Loss of Cardiac Splicing Regulator RBM20 Is Associated With Early-Onset Atrial Fibrillation.

We showed an association between atrial fibrillation and rare loss-of-function (LOF) variants in the cardiac splicing regulator RBM20 in 2 independent cohorts. In a rat model with loss of RBM20, we demonstrated altered splicing of sarcomere genes (NEXN, TTN, TPM1, MYOM1, and LDB3), and differential expression in key cardiac genes. We identified altered sarcomere and mitochondrial structure on electron microscopy imaging and found compromised mitochondrial function. Finally, we demonstrated that 3 novel LOF variants in RBM20, identified in patients with atrial fibrillation, lead to significantly reduced splicing activity. Our results implicate alternative splicing as a novel proarrhythmic mechanism in the atria.

Identifying excessive chronic alcohol use with phosphatidylethanol in patients with suspected severe injury-results from the IDART study.

INTRODUCTION: Acute and chronic alcohol use are well-known risk factors for accidents and injuries, and concurrent psychoactive drug use can increase injury risk further. Phosphatidylethanol (PEth) 16:0/18:1 is a biomarker used to determine alcohol consumption the previous 3-4 weeks. The aim was to investigate the prevalence of chronic alcohol use in trauma patients, as determined by PEth 16:0/18:1 concentrations, and how excessive chronic alcohol use relate to demographic variables, injury mechanisms and drug use. SETTING: Patients received at Norwegian trauma hospitals from March 2019 to February 2020. The study is part of the Impairing Drugs and Alcohol as Risk factors for Traumatic Injuries study. METHODS: All patients aged ≥ 16 years received with trauma team were included in the study. Data on injury date and mechanism, gender and age was registered. Blood samples were analyzed for 22 psychoactive medicinal and illicit drugs, ethanol and phosphatidylethanol 16:0/18:1. Regression analyses were conducted to assess associations between alcohol use and gender, age, injury mechanism and drug use. RESULTS AND CONCLUSION: Of the 4845 patients included in the study, 10% had PEth 16:0/18:1 concentration ≥ 600 nM (~430 ng/mL), indicative of excessive chronic alcohol use. Being male, between 44-61 years old, involved in violence, and testing positive for medicinal drugs was associated with excessive chronic alcohol use.Excessive chronic alcohol use was common among males, middle-aged, patients with violence as injury mechanism and those with medicinal drug use. These findings emphasize the need to detect and treat excessive chronic alcohol use among trauma patients.

Monkeypox Virus Immune Evasion and Eye Manifestation: Beyond Eyelid Implications.

Monkeypox virus (MPXV), belonging to the Poxviridae family and Orthopoxvirus genus, is closely related to the smallpox virus. Initial prodromal symptoms typically include headache, fever, and lymphadenopathy. This review aims to detail various ocular manifestations and immune evasion associated with the monkeypox viral infection and its complications, making it appropriate as a narrative review. Common external ocular manifestations of MPXV typically involve a generalized pustular rash, keratitis, discharges, and dried secretions related to conjunctival pustules, photophobia, and lacrimation. Orthopoxviruses can evade host immune responses by secreting proteins that antagonize the functions of host IFNγ, CC and CXC chemokines, IL-1ß, and the complement system. One of the most important transcription factors downstream of pattern recognition receptors binding is IRF3, which controls the expression of the crucial antiviral molecules IFNα and IFNß. We strongly recommend that ophthalmologists include MPXV as part of their differential diagnosis when they encounter similar cases presenting with ophthalmic manifestations such as conjunctivitis, blepharitis, or corneal lesions. Furthermore, because non-vaccinated individuals are more likely to exhibit these symptoms, it is recommended that healthcare administrators prioritize smallpox vaccination for at-risk groups, including very young children, pregnant women, older adults, and immunocompromised individuals, especially those in close contact with MPXV cases.

Prevalence of use and impairment from drugs and alcohol among trauma patients: A national prospective observational study.

BACKGROUND: Being under the influence of psychoactive substances increases the risk of involvement in and dying from a traumatic event. The study is a prospective population-based observational study that aims to determine the prevalence of use and likely impairment from psychoactive substances among patients with suspected severe traumatic injury. METHOD: This study was conducted at 35 of 38 Norwegian trauma hospitals from 1 March 2019 to 29 February 2020. All trauma admissions for patients aged ≥ 16 years admitted via trauma team activation during the study period were eligible for inclusion. Blood samples collected on admission were analysed for alcohol, benzodiazepines, benzodiazepine-like hypnotics (Z-drugs), opioids, stimulants, and cannabis (tetrahydrocannabinol). RESULTS: Of the 4878 trauma admissions included, psychoactive substances were detected in 1714 (35 %) and in 771 (45 %) of these, a combination of two or more psychoactive substances was detected. Regarding the level of impairment, 1373 (28 %) admissions revealed a concentration of one or more psychoactive substances indicating likely impairment, and 1052 (22 %) highly impairment. Alcohol was found in 1009 (21 %) admissions, benzodiazepines and Z-drugs in 613 (13 %), opioids in 467 (10 %), cannabis in 352 (7 %), and stimulants in 371 (8 %). Men aged 27-43 years and patients with violence-related trauma had the highest prevalence of psychoactive substance use with respectively 424 (50 %) and 275 (80 %) testing positive for one or more compounds. CONCLUSION: The results revealed psychoactive substances in 35 % of trauma admissions, 80 % of which were likely impaired at the time of traumatic injury. A combination of several psychoactive substances was common, and younger males and patients with violence-related injuries were most often impaired. Injury prevention strategies should focus on high-risk groups and involve the prescription of controlled substances. We should consider toxicological screening in trauma admissions and incorporation of toxicological data into trauma registries.

Approximating exposure therapy in the lab: Replacing the CS+ with a similar versus a different stimulus and including additional stimuli resembling the CS+ during extinction.

Recent studies have shown that extinction training including the conditional stimulus (CS+) and stimuli that are similar to the CS + enhances extinction retention and generalisation to novel stimuli. However, in a clinical setting, the CS+ is rarely available for use during exposure therapy. The aim of the present study was to determine if replacing the CS+ with a similar versus different stimulus, and including other similar stimuli during extinction, could reduce fear at test on par with extinction using the original CS+ with and without other similar stimuli. In an experiment conducted in a single session, participants completed a habituation phase followed by an acquisition phase using two dog images presented with (CS+) and without (CS-) an acoustic unconditional stimulus (US). Participants were randomly allocated to four extinction conditions: similar CS + dog with novel dog images (Similar replacement extinction condition); different CS + dog with novel dog images (Different replacement extinction condition); original CS + dog with novel dog images (Multiple extinction control condition); and original CS + without novel dog images (Standard extinction control condition). All participants completed a test phase with the original CSs followed by a generalisation test with another two novel dog images. All groups acquired, and then extinguished differential skin conductance responses (SCRs) with no differences observed between groups. Whereas the Similar replacement extinction group and the Multiple and Standard extinction control groups did not exhibit significant differential SCRs when re-exposed to the original CS + relative to the CS- at test, differential responding to the CSs was significant at test in the Different replacement extinction group. There were no significant differences between groups in SCRs to the two novel dog images during the generalisation phase and in between-phase subjective ratings. Findings suggest that replacement stimuli used during extinction should be as similar as possible to the CS + to reduce physiological arousal to the original CS+.

The influence of cross unconditional stimulus reinstatement on electrodermal responding and conditional stimulus valence in differential fear conditioning.

We examined whether the inhibitory Conditional Stimulus (CS)-no Unconditional Stimulus (US) association formed during extinction can be triggered by a novel US during the reinstatement of conditional electrodermal responding and self-reported CS valence in human differential fear conditioning. Participants were trained with either a shock or an aversive scream US before undergoing extinction. Participants then received either the same (i.e., shock_shock or scream_scream) or a different US during reinstatement (i.e., shock_scream, scream_shock). Differential conditioning across all indices was stronger when a shock US was used during acquisition. After reinstatement, electrodermal responding to both the CS+ and the CS- increased regardless of the type of US used during reinstatement (non-differential reinstatement). Differential CS valence evaluations were larger after reinstatement in the groups that received the same US during acquisition and reinstatement (differential reinstatement), but differential evaluations did not increase in the groups receiving a different US at reinstatement. This dissociation suggests that the reinstatement of negative stimulus valence and the reinstatement of expectancy learning may differ.

Aspirin-Triggered Resolvin D1 (AT-RvD1) Protects Mouse Skin against UVB-Induced Inflammation and Oxidative Stress.

Intense exposure to UVB radiation incites excessive production of reactive oxygen species (ROS) and inflammation. The resolution of inflammation is an active process orchestrated by a family of lipid molecules that includes AT-RvD1, a specialized proresolving lipid mediator (SPM). AT-RvD1 is derived from omega-3, which presents anti-inflammatory activity and reduces oxidative stress markers. The present work aims to investigate the protective effect of AT-RvD1 on UVB-induced inflammation and oxidative stress in hairless mice. Animals were first treated with 30, 100, and 300 pg/animal AT-RvD1 (i.v.) and then exposed to UVB (4.14 J/cm2). The results showed that 300 pg/animal of AT-RvD1 could restrict skin edema, neutrophil and mast cell infiltration, COX-2 mRNA expression, cytokine release, and MMP-9 activity and restore skin antioxidant capacity as per FRAP and ABTS assays and control O2•- production, lipoperoxidation, epidermal thickening, and sunburn cells development. AT-RvD1 could reverse the UVB-induced downregulation of Nrf2 and its downstream targets GSH, catalase, and NOQ-1. Our results suggest that by upregulating the Nrf2 pathway, AT-RvD1 promotes the expression of ARE genes, restoring the skin's natural antioxidant defense against UVB exposition to avoid oxidative stress, inflammation, and tissue damage.

The influence of instructions on generalised valence - conditional stimulus instructions after evaluative conditioning update the explicit and implicit evaluations of generalisation stimuli.

Generalisation in evaluative conditioning occurs when the valence acquired by a conditional stimulus (CS), after repeated pairing with an unconditional stimulus (US), spreads to stimuli that are similar to the CS (generalisation stimuli, GS). CS evaluations can be updated via CS instructions that conflict with prior conditioning (negative conditioning + positive instruction). We examined whether CS instructions can update GS evaluations after conditioning. We used alien stimuli where one alien (CSp) from a fictional group was paired with pleasant US images and another alien (CSu) from a different group was paired with unpleasant US images. The other members from the two groups were used as GSs. After conditioning, participants received negative CSp instructions and positive CSu instructions. In Experiment 1, explicit and implicit GS evaluations were measured before and after the instructions. In Experiment 2, we used a between-participants design where one group received positive/negative CS instructions while a control group received neutral instructions. In both experiments, the positive/negative CS instructions caused a reversal of explicit GS evaluations and an elimination of implicit GS evaluations. The findings suggest that generalised evaluations can change after CS instructions which may have implications for interventions aimed at reducing negative group attitudes.

Effects of pre-analytical sample care and analysis methodology on measures of metabolic acidosis in hemodialysis patients.

INTRODUCTION: We evaluated the effects of pre-analytical care on total carbon dioxide (tCO2 ) in hemodialysis patients, as calculated by blood gas analysis (ctCO2 ) or measured by an enzymatic assay (mtCO2 ). METHODS: Blood samples were collected via vascular access before dialysis sessions. For blood gas analysis, eight aliquots were collected, refrigerated or non-refrigerated, and analyzed at 0, 4, 8, and 24 h after collection. A blood sample was then collected for the enzymatic method and distributed into 14 aliquots. Half of the aliquots were refrigerated. The samples analyzed at time point 0 were centrifuged immediately. The remaining aliquots of both the refrigerated and non-refrigerated clusters were centrifuged before storage. Samples were analyzed at 4, 8, and 24 h post-collection. FINDINGS: By blood gas analysis, no significant change was found in bicarbonate values over time, either in the non-refrigerated or refrigerated samples. ctCO2 values during the experiment showed a minor but statistically significant increase of questionable clinical relevance in both non-refrigerated and refrigerated aliquots. In the enzymatic assay, the reduction in mtCO2 levels during the experiment was negligible. The median absolute reductions at the end of the experiment were 1.77, 1.21, 1.04, and 1.12 mmol/L for the non-centrifuged/non-refrigerated, centrifuged/non-refrigerated, non-centrifuged/refrigerated, and centrifuged/refrigerated aliquots, respectively. DISCUSSION: Our results suggest that measured or calculated tCO2 levels of capped and cooled samples are adequate for analyzing the acid-base status of hemodialysis patients, even when such determination is not performed immediately after collection.

Biomarker signature and pathophysiological pathways in patients with chronic heart failure and metabolic syndrome.

AIM: The comorbidities that collectively define metabolic syndrome are common in patients with heart failure. However, the role of metabolic syndrome in the pathophysiology of heart failure is not well understood. We therefore investigated the clinical and biomarker correlates of metabolic syndrome in patients with heart failure. METHODS AND RESULTS: In 1103 patients with heart failure, we compared the biomarker expression using a panel of 363 biomarkers among patients with (n = 468 [42%]) and without (n = 635 [58%]) metabolic syndrome. Subsequently, a pathway overrepresentation analysis was performed to identify key biological pathways. Findings were validated in an independent cohort of 1433 patients with heart failure of whom 615 (43%) had metabolic syndrome. Metabolic syndrome was defined as the presence of three or more of five criteria, including central obesity, elevated serum triglycerides, reduced high-density lipoprotein cholesterol, insulin resistance and hypertension. The most significantly elevated biomarkers in patients with metabolic syndrome were leptin (log2 fold change 0.92, p = 5.85 × 10-21 ), fatty acid-binding protein 4 (log2 fold change 0.61, p = 1.21 × 10-11 ), interleukin-1 receptor antagonist (log2 fold change 0.47, p = 1.95 × 10-13 ), tumour necrosis factor receptor superfamily member 11a (log2 fold change 0.35, p = 4.16 × 10-9 ), and proto-oncogene tyrosine-protein kinase receptor Ret (log2 fold change 0.31, p = 4.87 × 10-9 ). Network analysis identified 10 pathways in the index cohort and 6 in the validation cohort, all related to inflammation. The primary overlapping pathway in both the index and validation cohorts was up-regulation of the natural killer cell-mediated cytotoxicity pathway. CONCLUSION: Metabolic syndrome is highly prevalent in heart failure and is associated with biomarkers and pathways relating to obesity, lipid metabolism and immune responses underlying chronic inflammation.

Sympathetic activity is not a main cause of blood pressure reduction with exercise training in un-medicated middle-aged/older men.

BACKGROUND: This study tested the hypothesis that training reduces resting sympathetic activity and improves baroreflex control in both hypertensive and normotensive men but reduces blood pressure only in hypertensive men. METHODS: Middle-aged/older un-medicated stage-1 hypertensive males (mean age 55 ± 3 years; n = 13) and normotensive controls (mean age 60 ± 5 years; n = 12) participated in 8 weeks of supervised high-intensity interval spinning training. Before and after training, muscle sympathetic nerve activity (MSNA) and blood pressure were measured at rest and during a sympatho-excitatory cold pressor test (CPT). Based on the measurements, baroreceptor sensitivity and baroreceptor threshold were calculated. RESULTS: Resting MSNA and baroreceptor sensitivity were similar for the hypertensive and the normotensive groups. Training lowered MSNA (p < 0.05), expressed as burst frequency (burst/min), overall, and to a similar extent, in both groups (17% and 27%, respectively, in hypertensive and normotensive group), whereas blood pressure was only significantly (p < 0.05) lowered (by 4 mmHg in both systolic and diastolic pressure) in the hypertensive group. Training did not (p > 0.05) alter the MSNA or blood pressure response to CPT or increase baroreceptor sensitivity but reduced (p < 0.05) the baroreceptor threshold with a main effect for both groups. Training adherence and intensity were similar in both groups yet absolute maximal oxygen uptake increased by 15% in the normotensive group only. CONCLUSION: The dissociation between the training induced changes in resting MSNA, lack of change in baroreflex sensitivity and the change in blood pressure, suggests that MSNA is not a main cause of the blood pressure reduction with exercise training in un-medicated middle-aged/older men.

Child poverty and health inequalities in the UK: a guide for paediatricians.

One in three children in the UK lives in relative poverty. There are clear and consistent links between child poverty and paediatric morbidity and mortality. In this review, we discuss drivers for family poverty in the UK, and how this leads to poor child health outcomes. We present a framework for healthcare professionals and institutions to consider interventions and strategies relating to socioeconomic health inequalities. We will focus on approaches to mitigate the effects of child poverty on children using our services at a local level and outline the importance of healthcare workers advocating for structural and high-level policy change to address the deep-rooted societal problems that cause child poverty.

Shock loss measurements in non-ideal supersonic flows of organic vapors.

This paper presents the first ever direct measurements of total pressure losses across shocks in supersonic flows of organic vapors in non-ideal conditions, so in the thermodynamic region close to the liquid-vapor saturation curve and the critical point where the ideal gas law is not applicable. Experiments were carried out with fluid siloxane MM (hexamethyldisiloxane, C 6 H 18 OSi 2 ), commonly employed in medium-/high-temperature organic Rankine cycles (ORCs), in the Test Rig for Organic VApors (TROVA), a blowdown wind tunnel at the Laboratory of Compressible fluid dynamics for Renewable Energy Applications (CREA lab) of Politecnico di Milano. A total pressure probe was inserted in superheated MM vapor flow at Mach number ∼ 1.5 with total conditions in the range 215 - 230 ∘ C and 2 - 12 bar at varying levels of non-ideality, with a compressibility factor evaluated at total conditions between Z T = 0.68 - 0.98 . These operating conditions are representative of the first-stage stator of ORC turbines. Measured shock losses were compared with those calculated from pre-shock quantities by solving conservation equations across a normal shock, with differences always below 2 % attesting a satisfactory reliability of the implemented experimental procedure. An in-depth analysis was then carried out, highlighting the direct effects of non-ideality on shock intensity. Even at the mildly non-ideal conditions with Z T ≳ 0.70 considered here, non-ideality was responsible for a significantly stronger shock compared to the ideal gas limit at same pre-shock Mach number, with differences as large as 6 % .

Intolerance of uncertainty affects electrodermal responses during fear acquisition: Evidence from electrodermal responses to unconditional stimulus omission.

Past research has shown that Intolerance of Uncertainty (IU) affects Pavlovian fear conditioning processes. In particular, extinction of learned fear is delayed in those reporting high IU. Reports of differences during acquisition are less consistent with most of the studies reporting no evidence for effects of IU. This may be due to past studies' focus on first interval electrodermal responses or fear potentiated startle, rather than on indices that may better capture uncertainty - like the response to the absence of a probabilistic unconditional stimulus. The current analysis combined data across three experiments that employed a 50 % reinforcement schedule and assessed electrodermal responses and (in two experiments) ratings of conditional stimulus pleasantness. Participants scoring high on IU showed overall larger electrodermal first interval responses during habituation and acquisition but did not differ from those scoring low on IU in differential conditioning (the difference between CS+ and CS-), as indicated by electrodermal first or second interval responses or ratings of CS pleasantness. However, participants high in IU showed larger differential third interval electrodermal responses to the omission of the electro-tactile unconditional stimulus during acquisition. Some evidence for this difference emerged in each experiment, supporting the reliability of the result. The current results suggest that effects of IU emerge in conditions of high uncertainty in Pavlovian fear learning tasks, such as during the omission of probabilistic unconditional stimuli.

Conceptual generalisation in fear conditioning using single and multiple category exemplars as conditional stimuli - electrodermal responses and valence evaluations generalise to the broader category.

Conceptual generalisation occurs when conditional responses generalise to novel stimuli from the same category. Past research demonstrates that physiological fear responses generalise across categories, however, conceptual generalisation of stimulus valence evaluations during fear conditioning has not been examined. We investigated whether conceptual generalisation, as indexed by electrodermal responses and stimulus evaluations, would occur, and differ after training with single or multiple conditional stimuli (CSs). Stimuli from two of four categories (vegetables, farm animals, clothing, and office supplies) were used as the CS+ (followed by an electric stimulus) or CS- (presented alone). Generalisation was assessed by presenting novel stimuli from the CS categories after acquisition, extinction, and reinstatement. One category exemplar was used as the CS+ and CS- in the single group, whereas three exemplars were used as the CS+ and CS- in the multiple group. Electrodermal responses generalised in acquisition and extinction but did not differ between groups. In the multiple group, CS evaluations generalised in acquisition and extinction, whereas generalisation was not evident in the single group. Training with multiple CSs also resulted in the extinction of stimulus valence. The current findings have implications for future research examining the generalisation of valence and for exposure-based treatments of anxiety.

Conditional stimulus choices affect fear learning: Comparing fear conditioning with neutral faces and shapes or angry faces.

Past fear conditioning studies have used different types of conditional stimuli (CSs). Whether this choice affects learning outcomes in particular when neutral stimuli (e.g., neutral faces vs. shapes) are used is unclear. Data were aggregated across nine studies using an electric shock unconditional stimulus to test for differences in acquisition and extinction of electrodermal responses and self-reported CS pleasantness when CSs were neutral faces or shapes (Experiment 1, N = 594) and when CSs were angry or neutral faces (Experiment 2, N = 157). Reliable electrodermal conditioning was observed in all stimulus conditions. We found stronger differential conditioning in electrodermal second interval responses and CS pleasantness and more pronounced extinction in CS pleasantness for neutral shape than neutral face CSs, but no differences in electrodermal first interval responses, the most frequently reported index of fear conditioning. For angry and neutral face CSs, there were no differences during acquisition, but the extinction of first and second interval electrodermal conditioning to angry faces was retarded relative to neutral faces. Acquisition of differential CS pleasantness, which was reliably observed for neutral face CSs, was absent for angry face CSs. The current results suggest that fear conditioning with a neutral face and shape CSs yields broadly similar results with differences limited to second interval electrodermal responses and CS pleasantness ratings. Using angry face CSs resulted in impaired extinction of electrodermal indices and no differential CS pleasantness ratings and should only be considered in studies designed to address questions about these specific CS materials.

Influence of Particle Size on Ecotoxicity of Low-Density Polyethylene Microplastics, with and without Adsorbed Benzo-a-Pyrene, in Clam Scrobicularia plana.

This study investigated the ecotoxicological effects of differently sized (4-6 µm and 20-25 µm) low-density polyethylene (LDPE) microplastics (MPs), with and without adsorbed benzo-a-pyrene (BaP), in clam Scrobicularia plana. Biomarkers of oxidative stress (superoxide dismutase-SOD; catalase-CAT), biotransformation (glutathione-S-transferases-GST), oxidative damage (lipid peroxidation-LPO) and neurotoxicity (acetylcholinesterase-AChE) were analysed in gills and digestive glands at different time intervals for a total of 14 days of exposure. In order to have a better impact perspective of these contaminants, an integrated biomarker response index (IBR) and Health Index were applied. Biomarker alterations are apparently more related to smaller sized (4-6 µm) MPs in gills and to virgin LDPE MPs in the digestive gland according to IBR results, while the digestive gland was more affected by these MPs according to the health index.