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.

Efficacy, tolerability, and bone density outcomes of elagolix with add-back therapy for endometriosis-associated pain: 12 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 co-primary 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 versus 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% versus 23.7%; P≤.001) and nonmenstrual pelvic pain (51.3% versus 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.

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.

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.

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.

Skeletal Muscle Mitochondrial Morphology Negatively Affected in Mice Lacking Xin.

Altered mitochondrial structure and function are implicated in the functional decline of skeletal muscle. Numerous cytoskeletal proteins are known to affect mitochondrial homeostasis, but this complex network is still being unraveled. Here, we investigated mitochondrial alterations in mice lacking the cytoskeletal adapter protein, XIN (XIN-/-). XIN-/- and wild-type littermate male and female mice were fed a chow or high-fat diet (HFD; 60% kcal fat) for 8 weeks before analyses of their skeletal muscles was conducted. Immuno-electron microscopy (EM) and immunofluorescence staining revealed XIN in the mitochondria and peri-mitochondrial areas, as well as the myoplasm. Intermyofibrillar mitochondria in chow-fed XIN-/- mice were notably different from wild-type (large, and/or swollen in appearance). Succinate Dehydrogenase and Cytochrome Oxidase IV staining indicated greater evidence of mitochondrial enzyme activity in XIN-/- mice. No difference in body mass gains or glucose handling was observed between cohorts with HFD. However, EM revealed significantly greater mitochondrial density with evident structural abnormalities (swelling, reduced cristae density) in XIN-/- mice. Absolute Complex I and II-supported respiration was not different between groups, but relative to mitochondrial density, was significantly lower in XIN-/-. These results provide the first evidence for a role of XIN in maintaining mitochondrial morphology and function.

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.

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.

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.

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.

Ambulatory Blood Pressure Parameters Among Men With Hypogonadism Treated With Testosterone Transdermal Therapy.

OBJECTIVE: Studies are needed to examine the effects of testosterone replacement therapy (TRT) on ambulatory blood pressure (BP) parameters. This study assessed a testosterone transdermal system (TTS) using 24-hour ambulatory BP monitoring (ABPM). METHODS: In a single-arm, noninferiority trial conducted at 41 US sites, 168 men (mean age: 56.2 years) with hypogonadism not receiving TRT in the past 6 months were enrolled and received ≥1 study drug dose. Nightly TTS treatment was administered for 16 weeks (starting dose: 4 mg/d; min, max dose: 2, 6 mg/d) to achieve testosterone concentration of 400-930 ng/dL. The primary endpoint was mean change from baseline to week 16 in 24-hour systolic BP (SBP). Noninferiority was determined based on the upper bound of the 2-sided 95% CI <3.0 mmHg. RESULTS: 62 men had ≥85% study drug compliance and a valid week 16 ABPM session. Mean change from baseline to week 16 in 24-hour average SBP was 3.5 mmHg (95% CI, 1.2-5.8 mmHg; n=62). Since the upper limit of the CI was >3 mmHg, an effect of TTS could not be ruled out. Mean changes were larger at daytime vs nighttime and in subgroups of men with vs without hypertension. Cardiovascular adverse events (AEs) were rare (<2%) and nonserious; no major cardiovascular AEs were reported. CONCLUSION: A meaningful effect of 16-week TTS treatment on 24-hour average SBP among men with hypogonadism could not be ruled out based on the study's noninferiority criterion. The magnitude of mean changes observed may not be clinically meaningful regarding cardiovascular events.

Prognostic value of left atrial strain in aortic stenosis: A systematic review.

PURPOSE: Aortic stenosis (AS) is a common valvular heart disease with high morbidity and mortality. Recently, the association between peak atrial longitudinal strain (PALS) and AS clinical outcomes has been identified. This systematic review evaluates the prognostic value of PALS for adverse events in AS. METHODS: We performed a systematic literature review to identify clinical studies that evaluated Speckle-Tracking Echocardiography (STE)-derived PALS to predict adverse outcomes in patients with AS. We excluded studies that compared echocardiography to computed tomography and studies that focused on diseases other than AS. RESULTS: We included 18 studies reporting on 2660 patients. Patients with symptomatic AS had decreased PALS when compared to patients with asymptomatic AS. Patients with AS who had adverse events had decreased PALS when compared to patients with AS with no events. Each unit increase of PALS was independently associated with decreased risk for the primary endpoint. PALS cut-off values were associated with increased risk for the primary endpoint. CONCLUSION: This systematic review suggests PALS as an independent predictor for cardiovascular events in patients with AS and highlights the importance of evaluating LA mechanics for AS prognosis.

Chemotherapy-free treatment targeting fusions and driver mutations in KRAS wild-type pancreatic ductal adenocarcinoma, a case series.

Background: KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) represents a distinct entity with unique biology. The therapeutic impact of matched targeted therapy in these patients in a real-world setting, to date, is less established. Objectives: The aim of our study was to review our institutional database to identify the prevalence of actionable genomic alterations in patients with KRAS-WT tumors and to evaluate the therapeutic impact of matched targeted therapy in these patients. Design: We reviewed electronic medical records of patients with KRAS-WT PDAC and advanced disease (n = 14) who underwent clinical-grade tissue ± liquid next-generation sequencing (315-648 genes for tissue) between years 2015 and 2021. Methods: Demographic and disease characteristics were summarized using descriptive parameters. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: Of 236 PDAC patients, 14 had advanced/metastatic disease with KRAS-WT tumors. Median age at diagnosis was 66 years. There was a high frequency of potentially actionable genomic alterations, including three (21%) with BRAF alterations, two (14%) with fusions [RET-PCM1 and FGFR2-POC1B (N = 1 each)]; and one with a druggable EGFR (EGFR E746_A755delISERD) variant; two other patients had an STK11 and a MUTYH alteration. Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR-altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Duration of time on chemotherapy-free matched targeted therapy for these patients was 17+, 11, and 18+ months, respectively. Conclusion: Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.

The implementation of embedded researchers in policy, public services, and commercial settings: a systematic evidence and gap map.

BACKGROUND: Embedding researchers into policy and other settings may enhance research capacity within organisations to enable them to become more research active. We aimed to generate an evidence map on evaluations of embedded researcher interventions to (i) identify where systematic reviews and primary research are needed and (ii) develop conceptual understandings of 'embedded researchers'. We define 'embedded researchers' through a set of principles that incorporate elements such as the aim of activities, the types of relationships and learning involved, and the affiliations and identities adopted. METHODS: We included studies published across all sectors, searching fourteen databases, other web sources and two journals for evaluations published between 1991 and spring 2021. Data were extracted using a coding tool developed for this study. We identified new typologies of embedded researcher interventions through undertaking Latent Class Analysis. RESULTS: The map describes 229 evaluations spanning a variety of contexts. Our set of principles allowed us to move beyond a narrow focus on embedded researchers in name alone, towards consideration of the wide range of roles, activities, identities, and affiliations related to embedded researchers. We identified 108 different allied terms describing an embedded researcher. Embedded researcher activity spanned a continuum across lines of physical, cultural, institutional, and procedural embeddedness (from weaker to more intense forms of embeddedness) and took a range of forms that bridge or blur boundaries between academia and policy/practice. CONCLUSIONS: We developed a broad map of international embedded researcher activity in a wide range of sectors. The map suggests that embedded researcher interventions occupy a broader suite of models than previously acknowledged and our findings also offer insight on the type and nature of this literature. Given the clear policy interest in this area, a better understanding of the processes involved with becoming embedded within an organisation is needed. Further work is also necessary to address the challenges of evaluating the work of embedded researchers, including consideration for which outcome measures are most appropriate, to better understand their influence.

Novel echocardiographic pixel intensity quantification method for differentiating transthyretin cardiac amyloidosis from light chain cardiac amyloidosis and other phenocopies.

AIMS: Differentiating cardiac amyloidosis (CA) subtypes is important considering the significantly different therapies for transthyretin (ATTR)-CA and light chain (AL)-CA. Therefore, an echocardiographic method to distinguish ATTR-CA from AL-CA would provide significant value. We assessed a novel echocardiographic pixel intensity method to quantify myocardial calcification to differentiate ATTR-CA from phenocopies of CA and from AL-CA, specifically. METHODS AND RESULTS: 167 patients with ATTR-CA (n=53), AL-CA (n=32), hypertrophic cardiomyopathy (n=37), and advanced chronic kidney disease (n=45) were retrospectively evaluated. The septal reflectivity ratio (SRR) was measured as the average pixel intensity of the visible anterior septal wall divided by the average pixel intensity of the visible posterior lateral wall. SRR and other myocardial strain-based echocardiographic measures were evaluated with receiver operator characteristic analysis to evaluate accuracy in distinguishing ATTR-CA from AL-CA and other forms of left ventricular hypertrophy. Mean septal reflectivity ratio (SRR) was significantly higher in the ATTR-CA cohort compared to the other cohorts (p <0.001). SRR demonstrated the largest AUC (0.91, p<0.0001) for distinguishing ATTR from all other cohorts and specifically for distinguishing ATTR-CA from AL-CA (AUC=0.90, p<0.0001, specificity 96%, sensitivity 63%). There was excellent inter- and intra-operator reproducibility with an ICC of 0.91 (p <0.001) and 0.89 (p <0.001), respectively. CONCLUSION: The SRR is a reproducible and robust parameter for differentiating ATTR-CA from other phenocopies of CA and specifically ATTR-CA from AL-CA.

Methods used to conceptualize dimensions of health equity impacts of public health interventions in systematic reviews.

OBJECTIVES: Our aims were to, first, identify and summarize the use of methods, frameworks, and tools as a conceptual basis for investigating dimensions of equity impacts of public health interventions in systematic reviews including an equity focus. These include PROGRESS-Plus, which identifies key sociodemographic characteristics that determine health outcomes. Second, we aimed to document challenges and opportunities encountered in the application of such methods, as reported in systematic reviews. STUDY DESIGN AND SETTING: We conducted a methodological study, comprising an overview of systematic reviews with a focus on, or that aimed to assess, the equity impacts of public health interventions. We used electronic searches of the Cochrane Database of Systematic Reviews, the Database of Promoting Health Effectiveness Reviews (DoPHER), and the Finding Accessible Inequalities Research in Public Health Database, supplemented with automated searches of the OpenAlex dataset. An active learning algorithm was used to prioritize title-abstract records for manual screening against eligibility criteria. We extracted and analyzed a core dataset from a purposively selected sample of reviews, to summarize key characteristics and approaches to conceptualizing investigations of equity. RESULTS: We assessed 322 full-text reports for eligibility, from which we included 120 reports of systematic reviews. PROGRESS-Plus was the only formalized framework used to conceptualize dimensions of equity impacts. Most reviews were able to apply their intended methods to at least some degree. Where intended methods were unable to be applied fully, this was usually because primary research studies did not report the necessary information. A general rationale for focusing on equity impacts was often included, but few reviews explicitly justified their focus on (or exclusion of) specific dimensions. In addition to practical challenges such as data not being available, authors highlighted significant measurement and conceptual issues with applying these methods which may impair the ability to investigate and interpret differential impacts within and between studies. These issues included investigating constructs that lack standardized operationalization and measurement, and the complex nature of differential impacts, with dimensions that may interact with one another, as well as with particular temporal, personal, social or geographic contexts. CONCLUSION: PROGRESS-Plus is the predominant framework used in systematic reviews to conceptualize differential impacts of public health interventions by dimensions of equity. It appears sufficiently broad to encompass dimensions of equity examined in most investigations of this kind. However, PROGRESS-Plus does not necessarily ensure or guide critical thinking about more complex pathways, including interactions between dimensions of equity, and with wider contextual factors, and important practical, measurement and conceptual challenges remain. The findings from investigations of equity impacts in systematic reviews could be made more useful through more explicitly rationalized and considered approaches to the design, conduct and reporting of both primary research and the reviews themselves.

Morphology and chemical composition of Taiwan oil millet (Eccoilopus formosanus) epicuticular wax.

MAIN CONCLUSION: Taiwan oil millet has two types of epicuticular wax: platelet wax composed primarily of octacosanol and filament wax constituted essentially by the singular compound of octacosanoic acid. Taiwan oil millet (TOM-Eccoilopus formosanus) is an orphan crop cultivated by the Taiwan indigenous people. It has conspicuous white powder covering its leaf sheath indicating abundant epicuticular waxes, that may contribute to its resilience. Here, we characterized the epicuticular wax secretion in TOM leaf blade and leaf sheath using various microscopy techniques, as well as gas chromatography to determine its composition. Two kinds of waxes, platelet and filaments, were secreted in both the leaf blades and sheaths. The platelet wax is secreted ubiquitously by epidermal cells, whereas the filament wax is secreted by a specific cell called epidermal cork cells. The newly developed filament waxes were markedly re-synthesized by the epidermal cork cells through papillae protrusions on the external periclinal cell wall. Ultrastructural images of cork cell revealed the presence of cortical endoplasmic reticulum (ER) tubules along the periphery of plasma membrane (PM) and ER-PM contact sites (EPCS). The predominant wax component was a C28 primary alcohol in leaf blade, and a C28 free fatty acid in the leaf sheath, pseudopetiole and midrib. The wax morphology present in distinct plant organs corresponds to the specific chemical composition: platelet wax composed of alcohols exists mainly in the leaf blade, whereas filament wax constituted mainly by the singular compound C28 free fatty acids is present abundantly in leaf sheath. Our study clarifies the filament wax composition in relation to a previous study in sorghum. Both platelet and filament waxes comprise a protection barrier for TOM.