Upper limit of normal ALT levels in health and metabolic diseases: Pooled analysis of 423,355 individuals with bootstrap modelling.

INTRODUCTION: Given the global rise in obesity-related metabolic diseases, the upper limit of normal (ULN) alanine aminotransferase (ALT) in individuals with and without metabolic diseases may have changed. We performed a meta-analysis combined with bootstrap modelling to estimate the ALT ULN levels for individuals with and without metabolic diseases. METHODS AND RESULTS: Two separate searches of the PubMed, Embase and Cochrane databases were performed, one to identify healthy individuals which yielded 12 articles (349,367 individuals); another to include those with potential metabolic diseases but without known liver disease which yielded 35 articles (232,388 individuals). We estimated the mean ALT using a random-effects mixed model and the ULN level (95th-percentile value) via a bootstrap model with 10,000 resamples. In individuals without metabolic diseases and known liver disease, the ALT ULN levels were 32 U/L overall; 36 U/L in males and 28 U/L in females. In analyses that included individuals with metabolic diseases, the ALT ULN levels were 40 U/L among the overweight/obese (29 U/L if normal weight) and 36 U/L among those with type 2 diabetes mellitus (T2DM) (33 U/L if no T2DM). On meta-regression of study-level factors, body mass index (coefficient 1.49, 95% CI 0.11-2.86, p = 0.03), high-density lipoprotein (coefficient -0.47, 95% CI -0.85-(-0.08), p = 0.02) and triglycerides (coefficient 0.19, 95% CI 0.12-0.25, p < 0.0001) correlated with ALT. CONCLUSION: We provide expected ranges of ALT ULN levels for individuals without known liver disease without metabolic diseases and those with or without T2DM and/or are normal weight or overweight/obese. These data may have implications for clinical care and screening.

Determining the feasibility of a codesigned and personalised intervention (Veg4Me) to improve vegetable intake in young adults living in rural Australian communities: protocol for a randomised controlled trial.

INTRODUCTION: Diets low in vegetables are a main contributor to the health burden experienced by young adults in rural communities. Digital health interventions provide an accessible delivery model that can be personalised to meet the diverse preferences of young adults. A personalisable digital vegetable intake intervention (Veg4Me) was codesigned to meet the needs of young adults living in rural communities. This study will determine the feasibility of delivering a personalised Veg4Me programme and compare preliminary effects with a non-personalised Veg4Me (control). METHODS AND ANALYSIS: A 12-week assessor-blinded, two-arm, parallel randomised controlled trial will be undertaken from August 2023 until April 2024. A total of 150 eligible and consenting young adults (18-35 years; eat<5 serves of vegetables/day; have an internet connected mobile device/computer) living in Loddon Campaspe or Colac Otway Shire in Victoria, Australia, will be randomised to receive 12 weeks of personalised (intervention) or non-personalised (control) support to increase vegetable intake via a free web application (app; Veg4Me). The primary outcome is feasibility (recruitment, participation and retention rates). Secondary outcomes are user engagement, usability and experience, as well as vegetable intake, eating habits and digital health equity. Process evaluation will be conducted in a subsample of participants using semistructured interviews. Descriptive statistics will be presented for the personalised and non-personalised groups at baseline and 12 weeks. Generalised linear models will be used to evaluate group differences in outcomes. Interviews will be transcribed and analysed thematically. ETHICS AND DISSEMINATION: All procedures involving human subjects were approved by Deakin University's Human Ethics Advisory Group-Health (HEAG-H 06_2023) on 6 March 2023. Dissemination events will be held in the City of Greater Bendigo and the Colac Otway Shire. Summaries of the results will be disseminated to participants via email. Results will be disseminated to the scientific community through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Australia New Zealand Clinical Trials Registry, ACTRN12623000179639p, prospectively registered on 21 February 2023, according to the World Health Organizational Trial Registration Data Set. Universal Trial Number U1111-1284-9027.

Co-design of a personalised digital intervention to improve vegetable intake in adults living in Australian rural communities.

BACKGROUND: Diets low in vegetables are a main contributor to the health burden experienced by Australians living in rural communities. Given the ubiquity of smartphones and access to the Internet, digital interventions may offer an accessible delivery model for a dietary intervention in rural communities. However, no digital interventions to address low vegetable intake have been co-designed with adults living in rural areas. This paper describes the co-design of a digital intervention to improve vegetable intake with rural community members and research partners. METHODS: Active participants in the co-design process were adults ≥ 18 years living in three rural Australian communities (total n = 57) and research partners (n = 4) representing three local rural governments and one peak non-government health organisation. An iterative co-design process was undertaken to understand the needs (pre-design phase) and ideas (generative phase) of the target population. Eight online workshops and a community survey were conducted between July and December 2021. The MoSCoW prioritisation method was used to help participants identify the 'Must-have, Should-have, Could-have, and Won't-have or will not have right now' features and functions of the digital intervention. Workshops were transcribed and inductively analysed using NVivo. Convergent and divergent themes were identified between the workshops and community survey to identify how to implement the digital intervention in the community. RESULTS: Consensus was reached on a concept for a digital intervention that addressed individual and food environment barriers to vegetable intake, specific to rural communities. Implementation recommendations centred on (i) food literacy approaches to improve skills via access to vegetable-rich recipes and healthy eating resources, (ii) access to personalisation options and behaviour change support, and (iii) improving the community food environment by providing information on and access to local food initiatives. CONCLUSIONS: Rural-dwelling adults expressed preferences for personalised intervention features that can enhance food literacy and engagement with community food environments. This research will inform the development of the prototyping (evaluation phase) and feasibility testing (post-design phase) of this intervention.

Racial and ethnic disparities in untreated patients with hepatitis C virus-related hepatocellular carcinoma but not in those with sustained virologic response.

BACKGROUND: Racial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival. AIM: To evaluate the impact of HCV treatment on such disparities. METHODS: In a retrospective cohort study, we analysed 6069 patients with HCV-related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia. RESULTS: The mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%-15%, 20% vs. 10%-17% and 10% vs. 5%-7%, respectively; all p < 0.0001). Treatment rate with direct-acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients (p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10-year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients (p < 0.0001). There were no statistically significant differences among those with SVR (p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non-U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001). CONCLUSION: DAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection.

Incidence and predictors of hepatocellular carcinoma in NAFLD without diagnosed cirrhosis: a nationwide real-world U.S. study.

BACKGROUND: A substantial proportion of patients with nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) do not have cirrhosis. Data regarding the incidence and predictors of HCC development in NAFLD without cirrhosis are limited. We conducted a large, national study of NAFLD patients without documented cirrhosis to examine the incidence and predictors for HCC development. METHODS: This retrospective study included 751,603 NAFLD patients (54% female) without documented cirrhosis derived from the deidentified Optum Clinformatics® Data Mart Database. Patients with cirrhosis, platelets < 120,000/µL or FIB-4 values > 2.67 were excluded. RESULTS: The mean age was 53.7 ± 15.0 years, 45.9% were male, 39.5% had diabetes, 57.6% were White, 18.4% Hispanic, 8.2% Black and 4.9% were Asian. The mean platelet count was 264,000 ± 72,000/µL, and 96.3% of patients had a FIB-4 < 1.30. Over 1,686,607 person-years of follow-up, there were 76 incident cases of HCC, resulting in an HCC incidence rate of 0.05 per 1000 person-years. There was a higher HCC incidence rate among patients with platelets ≤ 150,000/µL, versus those with platelets > 150,000/µL (0.23 per 1000 person-years, vs. 0.04 per 1000 person-years, p = 0.02) but not in subgroup analyses for age, sex, race/ethnicity or diabetes. Using multivariable Cox proportional hazards model adjusted multiple confounders, platelet count ≤ 150,000/µL remained an independent predictor of HCC development (adjusted HR 5.80, 95% CI 1.67-20.1, p = 0.006). CONCLUSION: HCC incidence in NAFLD without documented cirrhosis was below the threshold for cost-effective HCC surveillance in overall and multiple subgroup analyses. Platelet count < 150,000/µL may be a useful predictor of HCC development in this population.

Delirium following traumatic brain injury in adolescents: Symptomatology and prediction of ability to return to school or employment 1-year post-injury.

BACKGROUND: There is a limited evidence-base describing clinical features of delirium in youth. What is known is largely extrapolated from studies of adults or samples with heterogeneous etiologies. It is unclear if the symptoms experienced by adolescents differ from those experienced by adults, or the degree to which delirium impacts the ability of adolescents to return to school or work. OBJECTIVE: To describe delirium symptomatology among adolescents following a severe traumatic brain injury (TBI). Symptoms were compared by adolescent delirium status and across age groups. Delirium and its relationship with adolescent employability 1 year post-injury was also examined. DESIGN: Exploratory secondary analysis of prospectively collected data. SETTING: Free-standing rehabilitation hospital. PATIENTS: Severely injured TBI Model Systems neurorehabilitation admissions (n = 243; median Glasgow Coma Scale = 7). The sample was divided into three age groups (adolescents, 16-21 years, n = 63; adults 22-49 years, n = 133; older adults ≥50 years, n = 47). INTERVENTIONS: Not applicable. MEASURES: We assessed patients using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria and the Delirium Rating Scale-Revised 98 (DRS-R-98). The employability item from the Disability Rating Scale was the primary 1-year outcome. RESULTS: Most items on the DRS-R-98 differentiated delirious from non-delirious adolescents. Only "delusions" differed among age groups. Among adolescents, delirium status 1 month post-TBI provided acceptable classification of employability prediction 1 year later (area under the curve [AUC]: 0.80, 95% confidence interval [CI]: 0.69-0.91, p < .001). Delirium symptom severity (AUC: 0.86, 95% CI: 0.68-1.03, SE: 0.09; p < .001) and days of post-traumatic amnesia (AUC: 0.85, 95% CI: 0.68-1.01, SE: 0.08; p < .001) provided excellent prediction of outcomes for TBI patients in delirium. CONCLUSIONS: Delirium symptomatology was similar among age groups and useful in differentiating the delirium status within the adolescent TBI group. Delirium and symptom severity at 1 month post-TBI were highly predictive of poor outcomes. Findings from this study support the utility of DRS-R-98 at 1 month post-injury to inform treatment and planning.

EEG based automated seizure detection - A survey of medical professionals.

Diagnosing and managing seizures presents substantial challenges for clinicians caring for patients with epilepsy. Although machine learning (ML) has been proposed for automated seizure detection using EEG data, there is little evidence of these technologies being broadly adopted in clinical practice. Moreover, there is a noticeable lack of surveys investigating this topic from the perspective of medical practitioners, which limits the understanding of the obstacles for the development of effective automated seizure detection. Besides the issue of generalisability and replicability seen in a small amount of studies, obstacles to the adoption of automated seizure detection remain largely unknown. To understand the obstacles preventing the application of seizure detection tools in clinical practice, we conducted a survey targeting medical professionals involved in the management of epilepsy. Our study aimed to gather insights on various factors such as the clinical utility, professional sentiment, benchmark requirements, and perceived barriers associated with the use of automated seizure detection tools. Our key findings are: I) The minimum acceptable sensitivity reported by most of our respondents (80%) seems achievable based on studies reported from most currently available ML-based EEG seizure detection algorithms, but replication studies often fail to meet this minimum. II) Respondents are receptive to the adoption of ML seizure detection tools and willing to spend time in training. III) The top three barriers for usage of such tools in clinical practice are related to availability, lack of training, and the blackbox nature of ML algorithms. Based on our findings, we developed a guide that can serve as a basis for developing ML-based seizure detection tools that meet the requirements of medical professionals, and foster the integration of these tools into clinical practice.

Estimating Patient-Level Uncertainty in Seizure Detection Using Group-Specific Out-of-Distribution Detection Technique.

Epilepsy is a chronic neurological disorder affecting around 1% of the global population, characterized by recurrent epileptic seizures. Accurate diagnosis and treatment are crucial for reducing mortality rates. Recent advancements in machine learning (ML) algorithms have shown potential in aiding clinicians with seizure detection in electroencephalography (EEG) data. However, these algorithms face significant challenges due to the patient-specific variability in seizure patterns and the limited availability of high-quality EEG data for training, causing erratic predictions. These erratic predictions are harmful, especially for high-stake domains in healthcare, negatively affecting patients. Therefore, ensuring safety in AI is of the utmost importance. In this study, we propose a novel ensemble method for uncertainty quantification to identify patients with low-confidence predictions in ML-based seizure detection algorithms. Our approach aims to mitigate high-risk predictions in previously unseen seizure patients, thereby enhancing the robustness of existing seizure detection algorithms. Additionally, our method can be implemented with most of the deep learning (DL) models. We evaluated the proposed method against established uncertainty detection techniques, demonstrating its effectiveness in identifying patients for whom the model's predictions are less certain. Our proposed method managed to achieve 87%, 89% and 75% in accuracy, specificity and sensitivity, respectively. This study represents a novel attempt to improve the reliability and robustness of DL algorithms in the domain of seizure detection. This study underscores the value of integrating uncertainty quantification into ML algorithms for seizure detection, offering clinicians a practical tool to gauge the applicability of ML models for individual patients.

Differences in liver and mortality outcomes of non-alcoholic fatty liver disease by race and ethnicity: A longitudinal real-world study.

BACKGROUND/AIMS: Understanding of nonalcoholic fatty liver disease (NAFLD) continues to expand, but the relationship between race and ethnicity and NAFLD outside the use of cross-sectional data is lacking. Using longitudinal data, we investigated the role of race and ethnicity in adverse outcomes in NAFLD patients. METHODS: Patients with NAFLD confirmed by imaging via manual chart review from any clinics at Stanford University Medical Center (1995-2021) were included. Primary study outcomes were incidence of liver events and mortality (overall and non-liver related). RESULTS: The study included 9,340 NAFLD patients: White (44.1%), Black (2.29%), Hispanic (27.9%), and Asian (25.7%) patients. For liver events, the cumulative 5-year incidence was highest among White (19.1%) patients, lowest among Black (7.9%) patients, and similar among Asian and Hispanic patients (~15%). The 5-year and 10-year cumulative overall mortality was highest for Black patients (9.2% and 15.0%, respectively, vs. 2.5-3.5% and 4.3-7.3% in other groups) as well as for non-liver mortality. On multivariable regression analysis, compared to White patients, only Asian group was associated with lower liver-related outcomes (aHR: 0.83, P=0.027), while Black patients were at more than two times higher risk of both non-liver related (aHR: 2.35, P=0.010) and overall mortality (aHR: 2.13, P=0.022) as well as Hispanic patients (overall mortality: aHR: 1.44, P=0.022). CONCLUSION: Compared to White patients, Black patients with NAFLD were at the highest risk for overall and non-liver-related mortality, followed by Hispanic patients with Asian patients at the lowest risk for all adverse outcomes. Culturally sensitive and appropriate programs may be needed for more successful interventions.

ß3 Receptor Signaling in Pregnant Human Myometrium Suggests a Role for ß3 Agonists as Tocolytics.

Preterm labor leading to preterm birth is the leading cause of infant morbidity and mortality. At the present time, nothing can reliably halt labor once it begins. The knowledge that agonists of the ß2 adrenergic receptor relax airway smooth muscle and are effective in the treatment of asthma led to the notion that ß2 mimetics would prevent preterm birth by relaxing uterine smooth muscle. The activation of cAMP-dependent protein kinase by ß2 receptors is unable to provide meaningful tocolysis. The failure of ß2 agonists such as ritodrine and terbutaline to prevent preterm birth suggests that the regulation of uterine smooth muscle is disparate from that of airway. Other smooth muscle quiescent-mediating molecules, such as nitric oxide, relax vascular smooth muscle in a cGMP-protein kinase G-dependent manner; however, nitric oxide activation of protein kinase G fails to explain the relaxation of the myometrium to nitric oxide. Moreover, nitric oxide-mediated relaxation is blunted in preterm labor, and thus, for this reason and because of the fall in maternal blood pressure, nitric oxide cannot be employed as a tocolytic. The ß3 adrenergic receptor-mediated relaxation of the human myometrium is claimed to be cAMP-dependent protein kinase-dependent. This is scientifically displeasing given the failure of ß2 agonists as tocolytics and suggests a non-canonical signaling role for ß3AR in myometrium. The addition of the ß3 agonist mirabegron to pregnant human myometrial strips in the tissue bath relaxes oxytocin-induced contractions. Mirabegron stimulates nitric oxide production in myometrial microvascular endothelial cells, and the relaxation of uterine tissue in vitro is partially blocked by the addition of the endothelial nitric oxide synthase blocker Nω-Nitro-L-arginine. Recent data suggest that both endothelial and smooth muscle cells respond to ß3 stimulation and contribute to relaxation through disparate signaling pathways. The repurposing of approved medications such as mirabegron (Mybetriq™) tested in human myometrium as uterine tocolytics can advance the prevention of preterm birth.

Influence of maternal psychological distress during COVID-19 pandemic on placental morphometry and texture.

The Coronavirus Disease 2019 (COVID-19) pandemic has been accompanied by increased prenatal maternal distress (PMD). PMD is associated with adverse pregnancy outcomes which may be mediated by the placenta. However, the potential impact of the pandemic on in vivo placental development remains unknown. To examine the impact of the pandemic and PMD on in vivo structural placental development using advanced magnetic resonance imaging (MRI), acquired anatomic images of the placenta from 63 pregnant women without known COVID-19 exposure during the pandemic and 165 pre-pandemic controls. Measures of placental morphometry and texture were extracted. PMD was determined from validated questionnaires. Generalized estimating equations were utilized to compare differences in PMD placental features between COVID-era and pre-pandemic cohorts. Maternal stress and depression scores were significantly higher in the pandemic cohort. Placental volume, thickness, gray level kurtosis, skewness and run length non-uniformity were increased in the pandemic cohort, while placental elongation, mean gray level and long run emphasis were decreased. PMD was a mediator of the association between pandemic status and placental features. Altered in vivo placental structure during the pandemic suggests an underappreciated link between disturbances in maternal environment and perturbed placental development. The long-term impact on offspring is currently under investigation.

Antiviral therapy substantially reduces HCC risk in patients with chronic hepatitis B infection in the indeterminate phase.

BACKGROUND AND AIMS: HCC risk in chronic hepatitis B (CHB) is higher in the indeterminate phase compared with the inactive phase. However, it is unclear if antiviral therapy reduces HCC risk in this population. We aimed to evaluate the association between antiviral therapy and HCC risk in the indeterminate phase. APPROACH AND RESULTS: We analyzed 855 adult (59% male), treatment-naïve patients with CHB infection without advanced fibrosis in the indeterminate phase at 14 centers (USA, Europe, and Asia). Inverse probability of treatment weighting (IPTW) was used to balance the treated (n = 405) and untreated (n = 450) groups. The primary outcome was HCC development. The mean age was 46±13 years, the median alanine transaminase was 38 (interquartile range, 24-52) U/L, the mean HBV DNA was 4.5±2.1 log 10 IU/mL, and 20% were HBeAg positive. The 2 groups were similar after IPTW. After IPTW (n = 819), the 5-, 10-, and 15-year cumulative HCC incidence was 3%, 4%, and 9% among treated patients (n = 394) versus 3%, 15%, and 19%, among untreated patients (n = 425), respectively ( p = 0.02), with consistent findings in subgroup analyses for age >35 years, males, HBeAg positive, HBV DNA>1000 IU/mL, and alanine transaminase

Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 persons.

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. We aimed to estimate the pooled global NAFLD incidence. METHODS: We performed a systematic review and meta-analysis of cohort studies of adults without NAFLD at baseline to evaluate the global incidence of ultrasound-diagnosed NAFLD. RESULTS: A total of 63 eligible studies (1,201,807 persons) were analyzed. Studies were from Mainland China/Hong Kong (n = 26), South Korea (n = 22), Japan (n = 14), other (n = 2, Sri Lanka, Israel); 63.8% were clinical center studies; median study year 2000 to 2016; 87% were good quality. Among the 1,201,807 persons at risk, 242,568 persons developed NAFLD, with an incidence rate of 4,612.8 (95% CI 3,931.5-5,294.2) per 100,000 person-years and no statistically significant differences by study sample size (p = 0.90) or study setting (p = 0.055). Males had higher incidence vs. females (5,943.8 vs. 3,671.7, p = 0.0013). Both the obese (vs. non-obese) and the overweight/obese groups (vs. normal weight) were about threefold more likely to develop NAFLD (8,669.6 vs. 2,963.9 and 8,416.6 vs. 3,358.2, respectively) (both p <0.0001). Smokers had higher incidence than non-smokers (8,043.2 vs. 4,689.7, p = 0.046). By meta-regression, adjusting for study year, study setting, and study location, study period of 2010 or after and study setting were associated with increased incidence (p = 0.010 and p = 0.055, respectively). By country, China had a higher NAFLD incidence compared to non-China regions (p = 0.012) and Japan a lower incidence compared to non-Japan regions (p = 0.005). CONCLUSIONS: NAFLD incidence is increasing with a current estimate of 4,613 new cases per 100,000 person-years. Males and overweight/obese individuals had significantly higher incidence rates compared to females and those of normal weight. Public health interventions for prevention of NAFLD are needed with a special emphasis on males, overweight/obese individuals, and higher risk regions. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD) affects approximately 30% of people worldwide and appears to be increasing, but data to estimate the incidence rate are limited. In this meta-analytic study of over 1.2 million people, we estimated an incidence rate of NAFLD of 46.13 per 1,000 person-years with significant differences by sex, BMI, geography, and time-period. As treatment options for NAFLD remain limited, prevention of NAFLD should remain the focus of public health strategies. Studies such as these can help policy makers in determining which and whether their interventions are impactful.

Protocol for a bandit-based response adaptive trial to evaluate the effectiveness of brief self-guided digital interventions for reducing psychological distress in university students: the Vibe Up study.

INTRODUCTION: Meta-analytical evidence confirms a range of interventions, including mindfulness, physical activity and sleep hygiene, can reduce psychological distress in university students. However, it is unclear which intervention is most effective. Artificial intelligence (AI)-driven adaptive trials may be an efficient method to determine what works best and for whom. The primary purpose of the study is to rank the effectiveness of mindfulness, physical activity, sleep hygiene and an active control on reducing distress, using a multiarm contextual bandit-based AI-adaptive trial method. Furthermore, the study will explore which interventions have the largest effect for students with different levels of baseline distress severity. METHODS AND ANALYSIS: The Vibe Up study is a pragmatically oriented, decentralised AI-adaptive group sequential randomised controlled trial comparing the effectiveness of one of three brief, 2-week digital self-guided interventions (mindfulness, physical activity or sleep hygiene) or active control (ecological momentary assessment) in reducing self-reported psychological distress in Australian university students. The adaptive trial methodology involves up to 12 sequential mini-trials that allow for the optimisation of allocation ratios. The primary outcome is change in psychological distress (Depression, Anxiety and Stress Scale, 21-item version, DASS-21 total score) from preintervention to postintervention. Secondary outcomes include change in physical activity, sleep quality and mindfulness from preintervention to postintervention. Planned contrasts will compare the four groups (ie, the three intervention and control) using self-reported psychological distress at prespecified time points for interim analyses. The study aims to determine the best performing intervention, as well as ranking of other interventions. ETHICS AND DISSEMINATION: Ethical approval was sought and obtained from the UNSW Sydney Human Research Ethics Committee (HREC A, HC200466). A trial protocol adhering to the requirements of the Guideline for Good Clinical Practice was prepared for and approved by the Sponsor, UNSW Sydney (Protocol number: HC200466_CTP). TRIAL REGISTRATION NUMBER: ACTRN12621001223820.

Minimalistic approach to enhanced recovery after pediatric scoliosis surgery.

PURPOSE: Prior studies of enhanced recovery protocols (ERP) have been conducted at large institutions with abundant resources. These results may not apply at institutions with less resources directed to quality improvement efforts. The purpose of this study was to assess the value of a minimalistic enhanced recovery protocol in reducing length of stay (LOS) following PSF for adolescent idiopathic scoliosis. We hypothesized that accelerated transition to oral pain medications and mobilization alone could shorten hospital length of stay in the absence of a formal multimodal pain regimen. METHODS: AIS patients aged 10-18 who underwent PSF at a tertiary pediatric hospital between January 1, 2014 and December 31, 2017 were reviewed. The study population was further narrowed to consecutive patients from a single surgeon's practice that piloted the modified ERP. Reservation from key stakeholders regarding the feasibility of implementing widespread protocol change led to the minimal alterations made to the postoperative protocol following PSF. Patients were divided into either the Standard Recovery Protocol (SRP) or Enhanced Recovery Protocol (ERP). Primary variables analyzed were hospital LOS, complications, readmissions, and total narcotic requirement. RESULTS: A total of 92 patients met inclusion criteria. SRP and ERP groups consisted of 44 (47.8%) and 48 (52.2%) patients. There was no difference between the two groups with regard to age, sex, and ASA score (p > 0.05). Fusion levels and EBL did not differ between treatment groups (p > 0.05). PCA pumps were discontinued later in the SRP group (39.5 ± 4.3 h) compared to the ERP group (17.4 ± 4.1 h, p < 0.0001). Narcotic requirement was similar between groups (p = 0.94) Patients in the SRP group had longer hospital stays than patients in the ERP group (p < 0.0001). 83% of the ERP group had LOS ≤ 3 days compared to 0% in the SRP group, whose mean LOS was 4.2 days. There was no difference in complications between the groups (2.2% vs 6.0%, p = 0.62). Readmission to the hospital within 30 days of surgery was rare in either group (2 SRP patients: 1 superior mesenteric artery syndrome, 1 bowel obstruction vs 0 ERP patients, p = 0.23). CONCLUSION: In this cohort, minor changes to the postoperative protocol following surgery for AIS led to a significant decrease in hospital length of stay. This minimalistic approach may ease implementation of an ERP in the setting of stakeholder apprehension.

Digital behaviour change interventions to increase vegetable intake in adults: a systematic review.

BACKGROUND: Digital interventions may help address low vegetable intake in adults, however there is limited understanding of the features that make them effective. We systematically reviewed digital interventions to increase vegetable intake to 1) describe the effectiveness of the interventions; 2) examine links between effectiveness and use of co-design, personalisation, behavioural theories, and/or a policy framework; and 3) identify other features that contribute to effectiveness. METHODS: A systematic search strategy was used to identify eligible studies from MEDLINE, Embase, PsycINFO, Scopus, CINAHL, Cochrane Library, INFORMIT, IEEE Xplore and Clinical Trial Registries, published between January 2000 and August 2022. Digital interventions to increase vegetable intake were included, with effective interventions identified based on statistically significant improvement in vegetable intake. To identify policy-action gaps, studies were mapped across the three domains of the NOURISHING framework (i.e., behaviour change communication, food environment, and food system). Risk of bias was assessed using Cochrane tools for randomized, cluster randomized and non-randomized trials. RESULTS: Of the 1,347 records identified, 30 studies were included. Risk of bias was high or serious in most studies (n = 25/30; 83%). Approximately one quarter of the included interventions (n = 8) were effective at improving vegetable intake. While the features of effective and ineffective interventions were similar, embedding of behaviour change theories (89% vs 61%) and inclusion of stakeholders in the design of the intervention (50% vs 38%) were more common among effective interventions. Only one (ineffective) intervention used true co-design. Although fewer effective interventions included personalisation (67% vs 81%), the degree of personalisation varied considerably between studies. All interventions mapped across the NOURISHING framework behaviour change communication domain, with one ineffective intervention also mapping across the food environment domain. CONCLUSION: Few digital interventions identified in this review were effective for increasing vegetable intake. Embedding behaviour change theories and involving stakeholders in intervention design may increase the likelihood of success. The under-utilisation of comprehensive co-design methods presents an opportunity to ensure that personalisation approaches better meet the needs of target populations. Moreover, future digital interventions should address both behaviour change and food environment influences on vegetable intake.

EEG datasets for seizure detection and prediction- A review.

Electroencephalogram (EEG) datasets from epilepsy patients have been used to develop seizure detection and prediction algorithms using machine learning (ML) techniques with the aim of implementing the learned model in a device. However, the format and structure of publicly available datasets are different from each other, and there is a lack of guidelines on the use of these datasets. This impacts the generatability, generalizability, and reproducibility of the results and findings produced by the studies. In this narrative review, we compiled and compared the different characteristics of the publicly available EEG datasets that are commonly used to develop seizure detection and prediction algorithms. We investigated the advantages and limitations of the characteristics of the EEG datasets. Based on our study, we identified 17 characteristics that make the EEG datasets unique from each other. We also briefly looked into how certain characteristics of the publicly available datasets affect the performance and outcome of a study, as well as the influences it has on the choice of ML techniques and preprocessing steps required to develop seizure detection and prediction algorithms. In conclusion, this study provides a guideline on the choice of publicly available EEG datasets to both clinicians and scientists working to develop a reproducible, generalizable, and effective seizure detection and prediction algorithm.

ß3 adrenergic receptor activation modulates connexin 43 activity to relax human myometrium.

Preterm labor, delivery prior to 37 completed weeks of gestation, is the leading cause of infant morbidity and mortality. ß3 adrenergic receptor protein expression is increased in the myometrium during pregnancy, and the agonist, mirabegron, relaxes the myometrium making the ß3 adrenergic receptor a potential therapeutic target in PTL. ß3 adrenergic receptor has been shown to activate the tyrosine kinase, Src, which can down regulate connexin 43, a contractile associated protein which promotes the formation of gap junctions that create an electrical syncytium. We hypothesize that mirabegron downregulates connexin 43, imparting quiescence effects on the myometrium. Employing contractile studies, we demonstrate that Src is involved in the mirabegron-induced relaxation of contracting pregnant human myometrial tissue strips. Western blot analysis demonstrates that Src kinase expression is decreased in both preterm and term laboring myometrial tissue. Imaging revealed that mirabegron stimulation of the ß3 adrenergic receptor phosphorylates tyrosine at position Y265 on connexin 43 in pregnant human uterine myocytes. Western blot analysis and immunofluorescent imaging indicate that mirabegron decreases the expression of connexin 43 and mediates relaxation over a 24-h exposure period, suggesting that mirabegron has long lasting quiescent effects on the human myometrium. The relationship between the ß3 adrenergic receptor and down regulation of the contractile associated protein connexin 43 through activation of Src kinase suggests that mirabegron may be useful in combination tocolysis.

Impaired in vivo feto-placental development is associated with neonatal neurobehavioral outcomes.

BACKGROUND: Fetal growth restriction (FGR) is a risk factor for neurodevelopmental problems, yet remains poorly understood. We sought to examine the relationship between intrauterine development and neonatal neurobehavior in pregnancies diagnosed with antenatal FGR. METHODS: We recruited women with singleton pregnancies diagnosed with FGR and measured placental and fetal brain volumes using MRI. NICU Network Neurobehavioral Scale (NNNS) assessments were performed at term equivalent age. Associations between intrauterine volumes and neurobehavioral outcomes were assessed using generalized estimating equation models. RESULTS: We enrolled 44 women diagnosed with FGR who underwent fetal MRI and 28 infants underwent NNNS assessments. Placental volumes were associated with increased self-regulation and decreased excitability; total brain, brainstem, cortical and subcortical gray matter (SCGM) volumes were positively associated with higher self-regulation; SCGM also was positively associated with higher quality of movement; increasing cerebellar volumes were positively associated with attention, decreased lethargy, non-optimal reflexes and need for special handling; brainstem volumes also were associated with decreased lethargy and non-optimal reflexes; cerebral and cortical white matter volumes were positively associated with hypotonicity. CONCLUSION: Disrupted intrauterine growth in pregnancies complicated by antenatally diagnosed FGR is associated with altered neonatal neurobehavior. Further work to determine long-term neurodevelopmental impacts is warranted. IMPACT: Fetal growth restriction is a risk factor for adverse neurodevelopment, but remains difficult to accurately identify. Intrauterine brain volumes are associated with infant neurobehavior. The antenatal diagnosis of fetal growth restriction is a risk factor for abnormal infant neurobehavior.

Novel identification and modulation of the mechanosensitive Piezo1 channel in human myometrium.

Approximately 10% of US births deliver preterm before 37 weeks of completed gestation. Premature infants are at risk for life-long debilitating morbidities and death, and spontaneous preterm labour explains 50% of preterm births. In all cases existing treatments are ineffective, and none are FDA approved. The mechanisms that initiate preterm labour are not well understood but may result from dysfunctional regulation of quiescence mechanisms. Human pregnancy is accompanied by large increases in blood flow, and the uterus must enlarge by orders of magnitude to accommodate the growing fetus. This mechanical strain suggests that stretch-activated channels may constitute a mechanism to explain gestational quiescence. Here we identify for the first time that Piezo1, a mechanosensitive cation channel, is present in the uterine smooth muscle and microvascular endothelium of pregnant myometrium. Piezo is downregulated during preterm labour, and stimulation of myometrial Piezo1 in an organ bath with the agonist Yoda1 relaxes the tissue in a dose-dependent fashion. Further, stimulation of Piezo1 while inhibiting protein kinase A, AKT, or endothelial nitric oxide synthase mutes the negative inotropic effects of Piezo1 activation, intimating that actions on the myocyte and endothelial nitric oxide signalling contribute to Piezo1-mediated contractile dynamics. Taken together, these data highlight the importance of stretch-activated channels in pregnancy maintenance and parturition, and identify Piezo1 as a tocolytic target of interest. KEY POINTS: Spontaneous preterm labour is a serious obstetric dilemma without a known cause or effective treatments. Piezo1 is a stretch-activated channel important to muscle contractile dynamics. Piezo1 is present in the myometrium and is dysregulated in women who experience preterm labour. Activation of Piezo1 by the agonist Yoda1 relaxes the myometrium in a dose-dependent fashion, indicating that Piezo1 modulation may have therapeutic benefits to treat preterm labour.