Protein nanoparticle vaccines induce potent neutralizing antibody responses against MERS-CoV.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that causes severe and often lethal respiratory illness in humans. The MERS-CoV spike (S) protein is the viral fusogen and the target of neutralizing antibodies, and has therefore been the focus of vaccine design efforts. Currently there are no licensed vaccines against MERS-CoV and only a few candidates have advanced to Phase I clinical trials. Here we developed MERS-CoV vaccines utilizing a computationally designed protein nanoparticle platform that has generated safe and immunogenic vaccines against various enveloped viruses, including a licensed vaccine for SARS-CoV-2. Two-component protein nanoparticles displaying MERS-CoV S-derived antigens induced robust neutralizing antibody responses and protected mice against challenge with mouse-adapted MERS-CoV. Electron microscopy polyclonal epitope mapping and serum competition assays revealed the specificities of the dominant antibody responses elicited by immunogens displaying the prefusion-stabilized S-2P trimer, receptor binding domain (RBD), or N-terminal domain (NTD). An RBD nanoparticle vaccine elicited antibodies targeting multiple non-overlapping epitopes in the RBD, whereas anti-NTD antibodies elicited by the S-2P- and NTD-based immunogens converged on a single antigenic site. Our findings demonstrate the potential of two-component nanoparticle vaccine candidates for MERS-CoV and suggest that this platform technology could be broadly applicable to betacoronavirus vaccine development.

Practice Patterns of Pancreatic Surgery Within the Military.

INTRODUCTION: Pancreatic surgery is technically challenging, with mortality rates at high-volume centers ranging from 0% to 5%. An inverse relationship between surgeon volume and perioperative mortality has been reported suggesting that patients benefit from experienced surgeons at high-volume centers. There is little published on the volume of pancreatic surgeries performed in military treatment facilities (MTF) and there is no centralization policy regarding pancreatic surgery. This study evaluates pancreatic procedures at MTFs. We hypothesize that a small group of MTFs perform most pancreatic procedures, including more complex pancreatic surgeries. METHODS: This is a retrospective review of de-identified data from MHS Mart (M2) from 2014 to 2020. The database contains patient data from all Defense Health Agency treatment facilities. Variables collected include number and types of pancreatic procedures performed and patient demographics. The primary endpoint was the number and type of surgery for each MTF. RESULTS: Twenty-six MTFs performed pancreatic surgeries from 2014 to 2020. There was a significant decrease in the number of cases from 2014 to 2020. Nine hospitals performed one surgery over eight years. The most common surgery was a distal pancreatectomy, followed by a pancreaticoduodenectomy. There was a decrease in the number of pancreaticoduodenectomies and distal pancreatectomies performed over this period. CONCLUSIONS: Pancreatic surgery is being performed at few MTFs with a downward trajectory over time. Further studies would be needed to assess the impact on patient care regarding postoperative complications, barriers to timely patient care, and impact on readiness of military surgeons.

The oral microbiome as a proxy for feed intake in dairy cattle.

Genetic material from rumen microorganisms can be found within the oral cavity, and hence there is potential in using the oral microbiome as a proxy of the ruminal microbiome. Feed intake (FI) influences the composition of rumen microbiota and might directly influence the oral microbiome in dairy cattle. Ruminal content samples (RS) from 29 cows were collected at the beginning of the study and also 42 d later (RS0 and RS42, respectively). Additionally, 18 oral samples were collected through buccal swabbing at d 42 (OS42) from randomly selected cows. Samples were used to characterize and compare the taxonomy and functionality of the oral microbiome using Nanopore sequencing and to evaluate the feasibility of using the oral microbiome to estimate FI. Up to 186 taxonomical features were found differentially abundant (DA) between RS and OS42. Similar results were observed when comparing OS42 to RS collected at different days. Microorganisms associated with the liquid fraction of the rumen were less abundant in OS42 as these were probably swallowed after regurgitation. Up to 1,102 KEGGs were found to be DA between RS and OS42 and these results differed when comparing time of collection, but differentially abundant KEGGs were mainly associated to metabolism in both situations. Models based on the oral microbiome and rumen microbiome differed in their selection of microbial groups and biological pathways to predict FI. In the rumen, fiber-associated microorganisms are considered suitable indicators of feed intake. On the other hand, biofilm formers like Gammaproteobacteria or Bacteroidia classes are deemed appropriate proxies for predicting feed intake from oral samples. Models from RS exhibited some predictive ability to estimate FI, but OS significantly outperformed them. The best lineal model to estimate FI was obtained with the relative abundance of taxonomical feature at genera level, achieving an average R2 equal to 0.88 within the training data, and a root mean square error equal to 3.46 ± 0.83 (standard deviation; SD) kg of DM/ as well as a Pearson correlation coefficient between observed and estimated FI of 0.48 ± 0.30 in the test data. The results from this study suggest that oral microbiome has potential to predict FI in dairy cattle, and it encourages validating this potential in other populations.

Effect of Makeup Use on Depressive Symptoms: An Open, Randomized and Controlled Trial.

INTRODUCTION: Depression is one of the most disabling diseases globally, with a high disease burden that generates high direct and indirect costs. The incidence of depression is twofold higher in adult women than in men. Biological and psychosocial factors constitute the pathophysiological bases of the condition and due to the complexity of the condition, current understanding is that the "treatment strategy must be multimodal". The objective of this study was to measure the effect of introducing the frequent use of makeup on improving depressive symptoms in adult women of medium-low purchasing power METHODS: Participants with the targeted profile who did not frequently use makeup were selected and randomised to receive (test group) or not (control group) stimuli and makeup products intended for encouraging the frequent use of makeup. The Zung Depression Self-Assessment Scale was used to assess depressive symptoms, with additional assessments on self-image perception using the mirror test and salivary cortisol level. RESULTS: The results demonstrated a sustained reduction in depressive symptoms (8.3 percentage points reduction in the Average Zung Index; P < 0.05), with a significant improvement in self-image perception (25% increase in the average score obtained in the mirror test; P < 0.05) and a specific influence on salivary cortisol levels (55% reduction in salivary cortisol concentration; P < 0.05) after the first makeup application. CONCLUSION: The results show that encouraging the frequent use of makeup, a practice that can be achieved by most people and which is simple and inexpensive to implement, can contribute to effective and sustainable improvement in the well-being and mental health of a significant portion of the population.

Measures of population immunity can predict the dominant clade of influenza A (H3N2) and reveal age-associated differences in susceptibility and specificity.

For antigenically variable pathogens such as influenza, strain fitness is partly determined by the relative availability of hosts susceptible to infection with that strain compared to others. Antibodies to the hemagglutinin (HA) and neuraminidase (NA) confer substantial protection against influenza infection. We asked if a cross-sectional antibody-derived estimate of population susceptibility to different clades of influenza A (H3N2) could predict the success of clades in the following season. We collected sera from 483 healthy individuals aged 1 to 90 years in the summer of 2017 and analyzed neutralizing responses to the HA and NA of representative strains. The clade to which neutralizing antibody titers were lowest, indicating greater population susceptibility, dominated the next season. Titers to different HA and NA clades varied dramatically between individuals but showed significant associations with age, suggesting dependence on correlated past exposures. Despite this correlation, inter-individual variability in antibody titers to H3N2 strains increased gradually with age. This study indicates how representative measures of population immunity might improve evolutionary forecasts and inform selective pressures on influenza.

Infection after intramedullary nailing of femoral and tibial diaphyseal fractures.

PURPOSE: Management of fracture-related infection (FRI) after intramedullary fixation (IF) is a challenge. The aim of the present study is to describe a series of 26 patients with FRI after IF and to evaluate factors possibly related to the outcome. METHODS: Baseline variables were obtained at the time of IF: age, sex, body mass index, affected bone, open fracture, substance abuse, use of an external fixator, type of nail, reaming, soft-tissue reconstruction and surveillance culture result. After diagnosis of the infection, information was obtained about the time interval between IF and diagnosis and classification according to both the Willeneger and Roth and Makridis systems. Treatment modalities were grouped and analysed according to: use of antimicrobials, surgical debridement, nail removal or retention and spacer use. Cultures of bone or deep soft tissues were performed. Patients were followed up for 12 months, and outcomes (remission, relapse, death and loss of follow-up) were evaluated, as well as fracture consolidation. RESULTS: Remission was observed in 42.3% of patients. There was no significant association between any baseline variable and outcome. There was a significant association between Makridis stage 2 classification and recurrence or death. Treatment strategy was not significantly associated with outcome, and 65.4% of cases had positive culture results, with Enterobacter cloacae as the predominant agent. Consolidation was observed in 81.8% of patients and was not significantly related to the outcome. CONCLUSION: There was a significant association between Makridis classification and the outcome. Consolidation rate was not associated with the outcome regarding the treatment of the infection.

Intelligent Care Management for Diabetic Foot Ulcers: A Scoping Review of Computer Vision and Machine Learning Techniques and Applications.

Ten percent of adults in the United States have a diagnosis of diabetes and up to a third of these individuals will develop a diabetic foot ulcer (DFU) in their lifetime. Of those who develop a DFU, a fifth will ultimately require amputation with a mortality rate of up to 70% within five years. The human suffering, economic burden, and disproportionate impact of diabetes on communities of color has led to increasing interest in the use of computer vision (CV) and machine learning (ML) techniques to aid the detection, characterization, monitoring, and even prediction of DFUs. Remote monitoring and automated classification are expected to revolutionize wound care by allowing patients to self-monitor their wound pathology, assist in the remote triaging of patients by clinicians, and allow for more immediate interventions when necessary. This scoping review provides an overview of applicable CV and ML techniques. This includes automated CV methods developed for remote assessment of wound photographs, as well as predictive ML algorithms that leverage heterogeneous data streams. We discuss the benefits of such applications and the role they may play in diabetic foot care moving forward. We highlight both the need for, and possibilities of, computational sensing systems to improve diabetic foot care and bring greater knowledge to patients in need.

Local structural flexibility drives oligomorphism in computationally designed protein assemblies.

Many naturally occurring protein assemblies have dynamic structures that allow them to perform specialized functions. For example, clathrin coats adopt a wide variety of architectures to adapt to vesicular cargos of various sizes. Although computational methods for designing novel self-assembling proteins have advanced substantially over the past decade, most existing methods focus on designing static structures with high accuracy. Here we characterize the structures of three distinct computationally designed protein assemblies that each form multiple unanticipated architectures, and identify flexibility in specific regions of the subunits of each assembly as the source of structural diversity. Cryo-EM single-particle reconstructions and native mass spectrometry showed that only two distinct architectures were observed in two of the three cases, while we obtained six cryo-EM reconstructions that likely represent a subset of the architectures present in solution in the third case. Structural modeling and molecular dynamics simulations indicated that the surprising observation of a defined range of architectures, instead of non-specific aggregation, can be explained by constrained flexibility within the building blocks. Our results suggest that deliberate use of structural flexibility as a design principle will allow exploration of previously inaccessible structural and functional space in designed protein assemblies.

Precisely patterned nanofibres made from extendable protein multiplexes.

Molecular systems with coincident cyclic and superhelical symmetry axes have considerable advantages for materials design as they can be readily lengthened or shortened by changing the length of the constituent monomers. Among proteins, alpha-helical coiled coils have such symmetric, extendable architectures, but are limited by the relatively fixed geometry and flexibility of the helical protomers. Here we describe a systematic approach to generating modular and rigid repeat protein oligomers with coincident C2 to C8 and superhelical symmetry axes that can be readily extended by repeat propagation. From these building blocks, we demonstrate that a wide range of unbounded fibres can be systematically designed by introducing hydrophilic surface patches that force staggering of the monomers; the geometry of such fibres can be precisely tuned by varying the number of repeat units in the monomer and the placement of the hydrophilic patches.

Multivalent antigen display on nanoparticle immunogens increases B cell clonotype diversity and neutralization breadth to pneumoviruses.

Nanoparticles for multivalent display and delivery of vaccine antigens have emerged as a promising avenue for enhancing B cell responses to protein subunit vaccines. Here, we evaluated B cell responses in rhesus macaques immunized with prefusion-stabilized respiratory syncytial virus (RSV) F glycoprotein trimer compared with nanoparticles displaying 10 or 20 copies of the same antigen. We show that multivalent display skews antibody specificities and drives epitope-focusing of responding B cells. Antibody cloning and repertoire sequencing revealed that focusing was driven by the expansion of clonally distinct B cells through recruitment of diverse precursors. We identified two antibody lineages that developed either ultrapotent neutralization or pneumovirus cross-neutralization from precursor B cells with low initial affinity for the RSV-F immunogen. This suggests that increased avidity by multivalent display facilitates the activation and recruitment of these cells. Diversification of the B cell response by multivalent nanoparticle immunogens has broad implications for vaccine design.

De novo design of highly selective miniprotein inhibitors of integrins αvß6 and αvß8.

The RGD (Arg-Gly-Asp)-binding integrins αvß6 and αvß8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvß6 and αvß8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvß6 and αvß8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvß6 and the αvß8 integrins. In a lung fibrosis mouse model, the αvß6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.

Germline-encoded specificities and the predictability of the B cell response.

Antibodies result from the competition of B cell lineages evolving under selection for improved antigen recognition, a process known as affinity maturation. High-affinity antibodies to pathogens such as HIV, influenza, and SARS-CoV-2 are frequently reported to arise from B cells whose receptors, the precursors to antibodies, are encoded by particular immunoglobulin alleles. This raises the possibility that the presence of particular germline alleles in the B cell repertoire is a major determinant of the quality of the antibody response. Alternatively, initial differences in germline alleles' propensities to form high-affinity receptors might be overcome by chance events during affinity maturation. We first investigate these scenarios in simulations: when germline-encoded fitness differences are large relative to the rate and effect size variation of somatic mutations, the same germline alleles persistently dominate the response of different individuals. In contrast, if germline-encoded advantages can be easily overcome by subsequent mutations, allele usage becomes increasingly divergent over time, a pattern we then observe in mice experimentally infected with influenza virus. We investigated whether affinity maturation might nonetheless strongly select for particular amino acid motifs across diverse genetic backgrounds, but we found no evidence of convergence to similar CDR3 sequences or amino acid substitutions. These results suggest that although germline-encoded specificities can lead to similar immune responses between individuals, diverse evolutionary routes to high affinity limit the genetic predictability of responses to infection and vaccination.

Simultaneous Estimation of Azimuth and Elevation Angles Using a Decision Tree-Based Method.

This study addresses the problem of accurately predicting azimuth and elevation angles of signals impinging on an antenna array employing Machine Learning (ML). Using the information obtained at a receiving system when a transmitter's signal hits it, a Decision Tree (DT) model is trained to estimate azimuth and elevation angles simultaneously. Simulation results demonstrate the robustness of the proposed DT-based method, showcasing its ability to predict the Direction of Arrival (DOA) in diverse conditions beyond the ones present in the training dataset, i.e., the results display the model's generalization capability. Additionally, the comparative analysis reveals that DT-based DOA estimation outperforms the state-of-the-art MUltiple SIgnal Classification (MUSIC) algorithm. Our results demonstrate an average reduction of over 90% in the prediction error and 50% in the prediction time achieved by our proposal when compared to the MUSIC algorithm. These results establish DTs as competitive alternatives for DOA estimation in signal reception systems.

Feasibility of Multiparametric Perfusion Assessment in Diabetic Foot Ulcer Using Intravoxel Incoherent Motion and Blood Oxygenation-Level Dependent MRI.

BACKGROUND: Patients with type-2 diabetes (T2DM) are at increased risk of developing diabetic foot ulcers (DFU) and experiencing impaired wound healing related to underlying microvascular disease. PURPOSE: To evaluate the sensitivity of intra-voxel incoherent motion (IVIM) and blood oxygen level dependent (BOLD) MRI to microvascular changes in patients with DFUs. STUDY TYPE: Case-control. POPULATION: 20 volunteers who were age and body mass index matched, including T2DM patients with DFUs (N = 10, mean age = 57.5 years), T2DM patients with controlled glycemia and without DFUs (DC, N = 5, mean age = 57.4 years) and healthy controls (HC, N = 5, mean age = 52.8 years). FIELD STRENGTH/SEQUENCE: 3T/multi-b-value IVIM and dynamic BOLD. ASSESSMENT: Resting IVIM parameters were obtained using a multi-b-value diffusion-weighted imaging sequence and two IVIM models were fit to obtain diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f) and microvascular volume fraction (MVF) parameters. Microvascular reactivity was evaluated by inducing an ischemic state in the foot with a blood pressure cuff during dynamic BOLD imaging. Perfusion indices were assessed in two regions of the foot: the medial plantar (MP) and lateral plantar (LP) regions. STATISTICAL TESTS: Effect sizes of group mean differences were assessed using Hedge's g adjusted for small sample sizes. RESULTS: DFU participants exhibited elevated D*, f, and MVF values in both regions (g ≥ 1.10) and increased D (g = 1.07) in the MP region compared to DC participants. DC participants showed reduced f and MVF compared to HC participants in the MP region (g ≥ 1.06). Finally, the DFU group showed reduced tolerance for ischemia in the LP region (g = -1.51) and blunted reperfusion response in both regions (g < -2.32) compared to the DC group during the cuff-occlusion challenge. DATA CONCLUSION: The combined use of IVIM and BOLD MRI shows promise in differentiating perfusion abnormalities in the feet of diabetic patients and suggests hyperperfusion in DFU patients. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

De novo design of highly selective miniprotein inhibitors of integrins αvß6 and αvß8.

The RGD (Arg-Gly-Asp)-binding integrins αvß6 and αvß8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between the two closely related integrin proteins and other RGD integrins, stabilize specific conformational states, and have sufficient stability enabling tissue restricted administration could have considerable therapeutic utility. Existing small molecules and antibody inhibitors do not have all of these properties, and hence there is a need for new approaches. Here we describe a method for computationally designing hyperstable RGD-containing miniproteins that are highly selective for a single RGD integrin heterodimer and conformational state, and use this strategy to design inhibitors of αvß6 and αvß8 with high selectivity. The αvß6 and αvß8 inhibitors have picomolar affinities for their targets, and >1000-fold selectivity over other RGD integrins. CryoEM structures are within 0.6-0.7Å root-mean-square deviation (RMSD) to the computational design models; the designed αvß6 inhibitor and native ligand stabilize the open conformation in contrast to the therapeutic anti-αvß6 antibody BG00011 that stabilizes the bent-closed conformation and caused on-target toxicity in patients with lung fibrosis, and the αvß8 inhibitor maintains the constitutively fixed extended-closed αvß8 conformation. In a mouse model of bleomycin-induced lung fibrosis, the αvß6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics when delivered via oropharyngeal administration mimicking inhalation, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.

An eosimiid primate of South Asian affinities in the Paleogene of Western Amazonia and the origin of New World monkeys.

Recent fossil discoveries in Western Amazonia revealed that two distinct anthropoid primate clades of African origin colonized South America near the Eocene/Oligocene transition (ca. 34 Ma). Here, we describe a diminutive fossil primate from Brazilian Amazonia and suggest that, surprisingly, a third clade of anthropoids was involved in the Paleogene colonization of South America by primates. This new taxon, Ashaninkacebus simpsoni gen. et sp. nov., has strong dental affinities with Asian African stem anthropoids: the Eosimiiformes. Morphology-based phylogenetic analyses of early Old World anthropoids and extinct and extant New World monkeys (platyrrhines) support relationships of both Ashaninkacebus and Amamria (late middle Eocene, North Africa) to the South Asian Eosimiidae. Afro-Arabia, then a mega island, played the role of a biogeographic stopover between South Asia and South America for anthropoid primates and hystricognathous rodents. The earliest primates from South America bear little adaptive resemblance to later Oligocene-early Miocene platyrrhine monkeys, and the scarcity of available paleontological data precludes elucidating firmly their affinities with or within Platyrrhini. Nonetheless, these data shed light on some of their life history traits, revealing a particularly small body size and a diet consisting primarily of insects and possibly fruit, which would have increased their chances of survival on a natural floating island during this extraordinary over-water trip to South America from Africa. Divergence-time estimates between Old and New World taxa indicate that the transatlantic dispersal(s) could source in the intense flooding events associated with the late middle Eocene climatic optimum (ca. 40.5 Ma) in Western Africa.

Integrated NMR and MS Analysis of the Plasma Metabolome Reveals Major Changes in One-Carbon, Lipid, and Amino Acid Metabolism in Severe and Fatal Cases of COVID-19.

Brazil has the second-highest COVID-19 death rate worldwide, and Rio de Janeiro is among the states with the highest rate in the country. Although vaccine coverage has been achieved, it is anticipated that COVID-19 will transition into an endemic disease. It is concerning that the molecular mechanisms underlying clinical evolution from mild to severe disease, as well as the mechanisms leading to long COVID-19, are not yet fully understood. NMR and MS-based metabolomics were used to identify metabolites associated with COVID-19 pathophysiology and disease outcome. Severe COVID-19 cases (n = 35) were enrolled in two reference centers in Rio de Janeiro within 72 h of ICU admission, alongside 12 non-infected control subjects. COVID-19 patients were grouped into survivors (n = 18) and non-survivors (n = 17). Choline-related metabolites, serine, glycine, and betaine, were reduced in severe COVID-19, indicating dysregulation in methyl donors. Non-survivors had higher levels of creatine/creatinine, 4-hydroxyproline, gluconic acid, and N-acetylserine, indicating liver and kidney dysfunction. Several changes were greater in women; thus, patients' sex should be considered in pandemic surveillance to achieve better disease stratification and improve outcomes. These metabolic alterations may be useful to monitor organ (dys) function and to understand the pathophysiology of acute and possibly post-acute COVID-19 syndromes.

Baseline Features and Reasons for Nonparticipation in the Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) Study, a Colorectal Cancer Screening Trial.

Importance: The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) randomized clinical trial sought to recruit 50 000 adults into a study comparing colorectal cancer (CRC) mortality outcomes after randomization to either an annual fecal immunochemical test (FIT) or colonoscopy. Objective: To (1) describe study participant characteristics and (2) examine who declined participation because of a preference for colonoscopy or stool testing (ie, fecal occult blood test [FOBT]/FIT) and assess that preference's association with geographic and temporal factors. Design, Setting, and Participants: This cross-sectional study within CONFIRM, which completed enrollment through 46 Department of Veterans Affairs medical centers between May 22, 2012, and December 1, 2017, with follow-up planned through 2028, comprised veterans aged 50 to 75 years with an average CRC risk and due for screening. Data were analyzed between March 7 and December 5, 2022. Exposure: Case report forms were used to capture enrolled participant data and reasons for declining participation among otherwise eligible individuals. Main Outcomes and Measures: Descriptive statistics were used to characterize the cohort overall and by intervention. Among individuals declining participation, logistic regression was used to compare preference for FOBT/FIT or colonoscopy by recruitment region and year. Results: A total of 50 126 participants were recruited (mean [SD] age, 59.1 [6.9] years; 46 618 [93.0%] male and 3508 [7.0%] female). The cohort was racially and ethnically diverse, with 748 (1.5%) identifying as Asian, 12 021 (24.0%) as Black, 415 (0.8%) as Native American or Alaska Native, 34 629 (69.1%) as White, and 1877 (3.7%) as other race, including multiracial; and 5734 (11.4%) as having Hispanic ethnicity. Of the 11 109 eligible individuals who declined participation (18.0%), 4824 (43.4%) declined due to a stated preference for a specific screening test, with FOBT/FIT being the most preferred method (2820 [58.5%]) vs colonoscopy (1958 [40.6%]; P < .001) or other screening tests (46 [1.0%] P < .001). Preference for FOBT/FIT was strongest in the West (963 of 1472 [65.4%]) and modest elsewhere, ranging from 199 of 371 (53.6%) in the Northeast to 884 of 1543 (57.3%) in the Midwest (P = .001). Adjusting for region, the preference for FOBT/FIT increased by 19% per recruitment year (odds ratio, 1.19; 95% CI, 1.14-1.25). Conclusions and Relevance: In this cross-sectional analysis of veterans choosing nonenrollment in the CONFIRM study, those who declined participation more often preferred FOBT or FIT over colonoscopy. This preference increased over time and was strongest in the western US and may provide insight into trends in CRC screening preferences.