Loss of hepatic PPARα in mice causes hypertension and cardiovascular disease.

The leading cause of death in patients with nonalcoholic fatty liver disease (NAFLD) is cardiovascular disease (CVD). However, the mechanisms are unknown. Mice deficient in hepatocyte proliferator-activated receptor-α (PPARα) (PparaHepKO) exhibit hepatic steatosis on a regular chow diet, making them prone to manifesting NAFLD. We hypothesized that the PparaHepKO mice might be predisposed to poorer cardiovascular phenotypes due to increased liver fat content. Therefore, we used PparaHepKO and littermate control mice fed a regular chow diet to avoid complications with a high-fat diet, such as insulin resistance and increased adiposity. After 30 wk on a standard diet, male PparaHepKO mice exhibited elevated hepatic fat content compared with littermates as measured by Echo MRI (11.95 ± 1.4 vs. 3.74 ± 1.4%, P < 0.05), hepatic triglycerides (1.4 ± 0.10 vs. 0.3 ± 0.01 mM, P < 0.05), and Oil Red O staining, despite body weight, fasting blood glucose, and insulin levels being the same as controls. The PparaHepKO mice also displayed elevated mean arterial blood pressure (121 ± 4 vs. 108 ± 2 mmHg, P < 0.05), impaired diastolic function, cardiac remodeling, and enhanced vascular stiffness. To determine mechanisms controlling the increase in stiffness in the aorta, we used state-of-the-art PamGene technology to measure kinase activity in this tissue. Our data suggest that the loss of hepatic PPARα induces alterations in the aortas that reduce the kinase activity of tropomyosin receptor kinases and p70S6K kinase, which might contribute to the pathogenesis of NAFLD-induced CVD. These data indicate that hepatic PPARα protects the cardiovascular system through some as-of-yet undefined mechanism.

The potential fire risk of emollients when dried on viscose bandages.

BACKGROUND: the potential fire risk of fabrics impregnated with emollients has been described within the health service, including ignition of bandages. The role of emollients in fire fatalities have also been included in coroner reports, as accelerating fires when present. AIMS: although changes in burning behaviour is known, no standard tests have been carried out on bandages which are often used in conjunction with emollients. METHOD: using a standard vertical flammability test, the flammability of viscose bandage was compared to when impregnated with nine dried on emollients with low to high and non-paraffin content. FINDINGS: the time to ignition was significantly reduced with an emollient present and the glowing time was longer. CONCLUSIONS: the same safety advice applies to viscose bandages as other fabrics with emollients; do not expose them to naked flames or high heat sources or allow emollients to build up on bandages.

Birds invest wingbeats to keep a steady head and reap the ultimate benefits of flying together.

Flapping flight is the most energetically demanding form of sustained forwards locomotion that vertebrates perform. Flock dynamics therefore have significant implications for energy expenditure. Despite this, no studies have quantified the biomechanical consequences of flying in a cluster flock or pair relative to flying solo. Here, we compared the flight characteristics of homing pigeons (Columba livia) flying solo and in pairs released from a site 7 km from home, using high-precision 5 Hz global positioning system (GPS) and 200 Hz tri-axial accelerometer bio-loggers. As expected, paired individuals benefitted from improved homing route accuracy, which reduced flight distance by 7% and time by 9%. However, realising these navigational gains involved substantial changes in flight kinematics and energetics. Both individuals in a pair increased their wingbeat frequency by 18% by decreasing the duration of their upstroke. This sharp increase in wingbeat frequency caused just a 3% increase in airspeed but reduced the oscillatory displacement of the body by 22%, which we hypothesise relates to an increased requirement for visual stability and manoeuvrability when flying in a flock or pair. The combination of the increase in airspeed and a higher wingbeat frequency would result in a minimum 2.2% increase in the total aerodynamic power requirements if the wingbeats were fully optimised. Overall, the enhanced navigational performance will offset any additional energetic costs as long as the metabolic power requirements are not increased above 9%. Our results demonstrate that the increases in wingbeat frequency when flying together have previously been underestimated by an order of magnitude and force reinterpretation of their mechanistic origin. We show that, for pigeons flying in pairs, two heads are better than one but keeping a steady head necessitates energetically costly kinematics.

Development of a professional competency framework for Australian sonographers-perspectives for developing competencies using a Delphi methodology.

BACKGROUND: Professional competencies are important for enhancing alignment between the needs of education, industry and health consumers, whilst describing public expectations around health professionals. The development of competency standards for the sonography profession defines the behaviours, skills and knowledge sonographers should demonstrate for each learning and experience level. OBJECTIVE: The objective of this project was to develop a set of professional competency standards for the sonography profession which described in depth the behaviours, skills and knowledge sonographers should demonstrate across multiple learning and experience levels. METHODS: Representatives of three Australian ultrasound professional associations and seven tertiary institutions involved in entry-level sonographer education in Australia formed a research team (RT). The RT recruited an expert panel that responded to six survey rounds. Using a Delphi methodology, the results and free-text comments from each previous round were fed back to participants in the subsequent survey rounds to achieve a consensus. RESULTS: The project developed a professional competency framework for sonographers, which included four major domains: detailed competency standards, sonographer knowledge, sonographer attitudes and a holistic competency matrix [https://doi.org/10.6084/m9.figshare.17148035.v2.]. CONCLUSION: The Delphi methodology is an effective way to develop professional competency standards. This paper describes the methods and challenges in developing such standards for sonographers which could be translated to other health professionals.

The common diabetes drug metformin can diminish the action of citral against Rhabdomyosarcoma cells in vitro.

Rhabdomyosarcoma (RMS) is a rare type of soft tissue sarcoma most commonly found in pediatric patients. Despite progress, new and improved drug regimens are needed to increase survival rates. Citral, a natural product plant oil can induce cell death in cancer cells. Another compound, metformin, isolated originally from French lilac and used by diabetics, has been shown to reduce the incidence of cancer in these patients. Application of citral to RMS cells showed increase in cell death, and RD and RH30 cells showed half maximal inhibitory concentration (IC50 ) values as low as 36.28 µM and 62.37 µM, respectively. It was also shown that the citral initiated cell apoptosis through an increase in reactive oxygen species (ROS) and free calcium. In comparison, metformin only showed moderate cell death in RMS cell lines at a very high concentration (1,000 µM). Combinatorial experiments, however, indicated that citral and metformin worked antagonistically when used together. In particular, the ability of metformin to quench the ROS induced by citral could lead to the suppression of activity. These results clearly indicate that while clinical use of citral is a promising anti-tumor therapy, caution should be exercised in patients using metformin for diabetes.

Delivering cognitive therapy for adolescent social anxiety disorder in NHS CAMHS: a qualitative analysis of the experiences of young people, their parents and clinicians-in-training.

BACKGROUND: Social anxiety disorder (SAD) is common. It usually starts in adolescence, and without treatment can disrupt key developmental milestones. Existing generic treatments are less effective for young people with SAD than with other anxiety disorders, but an adaptation of an effective adult therapy (CT-SAD-A) has shown promising results for adolescents. AIMS: The aim of this study was to conduct a qualitative exploration to contribute towards the evaluation of CT-SAD-A for adoption into Child and Adolescent Mental Health Services (CAMHS). METHOD: We used interpretative phenomenological analysis (IPA) to analyse the transcripts of interviews with a sample of six young people, six parents and seven clinicians who were learning the treatment. RESULTS: Three cross-cutting themes were identified: (i) endorsing the treatment; (ii) finding therapy to be collaborative and active; challenging but helpful; and (iii) navigating change in a complex setting. Young people and parents found the treatment to be useful and acceptable, although simultaneously challenging. This was echoed by the clinicians, with particular reference to integrating CT-SAD-A within community CAMHS settings. CONCLUSIONS: The acceptability of the treatment with young people, their parents and clinicians suggests further work is warranted in order to support its development and implementation within CAMHS settings.

Delivering cognitive therapy for adolescent social anxiety disorder in NHS CAMHS: a clinical and cost analysis.

BACKGROUND: Cognitive therapy, based on the Clark and Wells (1995) model, is a first-line treatment for adults with social anxiety disorder (SAD), and findings from research settings suggest it has promise for use with adolescents (Cognitive Therapy for Social Anxiety Disorder in Adolescents; CT-SAD-A). However, for the treatment to be suitable for delivery in routine clinical care, two questions need to be addressed. AIMS: Can therapists be trained to achieve good outcomes in routine Child and Adolescent Mental Health Services (CAMHS), and what are the costs associated with training and treatment? METHOD: CAMHS therapists working in two NHS trusts received training in CT-SAD-A. They delivered the treatment to adolescents with SAD during a period of supervised practice. We examined the clinical outcomes for the 12 patients treated during this period, and estimated costs associated with treatment and training. RESULTS: Treatment produced significant improvements in social anxiety symptoms, general anxiety and depression symptoms, and reductions in putative process measures. Seventy-five per cent (9 out of 12) patients showed a reliable and clinically significant improvement in social anxiety symptoms, and 64% (7/11) lost their primary diagnosis of SAD. The total cost to the NHS of the CT-SAD-A treatment was £4047 (SD = £1003) per adolescent treated, of which £1861 (SD = £358) referred to the specific estimated cost of face-to-face delivery; the remaining cost was for training and supervising therapists who were not previously familiar with the treatment. CONCLUSIONS: This study provides preliminary evidence that clinicians can deliver good patient outcomes for adolescents with SAD in routine CAMHS during a period of supervised practice after receiving a 2-day training workshop. Furthermore, the cost of delivering CT-SAD-A with adolescents appeared to be no more than the cost of delivering CT-SAD with adults.

Movement reveals reproductive tactics in male elephants.

Long-term bio-logging has the potential to reveal how movements, and hence life-history trade-offs, vary over a lifetime. Reproductive tactics in particular may vary as individuals' trade-off current investment versus lifetime fitness. Male African savanna elephants (Loxodona africana) provide a telling example of balancing body growth with reproductive fitness due to the combination of indeterminate growth and strongly delineated periods of sexual activity (musth), which results in reproductive tactics that alter with age. Our study aims to quantify the extent to which male elephants alter their movement patterns, and hence energetic allocation, in relation to (a) reproductive state and (b) age, and (c) to determine whether musth periods can be detected directly from GPS tracking data. We used a combination of GPS tracking data and visual observations of 25 male elephants ranging in age from 20 to 52 years to examine the influence of reproductive state and age on movement. We then used a three-state hidden Markov model (HMM) to detect musth behaviour in a subset of sequential tracking data. Our results demonstrate that male elephants increased their daily mean speed and range size with age and in musth. Furthermore, non-musth speed decreased with age, presumably reflecting a shift towards energy acquisition during non-musth. Thus, despite similar speeds and marginally larger ranges between reproductive states at age 20, by age 50, males were travelling 2.0 times faster in a 3.5 times larger area in musth relative to non-musth. The distinctiveness of musth periods over age 35 meant the three-state HMM could automatically detect musth movement with high sensitivity and specificity, but could not for the younger age class. We show that male elephants increased their energetic allocation into reproduction with age as the probability of reproductive success increases. Given that older male elephants tend to be both the target of legal trophy hunting and illegal poaching, man-made interference could drive fundamental changes in elephant reproductive tactics. Bio-logging, as our study reveals, has the potential both to quantify mature elephant reproductive tactics remotely and to be used to institute proactive management strategies around the reproductive behaviour of this charismatic keystone species.

Optimizing the use of biologgers for movement ecology research.

The paradigm-changing opportunities of biologging sensors for ecological research, especially movement ecology, are vast, but the crucial questions of how best to match the most appropriate sensors and sensor combinations to specific biological questions and how to analyse complex biologging data, are mostly ignored. Here, we fill this gap by reviewing how to optimize the use of biologging techniques to answer questions in movement ecology and synthesize this into an Integrated Biologging Framework (IBF). We highlight that multisensor approaches are a new frontier in biologging, while identifying current limitations and avenues for future development in sensor technology. We focus on the importance of efficient data exploration, and more advanced multidimensional visualization methods, combined with appropriate archiving and sharing approaches, to tackle the big data issues presented by biologging. We also discuss the challenges and opportunities in matching the peculiarities of specific sensor data to the statistical models used, highlighting at the same time the large advances which will be required in the latter to properly analyse biologging data. Taking advantage of the biologging revolution will require a large improvement in the theoretical and mathematical foundations of movement ecology, to include the rich set of high-frequency multivariate data, which greatly expand the fundamentally limited and coarse data that could be collected using location-only technology such as GPS. Equally important will be the establishment of multidisciplinary collaborations to catalyse the opportunities offered by current and future biologging technology. If this is achieved, clear potential exists for developing a vastly improved mechanistic understanding of animal movements and their roles in ecological processes and for building realistic predictive models.

Clinical syndromes and treatment location predict utility of carbapenem sparing therapies in ceftriaxone-non-susceptible Escherichia coli bloodstream infection.

BACKGROUND: Cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, intravenous fosfomycin and plazomicin represent potential carbapenem sparing agents for extended-spectrum-beta-lactamase or AmpC beta-lactamase producing Escherichia coli infection. However, available data is limited in predicting the volume of carbapenem therapy which could be substituted and real-world contraindications. METHODS: We determined the number of carbapenem days of therapy (DOT) which could be substituted and frequent contraindications accounting for antimicrobial susceptibility and site of infection in an unselected cohort with ceftriaxone-non-susceptible E. coli bacteremia at a single health network from 2015 to 2016. Individual patient data was used to calculate DOT and substitution for each agent. RESULTS: There were 108 episodes of E. coli bacteremia resulting in 67.2 carbapenem DOT/100 patient-days of antimicrobial therapy administered. Ceftazidime-avibactam could be used to substitute 36.2 DOT/100 patient-days (54%) for inpatient definitive therapy, ceftolozane-tazobactam for 34.7 DOT/100 patient-days (52%), cefiderocol for 27.1 DOT/100 patient-days (40%), fosfomycin for 23.3 DOT /100 patient-days (35%) and plazomicin for 27.1 DOT/100 patient-days (40%). Non-urinary tract source of infection was the most frequent contraindication to fosfomycin (25), plazomicin (26) and cefiderocol (26). Use in outpatient parenteral antimicrobial therapy (OPAT) programs accounted for 40% of DOT, all of which could be substituted if stability data allowed for ceftazidime-avibactam and ceftolozane-tazobactam. CONCLUSIONS: All tested agents could be used to replace a significant volume of carbapenem therapy. Establishing stability of these agents for use in OPAT is required for maximizing their use as carbapenem sparing agents while randomized clinical data is awaited for some of these agents in resistant E. coli bacteremia.

Wearable Vital Signs Monitoring for Patients With Asthma: A Review.

Worldwide,an estimated 461 000 people die from asthma attacks each year. While there remain treatments to alleviate asthma symptoms and reduce deaths, patient deterioration needs to be identified in sufficient time. To prevent asthma deterioration, patients need to be aware of personal and environmental triggers and monitor their asthma symptoms. The aim of this article is to provide a comprehensive review of the current state-of-the-art wearable sensors and devices that use vital signs for asthma patient monitoring and management. Among all vital signs, breathing rate and airflow sound are key indicators of asthmatic patients' health that can be measured directly using wearable sensors to provide continuous and constant patient monitoring or indirectly by estimations based on proven algorithms using electrocardiogram (ECG), photoplethysmogram (PPG), and chest movements. ECG and PPG signals are widely used in smart watches and chest bands, enabling easy integration of a more extensive body sensor framework for asthmatic exacerbation prediction. Other vital signs used in asthma patient monitoring include blood oxygen saturation, temperature, blood pressure, verbal sound, and pain responses. The use of wearable vital signs enabled a broad range of wearable sensor application scenarios for asthma monitoring and management.

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations.

Novel external quality assurance scheme for drug susceptibility testing of non-tuberculous mycobacteria: a multicentre pilot study.

OBJECTIVES: Our aim was to conduct a multicentre study involving laboratories participating in the European TB Reference Laboratory Network aiming to develop a pilot external quality assessment (EQA) scheme for drug susceptibility testing (DST) of non-tuberculous mycobacteria (NTM). METHODS: The study comprised a survey using a structured questionnaire followed by a pilot EQA round using identical panels of 10 Mycobacterium avium (MAV) and Mycobacterium abscessus (MAB) isolates. EQA results were received from 16 laboratories utilizing the broth microdilution method. Consensus modal MIC values were determined, and essential and categorical agreement rates were calculated. RESULTS: Twenty-four out of 31 laboratories (77.4%) reported DST for NTM routinely. Essential agreement ranged from 78.8% (amikacin) to 96.2% (linezolid) for MAV and from 76.0% (amikacin) to 100% (doxycycline) for MAB. Categorical agreement ranged from 56.8% (moxifloxacin) to 100% (clarithromycin) for MAV and from 53.6% (linezolid) to 100% (doxycycline) for MAB. CONCLUSIONS: Our results show that interlaboratory reproducibility of DST for NTM is insufficient, highlighting the need for expanding EQA schemes. As EQAs for Mycobacterium tuberculosis complex have led to more reliable and reproducible DST, we propose to follow a similar approach for clinically relevant NTM.

Impact of choice of feeding tubes on long-term swallow function following chemoradiotherapy for oropharyngeal carcinoma.

Background: Prior reports have raised concerns that a prophylactic gastrostomy may be detrimental to long-term swallow function. This study evaluates patient-reported swallow function following chemoradiotherapy for oropharyngeal carcinoma in relation to the use of a prophylactic gastrostomy or nasogastric (NG) tube as required. Material and methods: The MD Anderson Dysphagia Inventory (MDADI) was posted to 204 disease-free patients at least 2 years following chemoradiotherapy for oropharyngeal carcinoma between 2010 and 2014. Results: Overall, 181/204 (89%) patients returned questionnaire at a median of 34 months post-treatment. 97/181 (54%) and 84/181 (46%) were managed with an approach of a prophylactic gastrostomy or NG tube as required, respectively. A prophylactic gastrostomy was associated with higher rates of enteral feeding (92% vs. 58%, p < .001), lower median percentage weight loss (7.0% vs. 9.4%, p < .001), increased duration of enteral feed (median 3.3 vs. 1.1 months, p < .001). There was no significant difference in patient-reported swallow function measured by MDADI summary scores and subscales for patients managed with an approach of prophylactic gastrostomy or NG as required. Duration of enteral feed correlated negatively with composite MDADI scores. A subgroup of 116/181 (64%) patients were documented as having been offered a choice of enteral feeding approach and therefore can be considered to represent clinical equipoise; there were no significant differences in MDADI scores according to route. Conclusions: Despite concern regarding the use of a prophylactic gastrostomy in prior studies, the approaches of using a prophylactic gastrostomy or an NG tube as required to support patients during/after chemoradiotherapy for oropharyngeal carcinoma were associated with similar long-term swallow outcomes.

Homing pigeons (Columba livia) modulate wingbeat characteristics as a function of route familiarity.

Mechanisms of avian navigation have received considerable attention, but whether different navigational strategies are accompanied by different flight characteristics is unknown. Managing energy expenditure is critical for survival; therefore, understanding how flight characteristics, and hence energy allocation, potentially change with birds' familiarity with a navigational task could provide key insights into the costs of orientation. We addressed this question by examining changes in the wingbeat characteristics and airspeed of homing pigeons (Columba livia) as they learned a homing task. Twenty-one pigeons were released 20 times individually either 3.85 or 7.06 km from home. Birds were equipped with 5 Hz GPS trackers and 200 Hz tri-axial accelerometers. We found that, as the birds' route efficiency increased during the first six releases, their median peak-to-peak dorsal body (DB) acceleration and median DB amplitude also increased. This, in turn, led to higher airspeeds, suggesting that birds fly slower when traversing unfamiliar terrain. By contrast, after route efficiency stabilised, birds exhibited increasing wingbeat frequencies, which did not result in further increases in speed. Overall, higher wind support was also associated with lower wingbeat frequencies and increased DB amplitude. Our study suggests that the cost of early flights from an unfamiliar location may be higher than subsequent flights because of both inefficient routes (increased distance) and lower airspeeds (increased time). Furthermore, the results indicate, for the first time, that birds modulate their wingbeat characteristics as a function of navigational knowledge, and suggest that flight characteristics may be used as 'signatures' of birds' route familiarity.

Effectiveness of oseltamivir in reducing COVID-19-related in-hospital deaths: A pharmacoepidemiological study.

BACKGROUND: Oseltamivir is a low-cost antiviral agent that could support or complement treatment of COVID-19. This study assessed whether oseltamivir is effective in reducing COVID-19-related mortality. METHODS: This retrospective cohort study evaluated real-world data from a nationwide database of hospitalisation due to severe acute respiratory syndrome in Brazil. Propensity score matching was used to mimic a randomised controlled trial with 'oseltamivir' and 'no antivirals at all' as the intervention and control groups, respectively. RESULTS: A total of 21 480 and 268 486 patients admitted between February 2020 and January 2023 were included in the intervention and control groups, respectively. After matching, the odds ratio (OR) for death was 0.901 (95% confidence interval [CI] 0.873-0.930). The OR (95% CI) for death in patients who were admitted to the ICU, and on non-invasive or invasive ventilation was 0.868 (0.821-0.917), 0.935 (0.893-0.980), and 0.883 (0.814-0.958), respectively. CONCLUSIONS: Overall, the use of oseltamivir was associated with an attributable risk reduction of 2.50% (95% CI 1.77-3.29). Similar results were observed in patients who were admitted to the ICU, and on non-invasive or invasive ventilation. Oseltamivir is a low-cost potential antiviral treatment for COVID-19.

Cardiac lipotoxicity and fibrosis underlie impaired contractility in a mouse model of metabolic dysfunction-associated steatotic liver disease.

The leading cause of death among patients with metabolic dysfunction-associated steatotic liver disease (MASLD) is cardiovascular disease. A significant percentage of MASLD patients develop heart failure driven by functional and structural alterations in the heart. Previously, we observed cardiac dysfunction in hepatocyte-specific peroxisome proliferator-activated receptor alpha knockout (Ppara HepKO), a mouse model that exhibits hepatic steatosis independent of obesity and insulin resistance. The goal of the present study was to determine mechanisms that underlie hepatic steatosis-induced cardiac dysfunction in Ppara HepKO mice. Experiments were performed in 30-week-old Ppara HepKO and littermate control mice fed regular chow. We observed decreased cardiomyocyte contractility (0.17 ± 0.02 vs. 0.24 ± 0.02 µm, p < 0.05), increased cardiac triglyceride content (0.96 ± 0.13 vs. 0.68 ± 0.06 mM, p < 0.05), collagen type 1 (4.65 ± 0.25 vs. 0.31 ± 0.01 AU, p < 0.001), and collagen type 3 deposition (1.32 ± 0.46 vs. 0.05 ± 0.03 AU, p < 0.05). These changes were associated with increased apoptosis as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining (30.9 ± 4.7 vs. 13.1 ± 0.8%, p < 0.006) and western blots showing increased cleaved caspase-3 (0.27 ± 0.006 vs. 0.08 ± 0.01 AU, p < 0.003) and pro-caspase-3 (5.4 ± 1.5 vs. 0.5 ± 0.3 AU, p < 0.02), B-cell lymphoma protein 2-associated X (0.68 ± 0.07 vs. 0.04 ± 0.04 AU, p < 0.001), and reduced B-cell lymphoma protein 2 (0.29 ± 0.01 vs. 1.47 ± 0.54 AU, p < 0.05). We further observed elevated circulating natriuretic peptides and exercise intolerance in Ppara HepKO mice when compared to controls. Our data demonstrated that lipotoxicity, and fibrosis underlie cardiac dysfunction in MASLD.

Statistical analysis plan for a cluster randomised controlled trial to compare screening, feedback and intervention for child anxiety problems to usual school practice: identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i).

BACKGROUND: The Identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i) trial is being conducted to establish whether 'screening and intervention', consisting of usual school practice plus a pathway comprising screening, feedback and a brief parent-led online intervention (OSI: Online Support and Intervention for child anxiety), bring clinical and health economic benefits compared to usual school practice and assessment only - 'usual school practice', for children aged 8-9 years in the following: (1) the 'target population', who initially screen positive for anxiety problems according to a two-item parent-report child anxiety questionnaire - iCATS-2, and (2) the 'total population', comprising all children in participating classes. This article describes the detailed statistical analysis plan for the trial. METHODS AND DESIGN: iCATS-i2i is a definitive, superiority, pragmatic, school-based cluster randomised controlled trial (with internal pilot), with two parallel groups. Schools are randomised 1:1 to receive either screening and intervention or usual school practice. This article describes the following: trial objectives and outcomes; statistical analysis principles, including detailed estimand information necessary for aligning trial objectives, conduct, analyses and interpretation when there are different analysis populations and outcome measures to be considered; and planned main analyses, sensitivity and additional analyses. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN76119074. Registered on 4 January 2022.