Population-based Study of Gastric Cancer Survival and Associations in Rural Western Honduras.

BACKGROUND: Two-thirds of global cancer occur in low/middle income countries (LMICs). Northern Central America is the largest LMIC region in the western hemisphere, and lack cancer registries to guide cancer control. We conducted a gastric cancer (GC) survival study in rural western Honduras, characterized as having among the highest GC incidence rates in Latin America. METHODS: The cohort of incident GC diagnosed between 2002-2015 was studied with active follow-up, with household visits. The regional gastric cancer registry was primary for case identification, with completeness examination with hospital data and national death certificates. Cox regression models were used for survival calculations. RESULTS: Survival follow-up was achieved in 741/774 patients (95.7%). Household interviews were conducted in 74.1% (n=549). 65.7% were male, median age at diagnosis was 64 years, 24.5% were <55. 43.9% of tumors had pyloric obstruction. 45.2%, 43.2%, and 7.3% of histology was intestinal, diffuse, and mixed, respectively. 24.7% patients received treatment. 5-year survival rates were 9.9% for both males and females, 7.7% for age <45, and 7.9% for diffuse GC. Median survival time was 4.8 months (95%CI,4.2-5.6). In the final Cox regression model including age, sex, Lauren subtype, and poverty index, only treatment was significantly associated with survival (HR 2.43, 95%CI,1.8-3.2). CONCLUSIONS: Markedly low gastric cancer 5-year survival rates are observed in rural Central America. The majority of patients present with advanced disease, and a minority have access to therapy. IMPACT: The findings have implications for cancer control in the Central America LMICs and for U.S. Latino populations.

Modulation of gut microbiota composition and predicted metabolic capacity after nutritional programming with a plant-rich diet in Atlantic salmon (Salmo salar): insights across developmental stages.

To promote sustainable aquaculture, the formulation of Atlantic salmon (Salmo salar) feeds has changed in recent decades, focusing on replacing standard marine-based ingredients with plant-based alternatives, increasingly demonstrating successful outcomes in terms of fish performance. However, little is known about how these plant-based diets may impact the gut microbiota at first feeding and onwards. Nutritional programming (NP) is one strategy applied for exposing fish to a plant-based (V) diet at an early stage in life to promote full utilisation of plant-based ingredients and prevent potential adverse impacts of exposure to a plant-rich diet later in life. We investigated the impact of NP on gut microbiota by introducing fish to plant ingredients (V fish) during first feeding for a brief period of two weeks (stimulus phase) and compared those to fish fed a marine-based diet (M fish). Results demonstrated that V fish not only maintained growth performance at 16 (intermediate phase) and 22 (challenge phase) weeks post first feeding (wpff) when compared to M fish but also modulated gut microbiota. PERMANOVA general effects revealed gut microbiota dissimilarity by fish group (V vs. M fish) and phases (stimulus vs. intermediate vs. challenge). However, no interaction effect of both groups and phases was demonstrated, suggesting a sustained impact of V diet (nutritional history) on fish across time points/phases. Moreover, the V diet exerted a significant cumulative modulatory effect on the Atlantic salmon gut microbiota at 16 wpff that was not demonstrated at two wpff, although both fish groups were fed the M diet at 16 wpff. The nutritional history/dietary regime is the main NP influencing factor, whereas environmental and host factors significantly impacted microbiota composition in M fish. Microbial metabolic reactions of amino acid metabolism were higher in M fish when compared to V fish at two wpff suggesting microbiota played a role in digesting the essential amino acids of M feed. The excessive mucin O-degradation revealed in V fish at two wpff was mitigated in later life stages after NP, suggesting physiological adaptability and tolerance to V diet. Future studies are required to explore more fully how the microbiota functionally contributes to the NP.

Nonsurgical improvement of severe upper airway obstruction in infants with Robin sequence and cleft palate using Stanford Orthodontic Airway Plate treatment.

STUDY OBJECTIVES: Severe respiratory distress of neonates with Robin sequence (RS) is traditionally managed by surgery. Stanford Orthodontic Airway Plate treatment (SOAP) is a nonsurgical option. The study aimed to determine if SOAP can improve polysomnography (PSG) parameters of neonates with RS. METHODS: PSG of neonates with RS treated with SOAP at a single hospital were retrospectively analyzed. Patients without PSG at all 4 time points (pre-, start of-, mid-, and post-treatment) were excluded. Data were analyzed using a linear mixed effects model. RESULTS: Sixteen patients were included. All patients had cleft palate (CP). The median age (min, max) at the start of treatment was 1.1 months (0.5, 2.3) with the treatment duration of 4.5 months (3.5, 6.0). The mean obstructive apnea-hypopnea index (95% confidence interval) decreased from 39.3 events/hour (32.9, 45.7) to 12.2 events/hour (6.7, 17.7) (P < 0.001), obstructive apnea index decreased from 14.1 (11.2, 17.0) events/hour to 1.0 (-1.5, 3.5) events/hour (P < 0.001), and oxygen nadir increased from 79.9% (77.4, 82.5) to 88.2% (85.5, 90.8) (P < 0.001) between pre- and start of treatment. Respiratory improvements were sustained during and after the treatment. All patients avoided mandibular distraction osteogenesis or tracheostomy following SOAP. CONCLUSIONS: As being a rare diagnosis, the number of participants was, as expected, low. However, the current study demonstrates that SOAP can improve PSG parameters, demonstrating its potential utility before surgical interventions for neonates with RS and CP experiencing severe respiratory distress.

High Incidence of Gastric Cancer in El Salvador: A National Multisectorial Study 2000-2014.

BACKGROUND: Gastric adenocarcinoma (GC) is the fourth leading cause of global cancer mortality, and leading infection-associated cancer. GC has significant geographic variability, with a high incidence in East Asia and mountainous regions of Latin America. In the U.S., GC represents a marked disparity with incidence rates that are 2-3 times higher in Hispanics compared to non-Hispanic whites. METHODS: We conducted a national retrospective study of incident GC in El Salvador from to 2000-2014 to estimate the age-standardized incidence rate (ASIR) by using a combination of pathology and endoscopy databases. A unique multisectorial coalition was formed between the Ministry of Health (MINSAL) and ES Gastroenterology Society (AGEDES), representing public hospitals (n=5), governmental employee hospitals (ISSS, n=5), and private facilities (n=6), accounting for >95% of national endoscopy capacity. HER2 and EBV tumor status was ascertained in a representative sample during 2014-2016. RESULTS: 10,039 unique cases of GC were identified, 45.5% female, and mean age of 65. 21% and 9.4% were <55 and <45 years old, respectively. ASIRs (M, F) were 18.9 (95%CI;14.4-20.7) and 12.2 per 100,000 persons (95%CI;10.9-13.5), respectively, in the period 2010-2014 with all centers operational. Intestinal GC was 2.8 times more common than diffuse GC. 23.2% had partial or complete pyloric obstruction. The HER2 2+/3+ status was 16.7% and EBER positivity was 10.2%. CONCLUSIONS: A high incidence of gastric cancer was confirmed in El Salvador, and nearly half of patients were female. IMPACT: The findings have implications for cancer control in the Central America LMICs and for U.S. Latino populations.

Minimally Invasive Epilepsy Surgery.

Surgery remains a critical and often necessary intervention for a subset of patients with epilepsy. The overarching objective of surgical treatment has consistently been to enhance the quality of life for these individuals, either by achieving seizure freedom or by eliminating debilitating seizure types. This review specifically examines minimally invasive surgical approaches for epilepsy. Contemporary advancements have introduced a range of treatments that offer increased safety and efficacy compared to traditional open resective epilepsy surgeries. This manuscript provides a comprehensive review of these techniques and technologies.

Chemical herding as a multiplicative factor for top-down manipulation of colloids.

Colloidal particles can create reconfigurable nanomaterials, with applications such as color-changing, self-repairing, and self-regulating materials and reconfigurable drug delivery systems. However, top-down methods for manipulating colloids are limited in the scale they can control. We consider here a new method for using chemical reactions to multiply the effects of existing top-down colloidal manipulation methods to arrange large numbers of colloids with single-particle precision, which we refer to as chemical herding. Using simulation-based methods, we show that if a set of chemically active colloids (herders) can be steered using external forces (i.e., electrophoretic, dielectrophoretic, magnetic, or optical forces), then a larger set of colloids (followers) that move in response to the chemical gradients produced by the herders can be steered using the control algorithms given in this paper. We also derive bounds that predict the maximum number of particles that can be steered in this way, and we illustrate the effectiveness of this approach using Brownian dynamics simulations. Based on the theoretical results and simulations, we conclude that chemical herding is a viable method for multiplying the effects of existing colloidal manipulation methods to create useful structures and materials.

Trauma Laparoscopy: Time Efficient, Cost Effective, and Safe.

INTRODUCTION: Laparoscopy has demonstrated improved outcomes in abdominal surgery; however, its use in trauma has been less compelling. In this study, we hypothesize that laparoscopy may be observed to have lower costs and complications with similar operative times compared to open exploration in appropriately selected patients. METHODS: We retrospectively reviewed adult patients undergoing abdominal exploration after blunt and penetrating trauma at our level 1 center from 2008 to 2020. Data included mechanism, operative time, length of stay (LOS), hospital charges, and complications. Patients were grouped as follows: therapeutic and nontherapeutic diagnostic laparoscopy and celiotomy. Therapeutic procedures included suture repair of hollow viscus organs or diaphragm, evacuation of hematoma, and hemorrhage control of solid organ or mesenteric injury. Unstable patients, repair of major vascular injuries or resection of an organ or bowel were excluded. RESULTS: Two hundred ninety-six patients were included with comparable demographics. Diagnostic laparoscopy had shorter operative times, LOS, and lower hospital charges compared to diagnostic celiotomy controls. Similarly, therapeutic laparoscopy had shorter LOS and lower hospital costs compared to therapeutic celiotomy. The operative time was not statistically different in this comparison. Patients in the celiotomy groups had more postoperative complications. The differences in operative time, LOS and hospital charges were not statistically significant in the diagnostic laparoscopy compared to diagnostic laparoscopy converted to diagnostic celiotomy group, nor in the therapeutic laparoscopy compared to the diagnostic laparoscopy converted to therapeutic laparoscopy group. CONCLUSIONS: Laparoscopy can be used safely in penetrating and blunt abdominal trauma. In this cohort, laparoscopy was observed to have shorter operative times and LOS with lower hospital charges and fewer complications.

Heterotrimeric collagen helix with high specificity of assembly results in a rapid rate of folding.

The most abundant natural collagens form heterotrimeric triple helices. Synthetic mimics of collagen heterotrimers have been found to fold slowly, even compared to the already slow rates of homotrimeric helices. These prolonged folding rates are not understood. Here we compare the stabilities, specificities and folding rates of three heterotrimeric collagen mimics designed through a computationally assisted approach. The crystal structure of one ABC-type heterotrimer verified a well-controlled composition and register and elucidated the geometry of pairwise cation-π and axial and lateral salt bridges in the assembly. This collagen heterotrimer folds much faster (hours versus days) than comparable, well-designed systems. Circular dichroism and NMR data suggest the folding is frustrated by unproductive, competing heterotrimer species and these species must unwind before refolding into the thermodynamically favoured assembly. The heterotrimeric collagen folding rate is inhibited by the introduction of preformed competing triple-helical assemblies, which suggests that slow heterotrimer folding kinetics are dominated by the frustration of the energy landscape caused by competing triple helices.

Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes.

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

Modulation of metabolic and immunoregulatory pathways in the gut transcriptome of Atlantic salmon (Salmo salar L.) after early nutritional programming during first feeding with plant-based diet.

Introduction: Plant-based nutritional programming is the concept of exposing fish at very early life stages to a plant-based diet for a short duration to improve physiological responses when exposed to a similar plant-rich diet at a later developmental stage. The mechanisms of action underlying nutritional programming have not been fully deciphered, and the responses may be controlled at multiple levels. Methods: This 22-week study examines gut transcriptional changes after nutritional programming. Triplicate groups of Atlantic salmon were fed with a plant (V) vs. a marine-rich (M, control) diet for 2 weeks (stimulus phase) at the first exogenous feeding. Both stimulus fish groups (M and V fish) were then fed the M diet for 12 weeks (intermediate phase) and lastly fed the V diet (challenge phase) for 6 weeks, generating two dietary regimes (MMV and VMV) across phases. This study used a whole-transcriptome approach to analyse the effects of the V diet at the end of stimulus (short-term effects) and 22 weeks post-first feeding (long-term effects). After the stimulus, due to its developmental stage, the whole intestine was used, whereas, after the challenge, pyloric caeca and middle and distal intestines were examined. Results and discussion: At the stimulus end, genes with increased expression in V fish enriched pathways including regulatory epigenetic responses and lipid metabolism, and genes involved in innate immune response were downregulated. In the middle intestine at the end of the challenge, expression levels of genes of lipid, carbohydrate, and energy metabolism were increased in V fish, while M fish revealed increased expression of genes associated with autoimmune and acute adaptive immune response. The distal intestine of V fish showed increased expression of genes associated with immune response and potential immune tolerance. Conversely, the distal intestine of M fish at challenge revealed upregulation of lipid and carbohydrate metabolic pathways, tissue degeneration, and apoptotic responses. The present study demonstrated nutritional programming-associated changes in the intestinal transcriptome, with altered expression of genes involved in both immune responses and different metabolic processes. While there were limited changes in growth between the groups, the results show that there were transcriptional differences, suggesting a programming response, although the mechanism of this response still requires to be fully elucidated.

Ready, Set, Grow: From Micelles to Giant Vesicles via Biocatalytic Activation.

Controlling physicochemical processes that drive changes in supramolecular aggregates is an important objective toward creating artificial soft micro- and nanomachines. Previous research explored the morphology control of membrane-based materials subjected to externally imposed chemical stimuli. Here, we modulate the microscale morphology of pH-responsive assemblies by using biocatalysis to internally generate changes in global pH. Catalytic reactions offer flexibility in the mechanism and rate at which stimuli are introduced to responsive assemblies, ultimately enabling precision and control over size and morphology. We observed, by dynamic light scattering and fluorescence microscopy, substantial microscale differences between assemblies subjected to manually titrated pH changes compared to biocatalytically activated pH changes, including the growth of giant vesicles from micelles. Coarse-grained molecular dynamics simulations of these metastable self-assembled structures provided insight into the thermodynamics and kinetics of the preferred structures. These results demonstrate the feasibility of using biocatalytic reactions to modulate the size and morphology of supramolecular assemblies, from micelles to giant vesicles.

The landscape of rare genetic variants in familial Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a rare hematological malignancy. Risk for WM is elevated 20-fold among first-degree relatives of patients with WM. However, the list of variants and genes that cause WM remains incomplete. In this study we analyzed exomes from 64 WM pedigrees for evidence of genetic susceptibility for this malignancy. We determined the frequency of pathogenic (P) or likely pathogenic (LP) variants among patients with WM; performed variant- and gene-level association analyses with the set of 166 WM cases and 681 unaffected controls; and examined the segregation pattern of deleterious variants among affected members in each pedigree. We identified P/LP variants in TREX1 and SAMHD1 (genes that function at the interface between innate immune response, genotoxic surveillance, and DNA repair) segregating in patients with WM from 2 pedigrees. There were additional P/LP variants in cancer-predisposing genes (eg, POT1, RECQL4, PTPN11, PMS2). In variant- and gene-level analyses, no associations were statistically significant after multiple testing correction. On a pathway level, we observed involvement of genes that play a role in telomere maintenance (q-value = 0.02), regulation of innate immune response (q-value = 0.05), and DNA repair (q-value = 0.08). Affected members of each pedigree shared multiple deleterious variants (median, n = 18), but the overlap between the families was modest. In summary, P/LP variants in highly penetrant genes constitute a modest proportion of the deleterious variants; each pedigree is largely unique in its genetic architecture, and multiple genes are likely involved in the etiology of WM.

Detection of antibiotic resistant Enterobacterales in commercial raw pet food: a preliminary study.

Introduction: Raw diets have become popular in companion animal nutrition, but these diets may be contaminated with harmful bacteria because heat processing is not utilized to mitigate pathogens during the production process. We analyzed 24 commercially available frozen raw canine and feline diets for extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E). Methods: Samples were incubated in tryptic soy broth augmented with 50 µg/mL ampicillin to enrich for ESBL-E. ESBL-E were isolated using CHROMagar ESBL plates and isolate identification and antibiotic susceptibility testing were confirmed using the VITEK®2 instrument. Results: ESBL-E were isolated from 42% (10/24) of raw diets, with E. coli, Enterobacter cloacae complex and Klebsiella pneumoniae predominating. Most ESBL-E isolates (71%, 32/45) were multidrug-resistant. Direct plating of samples onto tryptic soy agar yielded bacterial counts >6 log10 for 2 samples from two different manufacturers. Conclusion: This preliminary study justifies further investigation into the potential contribution of raw diets to the dissemination of antibiotic resistant bacteria in companion animals and domestic living spaces.

Inclusion of oil from transgenic Camelina sativa in feed effectively supplies EPA and DHA to Atlantic salmon (Salmo salar) grown to market size in seawater pens.

Atlantic salmon were fed either a diet reflecting current commercial feeds with added oil supplied by a blend of fish oil and rapeseed oil (COM), or a diet formulated with oil from transgenic Camelina sativa containing 20% EPA + DHA (TCO). Salmon were grown from smolt to market size (>3 kg) in sea pens under semi-commercial conditions. There were no differences in growth, feed efficiency or survival between fish fed the TCO or COM diets at the end of the trial. Levels of EPA + DHA in flesh of salmon fed TCO were significantly higher than in fish fed COM. A 140 g fillet from TCO-fed salmon delivered 2.3 g of EPA + DHA, 67% of the weekly requirement level recommended by many health agencies, and 1.5-fold more than the 1.5 g of EPA + DHA for COM-fed fish. Oil from transgenic Camelina supported growth and improved the nutritional quality of farmed salmon in terms of increased "omega-3" supply for human consumers.

High Gastric Cancer Mortality and Years of Life Lost in Nicaragua: A Population-Based Study 1997 - 2012.

BACKGROUND: Gastric adenocarcinoma (GC) is the fourth leading cause of cancer-related mortality, and leading infection-associated cancer. GC has striking geographic variability, with high incidence in East Asia and mountainous Latin America. Reliable cancer data and population-based cancer registries (PBCRs) are lacking for the majority of LMICs, including the Central American Four region (CA-4, Nicaragua, El Salvador, Honduras, and Guatemala). METHODS: Mortality data for Nicaragua were obtained from the highly-rated Ministry of Health death registry. All the patients were diagnosed with gastric cancer between 1997 and 2012 (ICD-10 codes C16.0-C16.9) and death due to any cause were included in the study. Data on variables such as sex, age (stratified by 5-year age groups), municipality, urban/rural, altitude, and year of death were analyzed. RESULTS: A total of 3,886 stomach cancer deaths were reported in Nicaragua between 1997 and 2012, of which 2,214 (56.9%) were male. The ASMR were 13.1 and 8.7 per 100,000 habitants for males and females, respectively, and without significant change during the study period (APC= -0.7, P=0.2). An average of 17.9 years were lost per death (AYLL), accounting for 67,964 years of life lost (YYL). CONCLUSIONS: The burden of gastric cancer mortality is high in Nicaragua with significantly elevated ASMR, YYL, and AYLL. IMPACT: The projected increase in mortality portends the double cancer burden in northern Central America, with persistent infection-associated cancers and growing transition cancers (e.g., breast and colon cancers), which has implications for cancer control in Mesoamerica and U.S. Latino populations.

Vegetable Gardening and Health Outcomes in Older Cancer Survivors: A Randomized Clinical Trial.

Importance: Cancer survivors experience accelerated functional decline that threatens independence and quality of life. Previous studies have suggested that vegetable gardening may improve diet, physical activity, and physical function in this vulnerable population, which comprises more than 5% of the US population. Objective: To assess whether diet, physical activity and functioning, and other outcomes improved in older cancer survivors assigned to a vegetable gardening intervention compared with a waitlist. Design, Setting, and Participants: From May 11, 2016, to May 2, 2022, a 2-arm, assessor-blinded, crossover-designed, intent-to-treat, randomized clinical trial was conducted at cancer survivors' homes across Alabama. Medicare-eligible survivors of cancers with 5-year survival of 60% or more were registry ascertained and screened for suboptimal vegetable and fruit consumption (<5 servings per day), physical activity (<150 moderate-to-vigorous minutes per week), and physical function (36-Item Short Form Health Survey [SF-36] subscale score ≤90). Consented participants underwent baseline assessments, were randomly assigned to intervention or waitlisted arms, and were reassessed at 1-year follow-up. Intervention: One-year, home-based vegetable gardening intervention providing gardening supplies and mentorship by cooperative extension-certified master gardeners to plant and maintain spring, summer, and fall gardens. Waitlisted participants received the identical intervention after 12 months. Main Outcomes and Measures: The main outcome was a composite index of improvements in self-reported vegetable and fruit consumption, physical activity, and physical function corroborated by plasma α-carotene levels, accelerometry, and physical performance assessments, respectively. Results: Of 381 enrolled participants (mean [SD] age, 69.8 [6.4] years; range, 50-95 years; 263 [69.0%] female), 194 were assigned to the gardening intervention and 187 were waitlisted (attrition rates, 7.2% and 7.0%, respectively). Intent-to-treat analyses did not detect a significant improvement in the composite index of vegetable and fruit intake, moderate-vigorous physical activity, and physical function (intervention arm vs waitlisted arm, 4.5% vs 3.1%; P = .53) or between-arm differences in vegetable and fruit intake (mean difference, 0.3 [95% CI, -0.1 to 0.7] servings per day; P = .10). The intervention arm experienced a significant improvement in vegetable and fruit intake (mean increase, 0.3 [95% CI, 0.0-0.6] servings per day; P = .04). Significant improvements also were observed in the intervention arm vs waitlisted arm in physical performance (mean difference for 2-minute step test, 6.0 [95% CI, 0.8-11.2] steps; P = .03; for 30-second chair stand, 0.8 [95% CI, 0.1-1.5] repetitions; P = .02), perceived health (8.4 [95% CI, 3.0-13.9] points on a 100-point scale [higher scores indicate better health]; P = .003), and gut microbiome alpha diversity (84.1 [95% CI, 20.5-147.6] more observed species; P = .01). The COVID-19 pandemic significantly moderated effects (eg, odds of improvement in self-reported physical functioning were greater before vs during the pandemic: odds ratio, 2.17; 95% CI, 1.12-4.22; P = .02). Conclusions and Relevance: In this randomized clinical trial including older cancer survivors, a vegetable gardening intervention did not significantly improve a composite index of diet, physical activity, and physical function; however, survivors assigned to the intervention had significantly increased vegetable and fruit consumption and, compared with waitlisted survivors, experienced significant improvements in perceived health and physical performance. Further study in broader populations and during pandemic-free periods is needed to determine definitive benefits. Trial Registration: ClinicalTrials.gov Identifier: NCT02985411.

Implanted size and structural valve deterioration in the Edwards Magna bioprosthesis.

Background: The desire of patients to avoid anticoagulation, together with the potential of valve-in-valve (VIV) transcatheter aortic valve replacement (TAVR), have resulted in the increasing use of bioprosthetic valves for aortic valve replacement (AVR). While patient-prosthesis mismatch (PPM) is known to be an adverse risk after AVR, few studies have addressed the effect of PPM on valve durability. This study evaluates the role of valve size and hemodynamics on long term durability after AVR with a Magna bioprosthesis. Methods: We performed a retrospective, single-center evaluation of patients who underwent a surgical AVR procedure between June 2004 through December 2022 using the Magna bioprosthesis. Perioperative information and long-term follow-up data were sourced from the institution's Society for Thoracic Surgeons Adult Cardiac Surgery Registry and outcomes database. Cumulative incidence of freedom from reintervention were estimated accounting for competing events. Group comparisons used Gray's test. Results: Among 2,100 patients, the mean patient age was 69 years (range, 22-95 years), of whom 98% had native aortic valve disease, 32.5% had concomitant coronary bypass grafting, and 19% had mitral valve surgery. Median follow-up was 5.8 (1.9-9.4) years, during which 116 reinterventions were performed, including 74 explants and 42 VIV procedures. Nine hundred and twenty-eight patients died prior to reintervention. Incidence of all cause reintervention was 1.2%, 4.5%, and 11.7% at 5, 10, and 15 years, respectively. Smaller valve size was associated with worse survival (P<0.001), but not with reintervention. Higher mean gradient at implant was associated with increased late reintervention [sub-distribution hazard ratio: 1.016; 95% confidence interval (CI): 1.005 to 1.028; P=0.0047, n=1,661]. Conclusions: While reintervention rates are low for the Magna prosthesis at 15 years, the analysis is confounded by the competing risk of death. PPM, as reflected physiologically by elevated post-operative valve gradients, portends an increased risk of intervention. Further study is necessary to elucidate the mechanism of early stenosis in patients who progress to reintervention.

Is it the people or the place? The remarkable 30-year period of integrative physiology research in the Carlson Gymnasium at the University of Colorado Boulder.

Historically, programs of physical education and sport were housed in gymnasium buildings on academic campuses. As physical education evolved to the more scientifically focused successor departments of exercise science and kinesiology, faculty specialization developed in the physiology of exercise. With time, some faculty broadened their research to study the integrative physiology of other biological states and stressors. Through this series of events, a small group of integrative physiologists was formed in the Carlson Gymnasium at the University of Colorado Boulder during the 1990s with the goal of conducting novel biomedical research. The challenges were daunting: no contemporary core laboratory facilities, lack of temperature control, piercing external noise, pests, regular flooding, electrical power outages, and lack of funds for renovation. Despite these obstacles, the group established an innovative program of translational physiological research ranging from high-throughput molecular analyses to cell models to rodent studies to clinical trials in humans. These investigators supported their work with grant awards from the National Institutes of Health (NIH), Department of Defense, National Aeronautics and Space Administration (NASA), American Heart Association, and private research foundations totaling ∼$80 M in direct costs from the late 1980s to 2020. Collectively, the faculty and their laboratory personnel published ∼950 articles in peer-reviewed scientific journals. Over that period, 379 undergraduate students, 340 graduate students, 84 postdoctoral fellows, and dozens of junior research faculty received scientific training in Carlson, supported by >$21 M in extramural funding. What was accomplished by this handful of integrative physiologists speaks to the importance of the qualities of the investigators rather than their research facilities in determining scientific success.

Design and Discovery of a Potent and Selective Inhibitor of Integrin αvß1.

Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.