Critical shortfalls in the management of PBC: Results of a UK-wide, population-based evaluation of care delivery.

Background & Aims: Guidelines for the management of primary biliary cholangitis (PBC) were published by the British Society of Gastroenterology in 2018. In this study, we assessed adherence to these guidelines in the UK National Health Service (NHS). Methods: All NHS acute trusts were invited to contribute data between 1 January 2021 and 31 March 2022, assessing clinical care delivered to patients with PBC in the UK. Results: We obtained data for 8,968 patients with PBC and identified substantial gaps in care across all guideline domains. Ursodeoxycholic acid (UDCA) was used as first-line treatment in 88% of patients (n = 7,864) but was under-dosed in one-third (n = 1,964). Twenty percent of patients who were UDCA-untreated (202/998) and 50% of patients with inadequate UDCA response (1,074/2,102) received second-line treatment. More than one-third of patients were not assessed for fatigue (43%; n = 3,885) or pruritus (38%; n = 3,415) in the previous 2 years. Fifty percent of all patients with evidence of hepatic decompensation were discussed with a liver transplant centre (222/443). Appropriate use of second-line treatment and referral for liver transplantation was significantly better in specialist PBC treatment centres compared with non-specialist centres (p <0.001). Conclusions: Poor adherence to guidelines exists across all domains of PBC care in the NHS. Although specialist PBC treatment centres had greater adherence to guidelines, no single centre met all quality standards. Nationwide improvement in the delivery of PBC-related healthcare is required. Impact and implications: This population-based evaluation of primary biliary cholangitis, spanning four nations of the UK, highlights critical shortfalls in care delivery when measured across all guideline domains. These include the use of liver biopsy in diagnosis; referral practice for second-line treatment and/or liver transplant assessment; and the evaluation of symptoms, extrahepatic manifestations, and complications of cirrhosis. The authors therefore propose implementation of a dedicated primary biliary cholangitis care bundle that aims to minimise heterogeneity in clinical practice and maximise adherence to key guideline standards.

Extracting particle size distribution from laser speckle with a physics-enhanced autocorrelation-based estimator (PEACE).

Extracting quantitative information about highly scattering surfaces from an imaging system is challenging because the phase of the scattered light undergoes multiple folds upon propagation, resulting in complex speckle patterns. One specific application is the drying of wet powders in the pharmaceutical industry, where quantifying the particle size distribution (PSD) is of particular interest. A non-invasive and real-time monitoring probe in the drying process is required, but there is no suitable candidate for this purpose. In this report, we develop a theoretical relationship from the PSD to the speckle image and describe a physics-enhanced autocorrelation-based estimator (PEACE) machine learning algorithm for speckle analysis to measure the PSD of a powder surface. This method solves both the forward and inverse problems together and enjoys increased interpretability, since the machine learning approximator is regularized by the physical law.

Machine Learning-Derived Correlations for Scale-Up and Technology Transfer of Primary Nucleation Kinetics.

Scaling up and technology transfer of crystallization processes have been and continue to be a challenge. This is often due to the stochastic nature of primary nucleation, various scale dependencies of nucleation mechanisms, and the multitude of scale-up approaches. To better understand these dependencies, a series of isothermal induction time studies were performed across a range of vessel volumes, impeller types, and impeller speeds. From these measurements, the nucleation rate and growth time were estimated as parameters of an induction time distribution model. Then using machine learning techniques, correlations between the vessel hydrodynamic features, calculated from computational flow dynamic simulations, and nucleation kinetic parameters were analyzed. Of the 18 machine learning models trained, two models for the nucleation rate were found to have the best performance (in terms of % of predictions within experimental variance): a nonlinear random Forest model and a nonlinear gradient boosting model. For growth time, a nonlinear gradient boosting model was found to outperform the other models tested. These models were then ensembled to directly predict the probability of nucleation, at a given time, solely from hydrodynamic features with an overall root mean square error of 0.16. This work shows how machine learning approaches can be used to analyze limited datasets of induction times to provide insights into what hydrodynamic parameters should be considered in the scale-up of an unseeded crystallization process.

Geolocator-tracking seabird migration and moult reveal large-scale, temperature-driven isoscapes in the NE Atlantic.

RATIONALE: By combining precision satellite-tracking with blood sampling, seabirds can be used to validate marine carbon and nitrogen isoscapes, but it is unclear whether a comparable approach using low-precision light-level geolocators (GLS) and feather sampling can be similarly effective. METHODS: Here we used GLS to identify wintering areas of northern gannets (Morus bassanus) and sampled winter grown feathers (confirmed from image analysis of non-breeding birds) to test for spatial gradients in δ13 C and δ15 N in the NE Atlantic. RESULTS: By matching winter-grown feathers with the non-breeding location of tracked birds we found latitudinal gradients in δ13 C and δ15 N in neritic waters. Moreover, isotopic patterns were best explained by sea surface temperature. Similar isotope gradients were found in fish muscle sampled at local ports. CONCLUSIONS: Our study reveals the potential of using seabird GLS and feathers to reconstruct large-scale isotopic patterns.

Action slips in food choices: A measure of habits and goal-directed control.

We report a new, simple instrumental action-slip task, which sets goal-directed action against putative S-R associations. On each training trial, participants were presented with one of two stimuli (blue or green coloured screen). One stimulus (S1) signalled that one joystick response (R1-left or right push) would earn one of two rewards (O1-jellybeans or Pringles points). A second stimulus (S2) signalled a different instrumental relationship (S2:R2-O2). On each test trial, participants were told which outcome could be earnt (O1/O2) on that trial. They were required to withhold responding until the screen changed colour to S1 or S2. On congruent test trials, the stimulus presented (e.g., S1) was associated with the same response (R1) as the outcome available on that trial (O1). On incongruent test trials, in contrast, the outcome (e.g., O1) preceded a stimulus that was associated with a different response (e.g., S2). Hence, in order to obtain the outcome (O1) on incongruent trials, participants were required to suppress any tendency they might have to make the response associated with the stimulus (R2 in response to S2). In two experiments, participants made more errors on incongruent than congruent trials. This result suggests that, on incongruent trials, the stimulus drove responding (e.g., S2 increased R2 responding) in a manner that was inconsistent with goal-directed action (e.g., R1 responding to obtain O1)-an action slip. The results are discussed in terms of popular dual-process theories of instrumental action and a single-process alternative.

Pre-testing effects are target-specific and are not driven by a generalised state of curiosity.

Guessing an answer to an unfamiliar question prior to seeing the answer leads to better memory than studying alone (the pre-testing effect), which some theories attribute to increased curiosity. A similar effect occurs in general knowledge learning: people are more likely to recall information that they were initially curious to learn. Gruber and Ranganath [(2019). How curiosity enhances hippocampus-dependent memory: The prediction, appraisal, curiosity, and exploration (PACE) framework. Trends in Cognitive Sciences, 23(12), 1014-1025] argued that unanswered questions can cause a state of curiosity during which encoding is enhanced for the missing answer, but also for incidental information presented at the time. If pre-testing similarly induces curiosity, then it too should produce better memory for incidental information. We tested this idea in three experiments that varied the order, nature and timing of the incidental material presented within a pre-testing context. All three experiments demonstrated a reliable pre-testing effect for the targets, but no benefit for the incidental material presented before the target. This pattern suggests that the pre-testing effect is highly specific and is not consistent with a generalised state of curiosity.

Mechanistic Insight Into the Application of Alumina-Supported Pd Catalysts for the Hydrogenation of Nitrobenzene to Aniline.

Two Pd/γ-Al2O3 catalysts are examined for the vapor phase hydrogenation of nitrobenzene over the temperature range of 60-200 °C. A 1 wt % catalyst is selected as a reference material that is diluted with γ-alumina to produce a 0.3 wt % sample, which is representative of a metal loading linked to a candidate industrial specification aniline synthesis catalyst. Cyclohexanone oxime is identified as a by-product that is associated with reagent transformation. Temperature-programed infrared spectroscopy and temperature-programed desorption measurements of chemisorbed CO provide information on the morphology of the crystallites of the higher Pd loading catalyst. The lower Pd loading sample exhibits a higher aniline selectivity by virtue of minimization of product overhydrogenation. Reaction testing measurements that were undertaken employing elevated hydrogen flow rates lead to the proposition of separate reagent and product-derived by-product formation pathways, each of which occurs in a consecutive manner. A global reaction scheme is proposed that defines the by-product distribution accessible by the grades of catalyst examined. This information is helpful in defining product purification procedures that would be required in certain heat recovery scenarios connected with large-scale aniline production.

Theory protection: Do humans protect existing associative links?

Theories of associative learning often propose that learning is proportional to prediction error, or the difference between expected events and those that occur. Spicer et al. (2020) suggested an alternative, that humans might instead selectively attribute surprising outcomes to cues that they are not confident about, to maintain cue-outcome associations about which they are more confident. Spicer et al. reported three predictive learning experiments, the results of which were consistent with their proposal ("theory protection") rather than a prediction error account (Rescorla, 2001). The four experiments reported here further test theory protection against a prediction error account. Experiments 3 and 4 also test the proposals of Holmes et al. (2019), who suggested a function mapping learning to performance that can explain Spicer et al.'s results using a prediction-error framework. In contrast to the previous study, these experiments were based on inhibition rather than excitation. Participants were trained with a set of cues (represented by letters), each of which was followed by the presence or absence of an outcome (represented by + or -). Following this, a cue that previously caused the outcome (A+) was placed in compound with another cue (B) with an ambiguous causal status (e.g., a novel cue in Experiment 1). This compound (AB-) did not cause the outcome. Participants always learned more about B in the second training phase, despite A always having the greater prediction error. In Experiments 3 and 4, a cue with no apparent prediction error was learned about more than a cue with a large prediction error. Experiment 4 tested participants' relative confidence about the causal status of cues A and B prior to the AB- stage, producing findings that are consistent with theory protection and inconsistent with the predictions of Rescorla, and Holmes et al. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The benefits of impossible tests: Assessing the role of error-correction in the pretesting effect.

Relative to studying alone, guessing the meanings of unknown words can improve later recognition of their meanings, even if those guesses were incorrect - the pretesting effect (PTE). The error-correction hypothesis suggests that incorrect guesses produce error signals that promote memory for the meanings when they are revealed. The current research sought to test the error-correction explanation of the PTE. In three experiments, participants studied unfamiliar Finnish-English word pairs by either studying each complete pair or by guessing the English translation before its presentation. In the latter case, the participants also guessed which of two categories the word belonged to. Hence, guesses from the correct category were semantically closer to the true translation than guesses from the incorrect category. In Experiment 1, guessing increased subsequent recognition of the English translations, especially for translations that were presented on trials in which the participants' guesses were from the correct category. Experiment 2 replicated these target recognition effects while also demonstrating that they do not extend to associative recognition performance. Experiment 3 again replicated the target recognition pattern, while also examining participants' metacognitive recognition judgments. Participants correctly judged that their memory would be better after small than after large errors, but incorrectly believed that making any errors would be detrimental, relative to study-only. Overall, the data are inconsistent with the error-correction hypothesis; small, within-category errors produced better recognition than large, cross-category errors. Alternative theories, based on elaborative encoding and motivated learning, are considered.

Toward Real-Time Muscle Force Inference and Device Control via Optical-Flow-Tracked Muscle Deformation.

Despite the utility of musculoskeletal dynamics modeling, there exists no safe, noninvasive method of measuring in vivo muscle output force in real time - limiting both biomechanical insight into dexterous motion and intuitive control of assistive devices. In this paper, we demonstrate that muscle deformation constitutes a promising, yet unexplored signal from which to 1) infer such forces and 2) build novel device control schemes. Through a case study of the elbow joint on a preliminary cohort of 10 subjects, we show that muscle deformation (specifically, thickness change of the brachioradialis, as measured via ultrasound and tracked via optical flow) correlates well with elbow output force to an extent comparable with standard surface electromyography (sEMG) activation during varied isometric elbow contraction. We then show that, given real-time visual feedback, subjects can readily perform a trajectory tracking task using this deformation signal, and that they largely prefer this method to a comparable sEMG-based control scheme and perform the tracking task with similar accuracy. Together, these contributions illustrate muscle deformation's potential utility for both biomechanical study of individual muscle dynamics and device control, in a manner that - thanks to, unlike sEMG, the localized nature of the signal and its tight mechanistic coupling to output force - is readily extensible to multiple muscles and device degrees of freedom. To enable such future extensions, all modeling, tracking, and visualization software described in this paper, as well as all raw and processed data, have been made available on SimTK as part of the Open-Arm project (https://simtk.org/projects/openarm) for general research use.

Virtual phone clinics in orthopaedics: evaluation of clinical application and sustainability.

AIMS: Adoption of virtual clinics has been accelerated by the COVID-19 pandemic and they will continue to form an integral part of healthcare delivery. Our objective was to evaluate virtual clinics in orthopaedic practice and determine how to use them effectively and sustainably. METHODS: We surveyed 100 consecutive patients participating in orthopaedic virtual phone clinic (VPC) at an academic hospital to evaluate patient satisfaction against face-to-face (F2F) consultations and obtain suggestions for improving patient experience, and we surveyed 23 clinicians who conducted orthopaedic VPCs in 2020. Data were correlated with clinic outcomes, reason for consultation, diagnosis, patient age and clinician grade. Consultation duration, clinician-associated costs and reimbursement were analysed. Significance was tested using two-tailed Student's t-test and Fisher's exact test. RESULTS: Patient satisfaction (out of 5) for VPC was significantly lower than F2F (4.1 vs 4.5, p=0.0003), and a larger proportion of VPC scored <3 compared with F2F (11% vs 2%). Higher VPC scores were associated with appointments for delivering results and where patients felt clinical examination was not needed. Patients suggested introducing video capability, adhering to appointment time and offering the choice of VPC or F2F. Mean clinician satisfaction scores for VPC were 4.3/5 and suggested indications for VPC included: routine surveillance, communication of results, discussing/consenting for surgery and vulnerable patients. Integrating video, providing private rooms and offering patients time intervals for VPC were recommended. Current National Health Service VPC structures uses greater clinician resources and generates lower reimbursement than F2F consultations, resulting in 11.5% reduction in reimbursement. CONCLUSION: VPC plays a valuable role when clinical evaluation has been performed or considered not necessary. Offering the choice of VPC or F2F, adding video capability and providing a time interval for VPC may reduce resource use and increase satisfaction. We recommend renegotiating VPC tariffs and cost-neutral modifications of clinic structure.

Pretesting boosts item but not source memory.

Two experiments examined the effect of pretesting on target recognition and source memory. In an initial encoding phase, participants attempted to learn the common English definitions of rare English words. For each rare word, the participants either guessed the definition of the rare English word before it was revealed (Pretest condition) or just studied the complete word pair without first guessing the definition (Read-only condition). To manipulate source information, the targets were either presented in different colours (Experiment 1) or lists (Experiment 2). In both experiments, the participants correctly recognised more targets from Pretest trials than Read-only trials, but showed no difference in source memory. Pretesting, therefore, appears to improve target recognition memory, but not memory for contextual information. The results are discussed in relation to semantic and episodic theories of the pretesting effect.

Similarities and differences: Comment on Chan et al. (2021).

Spicer et al. (2020) reported a series of causal learning experiments in which participants appeared to learn most readily about cues when they were not certain of their causal status and proposed that their results were a consequence of participants' use of theory protection. In the present issue, Chan et al. (2021) present an alternative view, using a modification of Rescorla and Wagner's (1972) influential model of learning. Although the explanation offered by Chan et al. appears very different from that suggested by Spicer et al., there are conceptual commonalities. Here we briefly discuss the similarities and differences of the 2 approaches and agree with Chan et al.'s proposal that the best way to advance the debate will be to test situations in which the 2 theories make differing predictions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Pretesting boosts recognition, but not cued recall, of targets from unrelated word pairs.

Attempting to retrieve the answer to a question on an initial test can improve memory for that answer on a subsequent test, relative to an equivalent study period. Such retrieval attempts can be beneficial even when they are unsuccessful, although this benefit is usually only seen with related word pairs. Three experiments examined the effects of pretesting for both related (e.g., pond-frog) and unrelated (e.g., pillow-leaf) word pairs on cued recall and target recognition. Pretesting improved subsequent cued recall performance for related but not for unrelated word pairs, relative to simply studying the word pairs. Tests of target recognition, by contrast, revealed benefits of pretesting for memory of targets from both related and unrelated word pairs. These data challenge popular theories that suggest that the pretesting effect depends on partial activation of the target during the pretesting phase.

Human appetitive Pavlovian-to-instrumental transfer: a goal-directed account.

Pavlovian-to-instrumental transfer (PIT) tasks assess the impact of environmental stimuli on instrumental actions. Since their initial translation from animal to human experiments, PIT tasks have provided insight into the mechanisms that underlie reward-based behaviour. This review first examines the main types of PIT tasks used in humans. We then seek to contribute to the current debate as to whether human PIT effects reflect a controlled, goal-directed process, or a more automatic, non-goal-directed mechanism. We argue that the data favour a goal-directed process. The extent to which the major theories of PIT can account for these data is then explored. We discuss a number of associative accounts of PIT as well as dual-process versions of these theories. Ultimately, however, we favour a propositional account, in which human PIT effects are suggested to be driven by both perceived outcome availability and outcome value. In the final section of the review, we present the potential objections to the propositional approach that we anticipate from advocates of associative link theories and our response to them. We also identify areas for future research.

Toward High Selectivity Aniline Synthesis Catalysis at Elevated Temperatures.

In connection with an initiative to enhance heat recovery from the large-scale operation of a heterogeneously catalyzed nitrobenzene hydrogenation process to produce aniline, it is necessary to operate the process at elevated temperatures (>100 °C), a condition that can compromise aniline selectivity. Alumina-supported palladium catalysts are selected as candidate materials that can provide sustained aniline yields at elevated temperatures. Two Pd/Al2O3 catalysts are examined that possess comparable mean Pd particle sizes (∼5 nm) for different Pd loading: 5 wt % Pd/Al2O3 and 0.3 wt % Pd/Al2O3. The higher Pd loading sample represents a reference catalyst for which the Pd crystallite morphology has previously been established. The lower Pd loading technical catalyst more closely corresponds to industrial specifications. The morphology of the Pd crystallites of the 0.3 wt % Pd/Al2O3 sample is explored by means of temperature-programmed infrared spectroscopy of chemisorbed CO. Reaction testing over the range of 60-180 °C shows effectively complete nitrobenzene conversion for both catalysts but with distinction in their selectivity profiles. The low loading catalyst is favored as it maximizes aniline selectivity and avoids the formation of overhydrogenated products. A plot of aniline yield as a function of WHSV for the 0.3 wt % Pd/Al2O3 catalyst at 100 °C yields a "volcano" like curve, indicating aniline selectivity to be sensitive to residence time. These observations are brought together to provide an indication of an aniline synthesis catalyst specification suited to a unit operation equipped for enhanced heat transfer.

Investigation of deltamethrin resistance in salmon lice (Lepeophtheirus salmonis) provides no evidence for roles of mutations in voltage-gated sodium channels.

BACKGROUND: The pyrethroid deltamethrin is used to treat infestations of farmed salmon by parasitic salmon lice, Lepeophtheirus salmonis (Krøyer). However, the efficacy of deltamethrin for salmon delousing is threatened by resistance development. In terrestrial arthropods, knockdown resistance (kdr) mutations of the voltage-gated sodium channel (Nav ), the molecular target for pyrethroids, can cause deltamethrin resistance. A putative kdr mutation of an L. salmonis sodium channel homologue (LsNav 1.3 I936V) has been identified previously. At the same time, deltamethrin resistance of L. salmonis has been shown to be inherited maternally and to be associated with mitochondrial DNA (mtDNA) mutations. This study assessed potential roles of the above putative kdr mutation as a determinant of deltamethrin resistance in laboratory strains and field populations of L. salmonis. RESULTS: The deltamethrin-resistant L. salmonis strain IoA-02 expresses the LsNav 1.3 I936V mutation but was susceptible to the non-ester pyrethroid etofenprox, a compound against which pyrethroid-resistant arthropods are usually cross-resistant if resistance is caused by Nav mutations. In a family derived from a cross between an IoA-02 male and a drug-susceptible female lacking the kdr mutation, deltamethrin resistance was not associated with the genotype at the LsNav 1.3 locus (P > 0.05). Similarly, in Scottish field populations of L. salmonis, LsNav 1.3 I936V showed no association with deltamethrin resistance. By contrast, genotypes at the mtDNA loci A14013G and A9030G were significantly associated with deltamethrin resistance (P < 0.001). CONCLUSION: In the studied L. salmonis isolates, deltamethrin resistance was unrelated to the LsNav 1.3 I936V mutation, but showed close association with mtDNA mutations.

Noncanonical IL6 Signaling-Mediated Activation of YAP Regulates Cell Migration and Invasion in Ovarian Clear Cell Cancer.

Ovarian clear cell adenocarcinoma (OCCA) is characterized by a particularly poor response to conventional chemotherapy and a short overall survival time in women with established disease. The development of targeted treatments for OCCA relies on a better understanding of its molecular characteristics. IL6 is strongly expressed in OCCA and may therefore provide a novel therapeutic target. Here we use CRISPR/Cas9 and conditional short hairpin interfering RNA to perform loss-of-function studies in human OCCA cell lines to explore the requirement for IL6 in vitro and in vivo. While reduction of IL6 expression exerted limited effects in vitro, its attenuation significantly impaired tumor growth and neovascularization in vivo. In contrast to typical signaling via STAT3, IL6 in OCCA signaled via a noncanonical pathway involving gp130, Src, and the Hippo pathway protein YAP. A high-throughput combination drug screen identified agents that enhanced cell killing following reduction of IL6 signaling. Intersection of screen hits obtained from two cell lines and orthogonal approaches to attenuation of IL6 yielded AKT and EGFR inhibitors as enhancers of the inhibitory monoclonal IL6 receptor antibody tocilizumab. This study defines for the first time the requirements for, and mechanisms of, signaling by IL6 in human OCCA cell lines and identifies potential combinatory therapeutic approaches. Given the molecular diversity of OCCA, further in vitro and in vivo studies are warranted to determine whether such approaches will overcome the limited efficacy of tocilizumab observed in ovarian cancer to date. SIGNIFICANCE: This study defines the requirements for and mechanisms of noncanonical signaling by IL6 in human ovarian clear cell adenocarcinoma cell lines and identifies combinatory therapeutic approaches to be explored clinically.

Theory protection in associative learning: Humans maintain certain beliefs in a manner that violates prediction error.

Three experiments were conducted to investigate a possible role for certainty in human causal learning. In these experiments, human participants were initially trained with a set of cues, each of which was followed by the presence or absence of an outcome. In a subsequent training stage, 2 of these cues were trained in a causal compound, and the change in associative strength for each of the cues was compared, using a procedure based on Rescorla (2001). In each experiment, the cues differed in both their causal certainty (on the part of participants) and size of their prediction error (with respect to the outcome). The cue with the larger prediction error was always the cue with the more certain causal status. According to established prediction error models (Bush & Mosteller, 1951; Rescorla, 2001; Rescorla & Wagner, 1972), a larger prediction error should result in a greater updating of associative strength. However, the opposite was observed, as participants always learned more about the cue with the smaller prediction error. A plausible explanation is that participants engaged in a form of theory protection, in which they were resistant to updating their existing beliefs about cues with a certain causal status. Instead, participants appeared to attribute outcomes to cues with a comparatively uncertain causal status, in an apparent violation of prediction error. The potential role of attentional processes (Mackintosh, 1975; Pearce & Hall, 1980) in explaining these results is also discussed. (PsycInfo Database Record (c) 2020 APA, all rights reserved).