects on the absolute response magnitudes for a population of cells, which could be used as the neural code for stimulus intensity in this system. These effects are called intensity mixture interactions (Figs. 6-11). Intensity mixture interactions occurred for approximately 50% of the binary mixtures and were almost exclusively suppression (Figs. 12 and 13). The intensity mixture interactions were concentration independent. 5. The results suggest that mixture interactions in individual olfactory cells can result in intensity mixture interactions in the neuronal population such that there is a decrease in sensitivity to binary mixtures relative to what is expected based on the responses to individual components of the mixtures.

Responses of olfactory receptor cells of spiny lobsters to binary mixtures. II. Pattern mixture interactions.

1. The effect of mixture interactions in individual olfactory receptor cells of the spiny lobster on neural coding of odorant quality of binary mixtures and their components is examined in this paper. Extracellular responses of 98 olfactory receptor cells in the antennules of spiny lobsters to seven compounds [adenosine-5'-monophosphate (AMP), betaine (Bet), L-cysteine (Cys), L-glutamate (Glu), ammonium chloride (NH4), DL-succinate (Suc), taurine (Tau)] and their binary mixtures were recorded, and mixture interactions in individual olfactory receptor cells were identified. 2. Coding of odorant quality was evaluated by examining across neuron patterns (ANPs)--the relative response magnitudes across neuronal populations. ANPs are a feature of the neuronal population response and are a possible concentration-independent code of odorant quality in this system, as indicated by previous studies and present results. 3. For most binary mixtures the diversity of types and degrees of mixture interactions across the individual cells of a population of cells resulted in ANPs for each mixture to be different from the ANPs for the components of the mixture and different from the ANP predicted for the mixture from the responses to the components (Figs. 2-10). These effects are called pattern mixture interactions (PMIs). PMIs occurred for most binary mixtures, even those that did not produce statistically significant intensity mixture interactions (IMIs) for this same population of cells. 4. The results suggest that PMIs can influence coding of stimulus quality, in some cases by causing an improvement of the contrast between the quality of mixtures and some of their components.

Chemosensory responses to mixtures: a model based on composition of receptor cell types.

Previous mixture models have assumed that members of a population of chemoreceptor cells are homogeneous in type, i.e., with either single shared or multiple independent receptor sites. In reality, many chemosensory systems actually consist of a heterogeneous population of receptor cells, consisting of both highly specific cells as well as more broadly and variably tuned cells. A mixed receptor composition model for binary mixtures is described which can be applied to chemosensory systems with heterogeneous receptor cell compositions. The model incorporates information on a) the number of receptor sites/transduction processes per cell, b) the specificity of receptor cells, and c) the contribution of the magnitude of response of each receptor cell to the overall response magnitude of the population of all receptor cells. The predictions of this model can be compared to behavioral responses of animals towards binary mixtures, or at any level of sensory processing which involves the input of the receptor cell population, in order to detect possible mixture interactions.

Mixture suppression in behavior: the antennular flick response in the spiny lobster towards binary odorant mixtures.

The behavioral responses of Florida spiny lobsters towards various concentrations of binary mixtures and their constituents (AMP, betaine, cysteine, succinate, and taurine) were measured using an antennular flicking assay. The rate of flicking increases with dose and has low thresholds: flick rates towards each of the five chemicals increased with concentration with thresholds between 1 nM and 100 microM. A mixed receptor composition model, which incorporates knowledge of the composition of receptor site types and their distribution across receptor cells (15), was used to predict responses to binary mixtures based on responses to the individual constituents. Nine of the ten binary mixtures elicited response magnitudes which were less than predicted by this model, suggesting mixture suppression. These mixture interactions appear to be independent of the concentration of the mixture tested; rather, they occur with the same magnitude at all concentrations. These behavioral results corroborate findings in olfactory receptor cell studies which indicate the significant prevalence of mixture suppression towards some of the same binary mixtures (19,20).

Differential associative conditioning and olfactory discrimination in the spiny lobster Panulirus argus.

A differential aversive associative conditioning paradigm was used to assess the ability of the spiny lobster Panulirus argus both to associatively learn not to respond to the odorant stimulus to which it was conditioned and to discriminate between odorants. The paradigm consisted of pairing an aversive stimulus (pseudopredator) with a conditioned chemical stimulus (shrimp mixture). Four artificial mixtures (crab, mullet, oyster, and shrimp), each at 0.05 and 0.5 mM, were presented to the animals prior to, during, and following conditioning to both concentrations of the shrimp mixture. Pre- vs postconditioning changes in three types of behavioral responses (and an index based on a composite of these three behaviors) were used as indicators of learned aversions. Olfactory discrimination abilities were determined by comparing the aversion to the conditioned mixture with the aversions to the three nonconditioned mixtures. A high degree of associative learning was attained after 10 pairings of the pseudopredator with the shrimp mixture over a period of 5 test days. According to the aversion index, animals conditioned to shrimp mixture perceived crab mixture as being more similar to shrimp mixture than were mullet and oyster mixtures, but all three nonconditioned mixtures were perceived as being significantly different from the shrimp mixture. These results are in concordance with results of a cluster analysis based on the mixture compositions, which indicates that shrimp and crab mixtures are compositionally similar, while mullet and oyster mixtures are compositionally distinct from the shrimp mixture.

Development of chemically mediated prey-search response in postlarval lobsters (Homarus americanus) through feeding experience.

Postlarval lobsters were fed live amphipods (Gammarus oceanicus), soft clam spat (Mya arenaria), or frozen brine shrimp (Artemia salina) for five weeks in order to determine by behavioral bioassay if chemically mediated prey-search behavior is established by feeding experience. Chemosensory responses of predatorily naive lobsters to live clam and amphipod metabolites were low and erratic. After five weeks, amphipod-fed lobsters had developed strong responses towards amphipod metabolites but not clam metabolites. In contrast, clam-fed lobsters did not develop responses to either prey. Chemical fractionation of amphipod metabolites indicated that attractants were confined to the same fraction as for prey extracts, i.e., polar, low-molecular-weight compounds. Survival (80-90%) was similar for each diet group; growth was greatest for amphipod-fed lobsters (100%), followed by clam-fed lobsters (72%) and brine shrimp-fed lobsters (18%); and feeding rates increased for amphipod-fed lobsters and decreased for clam-fed lobsters. Coloration of lobsters indicated that only amphipod diet provided desirable pigments. Differences in ingestive conditioning results between clamfed and amphipod-fed lobsters may have been related to (1) clam metabolites being qualitatively or quantitatively less attractive than amphipod metabolites or (2) differences in the predisposition of lobsters to show ingestive conditioning to different prey and their associated metabolites as a function of quality of prey as a diet.

Attraction of predatorily naive postlarval lobsters to extracts of metabolites of common prey:Mytilus edulis, Mya arenaria, Cancer irroratus, andAsterias vulgaris.

Postlarval lobsters (4th-7th stage) exclusively fed frozen brine shrimp (Artemia saline) were assayed for food-search response to extracts and metabolites from four common prey: soft clams (Mya arenaria), blue mussels (Mytilus edulis), rock crabs (Cancer irroratus), and sea stars (Asterias vulgaris). Concentrations of soluble primary amines, protein, and ammonia in prey tissues and metabolites were determined. No significant responses were observed for any prey metabolites diluted to 1 and 10%, while onlyA. vulgaris evoked a significant response at full strength, suggesting that predatorily naive lobsters have yet to develop more pronounced chemosensory responses shown by field-collected lobsters. Removal of protein with retention of small-molecular-weight polar molecules did not appear to affect response to prey extracts. EC50s, as micromoles per liter amines, computed from prey extract dose-response curves indicate differences per unit amine between prey extracts, withA. vulgaris extract more potent as an attractant than either bivalve extract.C. irroratus extract was equally attractive as the other three extracts. Ammonia levels excreted into seawater over 3 hr were similar for all prey species, while soluble primary amines and proteins were undetectable. Ammonia and protein per gram whole prey varied significantly between extracts of prey species, while primary amines were similar. Lobsters may be attracted preferentially to carrion species with higher concentrations of amines and/or higher potency of attractants per unit amine.