Adaptation to soil type contributes little to local adaptation in an Italian and a Swedish ecotype of Arabidopsis thaliana on contrasting soils.

Natural populations are subject to selection caused by a range of biotic and abiotic factors in their native habitats. Identifying these agents of selection and quantifying their effects is key to understanding how populations adapt to local conditions. We performed a factorial reciprocal-transplant experiment using locally adapted ecotypes of Arabidopsis thaliana at their native sites to distinguish the contributions of adaptation to soil type and climate. Overall adaptive differentiation was strong at both sites. However, we found only very small differences in the strength of selection on local and non-local soil, and adaptation to soil type at most constituted only a few per cent of overall adaptive differentiation. These results indicate that local climatic conditions rather than soil type are the primary driver of adaptive differentiation between these ecotypes.

Altered Movement Coordination during Functional Reach Tasks in Patients with Chronic Low Back Pain and Its Relationship to Numerical Pain Rating Scores.

Identifying the effects of pain catastrophizing on movement patterns in people with chronic low back pain (CLBP) has important clinical implications for treatment approaches. Prior research has shown people with CLBP have decreased lumbar-hip ratios during trunk flexion movements, indicating a decrease in the contribution of lumbar flexion relative to hip flexion during trunk flexion. In this study, we aim to explore the relationship between pain catastrophizing and movement patterns during trunk flexion in a CLBP population. Participants with CLBP (N = 98, male = 59, age = 39.1 ± 13.0) completed a virtual reality standardized reaching task that necessitated a progressively larger amount of trunk flexion. Specifically, participants reached for four virtual targets to elicit 15°, 30°, 45°, and 60° trunk flexion in the mid-sagittal plane. Lumbar flexion was derived from the motion data. Self-report measures of numerical pain ratings, kinesiophobia, and pain catastrophizing were obtained. Pain catastrophizing leads to decreased lumbar flexion angles during forward reaching. This effect is greater in females than males.

36-year study reveals stability of a wild wheat population across microhabitats.

Long-term genetic studies of wild populations are very scarce, but are essential for connecting ecological and population genetics models, and for understanding the dynamics of biodiversity. We present a study of a wild wheat population sampled over a 36-year period at high spatial resolution. We genotyped 832 individuals from regular sampling along transects during the course of the experiment. Genotypes were clustered into ecological microhabitats over scales of tens of metres, and this clustering was remarkably stable over the 36 generations of the study. Simulations show that it is difficult to determine whether this spatial and temporal stability reflects extremely limited dispersal or fine-scale local adaptation to ecological parameters. Using a common-garden experiment, we showed that the genotypes found in distinct microhabitats differ phenotypically. Our results provide a rare insight into the population genetics of a natural population over a long monitoring period.

A systematic review and network meta-analysis of psychological, psychosocial, pharmacological, physical and combined treatments for adults with a new episode of depression.

Background: Various effective treatments for depression exist. We aimed to identify the most effective first-line treatments for new episodes of less and more severe depression (defined by depression scale cut-off scores), to update NICE guidance on the management of Depression in Adults in England. Methods: Systematic review and network meta-analysis of randomised controlled trials (RCTs) published up to June 2020 (PROSPERO registration number CRD42019151328). We analysed interventions by class and individually. The primary efficacy outcome was depressive symptom change (expressed as standardised mean difference [SMD]). The review for this outcome was updated in November 2023. Findings: We included 676 RCTs, 105,477 participants and 63 treatment classes. For less severe depression, group cognitive/cognitive behavioural therapy (CT/CBT) class was efficacious versus treatment as usual [TAU], the reference treatment for this population [SMD -1.01 (95% Credible Interval [CrI] -1.76; -0.06)]. For more severe depression, efficacious classes versus pill placebo (reference treatment for this population) included combined individual CT/CBT with antidepressants [-1.18 (-2.07; -0.44)], individual behavioural therapies [-0.86 (-1.65; -0.16)], combined light therapy with antidepressants [-0.86 (-1.59; -0.12)], combined acupuncture with antidepressants [-0.78 (-1.12; -0.44)], individual CT/CBT [-0.78 (-1.42; -0.33)], mirtazapine [-0.35 (-0.48; -0.22)], serotonin and norepinephrine reuptake inhibitors [-0.32 (-0.43; -0.22)], tricyclic antidepressants [-0.29 (-0.50; -0.05)], and selective serotonin reuptake inhibitors [-0.24 (-0.32; -0.16)]. Additional treatments showed evidence of efficacy at the intervention level. Evidence for less and more severe depression was of low and low-to-moderate quality, respectively. In the 2023 update, group yoga and self-help without support emerged as efficacious for less severe depression. For more severe depression, combined group exercise with antidepressants emerged as efficacious, whereas combined light therapy with antidepressants failed to remain efficacious. Interpretation: Group CT/CBT (and possibly group yoga and self-help) appears efficacious in less severe depression, whereas antidepressants do not show evidence of effect. Combined antidepressants with individual CT/CBT, acupuncture and, possibly, group exercise, individual psychological therapies (behavioural therapies, CT/CBT) alone, and antidepressants alone appear efficacious in more severe depression. Quality of evidence, cost-effectiveness, applicability and implementation issues also need to be considered when formulating clinical practice recommendations. Funding: National Institute for Health and Care Excellence.

An autoregulatory poison exon in Smndc1 is conserved across kingdoms and influences organism growth.

Many of the most highly conserved elements in the human genome are "poison exons," alternatively spliced exons that contain premature termination codons and permit post-transcriptional regulation of mRNA abundance through induction of nonsense-mediated mRNA decay (NMD). Poison exons are widely assumed to be highly conserved due to their presumed importance for organismal fitness, but this functional importance has never been tested in the context of a whole organism. Here, we report that a poison exon in Smndc1 is conserved across mammals and plants and plays a molecular autoregulatory function in both kingdoms. We generated mouse and A. thaliana models lacking this poison exon to find its loss leads to deregulation of SMNDC1 protein levels, pervasive alterations in mRNA processing, and organismal size restriction. Together, these models demonstrate the importance of poison exons for both molecular and organismal phenotypes that likely explain their extraordinary conservation.

Zinc-Air Hearing Aid Batteries: An Analysis of Functional Performance.

BACKGROUND: The aim of this study was to evaluate the performance of three disposable hearing aid battery brands available in Wales. Hearing-impaired individuals who utilise hearing aids rely on the functionality of their devices, which is often contingent upon the quality and longevity of disposable batteries. MATERIALS AND METHODS: A grey literature review foregrounded the battery standards. The "real-life" use of batteries was supplemented through laboratory testing. Parameters relating to performance quality were used to quantify an overall service life of five PR44- and four PR48-size batteries per manufacturer. RESULTS: The literature review signalled a large gap in hearing aid battery consumption research. All battery brands underperformed compared to their specifications but met IEC standards. CONCLUSIONS: Revisions to battery consumption test conditions should reflect new technological features and refine expectations of real-life use. It was possible to statistically identify the best performing hearing aid battery brand.

Assessment of echocardiographic interpretation of dual-lumen cannula during venovenous extracorporeal membrane oxygenation use for pediatric respiratory failure.

PURPOSE: Echocardiography is considered essential during cannulation placement and manipulations. Literature evaluating transthoracic echocardiography (TTE) usage during pediatric VV-ECMO is scant. The purpose of this study is to describe the use of echocardiography during VV-ECMO at a large, quaternary children's hospital. METHODS: A retrospective, single-year cohort study was performed of pediatric patients on VV-ECMO via dual-lumen cannula at our institution from January 2019 through December 2019. For each echocardiogram, final cannula component (re-infusion port (ReP), distal tip, proximal port and distal port) positions were evaluated by one echocardiographer. For TTEs with ReP in the right atrium, two echocardiographers independently evaluated ReP direction using 2-point (Yes/No) and 4-point scales, which were semi-quantitative protocols using color Doppler images to estimate ReP jet direction to the tricuspid valve. Cohen's kappa or weighted kappa was used to measure interrater agreement. RESULTS: During study period, 11 patients (64% male) received VV-ECMO with 49 TTEs and one transesophageal echocardiogram performed. The median patient age was 4.3 years [IQR: 1.1-11.5] and median VV-ECMO run time of 192 h [90-349]. The median time between TTEs on VV-ECMO was 34 h [8.3-65]. Most common position for the ReP was the right atrium (n = 33, 67%), and ReP location was not identified in five TTEs (10%). For ReP flow direction, echocardiographers agreed on 82% of TTEs using 2-point evaluation. There was only moderate agreement between echocardiographers on the 2-point and 4-point assessments (k = .54, kw = .46 respectively). CONCLUSIONS: TTE is the predominant cardiac ultrasound modality used during VV-ECMO for pediatric respiratory failure. Subjective evaluation of VV-ECMO ReP jet direction in the right atrium is challenging, regardless of assessment method.

Beyond the standard GWAS - a guide for plant biologists.

Classic genome-wide association studies (GWAS) look for associations between individual SNPs and phenotypes of interest. With the rapid progress of high-throughput genotyping and phenotyping technologies, GWAS have become increasingly powerful for detecting genetic determinants and their molecular mechanisms underpinning natural phenotypic variation. However, GWAS frequently yield results with neither expected nor promising loci, nor any significant associations. This is often because associations between SNPs and a single phenotype are confounded, for example with the environment, other traits, or complex genetic structures. Such confounding can mask true genotype-phenotype associations, or inflate spurious associations. To address these problems, numerous methods have been developed that go beyond the standard model. Such advanced GWAS models are flexible and can offer improved statistical power for understanding the genetics underlying complex traits. Despite this advantage, these models have not been widely adopted and implemented compared to the standard GWAS approach, partly because this literature is diverse and often technical. In this review, our aim is to provide an overview of the application and the benefits of various advanced GWAS models for handling complex traits and genetic structures, targeting plant biologists who wish to carry out GWAS more effectively.

Correlation of the Size of Adenoids With Impedance Audiometry Findings.

Introduction Adenoid tissue is part of the first line of immunity of the upper aero-digestive tract. It is located in the postero-superior wall of the nasopharynx behind the choana. Adenoid hypertrophy, a common childhood disorder, significantly contributes to the pathogenesis of otitis media with effusion (OME), which is the leading cause of hearing impairment in young children. This condition can result in delayed speech, poor academic performance, and language development issues. Assessing the size of the adenoids and their correlation with OME is crucial, as undiagnosed cases can lead to complications such as atelectasis of the tympanic membrane and cholesteatoma. Clinical examination of the nose alone is often insufficient, and children do not cooperate for nasal endoscopy. Therefore, a lateral radiograph of the skull is considered the most reliable method for assessing the adenoid size. The size of the adenoids can affect Eustachian tube patency, which is reflected in the results of impedance audiometry. This study aimed to correlate the size of adenoids with impedance audiometry findings. Methods This cross-sectional observational study was conducted in the Department of Otorhinolaryngology of a tertiary care hospital from October 1, 2022, to March 31, 2024. A sample size of 50 patients was taken for the study. The inclusion criterion of selection of the patients included patients aged 3 to 15 years, who suffered from recurrent attacks of upper respiratory tract infections, particularly those with adenoid facies confirmed by X-ray with a non-perforated tympanic membrane. Exclusion criteria encompassed patients below 3 or above 15 years, and those with acute or chronic suppurative otitis media, craniofacial anomalies, or nasal pathologies like polyps. Adenoids were graded using X-ray imaging of the nasopharynx, and correlations between the adenoid size and impedance audiometry findings, such as middle ear pressure and compliance, were analyzed.  Results The study assessed the relationship between the adenoid size and impedance audiometry findings, focusing on middle ear pressure and compliance, as well as the occurrence of OME. The results indicated a significant decline in middle ear pressure with increasing adenoid grades. Specifically, adenoid grade 1 had an average pressure of -3.50 daPa, while grade 4 had the lowest average pressure at -119.72 daPa. This trend was statistically significant with a p-value of 0.00042. Similarly, compliance values also decreased with higher adenoid grades. Grade 1 had an average compliance of 0.64 ml, whereas grade 4 had the lowest average compliance at 0.28 ml. This relationship was statistically significant, as indicated by a p-value of 0.0048. Additionally, the analysis showed that a significant majority of patients with enlarged adenoids also presented with OME, highlighting a strong association between adenoid hypertrophy and this condition. Conclusion The study concluded that larger adenoids were associated with lower middle ear pressure and reduced compliance. Additionally, a significant majority of patients with enlarged adenoids also had OME. This underscores the importance of evaluating adenoid hypertrophy in the context of OME due to its potential impact on childhood hearing and development.

Defensive healthcare practice: systematic review of qualitative evidence.

OBJECTIVE: To synthesise qualitative evidence on clinicians' views and experiences of defensive practice. DESIGN: Systematic review of qualitative data. DATA SOURCES: MEDLINE, Embase, PsycINFO, AMED, Maternity and Infant Care, CINAHL, ASSIA, Sociological Abstracts, Proquest Dissertations & Theses and PROSPERO were searched from 2000 to October 2023. ELIGIBILITY CRITERIA: We included English-language studies of clinicians which reported qualitative data on the impact of litigation or complaints on clinical practice. DATA EXTRACTION AND SYNTHESIS: We coded findings data line by line using a grounded theory approach. We assessed quality using Hawker et al's tool and synthesised data thematically. RESULTS: 17 studies were included. Participants identify a range of clinical decisions which may be defensively motivated, relating to diagnosis and documentation as well as to treatment. Defensive practice often relates to a diffuse sense of risk rather than the direct threat of litigation and may overlap with other motivations, such as perceived pressure from patients or the desire to avoid harm. Defensive practice is seen to be harmful in many ways, but again, these perceptions may gain force from broader narratives of mistrust and disempowerment, as much as from the risk of litigation. CONCLUSIONS: The idea of defensive practice, as enacted, is more complex than some theoretical accounts suggest and may often function to express broader concerns about the work of clinical care. The qualitative evidence calls into question the view of defensive practice as a key mediator linking litigation risk to inappropriate treatment and excess costs.

Trace amine-associated receptor 1 (TAAR1) agonism for psychosis: a living systematic review and meta-analysis of human and non-human data.

Background: Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies. Methods: We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses. Results: Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D 2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling. Conclusions: TAAR1 agonists may be less efficacious than dopamine D 2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted. Registration: PROSPERO-ID: CRD42023451628.

There is a need for more effective treatments for psychosis, including schizophrenia. Psychosis is a collection of mental health symptoms, such as hearing voices, that can cause distress and impair functioning. These symptoms are thought to be caused by changes in a chemical messenger system in the brain called dopamine. Currently used antipsychotic medications target brain receptors that respond to dopamine. They are not effective in some people and can cause uncomfortable adverse events, such as weight gain and movement disorders, especially with long-term use. A new type of drug is the trace amine-associated receptor 1 (TAAR1) agonists. These drugs act on different brain receptors that can affect the activity of the dopamine system, but do not directly bind to dopamine receptors. We aimed to understand if TAAR1 agonists can reduce symptoms of psychosis, what adverse events they might have, and how they work. We did this by reviewing and collating all available evidence until November 2023. This is a "living" systematic review, so it will be regularly updated in the future. We looked at both human and animal studies investigating TAAR1 agonists. Human studies suggested that two TAAR1 agonists (namely, ulotaront or ralmitaront) might have little to no effect on reducing symptoms of psychosis compared to placebo in people with schizophrenia. They seemed to cause fewer adverse events than current antipsychotics. Data from animal studies suggested that TAAR1 agonists had some positive effects but potentially smaller than other antipsychotics. There were little to no data from both human and animal studies about how TAAR1 agonists actually work. From the current evidence we are uncertain about these results. With the ongoing development of new TAAR1 agonists, more evidence is needed to understand their potential role in the treatment of psychosis.

Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: twelve months of an ongoing randomized phase 3 trial.

BACKGROUND: Elagolix, an approved oral treatment for endometriosis-associated pain, has been associated with hypoestrogenic effects when used as monotherapy. Hormonal add-back therapy has the potential to mitigate these effects. OBJECTIVE: To evaluate efficacy, tolerability, and bone density outcomes of elagolix 200 mg twice daily with 1 mg estradiol/0.5 mg norethindrone acetate (add-back) therapy once daily compared with placebo in premenopausal women with moderate-to-severe endometriosis-associated pain. STUDY DESIGN: This ongoing, 48-month, phase 3 study consists of a 12-month double-blind period, with randomization 4:1:2 to elagolix 200 mg twice daily with add-back therapy, elagolix 200 mg twice daily monotherapy for 6 months followed by elagolix with add-back therapy, or placebo. The coprimary endpoints were proportion of patients with clinical improvement (termed "responders") in dysmenorrhea and nonmenstrual pelvic pain at month 6. We report 12-month results on efficacy of elagolix with add-back therapy vs placebo in reducing dysmenorrhea, nonmenstrual pelvic pain, dyspareunia, and fatigue. Tolerability assessments include adverse events and change from baseline in bone mineral density. RESULTS: A total of 679 patients were randomized to elagolix with add-back therapy (n=389), elagolix monotherapy (n=97), or placebo (n=193). Compared with patients randomized to placebo, a significantly greater proportion of patients randomized to elagolix with add-back therapy responded with clinical improvement in dysmenorrhea (62.8% vs 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% vs 36.8%; P≤.001) at 6 months. Compared with placebo, elagolix with add-back therapy produced significantly greater improvement from baseline in 7 hierarchically ranked secondary endpoints including dysmenorrhea (months 12, 6, 3), nonmenstrual pelvic pain (months 12, 6, 3), and fatigue (months 6) (all P<.01). Overall, the incidence of adverse events was 73.8% with elagolix plus add-back therapy and 66.8% with placebo. The rate of severe and serious adverse events did not meaningfully differ between treatment groups. Study drug discontinuations associated with adverse events were low in patients receiving elagolix with add-back therapy (12.6%) and those receiving placebo (9.8%). Patients randomized to elagolix monotherapy exhibited decreases from baseline in bone mineral density of -2.43% (lumbar spine), -1.54% (total hip), and -1.78% (femoral neck) at month 6. When add-back therapy was added to elagolix at month 6, the change from baseline in bone mineral density remained in a similar range of -1.58% to -1.83% at month 12. However, patients who received elagolix plus add-back therapy from baseline exhibited little change from baseline in bone mineral density (<1% change) at months 6 and 12. CONCLUSION: Compared with placebo, elagolix with add-back therapy resulted in significant, clinically meaningful improvement in dysmenorrhea, nonmenstrual pelvic pain, and fatigue at 6 months that continued until month 12 for both dysmenorrhea and nonmenstrual pelvic pain. Elagolix with add-back therapy was generally well tolerated. Loss of bone mineral density at 12 months was greater in patients who received elagolix with add-back therapy than those who received placebo. However, the change in bone mineral density with elagolix plus add-back therapy was <1% and was attenuated compared with bone loss observed with elagolix monotherapy.

Variation in dentist participation between dental medicaid managed care organizations.

OBJECTIVES: Dentists' Medicaid participation is a critical factor affecting dental care access for Medicaid beneficiaries. An important gap in existing literature is the variation in participation across Medicaid dental Managed Care Organizations (MCOs) in states with more than one. This study examined the variation in participation overall and in predictors of dentist participation between two MCOs in Iowa's Dental Medicaid program. METHODS: Data were obtained from a survey of Iowa private practice dentists (n = 1256). Responding general dentists (n = 497) were included in the final analytic sample. Univariate, bivariate, and multivariable logistic regression analyses were conducted to examine demographic and practice characteristics associated with dentist participation (acceptance of new Medicaid patients) between MCOs and by age category. RESULTS: Among respondents, the proportions accepting new adults with Medicaid were 26% (MCO 1) and 7% (MCO 2); for children, they were 40% (MCO 1) and 11% (MCO 2). For adults, dentists who were too busy (MCO1) and solo practice dentists (MCO2) were positively significantly associated with the acceptance of new patients. For children, group and rural practice dentists, as well as dentists who worked <32 h/week were positively significantly associated with acceptance of new patients with MCO1. CONCLUSIONS: There was considerable variation in dentist-reported acceptance of new adult and child Medicaid patients, and in the factors affecting acceptance of new patients between MCOs in Iowa dental Medicaid. Future studies of Medicaid participation should consider variations by MCO in states with more than one dental MCO so as not to miss important factors affecting Medicaid participation.

Electronic cigarettes and subsequent use of cigarettes in young people: An evidence and gap map.

BACKGROUND AND AIMS: The use of e-cigarettes may influence later smoking uptake in young people. Evidence and gap maps (EGMs) are interactive on-line tools that display the evidence and gaps in a specific area of policy or research. The aim of this study was to map clusters and gaps in evidence exploring the relationship between e-cigarette use or availability and subsequent combustible tobacco use in people aged < 30 years. METHODS: We conducted an EGM of primary studies and systematic reviews. A framework and an interactive EGM was developed in consultation with an expert advisory group. A systematic search of five databases retrieved 9057 records, from which 134 studies were included. Systematic reviews were appraised using AMSTAR-2, and all included studies were coded into the EGM framework resulting in the interactive web-based EGM. A descriptive analysis of key characteristics of the identified evidence clusters and gaps resulted in this report. RESULTS: Studies were completed between 2015 and 2023, with the first systematic reviews being published in 2017. Most studies were conducted in western high-income countries, predominantly the United States. Cohort studies were the most frequently used study design. The evidence is clustered on e-cigarette use as an exposure, with an absolute gap identified for evidence looking into the availability of e-cigarettes and subsequent cessation of cigarette smoking. We also found little evidence analysing equity factors, and little exploring characteristics of e-cigarette devices. CONCLUSIONS: This evidence and gap map (EGM) offers a tool to explore the available evidence regarding the e-cigarette use/availability and later cigarette smoking in people under the age of 30 years at the time of the search. The majority of the 134 reports is from high-income countries, with an uneven geographic distribution. Most of the systematic reviews are of lower quality, suggesting the need for higher-quality reviews. The evidence is clustered around e-cigarette use as an exposure and subsequent frequency/intensity of current combustible tobacco use. Gaps in evidence focusing on e-cigarette availability, as well as on the influence of equity factors may warrant further research. This EGM can support funders and researchers in identifying future research priorities, while guiding practitioners and policymakers to the current evidence base.

Colorectal cancer screening participation in First Nations populations worldwide: a systematic review and data synthesis.

Background: First Nations populations have poorer colorectal cancer (CRC) survival compared to non-First Nations populations. Whilst First Nations populations across the world are distinct, shared experiences of discrimination and oppression contribute to persistent health inequities. CRC screening improves survival, however screening rates in First Nations populations are poorly described. This study seeks to define participation rates in CRC screening in First Nations populations worldwide. Methods: A systematic literature search was conducted of PubMed, Embase, Cochrane Library, CINAHL, MEDLINE, grey literature, national registries and ClinicalTrials.gov. All sources were searched from their inception date to 18 February 2024. Studies were included if they reported CRC screening rates in adult (≥18 years) First Nations populations. We aimed to undertake a meta-analysis if there were sufficient data. Quality of papers were assessed using the Joanna Briggs Institute (JBI) appraisal tool. The study was registered with PROSPERO, CRD42020210181. Findings: The literature search identified 1723 potentially eligible published studies. After review, 57 studies were included, 50 from the United States (US), with the remaining studies from Australia, Aotearoa New Zealand (NZ), Canada, Dominica and Guatemala. Additionally, eleven non-indexed reports from national programs in Australia and NZ were included. There were insufficient data to undertake meta-analysis, therefore a systematic review and narrative synthesis were conducted. CRC screening definitions varied, and included stool-based screening, sigmoidoscopy and colonoscopy. US First Nations screening rates ranged between 4.0 and 79.2%, Australia reported 10.6-35.2%, NZ 18.4-49%, Canada 22.4-53.4%, Guatemala 2.2% and Dominica 4.2%. Fifty-five studies were assessed as moderate or high quality and two as low quality. Interpretation: Our findings suggested that there is wide variation in CRC screening participation rates across First Nations populations. Screening data are lacking in direct comparator groups and longitudinal outcomes. Disaggregation of screening data are required to better understand and address First Nations CRC outcome inequities. Funding: None.

Comparative Prevalence of Cerebrovascular Disease in Vietnamese Communities in South-Western Sydney.

Culturally and linguistically diverse (CALD) communities are growing globally. Understanding patterns of cerebrovascular disease in these communities may improve health outcomes. We aimed to compare the rates of transient ischaemic attack (TIA), ischaemic stroke (IS), intracerebral haemorrhage (ICH), intracranial atherosclerosis (ICAD), and stroke risk factors in Vietnamese-born residents of South-Western Sydney (SWS) with those of an Australian-born cohort. A 10-year retrospective analysis (2011-2020) was performed using data extracted from the Health Information Exchange database characterising stroke presentations and risk factor profiles. The rates of hypertension (83.7% vs. 70.3%, p < 0.001) and dyslipidaemia (81.0% vs. 68.2%, p < 0.001) were significantly higher in Vietnamese patients, while the rates of ischaemic heart disease (10.4% vs. 20.3%, p < 0.001), smoking (24.4% vs. 40.8%, p < 0.001), and alcohol abuse (>1 drink/day) (9.6% vs. 15.9%, p < 0.001) were lower. The rates of ICAD and ICH were higher in Vietnamese patients (30.9% vs. 6.9%, p < 0.001 and 24.7% vs. 14.4%, p = 0.002). Regression analysis revealed that diabetes (OR: 1.86; 95% CI: 1.14-3.04, p = 0.014) and glycosylated haemoglobin (OR: 1.51; 95% CI: 1.15-1.98, p = 0.003) were predictors of ICAD in Vietnamese patients. Vietnamese patients had higher rates of symptomatic ICAD and ICH, with unique risk factor profiles. Culturally specific interventions arising from these findings may more effectively reduce the community burden of disease.

Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.

Joint association of drinking alcohol and obesity in relation to cancer risk: A systematic review and data synthesis.

BACKGROUND: Rates of alcohol consumption and obesity are increasing in many Western populations. For some cancer types, both heavy alcohol consumption and obesity are independently associated with increased risk. Whether combined exposure to both synergistically increases an individual's risk of cancer is unclear. We performed a systematic review to assess whether alcohol and obesity interact to confer higher risk for cancer than the additive sum of their effects. METHODS: A systematic literature search was conducted from the inception date to 13 February 2024 of PubMed, Embase, Cochrane Library and Web of Science to identify studies of alcohol, obesity, and cancer risk. We aimed to undertake a meta-analysis if there were sufficient data. RESULTS: The literature search identified 17,740 potentially eligible studies. After review, 24 studies were included. Eleven reported on the association between alcohol consumption and cancer risk in individuals according to their body mass index (BMI), nine reported on the association between BMI and cancer risk in individuals according to their alcohol consumption, and six studies examined potential synergistic interactions between alcohol consumption and obesity on cancer risk. However, there were insufficient data and significant heterogeneity in the cancers studied to undertake meta-analysis, therefore a systemic review and narrative synthesis was conducted. Overall, there was no consistent pattern of interaction between alcohol use and overweight/obesity on cancer risk across cancer types. CONCLUSIONS: While alcohol and obesity are prevalent and important risk factors for a range of cancers, data are lacking on whether their combined exposure may synergistically increase an individual's risk for cancer. Further study across more cancer types is required to better understand the nature of interactions between alcohol use and obesity on cancer risk.

GLIDE Score: Scoring System for Prediction of Procedural Success in Tricuspid Valve Transcatheter Edge-to-Edge Repair.

BACKGROUND: Tricuspid valve transcatheter edge-to-edge repair (T-TEER) is the most widely used transcatheter therapy to treat patients with tricuspid regurgitation (TR). OBJECTIVES: The aim of this study was to develop a simple anatomical score to predict procedural outcomes of T-TEER. METHODS: All patients (n = 168) who underwent T-TEER between January 2017 and November 2022 at 2 centers were included in the derivation cohort. Additionally, 126 patients from 2 separate institutions served as a validation cohort. T-TEER was performed using 2 commercially available technologies. Core laboratory assessment of procedural transesophageal echocardiograms was used to determine septolateral and anteroposterior coaptation gap, leaflet morphology, septal leaflet length and retraction, chordal structure density, tethering height, en face TR jet morphology and TR jet location, image quality, and the presence of intracardiac leads. A scoring system was derived using univariable and multivariable logistic regression. Endpoints assessed were immediate postprocedural TR reduction ≥2 grades and TR grade moderate or less. RESULTS: The median age was 82 years (Q1-Q3: 78-84 years); 48% of patients were women; and patients presented with severe (55%), massive (36%), and torrential (8%) TR. Five variables (septolateral coaptation gap, chordal structure density, en face TR jet morphology, TR jet location, and image quality) were identified as best predicting procedural outcome and were incorporated in the GLIDE (Gap, Location, Image quality, density, en-face TR morphology) score (range 0-5). TR reduction ≥2 grades and TR grade moderate or less were observed in >90% of patients with GLIDE scores of 0 and 1 and in only 5.6% and 16.7% of those with GLIDE scores ≥4. The GLIDE score was then externally validated in a separate cohort (area under the curve: 0.77; 95% CI: 0.69-0.86). TR reduction significantly correlated with functional improvement assessed by NYHA functional class and 6-minute walk distance at 3 months. CONCLUSIONS: The GLIDE score is a simple, 5-component score that is readily obtained during patient imaging and can predict successful T-TEER.