An examination of the protective role of internalizing symptoms in adolescent substance use.

Although psychological symptoms are broadly considered to be risk factors for substance use, internalizing symptoms may be associated with lower risk for adolescent substance use after controlling for co-occurring externalizing symptoms. The present study explored two potential mediators of this protective association between internalizing symptoms and adolescent substance use: popularity and harm avoidance. The study used data from the Colorado Longitudinal Twin Study (LTS) and Colorado Adoption Project (CAP). Annual assessments of internalizing and externalizing symptoms and social competence were completed by parents and teachers at participant ages 7 to 16. Harm avoidance and substance use were assessed at age 17. In this sample, internalizing symptoms were associated with less frequent substance use, controlling for externalizing symptoms. We did not find evidence that popularity or harm avoidance accounts for the protective association of internalizing symptoms with adolescent substance use. Teacher-reported popularity was associated with less frequent substance use, suggesting that social connectedness in the school context may be a protective factor for adolescent substance use. Harm avoidance was not associated with substance use after accounting for internalizing and externalizing symptoms.

Oligodendroglioma patient survival is associated with circulating B-cells and age.

Background: Variations in survival among patients with oligodendroglioma are unexplained by known prognostic factors. To assess the impact of peripheral immune profiles on prognosis, we applied immunomethylomics analyses-DNA methylation of archived whole blood samples, to characterize immune cells. Methods: We compared the proportions of immune cells from patients with oligodendroglioma to other glioma subtypes and controls. We used recursive partitioning analysis (RPA) within the oligodendrogliomas to correlate with survival. Results: Patients with oligodendrogliomas (141) were median age at diagnosis of 44 years; 57% male; 75% White; 60% prior chemotherapy; and 25% on dexamethasone at sample collection. Patients with oligodendrogliomas had immune profiles more similar to controls than other glioma subtypes, though with notably lower B-cells. RPA of patients with oligodendrogliomas delineated 2 survival groups based on an interaction between age and B-naïve cells. Patients with longer survival (median 24.2 years) were ≤42 years of age with higher B-naïve cells versus worse survival (median 16.9 years) who were ≤42 years of age with lower B-naïve cells or >42 years of age (P = .00032). Patients with worse survival also had lower CD4- and CD8-naïve T-cells. Similar immune profiles were observed in an independent cohort of oligodendroglioma patients prior to surgery. Conclusions: Peripheral blood immune profiles in oligodendroglioma suggested that younger patients with lower B-naïve cells experienced shorter survival. Though our findings lack of validation cohort and use a heterogenous patient population, they suggest peripheral blood immune profiles may be prognostic for patients with glioma and warrant further investigation.

Evaluating guideline and registration policies among neurology journals: a cross-sectional analysis.

BACKGROUND: Neurological disorders have had a substantial rise the last three decades, imposing substantial burdens on both patients and healthcare costs. Consequently, the demand for high-quality research has become crucial for exploring effective treatment options. However, current neurology research has some limitations in terms of transparency, reproducibility, and reporting bias. The adoption of reporting guidelines (RGs) and trial registration policies has been proven to address these issues and improve research quality in other medical disciplines. It is unclear the extent to which these policies are being endorsed by neurology journals. Therefore, our study aims to evaluate the publishing policies of top neurology journals regarding RGs and trial registration. METHODS: For this cross-sectional study, neurology journals were identified using the 2021 Scopus CiteScore Tool. The top 100 journals were listed and screened for eligibility for our study. In a masked, duplicate fashion, investigators extracted data on journal characteristics, policies on RGs, and policies on trial registration using information from each journal's Instruction for Authors webpage. Additionally, investigators contacted journal editors to ensure information was current and accurate. No human participants were involved in this study. Our data collection and analyses were performed from December 14, 2022, to January 9, 2023. RESULTS: Of the 356 neurology journals identified, the top 100 were included into our sample. The five-year impact of these journals ranged from 50.844 to 2.226 (mean [SD], 7.82 [7.01]). Twenty-five (25.0%) journals did not require or recommend a single RG within their Instructions for Authors webpage, and a third (33.0%) did not require or recommend clinical trial registration. The most frequently mentioned RGs were CONSORT (64.6%), PRISMA (52.5%), and ARRIVE (53.1%). The least mentioned RG was QUOROM (1.0%), followed by MOOSE (9.0%), and SQUIRE (17.9%). CONCLUSIONS: While many top neurology journals endorse the use of RGs and trial registries, there are still areas where their adoption can be improved. Addressing these shortcomings leads to further advancements in the field of neurology, resulting in higher-quality research and better outcomes for patients.

Do local and landscape context affect the attractiveness of flower gardens to bees?

Planting floral resources is a common strategy for increasing the abundance and diversity of beneficial flower-visiting insects in human-modified systems. However, the context of the local area and surrounding landscape may affect the attractiveness of these floral resource provisioning plots. We compared the relative effects of local floral resources and surrounding urban land-use on the abundance of bees on flowering plants in common gardens in eastern Tennessee, USA. We planted four types of common garden plots at each of five different landscapes representing a variety of surrounding land use: 1) Urban Garden, 2) Forage Grassland, 3) Mixed Agriculture, 4) Forest, and 5) Organic Farm. Each common garden plot type had a fixed plant community representing one of three plant families (Asteraceae, Fabaceae, Lamiaceae) or a mix of all three, and all four common gardens were replicated at all the sites. We concurrently sampled bees in the garden plots and in a 50 m radius (local area) around the garden plots. We found that the size of the floral display (i.e. the visual display size of flowers) and diversity of flowers in the local area did not affect bee abundance or species richness in the garden plots. Although there was a significant positive association between developed land use in a 2 km radius and bee abundance in the gardens, the effect was small, and there was no relationship between land use and bee abundance or species richness in the local area. There were significant differences in the composition of the bee community between the local area and garden plots, but the largest determinants of bee community composition and species richness in the gardens were floral display size and variation in the garden plant species in bloom. This finding is promising for anyone wishing to promote pollinator populations by providing more floral resources.

Faecal source apportionment using molecular methods: A proof of concept using the FEAST algorithm.

Faecal contamination of freshwater and marine environments represents a significant risk for public health, recreational activity and food safety, and tools for evaluating complex multi-source contamination remain largely in the development phase. We evaluated the efficacy of the Fast Expectation Maximization (FEAST) microbial source tracking (MST) algorithm to apportion sources of faecal contamination among four mammalian species of interest in coastal waters in New Zealand. Using 16S ribosomal DNA metabarcoding of faecal samples from cows, fur seals, and sheep, as well as human wastewater, we aimed to differentiate and quantify the contribution of these sources in mixed faecal samples. Multivariate analysis confirmed significant differences in the microbial communities associated with each mammalian source, with specific bacterial classes indicative of different sources. The FEAST algorithm was tested using mixed DNA and mixed faecal samples, and we found that the algorithm correctly assigned the dominant source from all samples, but underestimated the dominant source's proportional contribution. This underestimation suggests the need for further refinement and validation to ensure accurate source apportionment in environmental samples where the faecal signal is likely to be a minor component. Despite these limitations, the findings of our study, in combination with the evidence from others who have tested the FEAST algorithm in environmental settings, indicates that it represents an advance on existing tools for microbial source tracking and may become a useful addition to the toolbox for environmental management.

The World Society for Pediatric and Congenital Heart Surgery: 2024 Update of the World Database for Pediatric and Congenital Heart Surgery.

BACKGROUND: The World Database for Pediatric and Congenital Heart Surgery (WDPCHS), sponsored by the World Society for Pediatric and Congenital Heart Surgery (WSPCHS), provides complex congenital heart surgery outcomes analyses for member programs. This report represents the seven-year descriptive analysis of outcomes from active members of the WDPCHS. METHODS: Individual institutions submit data based on the specific procedure via a password protected platform. The data are collected, stored, and analyzed at Kirklin Solutions Inc., based in Birmingham, Alabama. This report presents a descriptive analysis of these procedures submitted from January 1, 2017, to December 31, 2023. RESULTS: A total of 50,174 procedures were submitted with an overall mortality of 4.6%. The majority of submissions were from Asian countries. The majority of cases submitted from these countries were of STAT mortality category I and II. Repair of a ventricular septal defect (with a mortality of 0.8%) and correction of tetralogy of Fallot (2.0% mortality) were the most common procedures submitted to the database. CONCLUSIONS: The WSPCHS accomplished one of its missions in 2017 when the WDPCHS began accepting data from pediatric and congenital heart surgery programs across the globe. In doing so, it became one of the first organizations to create a platform for the exchange of knowledge and experience, regardless of the socioeconomic status of the particular program or country.

Clinical outcomes of patients receiving long-term fondaparinux for thrombotic antiphospholipid syndrome.

INTRODUCTION: Vitamin-K antagonists (VKA) are considered the first-line anticoagulants for thrombotic antiphospholipid syndrome (TAPS), particularly with triple positivity or arterial events. However, thrombotic recurrence remains high despite anticoagulation and other clinical issues may arise. Long-term parenteral anticoagulants may therefore be considered, however little is known about the viability of fondaparinux in this setting. MATERIALS AND METHODS: We describe the efficacy and safety of long-term fondaparinux for TAPS (>3-months duration) treated at a single centre in the UK. Clinical features and the outcomes of recurrence and bleeding were reviewed using electronic patient records. RESULTS: 46 patients were identified with history of either venous or arterial TAPS and a total 175 patient-years using fondaparinux (median duration 2.7 years/patient (IQR 1.4-4.8)). 43 (93%) had VKA as first-line anticoagulation with a median duration of 6.5 years (IQR 4.0 - 9.8). All patients received fondaparinux as second-to fourth-line anticoagulation.Thrombosis recurrence occurred in 1 (1%) patient (0.6 events/100-patient years). Major, clinically relevant non-major (CRNM) or minor bleeding occurred in 2 (7%), 5 (10.9%) and 8 (17.4%) patients respectively. Major/CRNM bleeding rates were 1.1 and 2.9 events/100-patient-years. Age >65years was associated with bleeding (p = .047) and concurrent antiplatelets were associated with major/CRNM bleeding (p = .011). Logistic regression showed increasing age was associated with bleeding (OR = 1.097, p = .009). CONCLUSIONS: We suggest that fondaparinux may be used for TAPS when VKA is not appropriate. Thrombotic recurrence was infrequent, and the number of major bleeding events appeared comparable to conventional therapies.

Experimental evolution suggests rapid assembly of the 'selfing syndrome' from standing variation in Mimulus guttatus.

Ecological and evolutionary changes are likely to occur rapidly when outcrossing populations experience pollinator loss. However, the number and identify of plant traits that will respond to this form of selection, as well as the overall predictability of evolutionary responses, remain unclear. We experimentally evolved 20 large replicate populations of Mimulus guttatus for 10 generations under three treatments: pure outcrossing, mixed mating (10% outcrossing) and pure selfing. These populations were founded from the same genetically diverse and outcrossing natural population. After 10 generations, all measured traits evolved with flower size, phenology, and reproductive traits diverging consistently among mating system treatments. Autogamy increased dramatically in the selfing treatment, but the magnitude of adaptation only becomes clear once inbreeding depression is factored out. Selfing treatment plants evolved reduced stigma-anther separation, and also exhibited declines in flower size and per-flower reproductive capacity. Flower size also declined in selfing populations but this was driven mainly by inbreeding depression and cannot be attributed to adaptation towards the selfing syndrome. Generally, the mixed mating populations evolved trait values intermediate to the fully selfing and outcrossing populations. Overall, our experimental treatments reiterated differences that have been documented in interspecific comparisons between selfing and outcrossing species pairs. Given that such contrasts involve species separated by thousands or even millions of generations, it is noteworthy that large evolutionary responses were obtained from genetic variation segregating within a single natural population.

Durability for 12 months of antibody response to a booster dose of monovalent BNT162b2 in adults who had initially received 2 doses of inactivated vaccine.

This study examined the strength and durability of antibody responses in 277 adults who received a heterologous third dose of the BNT162b2 vaccine, following two doses of an inactivated vaccine. Neutralizing antibody levels against both the ancestral virus and Omicron BA.2 subvariant decreased from one month to 6 months after the third dose, and were then maintained at 12 months. Participants who received both a fourth dose and reported a SARS-CoV-2 infection had the highest antibody titers at 365 days after the third dose. Individuals with chronic medical conditions had lower antibody levels against the Omicron BA.2 subvariant at 12 months after the third dose. The results suggest that the heterologous third dose provides durable neutralizing antibody responses, which may be influenced by subsequent infection or vaccination and pre-existing medical conditions. These findings may help explain the differences in immune protection between vaccination and natural infection.

Patient Factors Associated With Reimplantation After Girdlestone Resection Arthroplasty for Treatment of Periprosthetic Joint Infections of the Hip.

INTRODUCTION: For patients unsuitable for prosthesis reimplantation or temporary spacer placement, Girdlestone resection arthroplasty (GRA) is a suitable option to eliminate infection. Using a large-scale database, this study aims to determine factors associated with reimplantation. METHODS: This study included patients who underwent GRA and subsequent total hip arthroplasty (2012 to 2015 Medicare Limited Data Set with ≥5-year follow-up). A mixed-effects model measured associations between patient characteristics and reimplantation. Odds ratios (OR) with 95% confidence intervals (CI) were reported. RESULTS: Among 2,772 GRA cases, 2,025 (73.1%) were reimplanted (median time to reimplantation 3.0 months). In multivariable analysis, patient factors associated with reduced odds of reimplantation were increased age (OR 0.96; CI, 0.94 to 0.97; P < 0.0001), Black race (OR, 0.58; CI, 0.37 to 0.90; P = 0.0149), obesity (OR, 0.74; CI, 0.58 to 0.94; P = 0.0150), and increased Deyo-Charlson comorbidities (1 comorbidity: OR, 0.78; CI, 0.61 to 0.99; P = 0.0453; two comorbidities: OR, 0.53; CI, 0.39 to 0.71; P < 0.0001; ≥3 comorbidities: OR, 0.69; CI, 0.49 to 0.95; P = 0.0244). Male (versus female) patients, however, had increased odds of reimplantation (OR, 1.64; CI, 1.32 to 2.02; P < 0.0001). DISCUSSION: Age, race, and comorbidities influence the likelihood of reimplantation after GRA. Owing to variability in patients who undergo additional surgery, additional studies should be conducted to determine the rationale of patient selection.

Substrate interactions guide cyclase engineering and lasso peptide diversification.

Lasso peptides are a diverse class of naturally occurring, highly stable molecules kinetically trapped in a distinctive [1]rotaxane conformation. How the ATP-dependent lasso cyclase constrains a relatively unstructured substrate peptide into a low entropy product has remained a mystery owing to poor enzyme stability and activity in vitro. In this study, we combined substrate tolerance data with structural predictions, bioinformatic analysis, molecular dynamics simulations and mutational scanning to construct a model for the three-dimensional orientation of the substrate peptide in the lasso cyclase active site. Predicted peptide cyclase molecular contacts were validated by rationally engineering multiple, phylogenetically diverse lasso cyclases to accept substrates rejected by the wild-type enzymes. Finally, we demonstrate the utility of lasso cyclase engineering by robustly producing previously inaccessible variants that tightly bind to integrin αvß8, which is a primary activator of transforming growth factor ß and, thus, an important anti-cancer target.

The potential clinical utility of an artificial intelligence model for identification of vertebral compression fractures in chest radiographs.

PURPOSE: To assess the ability of the Annalise Enterprise CXR Triage Trauma artificial intelligence model to identify vertebral compression fractures on chest radiographs and its potential to address undiagnosed osteoporosis and its treatment. MATERIALS AND METHODS: This retrospective study used a consecutive cohort of 596 chest radiographs from four U.S. hospitals between 2015 and 2021. Each radiograph included both frontal (anteroposterior or posteroanterior) and lateral projections. These radiographs were assessed for the presence of vertebral compression fracture in a consensus manner by up to three thoracic radiologists. The model then performed inference on the cases. A chart review was also performed for the presence of osteoporosis-related ICD-10 diagnostic codes and medication use for the study period and an additional year of follow up. RESULTS: The model successfully completed inference on 595 cases (99.8%); these cases included 272 positive cases and 323 negative cases. The model performed with area under the receiver operating characteristic curve of 0.955 (95% CI: 0.939 to 0.968), sensitivity 89.3% (95% CI: 85.7 to 92.7%) and specificity 89.2% (95% CI: 85.4 to 92.3%). Out of the 236 true-positive cases (i.e., correctly identified vertebral compression fractures by the model) with available chart information, only 86 (36.4%) had a diagnosis of vertebral compression fracture and 140 (59.3%) had a diagnosis of either osteoporosis or osteopenia; only 78 (33.1%) were receiving a disease modifying medication for osteoporosis. CONCLUSION: The model identified vertebral compression fracture accurately with a sensitivity 89.3% (95% CI: 85.7 to 92.7%) and specificity of 89.2% (95% CI: 85.4 to 92.3%). Its automated use could help identify patients who have undiagnosed osteoporosis and who may benefit from taking disease modifying medications.

Regular whole blood donation and gastrointestinal, breast, colorectal and haematological cancer risk among blood donors in Australia.

BACKGROUND AND OBJECTIVES: Several studies have suggested that blood donors have lower risk of gastrointestinal and breast cancers, whereas some have indicated an increased risk of haematological cancers. We examined these associations by appropriately adjusting the 'healthy donor effect' (HDE). MATERIALS AND METHODS: We examined the risk of gastrointestinal/colorectal, breast and haematological cancers in regular high-frequency whole blood (WB) donors using the Sax Institute's 45 and Up Study data linked with blood donation and other health-related data. We calculated 5-year cancer risks, risk differences and risk ratios. To mitigate HDE, we used 5-year qualification period to select the exposure groups, and applied statistical adjustments using inverse probability weighting, along with other advanced doubly robust g-methods. RESULTS: We identified 2867 (42.4%) as regular high-frequency and 3888 (57.6%) as low-frequency donors. The inverse probability weighted 5-year risk difference between high and low-frequency donors for gastrointestinal/colorectal cancer was 0.2% (95% CI, -0.1% to 0.5%) with a risk ratio of 1.25 (0.83-1.68). For breast cancer, the risk difference was -0.2% (-0.9% to 0.4%), with a risk ratio of 0.87 (0.48-1.26). Regarding haematological cancers, the risk difference was 0.0% (-0.3% to 0.5%) with a risk ratio of 0.97 (0.55-1.40). Our doubly robust estimators targeted minimum loss-based estimator (TMLE) and sequentially doubly robust (SDR) estimator, yielded similar results, but none of the findings were statistically significant. CONCLUSION: After applying methods to mitigate the HDE, we did not find any statistically significant differences in the risk of gastrointestinal/colorectal, breast and haematological cancers between regular high-frequency and low-frequency WB donors.

Molecular forecasting of domoic acid during a pervasive toxic diatom bloom.

In 2015, the largest recorded harmful algal bloom (HAB) occurred in the Northeast Pacific, causing nearly 100 million dollars in damages to fisheries and killing many protected marine mammals. Dominated by the toxic diatom Pseudo-nitzschia australis, this bloom produced high levels of the neurotoxin domoic acid (DA). Through molecular and transcriptional characterization of 52 near-weekly phytoplankton net-tow samples collected at a bloom hotspot in Monterey Bay, California, we identified active transcription of known DA biosynthesis (dab) genes from the three identified toxigenic species, including P. australis as the primary origin of toxicity. Elevated expression of silicon transporters (sit1) during the bloom supports the previously hypothesized role of dissolved silica (Si) exhaustion in contributing to bloom physiology and toxicity. We find that coexpression of the dabA and sit1 genes serves as a robust predictor of DA one week in advance, potentially enabling the forecasting of DA-producing HABs. We additionally present evidence that low levels of iron could have colimited the diatom population along with low Si. Iron limitation represents an overlooked driver of both toxin production and ecological success of the low-iron-adapted Pseudo-nitzschia genus during the 2015 bloom, and increasing pervasiveness of iron limitation may fuel the escalating magnitude and frequency of toxic Pseudo-nitzschia blooms globally. Our results advance understanding of bloom physiology underlying toxin production, bloom prediction, and the impact of global change on toxic blooms.

Relevance of the community pharmacy policy environment to pharmacists' performance, as reflected in stakeholders' perspectives on professionalism and standards.

Background: A complex array of legislation, regulation, policies and aspirational statements by governments, statutory agencies and pharmacy organisations constitutes the policy environment that influences Australian community pharmacy, including pharmacists' performance. Objective: The objective was to assess the relevance of the policy environment to Australian community pharmacists' performance by examining stakeholders' perspectives on their professionalism and standards. Methods: Inductive thematic analysis was undertaken on 38 semi-structured interviews of purposively selected individuals including pharmacists and other key stakeholders, from 4 socio-ecological strata (societal, community, organisational, and individual) that have influence on the person to person interaction that a consumer may have with a pharmacist in a community pharmacy. Results: As indicators of their performance, pharmacists' professionalism and compliance with standards can no longer be assumed; they must be demonstrated. However, the current dispensing funding model compromises their ability to demonstrate professionalism and policy is lacking in relation to monitoring and rewarding standards. These shortcomings are further compromised by a growth in commercialism in community pharmacy which impacts the delivery of professional services. Conclusion: The findings of this study have implications for pharmacy as an autonomously regulated profession in Australia. Dispensing funding policy could better support and reward quality in pharmacists' performance, and there is strong support for compulsory monitoring of standards. Compliance with a nation-wide quality framework, and provision of a minimum set of professional services should be an obligatory requirement of all community pharmacies.

Real-Time Exposure to Negative News Media and Suicidal Ideation Intensity Among LGBTQ+ Young Adults.

Importance: With a recent surge in anti-lesbian, gay, bisexual, transgender, or queer (LGBTQ+) policies and associated news and media coverage, there is a need to study the association of LGBTQ+ focused news or media exposure and short-term changes in suicidal ideation (SI) among LGBTQ+ youth. Objective: To examine within-person direct and indirect associations between exposure to general and LGBTQ+ negative news or media and SI intensity through expectations of rejection. Design, Setting, and Participants: This intensive longitudinal cohort study used a smartphone-based ecological momentary assessment (EMA) protocol wherein participants responded to EMAs 3 times per day for 28 consecutive days. Young adults aged 18 to 24 years who self-identified as LGBTQ+, resided in Tennessee, and had past-year SI and at least mild depression (defined as a score ≥5 on the Patient Health Questionnaire-9) were eligible for inclusion. Participants were recruited through social media advertisements, LGBTQ+ community organizations, and mental and behavioral health clinics. Participants were recruited between March 30, 2023, and August 23, 2023, and data analyses were conducted from August 28, 2023, through April 20, 2024. Exposures: At each EMA, participants reported on recent exposure to negative news or media. A 3-level categorical exposure variable denoted (1) no news or media exposure (reference); (2) exposure to general negative news or media; and (3) exposure to LGBTQ+ negative news or media. Each EMA also assessed expectations of rejection due to LGBTQ+ identity on a scale of 0 (not at all) through 10 (very much). Main Outcomes and Measures: Three primary outcomes assessed current (ie, "right now") intensity of active SI, passive SI, and self-harm ideation, each measured on a scale from 0 (not at all) to 10 (very strong). Multilevel modeling approaches were used to account for the hierarchical structure of EMA data, with assessments (level 1) nested within people (level 2). Linear mixed models and multilevel mediation models were used to examine within-person associations between exposure to negative news or media and the 3 primary outcomes, as well as the mediating role of expectations of rejection. Results: Of 31 total participants, 22 were assigned female sex at birth (71%), and 16 (52%) self-identified as transgender or gender diverse. The median (IQR) participant age was 21 (18-22) years, and a total of 2189 EMAs were completed, with a median (range) compliance of 90.5% (41.7%-100%). At the within-person level, recent exposure to LGBTQ+ negative news or media was significantly associated with increased active SI (estimate [b], 0.14; 95% CI, 0.04-0.25; P = .009), passive SI (b, 0.23; 95% CI, 0.04-0.41; P = .02), and self-harm ideation (b, 0.13; 95% CI, 0.02-0.23; P = .02). No statistically significant associations were detected for exposure to general negative news or media. In multilevel mediation models, heightened expectations of rejection explained some of the total effect of exposure to LGBTQ+ negative news or media on active SI (23%) and passive SI (37%). Conclusions and Relevance: This intensive longitudinal cohort study found that SI intensity modestly increased in the hours immediately following exposure to LGBTQ+ negative news or media among LGBTQ+ young adults. These findings have timely implications for research and intervention, particularly within sociopolitical and geographic contexts where news or media coverage about LGBTQ+ topics is intensified.

Healthy First-Degree Relatives From Multiplex Families vs Simplex Families Have a Higher Subclinical Intestinal Inflammation, a Distinct Fecal Microbial Signature, and Harbor a Higher Risk of Developing Crohn's Disease.

BACKGROUND & AIMS: Unaffected first-degree relatives (FDRs) from families with ≥2 affected FDRs with Crohn's disease (CD, multiplex families) have a high risk of developing CD, although the underlying mechanisms driving this risk are poorly understood. We aimed to identify differences in biomarkers between FDRs from multiplex vs simplex families and investigate the risk of future CD onset accounting for potential confounders. METHODS: We assessed the Crohn's and Colitis Canada Genetic Environmental Microbial cohort of healthy FDRs of patients with CD. Genome-wide CD-polygenic risk scores, urinary fractional excretion of lactulose-to-mannitol ratio, fecal calprotectin (FCP), and fecal 16S ribosomal RNA microbiome were measured at recruitment. Associations between CD multiplex status and baseline biomarkers were determined using generalized estimating equations models. Cox models were used to assess the risk of future CD onset. RESULTS: There were 4051 participants from simplex families and 334 from CD multiplex families. CD multiplex status was significantly associated with higher baseline FCP (P = .026) but not with baseline CD-polygenic risk scores or the lactulose-to-mannitol ratio. Three bacterial genera were found to be differentially abundant between both groups. CD multiplex status at recruitment was independently associated with an increased risk of developing CD (adjusted hazard ratio, 3.65; 95% confidence interval, 2.18-6.11, P < .001). CONCLUSION: Within FDRs of patients with CD, participants from multiplex families had a 3-fold increased risk of CD onset, a higher FCP, and an altered bacterial composition, but not genetic burden or altered gut permeability. These results suggest that putative environmental factors might be enriched in FDRs from multiplex families.

Magnetic augmentation through multi-gradient coupling enables direct and programmable profiling of circulating biomarkers.

Conventional magnetic biosensing technologies have reduced analytical capacity for magnetic field dimensionality and require extensive sample processing. To address these challenges, we spatially engineer 3D magnetic response gradients for direct and programmable molecular detection in native biofluids. Named magnetic augmentation through triple-gradient coupling for high-performance detection (MATCH), the technology comprises gradient-distributed magnetic nanoparticles encapsulated within responsive hydrogel pillars and suspended above a magnetic sensor array. This configuration enables multi-gradient matching to achieve optimal magnetic activation, response and transduction, respectively. Through focused activation by target biomarkers, the platform preferentially releases sensor-proximal nanoparticles, generating response gradients that complement the sensor's intrinsic detection capability. By implementing an upstream module that recognizes different biomarkers and releases universal activation molecules, the technology achieves programmable detection of various circulating biomarkers in native plasma. It bypasses conventional magnetic labeling, completes in <60 minutes and achieves sensitive detection (down to 10 RNA and 1000 protein copies). We apply the MATCH to measure RNAs and proteins directly in patient plasma, achieving accurate cancer classification.