Association of a rapidly selected 4.3kb transposon-containing structural variation with a P450-based resistance to pyrethroids in the African malaria vector Anopheles funestus.

Deciphering the evolutionary forces controlling insecticide resistance in malaria vectors remains a prerequisite to designing molecular tools to detect and assess resistance impact on control tools. Here, we demonstrate that a 4.3kb transposon-containing structural variation is associated with pyrethroid resistance in central/eastern African populations of the malaria vector Anopheles funestus. In this study, we analysed Pooled template sequencing data and direct sequencing to identify an insertion of 4.3kb containing a putative retro-transposon in the intergenic region of two P450s CYP6P5-CYP6P9b in mosquitoes of the malaria vector Anopheles funestus from Uganda. We then designed a PCR assay to track its spread temporally and regionally and decipher its role in insecticide resistance. The insertion originates in or near Uganda in East Africa, where it is fixed and has spread to high frequencies in the Central African nation of Cameroon but is still at low frequency in West Africa and absent in Southern Africa. A marked and rapid selection was observed with the 4.3kb-SV frequency increasing from 3% in 2014 to 98% in 2021 in Cameroon. A strong association was established between this SV and pyrethroid resistance in field populations and is reducing pyrethroid-only nets' efficacy. Genetic crosses and qRT-PCR revealed that this SV enhances the expression of CYP6P9a/b but not CYP6P5. Within this structural variant (SV), we identified putative binding sites for transcription factors associated with the regulation of detoxification genes. An inverse correlation was observed between the 4.3kb SV and malaria parasite infection, indicating that mosquitoes lacking the 4.3kb SV were more frequently infected compared to those possessing it. Our findings highlight the underexplored role and rapid spread of SVs in the evolution of insecticide resistance and provide additional tools for molecular surveillance of insecticide resistance.

The duplicated P450s CYP6P9a/b drive carbamates and pyrethroids cross-resistance in the major African malaria vector Anopheles funestus.

Cross-resistance to insecticides in multiple resistant malaria vectors is hampering resistance management. Understanding its underlying molecular basis is critical to implementation of suitable insecticide-based interventions. Here, we established that the tandemly duplicated cytochrome P450s, CYP6P9a/b are driving carbamate and pyrethroid cross-resistance in Southern African populations of the major malaria vector Anopheles funestus. Transcriptome sequencing revealed that cytochrome P450s are the most over-expressed genes in bendiocarb and permethrin-resistant An. funestus. The CYP6P9a and CYP6P9b genes are overexpressed in resistant An. funestus from Southern Africa (Malawi) versus susceptible An. funestus (Fold change (FC) is 53.4 and 17 respectively), while the CYP6P4a and CYP6P4b genes are overexpressed in resistant An. funestus in Ghana, West Africa, (FC is 41.1 and 17.2 respectively). Other up-regulated genes in resistant An. funestus include several additional cytochrome P450s (e.g. CYP9J5, CYP6P2, CYP6P5), glutathione-S transferases, ATP-binding cassette transporters, digestive enzymes, microRNA and transcription factors (FC<7). Targeted enrichment sequencing strongly linked a known major pyrethroid resistance locus (rp1) to carbamate resistance centering around CYP6P9a/b. In bendiocarb resistant An. funestus, this locus exhibits a reduced nucleotide diversity, significant p-values when comparing allele frequencies, and the most non-synonymous substitutions. Recombinant enzyme metabolism assays showed that both CYP6P9a/b metabolize carbamates. Transgenic expression of CYP6P9a/b in Drosophila melanogaster revealed that flies expressing both genes were significantly more resistant to carbamates than controls. Furthermore, a strong correlation was observed between carbamate resistance and CYP6P9a genotypes with homozygote resistant An. funestus (CYP6P9a and the 6.5kb enhancer structural variant) exhibiting a greater ability to withstand bendiocarb/propoxur exposure than homozygote CYP6P9a_susceptible (e.g Odds ratio = 20.8, P<0.0001 for bendiocarb) and heterozygotes (OR = 9.7, P<0.0001). Double homozygote resistant genotype (RR/RR) were even more able to survive than any other genotype combination showing an additive effect. This study highlights the risk that pyrethroid resistance escalation poses to the efficacy of other classes of insecticides. Available metabolic resistance DNA-based diagnostic assays should be used by control programs to monitor cross-resistance between insecticides before implementing new interventions.

Towards cascading genetic risk in Alzheimer's disease.

Alzheimer's disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimer's disease. Here, we investigate whether genetic risk for Alzheimer's disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimer's disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer's disease, in addition to opening therapeutic windows for targeted interventions.

Engineered Wnt7a ligands rescue blood-brain barrier and cognitive deficits in a COVID-19 mouse model.

Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating cerebrovascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection. To this end, we performed unbiased transcriptional analysis to identify brain endothelial cell signalling pathways dysregulated by mouse adapted SARS-CoV-2 MA10 in aged immunocompetent C57Bl/6 mice in vivo. This analysis revealed significant suppression of Wnt/ß-catenin signalling, a critical regulator of blood-brain barrier (BBB) integrity. We therefore hypothesized that enhancing cerebrovascular Wnt/ß-catenin activity would offer protection against BBB permeability, neuroinflammation, and neurological signs in acute infection. Indeed, we found that delivery of cerebrovascular-targeted, engineered Wnt7a ligands protected BBB integrity, reduced T-cell infiltration of the brain, and reduced microglial activation in SARS-CoV-2 infection. Importantly, this strategy also mitigated SARS-CoV-2 induced deficits in the novel object recognition assay for learning and memory and the pole descent task for bradykinesia. These observations suggest that enhancement of Wnt/ß-catenin signalling or its downstream effectors could be potential interventional strategies for restoring cognitive health following viral infections.

Standardised training for endoscopic mucosal resection of large non-pedunculated colorectal polyps to reduce recurrence (*STAR-LNPCP study): a multicentre cluster randomised trial.

OBJECTIVE: Endoscopic mucosal resection (EMR) is the preferred treatment for non-invasive large (≥20 mm) non-pedunculated colorectal polyps (LNPCPs) but is associated with an early recurrence rate of up to 30%. We evaluated whether standardised EMR training could reduce recurrence rates in Dutch community hospitals. DESIGN: In this multicentre cluster randomised trial, 59 endoscopists from 30 hospitals were randomly assigned to the intervention group (e-learning and 2-day training including hands-on session) or control group. From April 2019 to August 2021, all consecutive EMR-treated LNPCPs were included. Primary endpoint was recurrence rate after 6 months. RESULTS: A total of 1412 LNPCPs were included; 699 in the intervention group and 713 in the control group (median size 30 mm vs 30 mm, 45% vs 52% size, morphology, site and access (SMSA) score IV, 64% vs 64% proximal location). Recurrence rates were lower in the intervention group compared with controls (13% vs 25%, OR 0.43; 95% CI 0.23 to 0.78; p=0.005) with similar complication rates (8% vs 9%, OR 0.93; 95% CI 0.64 to 1.36; p=0.720). Recurrences were more often unifocal in the intervention group (92% vs 76%; p=0.006). In sensitivity analysis, the benefit of the intervention on recurrence rate was only observed in the 20-40 mm LNPCPs (5% vs 20% in 20-29 mm, p=0.001; 10% vs 21% in 30-39 mm, p=0.013) but less evident in ≥40 mm LNPCPs (24% vs 31%; p=0.151). In a post hoc analysis, the training effect was maintained in the study group, while in the control group the recurrence rate remained high. CONCLUSION: A compact standardised EMR training for LNPCPs significantly reduced recurrences in community hospitals. This strongly argues for a national dedicated training programme for endoscopists performing EMR of ≥20 mm LNPCPs. Interestingly, in sensitivity analysis, this benefit was limited for LNPCPs ≥40 mm. TRIAL REGISTRATION NUMBER: NTR7477.

Prevalence of neoplasia at colonoscopy among testicular cancer survivors treated with platinum-based chemotherapy.

Testicular cancer survivors (TCS) treated with platinum-based chemotherapy have an increased risk of colorectal cancer (CRC). We determined the yield of colonoscopy in TCS to assess its potential in reducing CRC incidence and mortality. We conducted a colonoscopy screening study among TCS in four Dutch hospitals to assess the yield of colorectal neoplasia. Neoplasia was defined as adenomas, serrated polyps (SPs), advanced adenomas (AAs: ≥10 mm diameter, high-grade dysplasia or ≥25% villous component), advanced serrated polyps (ASPs: ≥10 mm diameter or dysplasia) or CRC. Advanced neoplasia (AN) was defined as AA, ASP or CRC. Colonoscopy yield was compared to average-risk American males who underwent screening colonoscopy (n = 24,193) using a propensity score matched analysis, adjusted for age, smoking status, alcohol consumption and body mass index. A total of 137 TCS underwent colonoscopy. Median age was 50 years among TCS (IQR 43-57) vs 55 years (IQR 51-62) among American controls. A total of 126 TCS were matched to 602 controls. The prevalence of AN was higher in TCS than in controls (8.7% vs 1.7%; P = .0002). Nonadvanced adenomas and SPs were detected in 45.2% of TCS vs 5.5% of controls (P < .0001). No lesions were detected in 46.0% of TCS vs 92.9% of controls (P < .0001). TCS treated with platinum-based chemotherapy have a higher prevalence of neoplasia and AN than matched controls. These results support our hypothesis that platinum-based chemotherapy increases the risk of colorectal neoplasia in TCS. Cost-effectiveness studies are warranted to ascertain the threshold of AN prevalence that justifies the recommendation of colonoscopy for TCS.

Nano-optical theory of planar x-ray waveguides.

X-ray waveguides are routinely used at synchrotron light sources in imaging setups and as a platform for experiments with quantum emitters, providing nanometer-sized confinement - even x-ray optics on a chip has been showcased. X-ray waveguides are weakly guiding and experience significant material absorption, such that the established waveguide theory is not immediately applicable. Here, a general self-contained nano-optical theory of planar waveguides is derived, which is appropriate for hard x-ray energies. Solutions of the electromagnetic fields and its Green's functions are derived in detail. Asymptotic expansions into resonant and non-resonant modes are derived, which are particularly useful in the presence of strong material absorption. A method to reliably find the resonant modes of x-ray waveguide structures is presented. Based on the general theory, certain common experimental geometries, namely evanescent coupling in grazing-incidence, front-coupling in forward-incidence and radiation from buried emitters, are discussed in more detail. Complementing the analytic discussion, numerical tools are provided and applied to quantitatively extract the main figures of merit. The theory provides an analytic foundation for the interpretation of past and future experiments and, combined with the numerical tools, will facilitate the computer-aided design of x-ray waveguides.

Advancing Optoglycomics: Two Orthogonal Azobenzene Glycoside Antennas in One Glycocluster - Synthesis, Switching Cycles, Kinetics and Molecular Dynamics.

Carbohydrate recognition is essential for numerous biological processes and is governed by various factors within the supramolecular environment of the cell. Photoswitchable glycoconjugates have proven as valuable tools for the investigation and modulation of carbohydrate recognition as they allow to control the relative orientation of sugar ligands by light. We have synthesized a biantennary glycocluster in which two glycoazobenzene antennas are conjugated to the 3- and 6-position of a scaffold glycoside. Orthogonal isomerization of the photoswitchable units was made possible by the different conjugation of the azobenzene moieties via an oxygen and a sulfur atom, respectively, and the ortho-fluorination of one of the azobenzene units. This design enabled a switching cycle comprising the EE, EZ and the ZZ isomer. This is the first example of an orthogonally photoswitchable glycocluster. The full analysis of its photochromic properties included the investigation of the isolated glycoazobenzene antennas allowing the comparison of the intra- versus the intermolecular orthogonal photoswitching. The kinetics of the thermal relaxation were analyzed in detail. A molecular dynamics study shows that indeed, the relative orientation of the glycoantennas and the distances between the terminal sugar ligands significantly vary depending on the isomeric state, as intended.

A systematic review of the epidemiology evidence on talc and cancer.

Over the past several decades, there have been many epidemiology studies on talc and cancer published in the scientific literature, and several reviews and meta-analyses of talc and respiratory, female reproductive, and stomach cancers, specifically. To help provide a resource for the evaluation of talc as a potential human carcinogen, we applied a consistent set of examination methods and criteria for all epidemiology studies that examined the association between talc exposure (by various routes) and cancers (of various types). We identified 30 cohort, 35 case-control, and 12 pooled studies that evaluated occupational, medicinal, and personal-care product talc exposure and cancers of the respiratory system, the female reproductive tract, the gastrointestinal tract, the urinary system, the lymphohematopoietic system, the prostate, male genital organs, and the central nervous system, as well as skin, eye, bone, connective tissue, peritoneal, and breast cancers. We tabulated study characteristics, quality, and results in a systematic manner, and evaluated all cancer types for which studies of at least three unique populations were available in a narrative review. We focused on study quality aspects most likely to impact the interpretation of results. We found that only one study, of medicinal talc use, evaluated direct exposure measurements for any individuals, though some used semi-quantitative exposure metrics, and few studies adequately assessed potential confounders. The only consistent associations were with ovarian cancer in case-control studies and these associations were likely impacted by recall and potentially other biases. This systematic review indicates that epidemiology studies do not support a causal association between occupational, medicinal, or personal talc exposure and any cancer in humans.

Differences in treatment of stage I colorectal cancers: a population-based study of colorectal cancers detected within and outside of a screening program.

BACKGROUND: Screen-detected colorectal cancers (CRCs) are often treated less invasively than stage-matched non-screen-detected CRCs, but the reasons for this are not fully understood. This study evaluated the treatment of stage I CRCs detected within and outside of the screening program in the Netherlands. METHODS : Data from the Netherlands Cancer Registry for all stage I CRCs diagnosed between January 1, 2008 and December 31, 2020 were analyzed, comparing patient, tumor, and treatment characteristics of screen-detected and non-screen-detected stage I CRCs. Multivariable logistic regression was used to assess the association between treatment (local excision only vs. surgical oncologic resection) and patient and tumor characteristics, stratified for T stage and tumor location. RESULTS: Screen-detected stage I CRCs were relatively more often T1 than T2 compared with non-screen-detected stage I CRCs (66.9 % vs. 53.3 %; P < 0.001). When only T1 tumors were considered, both screen-detected colon and rectal cancers were more often treated with local excision only than non-screen-detected T1 cancers (odds ratio [OR] 2.19, 95 %CI 1.93-2.49; and OR 1.29, 95 %CI 1.05-1.59, respectively), adjusted for sex, tumor location, lymphovascular invasion (LVI) status, and tumor differentiation. CONCLUSIONS : Less invasive treatment of screen-detected stage I CRC is partly explained by the higher rate of T1 cancers compared with non-screen-detected stage I CRCs. T1 stage I screen-detected CRCs were also more likely to undergo less invasive treatment than non-screen-detected CRCs, adjusted for risk factors such as LVI and tumor differentiation. Future research should investigate whether the choice of local excision was related to unidentified cancer-related factors or the expertise of the endoscopists.

Colorectal polypectomy and endoscopic mucosal resection: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2024.

1: ESGE recommends cold snare polypectomy (CSP), to include a clear margin of normal tissue (1-2 mm) surrounding the polyp, for the removal of diminutive polyps (≤ 5 mm).Strong recommendation, high quality of evidence. 2: ESGE recommends against the use of cold biopsy forceps excision because of its high rate of incomplete resection.Strong recommendation, moderate quality of evidence. 3: ESGE recommends CSP, to include a clear margin of normal tissue (1-2 mm) surrounding the polyp, for the removal of small polyps (6-9 mm).Strong recommendation, high quality of evidence. 4: ESGE recommends hot snare polypectomy for the removal of nonpedunculated adenomatous polyps of 10-19 mm in size.Strong recommendation, high quality of evidence. 5: ESGE recommends conventional (diathermy-based) endoscopic mucosal resection (EMR) for large (≥ 20 mm) nonpedunculated adenomatous polyps (LNPCPs).Strong recommendation, high quality of evidence. 6: ESGE suggests that underwater EMR can be considered an alternative to conventional hot EMR for the treatment of adenomatous LNPCPs.Weak recommendation, moderate quality of evidence. 7: Endoscopic submucosal dissection (ESD) may also be suggested as an alternative for removal of LNPCPs of ≥ 20 mm in selected cases and in high-volume centers.Weak recommendation, low quality evidence. 8: ESGE recommends that, after piecemeal EMR of LNPCPs by hot snare, the resection margins should be treated by thermal ablation using snare-tip soft coagulation to prevent adenoma recurrence.Strong recommendation, high quality of evidence. 9: ESGE recommends (piecemeal) cold snare polypectomy or cold EMR for SSLs of all sizes without suspected dysplasia.Strong recommendation, moderate quality of evidence. 10: ESGE recommends prophylactic endoscopic clip closure of the mucosal defect after EMR of LNPCPs in the right colon to reduce to reduce the risk of delayed bleeding.Strong recommendation, high quality of evidence. 11: ESGE recommends that en bloc resection techniques, such as en bloc EMR, ESD, endoscopic intermuscular dissection, endoscopic full-thickness resection, or surgery should be the techniques of choice in cases with suspected superficial invasive carcinoma, which otherwise cannot be removed en bloc by standard polypectomy or EMR.Strong recommendation, moderate quality of evidence.

Effect of optical diagnosis training on recognition and treatment of submucosal invasive colorectal cancer in community hospitals: a prospective multicenter intervention study.

BACKGROUND: Recognition of submucosal invasive colorectal cancer (T1 CRC) is difficult, with sensitivities of 35 %-60 % in Western countries. We evaluated the real-life effects of training in the OPTICAL model, a recently developed structured and validated prediction model, in Dutch community hospitals. METHODS: In this prospective multicenter study (OPTICAL II), 383 endoscopists from 40 hospitals were invited to follow an e-learning program on the OPTICAL model, to increase sensitivity in detecting T1 CRC in nonpedunculated polyps. Real-life recognition of T1 CRC was then evaluated in 25 hospitals. Endoscopic and pathologic reports of T1 CRCs detected during the next year were collected retrospectively, with endoscopists unaware of this evaluation. Sensitivity for T1 CRC recognition, R0 resection rate, and treatment modality were compared for trained vs. untrained endoscopists. RESULTS: 1 year after e-learning, 528 nonpedunculated T1 CRCs were recorded for endoscopies performed by 251 endoscopists (118 [47 %] trained). Median T1 CRC size was 20 mm. Lesions were mainly located in the distal colorectum (66 %). Trained endoscopists recognized T1 CRCs more frequently than untrained endoscopists (sensitivity 74 % vs. 62 %; mixed model analysis odds ratio [OR] 2.90, 95 %CI 1.54-5.45). R0 resection rate was higher for T1 CRCs detected by trained endoscopists (69 % vs. 56 %; OR 1.73, 95 %CI 1.03-2.91). CONCLUSION: Training in optical recognition of T1 CRCs in community hospitals was associated with increased recognition of T1 CRCs, leading to higher en bloc and R0 resection rates. This may be an important step toward more organ-preserving strategies.

Oncologic outcomes of screen-detected and non-screen-detected T1 colorectal cancers.

BACKGROUND: The incidence of T1 colorectal cancer (CRC) has increased with the implementation of CRC screening programs. It is unknown whether the outcomes and risk models for T1 CRC based on non-screen-detected patients can be extrapolated to screen-detected T1 CRC. This study aimed to compare the stage distribution and oncologic outcomes of T1 CRC patients within and outside the screening program. METHODS: Data from T1 CRC patients diagnosed between 2014 and 2017 were collected from 12 hospitals in the Netherlands. The presence of lymph node metastasis (LNM) at diagnosis was compared between screen-detected and non-screen-detected patients using multivariable logistic regression. Cox proportional hazard regression was used to analyze differences in the time to recurrence (TTR), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival. Additionally, the performance of conventional risk factors for LNM was evaluated across the groups. RESULTS: 1803 patients were included (1114 [62%] screen-detected), with median follow-up of 51 months (interquartile range 30). The proportion of LNM did not significantly differ between screen- and non-screen-detected patients (12.6% vs. 8.9%; odds ratio 1.41; 95%CI 0.89-2.23); a prediction model for LNM performed equally in both groups. The 3- and 5-year TTR, MFS, and CSS were similar for patients within and outside the screening program. However, overall survival was significantly longer in screen-detected T1 CRC patients (adjusted hazard ratio 0.51; 95%CI 0.38-0.68). CONCLUSIONS: Screen-detected and non-screen-detected T1 CRCs have similar stage distributions and oncologic outcomes and can therefore be treated equally. However, screen-detected T1 CRC patients exhibit a lower rate of non-CRC-related mortality, resulting in longer overall survival.

Endothelial Cell APOE3 Regulates Neurovascular, Neuronal, and Behavioral Function.

BACKGROUND: Specialized brain endothelial cells and human APOE3 are independently important for neurovascular function, yet whether APOE3 expression by endothelial cells contributes to brain function is currently unknown. In the present study, we determined whether the loss of endothelial cell APOE3 impacts brain vascular and neural function. METHODS: We developed APOE3fl/fl/Cdh5(PAC)-CreERT2+/- (APOE3Cre+/-) and APOE3fl/fl/Cdh5(PAC)-CreERT2-/- (APOE3Cre-/-, control) mice and induced endothelial cell APOE3 knockdown with tamoxifen at ≈4 to 5 weeks of age. Neurovascular and neuronal function were evaluated by biochemistry, immunohistochemistry, behavioral testing, and electrophysiology at 9 months of age. RESULTS: We found that the loss of endothelial APOE3 expression was sufficient to cause neurovascular dysfunction including higher permeability and lower vessel coverage in tandem with deficits in spatial memory and fear memory extinction and a disruption of cortical excitatory/inhibitory balance. CONCLUSIONS: Our data collectively support the novel concept that endothelial APOE3 plays a critical role in the regulation of the neurovasculature, neural circuit function, and behavior.

Generative Pre-trained Transformer 4 makes cardiovascular magnetic resonance reports easy to understand.

BACKGROUND: Patients are increasingly using Generative Pre-trained Transformer 4 (GPT-4) to better understand their own radiology findings. PURPOSE: To evaluate the performance of GPT-4 in transforming cardiovascular magnetic resonance (CMR) reports into text that is comprehensible to medical laypersons. METHODS: ChatGPT with GPT-4 architecture was used to generate three different explained versions of 20 various CMR reports (n = 60) using the same prompt: "Explain the radiology report in a language understandable to a medical layperson". Two cardiovascular radiologists evaluated understandability, factual correctness, completeness of relevant findings, and lack of potential harm, while 13 medical laypersons evaluated the understandability of the original and the GPT-4 reports on a Likert scale (1 "strongly disagree", 5 "strongly agree"). Readability was measured using the Automated Readability Index (ARI). Linear mixed-effects models (values given as median [interquartile range]) and intraclass correlation coefficient (ICC) were used for statistical analysis. RESULTS: GPT-4 reports were generated on average in 52 s ± 13. GPT-4 reports achieved a lower ARI score (10 [9-12] vs 5 [4-6]; p < 0.001) and were subjectively easier to understand for laypersons than original reports (1 [1] vs 4 [4,5]; p < 0.001). Eighteen out of 20 (90%) standard CMR reports and 2/60 (3%) GPT-generated reports had an ARI score corresponding to the 8th grade level or higher. Radiologists' ratings of the GPT-4 reports reached high levels for correctness (5 [4, 5]), completeness (5 [5]), and lack of potential harm (5 [5]); with "strong agreement" for factual correctness in 94% (113/120) and completeness of relevant findings in 81% (97/120) of reports. Test-retest agreement for layperson understandability ratings between the three simplified reports generated from the same original report was substantial (ICC: 0.62; p < 0.001). Interrater agreement between radiologists was almost perfect for lack of potential harm (ICC: 0.93, p < 0.001) and moderate to substantial for completeness (ICC: 0.76, p < 0.001) and factual correctness (ICC: 0.55, p < 0.001). CONCLUSION: GPT-4 can reliably transform complex CMR reports into more understandable, layperson-friendly language while largely maintaining factual correctness and completeness, and can thus help convey patient-relevant radiology information in an easy-to-understand manner.

A data-driven study of Alzheimer's disease related amyloid and tau pathology progression.

Amyloid-ß is thought to facilitate the spread of tau throughout the neocortex in Alzheimer's disease, though how this occurs is not well understood. This is because of the spatial discordance between amyloid-ß, which accumulates in the neocortex, and tau, which accumulates in the medial temporal lobe during ageing. There is evidence that in some cases amyloid-ß-independent tau spreads beyond the medial temporal lobe where it may interact with neocortical amyloid-ß. This suggests that there may be multiple distinct spatiotemporal subtypes of Alzheimer's-related protein aggregation, with potentially different demographic and genetic risk profiles. We investigated this hypothesis, applying data-driven disease progression subtyping models to post-mortem neuropathology and in vivo PET-based measures from two large observational studies: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP). We consistently identified 'amyloid-first' and 'tau-first' subtypes using cross-sectional information from both studies. In the amyloid-first subtype, extensive neocortical amyloid-ß precedes the spread of tau beyond the medial temporal lobe, while in the tau-first subtype, mild tau accumulates in medial temporal and neocortical areas prior to interacting with amyloid-ß. As expected, we found a higher prevalence of the amyloid-first subtype among apolipoprotein E (APOE) ε4 allele carriers while the tau-first subtype was more common among APOE ε4 non-carriers. Within tau-first APOE ε4 carriers, we found an increased rate of amyloid-ß accumulation (via longitudinal amyloid PET), suggesting that this rare group may belong within the Alzheimer's disease continuum. We also found that tau-first APOE ε4 carriers had several fewer years of education than other groups, suggesting a role for modifiable risk factors in facilitating amyloid-ß-independent tau. Tau-first APOE ε4 non-carriers, in contrast, recapitulated many of the features of primary age-related tauopathy. The rate of longitudinal amyloid-ß and tau accumulation (both measured via PET) within this group did not differ from normal ageing, supporting the distinction of primary age-related tauopathy from Alzheimer's disease. We also found reduced longitudinal subtype consistency within tau-first APOE ε4 non-carriers, suggesting additional heterogeneity within this group. Our findings support the idea that amyloid-ß and tau may begin as independent processes in spatially disconnected regions, with widespread neocortical tau resulting from the local interaction of amyloid-ß and tau. The site of this interaction may be subtype-dependent: medial temporal lobe in amyloid-first, neocortex in tau-first. These insights into the dynamics of amyloid-ß and tau may inform research and clinical trials that target these pathologies.

Rapid energy-efficient manufacturing of polymers and composites via frontal polymerization.

Thermoset polymers and composite materials are integral to today's aerospace, automotive, marine and energy industries and will be vital to the next generation of lightweight, energy-efficient structures in these enterprises, owing to their excellent specific stiffness and strength, thermal stability and chemical resistance1-5. The manufacture of high-performance thermoset components requires the monomer to be cured at high temperatures (around 180 °C) for several hours, under a combined external pressure and internal vacuum 6 . Curing is generally accomplished using large autoclaves or ovens that scale in size with the component. Hence this traditional curing approach is slow, requires a large amount of energy and involves substantial capital investment6,7. Frontal polymerization is a promising alternative curing strategy, in which a self-propagating exothermic reaction wave transforms liquid monomers to fully cured polymers. We report here the frontal polymerization of a high-performance thermoset polymer that allows the rapid fabrication of parts with microscale features, three-dimensional printed structures and carbon-fibre-reinforced polymer composites. Precise control of the polymerization kinetics at both ambient and elevated temperatures allows stable monomer solutions to transform into fully cured polymers within seconds, reducing energy requirements and cure times by several orders of magnitude compared with conventional oven or autoclave curing approaches. The resulting polymer and composite parts possess similar mechanical properties to those cured conventionally. This curing strategy greatly improves the efficiency of manufacturing of high-performance polymers and composites, and is widely applicable to many industries.

Spatial Dependency in Stubble-Borne Pyrenophora teres f. teres and Influence of Sample Support Size on DNA Concentration and Fungicide Resistance Frequency.

Fungicide resistance in foliar fungal pathogens is an increasing challenge to crop production. Yield impacts due to loss of fungicide efficacy may be reduced through effective surveillance and appropriate management intervention. For stubble-borne pathogens, off-season crop residues may be used to monitor fungicide resistance to inform pre-planting decisions; however, appropriate sampling strategies and support sizes for crop residues have not previously been considered. Here, we used Pyrenophora teres f. teres (Ptt) with resistance to demethylase inhibitor fungicides as a model system to assess spatial dependency and to compare the effects of different sampling strategies and support sizes on pathogen density (Ptt DNA concentration) and the frequency of fungicide resistance mutation. The results showed that sampling strategies (hand-picked versus raked) did not affect estimates of pathogen density or fungicide resistance frequency; however, sample variances were lower from raked samples. The effects of differing sample support size, as the size of the collection area (1.2, 8.6, or 60 m2), on fungicide resistance frequency were not evident (P > 0.05). However, measures of pathogen density increased with area size (P < 0.05); the 60 m2 area yielded the highest Ptt DNA concentration and produced the lowest number of pathogen-absent samples. Sample variances for pathogen density and fungicide resistance frequency were generally homogeneous between area sizes. The pattern of pathogen density was spatially independent; however, spatial dependency was identified for fungicide resistance frequency, with a range of 110 m, in one of the two fields surveyed. Collectively, the results inform designs for monitoring of fungicide resistance in stubble-borne pathogens.

Joint developmental trajectories of internalizing and externalizing problems from mid-childhood to late adolescence and childhood risk factors: Findings from a prospective pre-birth cohort.

There is limited evidence on heterogenous co-developmental trajectories of internalizing (INT) and externalizing (EXT) problems from childhood to adolescence and predictors of these joint trajectories. We utilized longitudinal data from Raine Study participants (n = 2393) to identify these joint trajectories from 5 to 17 years using parallel-process latent class growth analysis and analyze childhood individual and family risk factors predicting these joint trajectories using multinomial logistic regression. Five trajectory classes were identified: Low-problems (Low-INT/Low-EXT, 29%), Moderate Externalizing (Moderate-EXT/Low-INT, 26.5%), Primary Internalizing (Moderate High-INT/Low-EXT, 17.5%), Co-occurring (High-INT/High-EXT, 17%), High Co-occurring (Very High-EXT/High-INT, 10%). Children classified in Co-occurring and High Co-occurring trajectories (27% of the sample) exhibited clinically meaningful co-occurring problem behaviors and experienced more adverse childhood risk-factors than other three trajectories. Compared with Low-problems: parental marital problems, low family income, and absent father predicted Co-occurring and High Co-occurring trajectories; maternal mental health problems commonly predicted Primary Internalizing, Co-occurring, and High Co-occurring trajectories; male sex and parental tobacco-smoking uniquely predicted High Co-occurring membership; other substance smoking uniquely predicted Co-occurring membership; speech difficulty uniquely predicted Primary Internalizing membership; child's temper-tantrums predicted all four trajectories, with increased odds ratios for High Co-occurring (OR = 8.95) and Co-occurring (OR = 6.07). Finding two co-occurring trajectories emphasizes the importance of early childhood interventions addressing comorbidity.

Gut Bacteria Provide Genetic and Molecular Reporter Systems to Identify Specific Diseases.

With genetic information gained from next-generation sequencing (NGS) and genome-wide association studies (GWAS), it is now possible to select for genes that encode reporter molecules that may be used to detect abnormalities such as alcohol-related liver disease (ARLD), cancer, cognitive impairment, multiple sclerosis (MS), diabesity, and ischemic stroke (IS). This, however, requires a thorough understanding of the gut-brain axis (GBA), the effect diets have on the selection of gut microbiota, conditions that influence the expression of microbial genes, and human physiology. Bacterial metabolites such as short-chain fatty acids (SCFAs) play a major role in gut homeostasis, maintain intestinal epithelial cells (IECs), and regulate the immune system, neurological, and endocrine functions. Changes in butyrate levels may serve as an early warning of colon cancer. Other cancer-reporting molecules are colibactin, a genotoxin produced by polyketide synthetase-positive Escherichia coli strains, and spermine oxidase (SMO). Increased butyrate levels are also associated with inflammation and impaired cognition. Dysbiosis may lead to increased production of oxidized low-density lipoproteins (OX-LDLs), known to restrict blood vessels and cause hypertension. Sudden changes in SCFA levels may also serve as a warning of IS. Early signs of ARLD may be detected by an increase in regenerating islet-derived 3 gamma (REG3G), which is associated with changes in the secretion of mucin-2 (Muc2). Pro-inflammatory molecules such as cytokines, interferons, and TNF may serve as early reporters of MS. Other examples of microbial enzymes and metabolites that may be used as reporters in the early detection of life-threatening diseases are reviewed.