Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors.

CD8 T cell responses against different tumor neoantigens occur simultaneously, yet little is known about the interplay between responses and its impact on T cell function and tumor control. In mouse lung adenocarcinoma, we found that immunodominance is established in tumors, wherein CD8 T cell expansion is predominantly driven by the antigen that most stably binds MHC. T cells responding to subdominant antigens were enriched for a TCF1+ progenitor phenotype correlated with response to immune checkpoint blockade (ICB) therapy. However, the subdominant T cell response did not preferentially benefit from ICB due to a dysfunctional subset of TCF1+ cells marked by CCR6 and Tc17 differentiation. Analysis of human samples and sequencing datasets revealed that CCR6+ TCF1+ cells exist across human cancers and are not correlated with ICB response. Vaccination eliminated CCR6+ TCF1+ cells and dramatically improved the subdominant response, highlighting a strategy to optimally engage concurrent neoantigen responses against tumors.

OpenFold: retraining AlphaFold2 yields new insights into its learning mechanisms and capacity for generalization.

AlphaFold2 revolutionized structural biology with the ability to predict protein structures with exceptionally high accuracy. Its implementation, however, lacks the code and data required to train new models. These are necessary to (1) tackle new tasks, like protein-ligand complex structure prediction, (2) investigate the process by which the model learns and (3) assess the model's capacity to generalize to unseen regions of fold space. Here we report OpenFold, a fast, memory efficient and trainable implementation of AlphaFold2. We train OpenFold from scratch, matching the accuracy of AlphaFold2. Having established parity, we find that OpenFold is remarkably robust at generalizing even when the size and diversity of its training set is deliberately limited, including near-complete elisions of classes of secondary structure elements. By analyzing intermediate structures produced during training, we also gain insights into the hierarchical manner in which OpenFold learns to fold. In sum, our studies demonstrate the power and utility of OpenFold, which we believe will prove to be a crucial resource for the protein modeling community.

ZCCHC3 is a stress granule zinc knuckle protein that strongly suppresses LINE-1 retrotransposition.

Retrotransposons have generated about half of the human genome and LINE-1s (L1s) are the only autonomously active retrotransposons. The cell has evolved an arsenal of defense mechanisms to protect against retrotransposition with factors we are only beginning to understand. In this study, we investigate Zinc Finger CCHC-Type Containing 3 (ZCCHC3), a gag-like zinc knuckle protein recently reported to function in the innate immune response to infecting viruses. We show that ZCCHC3 also severely restricts human retrotransposons and associates with the L1 ORF1p ribonucleoprotein particle. We identify ZCCHC3 as a bona fide stress granule protein, and its association with LINE-1 is further supported by colocalization with L1 ORF1 protein in stress granules, dense cytoplasmic aggregations of proteins and RNAs that contain stalled translation pre-initiation complexes and form when the cell is under stress. Our work also draws links between ZCCHC3 and the anti-viral and retrotransposon restriction factors Mov10 RISC Complex RNA Helicase (MOV10) and Zinc Finger CCCH-Type, Antiviral 1 (ZC3HAV1, also called ZAP). Furthermore, collective evidence from subcellular localization, co-immunoprecipitation, and velocity gradient centrifugation connects ZCCHC3 with the RNA exosome, a multi-subunit ribonuclease complex capable of degrading various species of RNA molecules and that has previously been linked with retrotransposon control.

Dietary Acculturation Is Associated With Altered Gut Microbiome, Circulating Metabolites, and Cardiovascular Disease Risk in US Hispanics and Latinos: Results From HCHS/SOL.

BACKGROUND: Dietary acculturation, or adoption of dominant culture diet by migrant groups, influences human health. We aimed to examine dietary acculturation and its relationships with cardiovascular disease (CVD), gut microbiota, and blood metabolites among US Hispanic and Latino adults. METHODS: In the HCHS/SOL (Hispanic Community Health Study/Study of Latinos), US exposure was defined by years in the United States (50 states and Washington, DC) and US nativity. A dietary acculturation pattern was derived from 14 172 participants with two 24-hour dietary recalls at baseline (2008-2011) using least absolute shrinkage and selection operator regression, with food groups as predictors of US exposure. We evaluated associations of dietary acculturation with incident CVD across ≈7 years of follow-up (n=211/14 172 cases/total) and gut microbiota (n=2349; visit 2, 2014 to 2017). Serum metabolites associated with both dietary acculturation-related gut microbiota (n=694) and incident CVD (n=108/5256 cases/total) were used as proxy measures to assess the association of diet-related gut microbiome with incident CVD. RESULTS: We identified an empirical US-oriented dietary acculturation score that increased with US exposure. Higher dietary acculturation score was associated with higher risk of incident CVD (hazard ratio per SD, 1.33 [95% CI, 1.13-1.57]), adjusted for sociodemographic, lifestyle, and clinical factors. Sixty-nine microbial species (17 enriched from diverse species, 52 depleted mainly from fiber-utilizing Clostridia and Prevotella species) were associated with dietary acculturation, driven by lower intakes of whole grains, beans, and fruits and higher intakes of refined grains. Twenty-five metabolites, involved predominantly in fatty acid and glycerophospholipid metabolism (eg, branched-chain 14:0 dicarboxylic acid** and glycerophosphoethanolamine), were associated with both diet acculturation-related gut microbiota and incident CVD. Proxy association analysis based on these metabolites suggested a positive relationship between diet acculturation-related microbiome and risk of CVD (r=0.70, P<0.001). CONCLUSIONS: Among US Hispanic and Latino adults, greater dietary acculturation was associated with elevated CVD risk, possibly through alterations in gut microbiota and related metabolites. Diet and microbiota-targeted interventions may offer opportunities to mitigate CVD burdens of dietary acculturation.

Oncolytic DNX-2401 Virus for Pediatric Diffuse Intrinsic Pontine Glioma.

BACKGROUND: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. METHODS: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. RESULTS: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. CONCLUSIONS: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).

Global mapping of RNA homodimers in living cells.

RNA homodimerization is important for various physiological processes, including the assembly of membraneless organelles, RNA subcellular localization, and packaging of viral genomes. However, understanding RNA dimerization has been hampered by the lack of systematic in vivo detection methods. Here, we show that CLASH, PARIS, and other RNA proximity ligation methods detect RNA homodimers transcriptome-wide as "overlapping" chimeric reads that contain more than one copy of the same sequence. Analyzing published proximity ligation data sets, we show that RNA:RNA homodimers mediated by direct base-pairing are rare across the human transcriptome, but highly enriched in specific transcripts, including U8 snoRNA, U2 snRNA, and a subset of tRNAs. Mutations in the homodimerization domain of U8 snoRNA impede dimerization in vitro and disrupt zebrafish development in vivo, suggesting an evolutionarily conserved role of this domain. Analysis of virus-infected cells reveals homodimerization of SARS-CoV-2 and Zika genomes, mediated by specific palindromic sequences located within protein-coding regions of N gene in SARS-CoV-2 and NS2A gene in Zika. We speculate that regions of viral genomes involved in homodimerization may constitute effective targets for antiviral therapies.

Chimeric oncolytic adenovirus evades neutralizing antibodies from human patients and exhibits enhanced anti-glioma efficacy in immunized mice.

Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections. Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients. Past studies have examined the effects of neutralizing antibodies during systemic virus injections, but largely overlooked their impact during local virus injections into the brain. We found that immunoglobulins colocalized with viral proteins upon local oncolytic virotherapy of brain tumors, warranting a strategy to prevent virus neutralization and maximize oncolysis. Thus, we generated a chimeric virus, Delta-24-RGD-H43m, by replacing the capsid protein HVRs from the serotype 5-based Delta-24-RGD with those from the rare serotype 43. Delta-24-RGD-H43m evaded neutralizing anti-Ad5 antibodies and conferred a higher rate of long-term survival than Delta-24-RGD in glioma-bearing mice. Importantly, Delta-24-RGD-H43m activity was significantly more resistant to neutralizing antibodies present in sera of glioma patients treated with Delta-24-RGD during a phase 1 clinical trial. These findings provide a framework for a novel treatment of glioma patients that have developed immunity against Delta-24-RGD.

Autophagy protein ULK1 interacts with and regulates SARM1 during axonal injury.

Autophagy is a cellular catabolic pathway generally thought to be neuroprotective. However, autophagy and in particular its upstream regulator, the ULK1 kinase, can also promote axonal degeneration. We examined the role and the mechanisms of autophagy in axonal degeneration using a mouse model of contusive spinal cord injury (SCI). Consistent with activation of autophagy during axonal degeneration following SCI, autophagosome marker LC3, ULK1 kinase, and ULK1 target, phospho-ATG13, accumulated in the axonal bulbs and injured axons. SARM1, a TIR NADase with a pivotal role in axonal degeneration, colocalized with ULK1 within 1 h after SCI, suggesting possible interaction between autophagy and SARM1-mediated axonal degeneration. In our in vitro experiments, inhibition of autophagy, including Ulk1 knockdown and ULK1 inhibitor, attenuated neurite fragmentation and reduced accumulation of SARM1 puncta in neurites of primary cortical neurons subjected to glutamate excitotoxicity. Immunoprecipitation data demonstrated that ULK1 physically interacted with SARM1 in vitro and in vivo and that SAM domains of SARM1 were necessary for ULK1-SARM1 complex formation. Consistent with a role in regulation of axonal degeneration, in primary cortical neurons ULK1-SARM1 interaction increased upon neurite damage. Supporting a role for autophagy and ULK1 in regulation of SARM1 in axonal degeneration in vivo, axonal ULK1 activation and accumulation of SARM1 were both decreased after SCI in Becn1+/- autophagy hypomorph mice compared to wild-type (WT) controls. These findings suggest a regulatory crosstalk between autophagy and axonal degeneration pathways, which is mediated through ULK1-SARM1 interaction and contributes to the ability of SARM1 to accumulate in injured axons.

Leishmaniinae: Evolutionary inferences based on protein expression profiles (PhyloQuant) congruent with phylogenetic relationships among Leishmania, Endotrypanum, Porcisia, Zelonia, Crithidia, and Leptomonas.

Evolutionary relationships among parasites of the subfamily Leishmaniinae, which comprises pathogen agents of leishmaniasis, were inferred based on differential protein expression profiles from mass spectrometry-based quantitative data using the PhyloQuant method. Evolutionary distances following identification and quantification of protein and peptide abundances using Proteome Discoverer and MaxQuant software were estimated for 11 species from six Leishmaniinae genera. Results clustered all dixenous species of the genus Leishmania, subgenera L. (Leishmania), L. (Viannia), and L. (Mundinia), sister to the dixenous species of genera Endotrypanum and Porcisia. Placed basal to the assemblage formed by all these parasites were the species of genera Zelonia, Crithidia, and Leptomonas, so far described as monoxenous of insects although eventually reported from humans. Inferences based on protein expression profiles were congruent with currently established phylogeny using DNA sequences. Our results reinforce PhyloQuant as a valuable approach to infer evolutionary relationships within Leishmaniinae, which is comprised of very tightly related trypanosomatids that are just beginning to be phylogenetically unraveled. In addition to evolutionary history, mapping of species-specific protein expression is paramount to understand differences in infection processes, tissue tropisms, potential to jump from insects to vertebrates including humans, and targets for species-specific diagnostic and drug development.

Combined impact of dynamic air pollution and transportation noise on cardiometabolic disorders in San Diego County.

Air pollution and noise exposure may synergistically contribute to increased cardiometabolic disorders; however, few studies have examined this potential interaction nor considered exposures beyond residential location. This study investigates the combined impact of dynamic air pollution and transportation noise on cardiometabolic disorders in San Diego County. Using the Community of Mine Study (2014-2017), 602 ethnically diverse participants were assessed for obesity, dyslipidemia, hypertension, and metabolic syndrome (MetS) using anthropometric measurements and biomarkers from blood samples. Time-weighted measures of exposure to PM2.5, NO2, road and aircraft noise were calculated using global positioning system (GPS) mobility data and Kernel Density Estimation. Generalized estimating equation models were used to analyze associations. Interactions were assessed on the multiplicative and additive scales using relative excess risk due to interaction (RERI). We found that air pollution and noise interact to affect metabolic disorders on both multiplicative and additive scales. The effect of noise on obesity and MetS was higher when air pollution was higher. The RERI of aircraft noise and NO2 on obesity and MetS were 0.13 (95%CI 0.03, 0.22) and 0.13 (95%CI 0.02, 0.25), respectively. This finding suggests that aircraft noise and air pollution may have synergistic effects on obesity and MetS.

Unlocking bacterial defense: Exploring the potent inhibition of NorA efflux pump by coumarin derivatives in Staphylococcus aureus.

The occurrence of bacterial resistance has been increasing, compromising the treatment of various infections. The high virulence of Staphylococcus aureus allows for the maintenance of the infectious process, causing many deaths and hospitalizations. The MepA and NorA efflux pumps are transporter proteins responsible for expelling antimicrobial agents such as fluoroquinolones from the bacterial cell. Coumarins are phenolic compounds that have been studied for their diverse biological actions, including against bacteria. A pharmacokinetic in silico characterization of compounds C10, C11, C13, and C14 was carried out according to the principles of Lipinski's Rule of Five, in addition to searching for similarity in ChemBL and subsequent search for publications in CAS SciFinder. All compounds were evaluated for their in vitro antibacterial and modulatory activity against standard and multidrug-resistant Gram-positive and Gram-negative strains. The effect of coumarins C9, C10, C11, C13, and C14 as efflux pump inhibitors in Staphylococcus aureus strains was evaluated using the microdilution method (MepA or NorA) and fluorimetry (NorA). The behavior of coumarins regarding the efflux pump was determined from their interaction properties with the membrane and coumarin-protein using molecular docking and molecular dynamics simulations. Only the isolated coumarin compound C13 showed antibacterial activity against standard strains of Staphylococcus aureus and Escherichia coli. However, the other tested coumarins showed modulatory capacity for fluoroquinolone and aminoglycoside antibacterials. Compounds C10, C13, and C14 were effective in reducing the MIC of both antibiotics for both multidrug-resistant strains, while C11 potentiated the effect of norfloxacin and gentamicin for Gram-positive and Gram-negative bacteria and only norfloxacin for Gram-negative. Only coumarin C14 produced synergistic effects when associated with ciprofloxacin in MepA-carrying strains. All tested coumarins have the ability to inhibit the NorA efflux pump present in Staphylococcus aureus, both in reducing the MIC and inducing increased ethidium bromide fluorescence emission in fluorimetry. The findings of this study offer an atomistic perspective on the potential of coumarins as active inhibitors of the NorA pump, highlighting their specific mode of action mainly targeting protein inhibition. In molecular docking, it was observed that coumarins are capable of interacting with various amino acid residues of the NorA pump. The simulation showed that coumarin C10 can cross the bilayer; however, the other coumarins interacted with the membrane but were unable to cross it. Coumarins demonstrated their potentiating role in the effect of norfloxacin through a dual mechanism: efflux pump inhibition through direct interaction with the protein (C9, C10, C11, and C13) and increased interaction with the membrane (C10 and C13). In the context of pharmacokinetic prediction studies, the studied structures have a suitable chemical profile for possible oral use. We suggest that coumarin derivatives may be an interesting alternative in the future for the treatment of resistant bacterial infections, with the possibility of a synergistic effect with other antibacterials, although further studies are needed to characterize their therapeutic effects and toxicity.

Epidemiology of infectious diseases in migrant populations from endemic or high-endemic countries: A multicentric primary care-based study in Spain.

OBJECTIVES: We aimed to evaluate the epidemiology of seven infections (Chagas disease, strongyloidiasis, schistosomiasis, human immunodeficiency virus, hepatitis B and C virus, and active tuberculosis) in migrant populations attended at primary care facilities in Catalonia, Spain. METHODS: This is a cross sectional study conducted from March to December 2018 at eight primary care centres in Catalonia, Spain where health professionals were recommended to systematically screen multiple infections in migrants considering the endemicity of the pathogens in their country of birth. Routine health data were retrospectively extracted from electronic health records of the primary care centres. The proportion of cases among individuals tested for each infection was estimated with its 95% confident interval (CI). Mixed-effects logistics regression models were conducted to assess any possible association between the exposure variables and the primary outcome. RESULTS: Out of the 15,780 migrants that attended primary care centres, 2410 individuals were tested for at least one infection. Of the 508 (21.1%) migrants diagnosed with at least one condition, a higher proportion originated from Sub-Saharan Africa (207, 40.7%), followed by South-East Europe (117, 23.0%) and Latin-America (88, 17.3%; p value <0.001). The proportion of migrants diagnosed with Chagas disease was 5/122 (4.1%, 95%CI 0.5-7.7), for strongyloidiasis 56/409 (13.7%, 95%CI 10.3-17.0) and for schistosomiasis 2/101 (2.0%, 95%CI 0.0-4.7) with very few cases tested. The estimated proportion for human immunodeficiency virus was 67/1176 (5.7%, 95%CI 4.4-7.0); 377/1478 (25.5%, 95%CI 23.3-27.7) for hepatitis B virus, with 108/1478 (7.3%, 95%CI 6.0-8.6) of them presenting an active infection, while 31/1433 (2.2%, 95%CI 1.4-2.9) were diagnosed with hepatitis C virus. One case of active tuberculosis was diagnosed after testing 172 migrant patients (0.6%, 95%CI 0.0-1.7). CONCLUSIONS: We estimated a high proportion of the studied infections in migrants from endemic areas. Country-specific estimations of the burden of infections in migrants are fundamental for the implementation of preventive interventions.

Retuning the potential of the electrochemical leaf.

The electrochemical leaf enables the electrification and control of multi-enzyme cascades by exploiting two discoveries: (i) the ability to electrify the photosynthetic enzyme ferredoxin NADP+ reductase (FNR), driving it to catalyse the interconversion of NADP+/NADPH whilst it is entrapped in a highly porous, metal oxide electrode, and (ii) the evidence that additional enzymes can be co-entrapped in the electrode pores where, through one NADP(H)-dependent enzyme, extended cascades can be driven by electrical connection to FNR, via NADP(H) recycling. By changing a critical active-site tyrosine to serine, FNR's exclusivity for NADP(H) is swapped for unphosphorylated NAD(H). Here we present an electrochemical study of this variant FNR, and show that in addition to the intended inversion of cofactor preference, this change to the active site has altered FNR's tuning of the flavin reduction potential, making it less reductive. Exploiting the ability to monitor the variant's activity with NADP(H) as a function of potential has revealed a trapped intermediate state, relieved only by applying a negative overpotential, which allows catalysis to proceed. Inhibition by NADP+ (very tightly bound) with respect to NAD(H) turnover was also revealed and interestingly, this inhibition changes depending on the applied potential. These findings are of critical importance for future exploitation of the electrochemical leaf.

Effectiveness of Interventions for Changing More Than One Behavior at a Time to Manage Chronic Conditions: A Systematic Review and Meta-analysis.

BACKGROUND: Health behaviors play a significant role in chronic disease management. Rather than being independent of one another, health behaviors often co-occur, suggesting that targeting more than one health behavior in an intervention has the potential to be more effective in promoting better health outcomes. PURPOSE: We aimed to conduct a systematic review and meta-analysis of randomized trials of interventions that target more than one behavior to examine the effectiveness of multiple health behavior change interventions in patients with chronic conditions. METHODS: Five electronic databases (Web of Science, PubMed, CINAHL, EMBASE, and Cochrane) were systematically searched in November 2023, and studies included in previous reviews were also consulted. We included randomized trials of interventions aiming to change more than one health behavior in individuals with chronic conditions. Two independent reviewers screened and extracted data, and used Cochrane's Risk of Bias 2 tool. Meta-analyses were conducted to estimate the effects of interventions on change in health behaviors. Results were presented as Cohen's d for continuous data, and risk ratio for dichotomous data. RESULTS: Sixty-one studies were included spanning a range of chronic diseases: cardiovascular (k = 25), type 2 diabetes (k = 15), hypertension (k = 10), cancer (k = 7), one or more chronic conditions (k = 3), and multiple conditions (k = 1). Most interventions aimed to change more than one behavior simultaneously (rather than in sequence) and most targeted three particular behaviors at once: "physical activity, diet and smoking" (k = 20). Meta-analysis of 43 eligible studies showed for continuous data (k = 29) a small to substantial positive effect on behavior change for all health behaviors (d = 0.081-2.003) except for smoking (d = -0.019). For dichotomous data (k = 23) all analyses showed positive effects of targeting more than one behavior on all behaviors (RR = 1.026-2.247). CONCLUSIONS: Targeting more than one behavior at a time is effective in chronic disease management and more research should be directed into developing the science of multiple behavior change.

Many recommendations suggest engaging in more than one health behavior to manage a chronic disease; however, most research trying to understand or support health behavior tends to focus on only one behavior. We wanted to clarify if interventions aiming to support people in changing more than one health behavior are effective and promote better health outcomes. We aimed to conduct a systematic review to summarize the effects of studies reporting randomized trials of interventions that target more than one behavior in people with a chronic condition. We found and analyzed 61 studies published up to November 2023 covering people with a variety of chronic diseases: cardiovascular conditions, type 2 diabetes, hypertension, cancer, and, in some studies, people with multiple conditions. Most interventions tried to change three particular behaviors at once (physical activity, diet, and smoking) and, overall, interventions that tried to change more than one behavior had positive effects on diet, physical activity, medication adherence, and alcohol consumption, but not smoking cessation. Findings highlight the benefits of targeting more than one behavior in health behavior change interventions. Future research could seek to identify if findings are similar across settings and populations and how they can inform routine healthcare and self-management interventions.

Designing and Evaluating a Hierarchical Framework for Matching Food Outlets across Multi-sourced Geospatial Datasets: a Case Study of San Diego County.

Research on retail food environment (RFE) relies on data availability and accuracy. However, the discrepancies in RFE datasets may lead to imprecision when measuring association with health outcomes. In this research, we present a two-tier hierarchical point of interest (POI) matching framework to compare and triangulate food outlets across multiple geospatial data sources. Two matching parameters were used including the geodesic distance between businesses and the similarity of business names according to Levenshtein distance (LD) and Double Metaphone (DM). Sensitivity analysis was conducted to determine thresholds of matching parameters. Our Tier 1 matching used more restricted parameters to generate high confidence-matched POIs, whereas in Tier 2 we opted for relaxed matching parameters and applied a weighted multi-attribute model on the previously unmatched records. Our case study in San Diego County, California used government, commercial, and crowdsourced data and returned 20.2% matched records from Tier 1 and 18.6% matched from Tier 2. Our manual validation shows a 100% matching rate for Tier 1 and up to 30.6% for Tier 2. Matched and unmatched records from Tier 1 were further analyzed for spatial patterns and categorical differences. Our hierarchical POI matching framework generated highly confident food POIs by conflating datasets and identified some food POIs that are unique to specific data sources. Triangulating RFE data can reduce uncertain and invalid POI listings when representing food environment using multiple data sources. Studies investigating associations between food environment and health outcomes may benefit from improved quality of RFE.

Exploring the impact of environmental exposure changes on metabolic biomarkers: A 6-month GPS-GIS study among women with overweight or obesity.

BACKGROUND: Little is known about the impact of environmental exposure change on metabolic biomarkers associated with cancer risk. Furthermore, this limited epidemiological evidence on metabolic biomarkers focused on residential exposure, without considering the activity space which can be done by modelling dynamic exposures. In this longitudinal study, we aimed to investigate the impact of environmental exposures change on metabolic biomarkers using GPS-GIS based measurements. METHODS: Among two weight loss interventions, the Reach for Health and the MENU studies, which included ∼460 women at risk of breast cancer or breast cancer survivors residing in Southern California, three metabolic biomarkers (insulin resistance, fasting glucose, and C-reactive protein) were assessed. Dynamic GPS-GIS based exposure to green spaces, recreation, walkability, NO2, and PM2.5 were calculated at baseline and 6 months follow-up using time-weighted spatial averaging. Generalized estimating equations models were used to examine the relationship between changes in environmental exposures and biomarker levels over time. RESULTS: Overall, six-month environmental exposure change was not associated with metabolic biomarkers change. Stratified analyses by level of environmental exposures at baseline revealed that reduced NO2 and PM2.5 exposure was associated with reduced fasting glucose concentration among women living in a healthier environment at baseline (ß -0.010, 95%CI -0.025, 0.005; ß -0.019, 95%CI -0.034, -0.003, respectively). Women living in poor environmental conditions at baseline and exposed to greener environments had decreased C-reactive protein concentrations (ß -1.001, 95%CI -1.888, -0.131). CONCLUSIONS: The impact of environmental exposure changes on metabolic biomarkers over time may be modified by baseline exposure conditions.

Geometric Cuts by an Autonomous Laser Osteotome Increase Stability in Mandibular Reconstruction With Free Fibula Grafts: A Cadaver Study.

BACKGROUND: Nonunion and plate exposure represent a major complication after mandibular reconstruction with free fibula flaps. These drawbacks may be resolved by geometric osteotomies increasing intersegmental bone contact area and stability. PURPOSE: The aim of this study was to compare intersegmental bone contact and stability of geometric osteotomies to straight osteotomies in mandibular reconstructions with free fibula grafts performed by robot-guided erbium-doped yttrium aluminum garnet laser osteotomy. STUDY DESIGN, SETTING, SAMPLE: This cadaveric in-vitro study was performed on fresh frozen human skull and fibula specimens. Computed tomography (CT) scans of all specimens were performed for virtual planning of mandibular resections and three-segment fibula reconstructions. The virtual planning was implemented in a Cold Ablation Robot-guided Laser Osteotome. PREDICTOR/EXPOSURE/INDEPENDENT VARIABLE: For predictor variables, straight and geometric puzzle-shaped osteotomies were designed at resection of the mandible and corresponding fibula reconstruction. MAIN OUTCOME VARIABLES: The primary outcome variable was the stability of the reconstructed mandible investigated by shearing tests. Moreover, secondary outcome variables were the duration of the laser osteotomies, the contact surface area, and the accuracy of the reconstruction, both evaluated on postsurgical CT scans. COVARIATES: Covariables were not applicable. ANALYSES: Data were reported as mean values (± standard deviation) and were statistically analyzed using an independent-sample t-test at a significance level of α = 0.05. Root mean square deviation was tested for accuracy. RESULTS: Eight skulls and 16 fibula specimens were used for the study. One hundred twelve successful laser osteotomies (96 straight and 16 geometrical) could be performed. Geometric osteotomies increased stability (110.2 ± 36.2 N vs 37.9 ± 20.1 N, P < .001) compared to straight osteotomies. Geometric osteotomy of the fibula took longer than straight osteotomies (10.9 ± 5.1 min vs 5.9 ± 2.2 min, P = .028) but could provide larger contact surface (431.2 ± 148.5 mm2 vs 226.1 ± 50.8 mm2, P = .04). Heat map analysis revealed a mean deviation between preoperational planning and postreconstructive CT scan of -0.8 ± 2.4 mm and a root mean square deviation of 2.51 mm. CONCLUSION AND RELEVANCE: Mandibular resection and reconstruction by fibula grafts can be accurately performed by a Cold Ablation Robot-guided Laser Osteotome without need for cutting guides. Osteotomy planning with geometric cuts offers higher stability and an increased bone contact area, which may enhance healing of the reconstructed mandible.

Twelve tips for Natural Language Processing in medical education program evaluation.

With the increasing application of Natural Language Processing (NLP) in Medicine at large, medical educators are urged to gain an understanding and implement NLP techniques within their own education programs to improve the workflow and make significant and rapid improvements in their programs. This paper aims to provide twelve essential tips inclusive of both conceptual and technical factors to facilitate the successful integration of NLP in medical education program evaluation. These twelve tips range from advising on various stages of planning the evaluation process, considerations for data collection, and reflections on preprocessing of data in preparation for analysis and interpretation of results. Using these twelve tips as a framework, medical researchers, educators, and administrators will have an understanding and reference to navigating applications of NLP and be able to unlock its potential for enhancing the evaluation of their own medical education programs.

Can pain be self-managed? Pain change in vulnerable participants to a health education programme.

Chronic pain exerts a significant impact on the quality of life, giving rise to both physical and psycho-social vulnerabilities. It not only leads to direct costs associated with treatments, but also results in indirect costs due to the reduced productivity of affected individuals. Chronic conditions can be improved by reducing modifiable risk factors. Various educational programs, including the Chronic Disease Self-Management Programme (CDSMP), have demonstrated the advantages of enhancing patient empowerment and health literacy. Nevertheless, their efficacy in addressing pain symptoms has received limited attention, especially concerning vulnerable populations. This research aims to assess the effectiveness of the CDSMP in alleviating pain among socio-economically vulnerable participants with chronic conditions. By accounting for a wide range of variables, and using data from the EFFICHRONIC project (EU health programme), we investigated the changes in pain levels after the intervention, among 1070 participants from five European countries. Our analyses revealed a significant reduction in pain following the intervention. This finding supports the notion that training programs can effectively ameliorate pain and alleviate its impact on the quality of life, particularly in vulnerable populations. Younger participants, as well as those with higher education levels and individuals experiencing higher levels of pain at baseline, were more likely to experience a reduction in their pain levels. These findings underscore the importance of recognising the social determinants of health. The study was registered at ClinicalTrials.gov (ISRCTN70517103).

Structural disconnectivity in postoperative delirium: A perioperative two-center cohort study in older patients.

BACKGROUND: Structural disconnectivity was found to precede dementia. Global white matter abnormalities might also be associated with postoperative delirium (POD). METHODS: We recruited older patients (≥65 years) without dementia that were scheduled for major surgery. Diffusion kurtosis imaging metrics were obtained preoperatively, after 3 and 12 months postoperatively. We calculated fractional anisotropy (FA), mean diffusivity (MD), mean kurtosis (MK), and free water (FW). A structured and validated delirium assessment was performed twice daily. RESULTS: Of 325 patients, 53 patients developed POD (16.3%). Preoperative global MD (standardized beta 0.27 [95% confidence interval [CI] 0.21-0.32] p < 0.001) was higher in patients with POD. Preoperative global MK (-0.07 [95% CI -0.11 to (-0.04)] p < 0.001) and FA (0.07 [95% CI -0.10 to (-0.04)] p < 0.001) were lower. When correcting for baseline diffusion, postoperative MD was lower after 3 months (0.05 [95% CI -0.08 to (-0.03)] p < 0.001; n = 183) and higher after 12 months (0.28 [95% CI 0.20-0.35] p < 0.001; n = 45) among patients with POD. DISCUSSION: Preoperative structural disconnectivity was associated with POD. POD might lead to white matter depletion 3 and 12 months after surgery.