mARC1 in MASLD: Modulation of lipid accumulation in human hepatocytes and adipocytes.

BACKGROUND: Mutations in the gene MTARC1 (mitochondrial amidoxime-reducing component 1) protect carriers from metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. MTARC1 encodes the mARC1 enzyme, which is localized to the mitochondria and has no known MASH-relevant molecular function. Our studies aimed to expand on the published human genetic mARC1 data and to observe the molecular effects of mARC1 modulation in preclinical MASH models. METHODS AND RESULTS: We identified a novel human structural variant deletion in MTARC1, which is associated with various biomarkers of liver health, including alanine aminotransferase levels. Phenome-wide Mendelian Randomization analyses additionally identified novel putatively causal associations between MTARC1 expression, and esophageal varices and cardiorespiratory traits. We observed that protective MTARC1 variants decreased protein accumulation in in vitro overexpression systems and used genetic tools to study mARC1 depletion in relevant human and mouse systems. Hepatocyte mARC1 knockdown in murine MASH models reduced body weight, liver steatosis, oxidative stress, cell death, and fibrogenesis markers. mARC1 siRNA treatment and overexpression modulated lipid accumulation and cell death consistently in primary human hepatocytes, hepatocyte cell lines, and primary human adipocytes. mARC1 depletion affected the accumulation of distinct lipid species and the expression of inflammatory and mitochondrial pathway genes/proteins in both in vitro and in vivo models. CONCLUSIONS: Depleting hepatocyte mARC1 improved metabolic dysfunction-associated steatotic liver disease-related outcomes. Given the functional role of mARC1 in human adipocyte lipid accumulation, systemic targeting of mARC1 should be considered when designing mARC1 therapies. Our data point to plasma lipid biomarkers predictive of mARC1 abundance, such as Ceramide 22:1. We propose future areas of study to describe the precise molecular function of mARC1, including lipid trafficking and subcellular location within or around the mitochondria and endoplasmic reticulum.

The impact of COVID-19 on acute psychiatric admissions for first and repeated episode psychosis.

BACKGROUND: There is limited evidence of the longer-term impact of the COVID-19 pandemic on acute admissions for psychosis in the UK. AIMS: We examined the impact of COVID-19 on rates of admissions for first and repeated episode psychosis, and changes in patient profile and seasonal patterns, over a period of 12 months. METHOD: We conducted a retrospective case note review of all patients admitted with a primary psychosis (F20-29 ICD 10 diagnosis) to an NHS psychiatric inpatient unit. We compared the 12 months pre-COVID-19 period between 1 March 2019 and 28 February 2020, and the 12 months post-COVID-19 period between 1 March 2020 and 28 February 2021. RESULTS: The results showed increase rates of admissions post-COVID-19 in both first and repeated episode psychosis, the patient profile had more females and older age in the repeated episode group, with increased employment rates. Combined group data for both pre- and post-COVID-19 periods showed an increased trend in spring and summer admissions, and even though not statistically significant, more pronounced post-COVID-19. CONCLUSIONS: Our findings highlight the effect of the COVID-19 pandemic on acute psychosis admissions over a 12-month period. The results provide evidence for the 'stress-pathogenesis' in the context of genetic vulnerability in psychosis. Preventative strategies in the context of the 'stress-pathogenesis model', improved access to and responsiveness within NHS transformation efforts needs to be adjusted to fit local need and environmental changes.

Prosodic and durational influences on the formant dynamics of Japanese vowels.

The relationship between prosodic structure and segmental realisation is a central question within phonetics. For vowels, this has been typically examined in terms of duration, leaving largely unanswered how prosodic boundaries influence spectral realisation. This study examines the influence of prosodic boundary strength-as well as duration and pauses-on vowel dynamics in spontaneous Japanese. While boundary strength has a marginal effect on dynamics, increased duration and pauses result in greater vowel peripherality and spectral change. These findings highlight the complex relationship between prosodic and segmental structure, and illustrate the importance of multifactorial analysis in corpus research.

ELEVATE - evaluating Temozolomide and Nivolumab in patients with advanced unresectable previously treated oesophagogastric adenocarcinoma with MGMT methylation: study protocol for a single arm phase II trial.

BACKGROUND: For patients with oesophagogastric adenocarcinoma, surgery is the only curative option and despite the use of multimodality therapy, which combines it with chemotherapy and/or radiotherapy, more than 50% of patients will relapse and die. Many UK patients present with advanced disease which is already inoperable or metastatic at diagnosis. For these patients, standard care chemotherapy only offers them survival of less than a year. Nivolumab, a checkpoint blockade inhibitor, has been found to work in some advanced cancers. It is proposed, for those where immunotherapy hasn't worked, that these immunologically evasive tumours need to be sensitized to immunotherapy drugs to allow them to act. METHODS: ELEVATE is a single arm phase II trial testing the overall response to nivolumab following temozolomide treatment in patients with advanced unresectable previously treated adenocarcinoma which is O6-methylguanine-DNA-methyltransferase (MGMT) methylated. 18 patients are being recruited from UK secondary care sites. To be eligible, participants must have been treated with at least 3 months of platinum and fluoropyrimidine chemotherapy. Participants will receive 50 mg/m2 temozolomide continuously for 3 months. If their disease progresses during the 3 months, they will stop temozolomide and start nivolumab at a dose of 240mg every 2 weeks. If there is no progression after 3 months the participant will continue taking temozolomide in combination with nivolumab. All treatment will stop once the participant progresses on nivolumab. The primary endpoint is the best overall response to nivolumab, using both Response Evaluation Criteria in Solid Tumours version 1.1 and immunotherapy modified Response Evaluation Criteria in Solid Tumours. Secondary endpoints include progression-free survival, overall survival, and quality of life. DISCUSSION: ELEVATE will provide evidence for whether giving nivolumab after temozolomide in patients with previously treated advanced oesophagogastric adenocarcinoma is safe and biologically effective prior to future randomised trials. TRIAL REGISTRATIONS: EudraCT Number: 2020-004771-41 (issued 01 October 2020); ISCRTN11398887 (registered 14 July 2021).

Service user experiences of care recommendations from the 2014 NICE guideline for bipolar disorder: a survey.

Clinical guidelines for mental health disorders produced by the National Institute of Care Excellence (NICE) emphasise a recovery-based approach clinical care with collaborative decision-making. The aim of the study was to explore service user experience of collaborative decision-making and recovery focussed care in relation to a NICE clinical guideline for bipolar disorder four years after publication. Participants with a clinical diagnosis of bipolar disorder were recruited from adult mental health services in four specialist mental health NHS Trusts through health professional or self-referral following advertisement. An online or written survey was designed with service user input to cover 40 NICE recommendations on recovery based or collaborative care. Participants completed the survey anonymously and independent of any health professional involvement. Of 222 participants, 72 (33.5%) reported to a great extent care was delivered in line with a positive recovery message; 55 (25.5%) reported that not much or no care was recovery based. Only four items (10%) on medication or the offer of crisis services were endorsed as collaborative decision-making with a health professional by >70% service users. Most decision-making in relation to the NICE clinical guideline for bipolar disorder was not delivered collaboratively and only some care was recovery focussed.

Sorafenib is associated with a reduced rate of tumour growth and liver function deterioration in HCV-induced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib has been the standard of care for patients with advanced hepatocellular carcinoma and although immunotherapeutic approaches are now challenging this position, it retains an advantage in HCV-seropositive patients. We aimed to quantify the rate of tumour progression in patients receiving sorafenib and relate this figure to survival, both overall, and according to viral status. METHODS: Using serial data from an international clinical trial we applied a joint model to combine survival and progression over time in order to estimate the rate of tumour growth as assessed by tumour burden and serum alpha-fetoprotein, and the impact of treatment on liver function. RESULTS: High tumour burden at baseline was associated with an increased risk of death. In patients still alive at the end of the study, the progression in relation to tumour burden was very low compared to those who died within the study. Overall, the change in mean tumour burden was 0.12 mm per day or an absolute growth rate of 3.6 mm/month. Median doubling time was 665 days. For those who progressed above 0.12 mm per day or the 12% rate, median survival was 234 days compared to 384 days if the rate was below 12%. Tumour growth rate and serum alpha-fetoprotein rise were significantly lower in those who were HCV seropositive as was the rate of decline in liver function. These results were replicated in 2 independent patient groups. CONCLUSION: Our analysis suggests that sorafenib treatment is associated with improved survival in patients with advanced hepatocellular carcinoma mainly by decreasing the rate of tumour growth and liver function deterioration among patients with HCV infection. LAY SUMMARY: Among patients receiving sorafenib for advanced hepatocellular carcinoma the rate of tumour growth (as assessed by changes in tumour size and the biomarker alpha-fetoprotein) and the deterioration of liver function is less in those who have the hepatitis C virus, than in those who do not.

Structured speaker variability in Japanese stops: Relationships within versus across cues to stop voicing.

A number of recent studies have observed that phonetic variability is constrained across speakers, where speakers exhibit limited variation in the signalling of phonological contrasts in spite of overall differences between speakers. This previous work focused predominantly on controlled laboratory speech and on contrasts in English and German, leaving unclear how such speaker variability is structured in spontaneous speech and in phonological contrasts that make substantial use of more than one acoustic cue. This study attempts to both address these empirical gaps and expand the empirical scope of research investigating structured variability by examining how speakers vary in the use of positive voice onset time and voicing during closure in marking the stop voicing contrast in Japanese spontaneous speech. Strong covarying relationships within each cue across speakers are observed, while between-cue relationships across speakers are much weaker, suggesting that structured variability is constrained by the language-specific phonetic implementation of linguistic contrasts.

Toward "English" Phonetics: Variability in the Pre-consonantal Voicing Effect Across English Dialects and Speakers.

Recent advances in access to spoken-language corpora and development of speech processing tools have made possible the performance of "large-scale" phonetic and sociolinguistic research. This study illustrates the usefulness of such a large-scale approach-using data from multiple corpora across a range of English dialects, collected, and analyzed with the SPADE project-to examine how the pre-consonantal Voicing Effect (longer vowels before voiced than voiceless obstruents, in e.g., bead vs. beat) is realized in spontaneous speech, and varies across dialects and individual speakers. Compared with previous reports of controlled laboratory speech, the Voicing Effect was found to be substantially smaller in spontaneous speech, but still influenced by the expected range of phonetic factors. Dialects of English differed substantially from each other in the size of the Voicing Effect, whilst individual speakers varied little relative to their particular dialect. This study demonstrates the value of large-scale phonetic research as a means of developing our understanding of the structure of speech variability, and illustrates how large-scale studies, such as those carried out within SPADE, can be applied to other questions in phonetic and sociolinguistic research.

Durational Evidence That Tokyo Japanese Vowel Devoicing Is Not Gradient Reduction.

A central question in the Japanese high vowel devoicing literature concerns whether vowels are devoiced through a categorical process or via gradient reduction. Examining how vowel height and consonantal voicing condition phrase-internal CV duration in a corpus of spontaneous Tokyo Japanese, it was found that CVs containing high vowels are substantially shorter before voiceless consonants, whilst non-high vowels do not exhibit comparable shortening. This quantitative difference between CV durations suggests a controlled temporal compression of the CV, consistent with views that Japanese vowel devoicing is produced through a categorical process targeting high vowels preceding voiceless consonants, and supports previous observations made of elicited productions.

A top-down saliency model with goal relevance.

Most visual saliency models that integrate top-down factors process task and context information using machine learning techniques. Although these methods have been successful in improving prediction accuracy for human attention, they require significant training data and are unable to provide an understanding of what makes information relevant to a task such that it will attract gaze. This means that we still lack a general theory for the interaction between task and attention or eye movements. Recently, Tanner and Itti (2017) proposed the theory of goal relevance to explain what makes information relevant to goals. In this work, we record eye movements of 80 participants who each played one of four variants of a Mario video game and construct a combined saliency model using features from three sources: bottom-up, learned top-down, and goal relevance. We use this model to predict the eye behavior and find that the addition of goal relevance significantly improves the Normalized Scanpath Saliency score of the model from 4.35 to 5.82 (p < 1 × 10-100).

Impact of the widespread pharmaceutical pollutant fluoxetine on behaviour and sperm traits in a freshwater fish.

Pharmaceutical pollutants are detected in aquatic habitats and wildlife tissues globally. One widespread contaminant of major concern is the antidepressant fluoxetine, which can affect behavioural and physiological processes in non-target species. Despite this, effects of fluoxetine on wildlife behaviour have seldom been investigated across multiple fitness-related contexts, especially at environmentally realistic concentrations. Accordingly, we examined impacts of 35-day fluoxetine exposure at two environmentally relevant concentrations (31 and 374 ng/L) across a suite of fitness-related contexts in wild-caught male mosquitofish (Gambusia holbrooki). First, we investigated anxiety-related behaviours (boldness, exploration and activity) in a novel environment (maze arena) and found no significant impacts of exposure. Second, we tested effects of fluoxetine in a reproductive context, including mating behaviour and sperm quality. We found that, relative to controls, fluoxetine exposure resulted in males spending a greater amount of time pursuing females. Further, low-exposed males were more likely to attempt copulation than unexposed males. Lastly, we investigated across-context behavioural correlations, and how fluoxetine exposure might affect such relationships. A significant positive correlation was detected in control fish between activity levels in the maze and time spent pursuing females in the reproductive assay. This relationship was disrupted by fluoxetine at both exposure levels. This is the first evidence that field-detected concentrations of a pharmaceutical pollutant can disturb across-context behavioural correlations in wildlife. Our findings provide clear evidence that fluoxetine can produce context-specific behavioural effects in fish and underscore how pharmaceutical exposure at field-detected concentrations can induce important shifts in wildlife behaviour.

The longitudinal effect of ejaculation on seminal vesicle fluid volume and whole-prostate ADC as measured on prostate MRI.

OBJECTIVE: To prospectively investigate the longitudinal effect of ejaculatory abstinence on MRI-measured seminal vesicle (SV) volume and whole-prostate ADC over consecutive days. METHODS: 15 healthy male volunteers (mean 35.9 years, range 27-53) underwent 3-T MRI at baseline and 1, 2 and 3 days post-ejaculation. Prostate and SV volumes were derived by volume segmentation and whole-gland apparent diffusion coefficient (ADC) values calculated. A mixed-effects linear regression compared ADC values and prostate/seminal vesicle volumes in each volunteer between studies in a pairwise manner. RESULTS: All subjects completed the four MRIs. Mean prostate volume was 22.45 cm3 (range 13.04-31.21 cm3), with no change between the four studies (p = 0.89-0.99). 13/15 subjects showed SV volume reduction from baseline to day 1, with group-mean decreasing from 6.45 to 4.80 cm3 (-25.6%, p < 0.001), and a significant reduction from baseline to day 2 (-18.1%, p = 0.002). There was a significant volume increase from both day 1 (+21.3%, p = 0.006) and day 2 (+10.2%, p = 0.022) to day 3 post-ejaculation. There was a significant reduction in ADC from 1.105 at baseline to 1.056 × 10-3 mm2/s at day 1 (mean -4.3%, p = 0.009). CONCLUSION: The longitudinal effect of ejaculation on SV volume was demonstrated. Significant reductions in SV volume and whole-gland ADC were observed post-ejaculation, supporting a 3-day period of abstinence before prostate MRI. KEY POINTS: • Seminal vesicle volume significantly reduced 24 h post-ejaculation remaining reduced at day 2 • Seminal vesicle fluid volume significantly increased from day 1 to day 3 post-ejaculation • There was a significant reduction in whole-gland prostate ADC values day 1 post-ejaculation • 3-day abstinence from ejaculation is required to ensure maximal seminal vesicle distension.

Case 243: Extramedullary Hematopoiesis in an Adrenal Myelolipoma.

History A 30-year-old man presented to the emergency department with epigastric pain. He was vomiting and in distress, and he had a history of thalassemia. Physical examination findings were unremarkable. Pertinent blood results were a hemoglobin level of 10.5 g/dL (6.52 mmol/L) (normal range, 13.5-18.0 g/dL [8.38-11.17 mmol/L]) and a bilirubin level of 62 µmol/L (normal range, 3-17 µmol/L). The remaining hematologic and biochemical results were normal. Aortic dissection was suspected clinically, so the patient was referred for imaging. Unenhanced and arterial phase computed tomographic (CT) images were acquired initially. Ultrasonography (US) (images not shown) and magnetic resonance (MR) imaging were performed subsequently. Because of the imaging findings, the patient was referred for surgery.

Goal relevance as a quantitative model of human task relevance.

The concept of relevance is used ubiquitously in everyday life. However, a general quantitative definition of relevance has been lacking, especially as pertains to quantifying the relevance of sensory observations to one's goals. We propose a theoretical definition for the information value of data observations with respect to a goal, which we call "goal relevance." We consider the probability distribution of an agent's subjective beliefs over how a goal can be achieved. When new data are observed, its goal relevance is measured as the Kullback-Leibler divergence between belief distributions before and after the observation. Theoretical predictions about the relevance of different obstacles in simulated environments agreed with the majority response of 38 human participants in 83.5% of trials, beating multiple machine-learning models. Our new definition of goal relevance is general, quantitative, explicit, and allows one to put a number onto the previously elusive notion of relevance of observations to a goal. (PsycINFO Database Record

Biologically plausible learning in neural networks with modulatory feedback.

Although Hebbian learning has long been a key component in understanding neural plasticity, it has not yet been successful in modeling modulatory feedback connections, which make up a significant portion of connections in the brain. We develop a new learning rule designed around the complications of learning modulatory feedback and composed of three simple concepts grounded in physiologically plausible evidence. Using border ownership as a prototypical example, we show that a Hebbian learning rule fails to properly learn modulatory connections, while our proposed rule correctly learns a stimulus-driven model. To the authors' knowledge, this is the first time a border ownership network has been learned. Additionally, we show that the rule can be used as a drop-in replacement for a Hebbian learning rule to learn a biologically consistent model of orientation selectivity, a network which lacks any modulatory connections. Our results predict that the mechanisms we use are integral for learning modulatory connections in the brain and furthermore that modulatory connections have a strong dependence on inhibition.

Reconciling Saliency and Object Center-Bias Hypotheses in Explaining Free-Viewing Fixations.

Predicting where people look in natural scenes has attracted a lot of interest in computer vision and computational neuroscience over the past two decades. Two seemingly contrasting categories of cues have been proposed to influence where people look: 1) low-level image saliency and 2) high-level semantic information. Our first contribution is to take a detailed look at these cues to confirm the hypothesis proposed by Henderson and Nuthmann and Henderson that observers tend to look at the center of objects. We analyzed fixation data for scene free-viewing over 17 observers on 60 object-annotated images with various types of objects. Images contained different types of scenes, such as natural scenes, line drawings, and 3-D rendered scenes. Our second contribution is to propose a simple combined model of low-level saliency and object center bias that outperforms each individual component significantly over our data, as well as on the Object and Semantic Images and Eye-tracking data set by Xu et al. The results reconcile saliency with object center-bias hypotheses and highlight that both types of cues are important in guiding fixations. Our work opens new directions to understand strategies that humans use in observing scenes and objects, and demonstrates the construction of combined models of low-level saliency and high-level object-based information.

GDF11 does not rescue aging-related pathological hypertrophy.

RATIONALE: Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor-ß super family of secreted factors. A recent study showed that reduced GDF11 blood levels with aging was associated with pathological cardiac hypertrophy (PCH) and restoring GDF11 to normal levels in old mice rescued PCH. OBJECTIVE: To determine whether and by what mechanism GDF11 rescues aging dependent PCH. METHODS AND RESULTS: Twenty-four-month-old C57BL/6 mice were given a daily injection of either recombinant (r) GDF11 at 0.1 mg/kg or vehicle for 28 days. rGDF11 bioactivity was confirmed in vitro. After treatment, rGDF11 levels were significantly increased, but there was no significant effect on either heart weight or body weight. Heart weight/body weight ratios of old mice were not different from 8- or 12-week-old animals, and the PCH marker atrial natriuretic peptide was not different in young versus old mice. Ejection fraction, internal ventricular dimension, and septal wall thickness were not significantly different between rGDF11 and vehicle-treated animals at baseline and remained unchanged at 1, 2, and 4 weeks of treatment. There was no difference in myocyte cross-sectional area rGDF11 versus vehicle-treated old animals. In vitro studies using phenylephrine-treated neonatal rat ventricular myocytes, to explore the putative antihypertrophic effects of GDF11, showed that GDF11 did not reduce neonatal rat ventricular myocytes hypertrophy, but instead induced hypertrophy. CONCLUSIONS: Our studies show that there is no age-related PCH in disease-free 24-month-old C57BL/6 mice and that restoring GDF11 in old mice has no effect on cardiac structure or function.

Radiological Evaluation of Abdominal Endovascular Aortic Aneurysm Repair.

Endovascular aortic aneurysm repair (EVAR) is an alternative to open surgical repair of aortic aneurysms offering lower perioperative mortality and morbidity. As experience increases, clinicians are undertaking complex repairs with hostile aortic anatomy using branched or fenestrated devices or extra components such as chimneys to ensure perfusion to visceral branch vessels whilst excluding the aneurysm. Defining the success of EVAR depends on both clinical and radiographic criteria, but ultimately depends on complete exclusion of the aneurysm from the circulation. Aortic stent grafts are monitored using a combination of imaging modalities including computed tomography angiography (CTA), ultrasonography, magnetic resonance imaging, plain films, and nuclear medicine studies. This article describes when and how to evaluate aortic stent grafts using each of these modalities along with the characteristic features of several of the main stent grafts currently used in clinical practice. The commonly encountered complications from EVAR are also discussed and how they can be detected using each imaging modality. As the radiation burden from serial follow up CTA imaging is now becoming a concern, different follow-up imaging strategies are proposed depending on the complexity of the repair and based on the relative merits and disadvantages of each imaging modality.