A new era for understanding amyloid structures and disease.

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-ß structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention.

Earth's evolving geodynamic regime recorded by titanium isotopes.

Earth's mantle has a two-layered structure, with the upper and lower mantle domains separated by a seismic discontinuity at about 660 km (refs. 1,2). The extent of mass transfer between these mantle domains throughout Earth's history is, however, poorly understood. Continental crust extraction results in Ti-stable isotopic fractionation, producing isotopically light melting residues3-7. Mantle recycling of these components can impart Ti isotope variability that is trackable in deep time. We report ultrahigh-precision 49Ti/47Ti ratios for chondrites, ancient terrestrial mantle-derived lavas ranging from 3.8 to 2.0 billion years ago (Ga) and modern ocean island basalts (OIBs). Our new Ti bulk silicate Earth (BSE) estimate based on chondrites is 0.052 ± 0.006‰ heavier than the modern upper mantle sampled by normal mid-ocean ridge basalts (N-MORBs). The 49Ti/47Ti ratio of Earth's upper mantle was chondritic before 3.5 Ga and evolved to a N-MORB-like composition between approximately 3.5 and 2.7 Ga, establishing that more continental crust was extracted during this epoch. The +0.052 ± 0.006‰ offset between BSE and N-MORBs requires that <30% of Earth's mantle equilibrated with recycled crustal material, implying limited mass exchange between the upper and lower mantle and, therefore, preservation of a primordial lower-mantle reservoir for most of Earth's geologic history. Modern OIBs record variable 49Ti/47Ti ratios ranging from chondritic to N-MORBs compositions, indicating continuing disruption of Earth's primordial mantle. Thus, modern-style plate tectonics with high mass transfer between the upper and lower mantle only represents a recent feature of Earth's history.

Social capital I: measurement and associations with economic mobility.

Social capital-the strength of an individual's social network and community-has been identified as a potential determinant of outcomes ranging from education to health1-8. However, efforts to understand what types of social capital matter for these outcomes have been hindered by a lack of social network data. Here, in the first of a pair of papers9, we use data on 21 billion friendships from Facebook to study social capital. We measure and analyse three types of social capital by ZIP (postal) code in the United States: (1) connectedness between different types of people, such as those with low versus high socioeconomic status (SES); (2) social cohesion, such as the extent of cliques in friendship networks; and (3) civic engagement, such as rates of volunteering. These measures vary substantially across areas, but are not highly correlated with each other. We demonstrate the importance of distinguishing these forms of social capital by analysing their associations with economic mobility across areas. The share of high-SES friends among individuals with low SES-which we term economic connectedness-is among the strongest predictors of upward income mobility identified to date10,11. Other social capital measures are not strongly associated with economic mobility. If children with low-SES parents were to grow up in counties with economic connectedness comparable to that of the average child with high-SES parents, their incomes in adulthood would increase by 20% on average. Differences in economic connectedness can explain well-known relationships between upward income mobility and racial segregation, poverty rates, and inequality12-14. To support further research and policy interventions, we publicly release privacy-protected statistics on social capital by ZIP code at https://www.socialcapital.org .

Social capital II: determinants of economic connectedness.

Low levels of social interaction across class lines have generated widespread concern1-4 and are associated with worse outcomes, such as lower rates of upward income mobility4-7. Here we analyse the determinants of cross-class interaction using data from Facebook, building on the analysis in our companion paper7. We show that about half of the social disconnection across socioeconomic lines-measured as the difference in the share of high-socioeconomic status (SES) friends between people with low and high SES-is explained by differences in exposure to people with high SES in groups such as schools and religious organizations. The other half is explained by friending bias-the tendency for people with low SES to befriend people with high SES at lower rates even conditional on exposure. Friending bias is shaped by the structure of the groups in which people interact. For example, friending bias is higher in larger and more diverse groups and lower in religious organizations than in schools and workplaces. Distinguishing exposure from friending bias is helpful for identifying interventions to increase cross-SES friendships (economic connectedness). Using fluctuations in the share of students with high SES across high school cohorts, we show that increases in high-SES exposure lead low-SES people to form more friendships with high-SES people in schools that exhibit low levels of friending bias. Thus, socioeconomic integration can increase economic connectedness in communities in which friending bias is low. By contrast, when friending bias is high, increasing cross-SES interactions among existing members may be necessary to increase economic connectedness. To support such efforts, we release privacy-protected statistics on economic connectedness, exposure and friending bias for each ZIP (postal) code, high school and college in the United States at https://www.socialcapital.org .

Rapid shifting of a deep magmatic source at Fagradalsfjall volcano, Iceland.

Recent Icelandic rifting events have illuminated the roles of centralized crustal magma reservoirs and lateral magma transport1-4, important characteristics of mid-ocean ridge magmatism1,5. A consequence of such shallow crustal processing of magmas4,5 is the overprinting of signatures that trace the origin, evolution and transport of melts in the uppermost mantle and lowermost crust6,7. Here we present unique insights into processes occurring in this zone from integrated petrologic and geochemical studies of the 2021 Fagradalsfjall eruption on the Reykjanes Peninsula in Iceland. Geochemical analyses of basalts erupted during the first 50 days of the eruption, combined with associated gas emissions, reveal direct sourcing from a near-Moho magma storage zone. Geochemical proxies, which signify different mantle compositions and melting conditions, changed at a rate unparalleled for individual basaltic eruptions globally. Initially, the erupted lava was dominated by melts sourced from the shallowest mantle but over the following three weeks became increasingly dominated by magmas generated at a greater depth. This exceptionally rapid trend in erupted compositions provides an unprecedented temporal record of magma mixing that filters the mantle signal, consistent with processing in near-Moho melt lenses containing 107-108 m3 of basaltic magma. Exposing previously inaccessible parts of this key magma processing zone to near-real-time investigations provides new insights into the timescales and operational mode of basaltic magma systems.

A Turing test of whether AI chatbots are behaviorally similar to humans.

We administer a Turing test to AI chatbots. We examine how chatbots behave in a suite of classic behavioral games that are designed to elicit characteristics such as trust, fairness, risk-aversion, cooperation, etc., as well as how they respond to a traditional Big-5 psychological survey that measures personality traits. ChatGPT-4 exhibits behavioral and personality traits that are statistically indistinguishable from a random human from tens of thousands of human subjects from more than 50 countries. Chatbots also modify their behavior based on previous experience and contexts "as if" they were learning from the interactions and change their behavior in response to different framings of the same strategic situation. Their behaviors are often distinct from average and modal human behaviors, in which case they tend to behave on the more altruistic and cooperative end of the distribution. We estimate that they act as if they are maximizing an average of their own and partner's payoffs.

Machine behaviour.

Machines powered by artificial intelligence increasingly mediate our social, cultural, economic and political interactions. Understanding the behaviour of artificial intelligence systems is essential to our ability to control their actions, reap their benefits and minimize their harms. Here we argue that this necessitates a broad scientific research agenda to study machine behaviour that incorporates and expands upon the discipline of computer science and includes insights from across the sciences. We first outline a set of questions that are fundamental to this emerging field and then explore the technical, legal and institutional constraints on the study of machine behaviour.

Learning through the grapevine and the impact of the breadth and depth of social networks.

We study how communication platforms can improve social learning without censoring or fact-checking messages, when they have members who deliberately and/or inadvertently distort information. Message fidelity depends on social network depth (how many times information can be relayed) and breadth (the number of others with whom a typical user shares information). We characterize how the expected number of true minus false messages depends on breadth and depth of the network and the noise structure. Message fidelity can be improved by capping depth or, if that is not possible, limiting breadth, e.g., by capping the number of people to whom someone can forward a given message. Although caps reduce total communication, they increase the fraction of received messages that have traveled shorter distances and have had less opportunity to be altered, thereby increasing the signal-to-noise ratio.

ß-Caryophyllene Inhibits Monoacylglycerol Lipase Activity and Increases 2-Arachidonoyl Glycerol Levels In Vivo: A New Mechanism of Endocannabinoid-Mediated Analgesia?

The mechanisms of ß-caryophyllene (BCP)-induced analgesia are not well studied. Here, we tested the efficacy of BCP in an acute postsurgical pain model and evaluated its effect on the endocannabinoid system. Rats were treated with vehicle and 10, 25, 50, and 75 mg/kg BCP. Paw withdrawal responses to mechanical stimuli were evaluated using an electronic von Frey anesthesiometer. Endocannabinoids, including 2-arachidonoylglycerol (2-AG), were also evaluated in plasma and tissues using high-performance liquid chromatography-tandem mass spectrometry. Monoacylglycerol lipase (MAGL) activity was evaluated in vitro as well as ex vivo. We observed a dose-dependent and time-dependent alleviation of hyperalgesia in incised paws up to 85% of the baseline value at 30 minutes after administration of BCP. We also observed dose-dependent increases in the 2-AG levels of about threefold after administration of BCP as compared with vehicle controls. Incubations of spinal cord tissue homogenates from BCP-treated rats with isotope-labeled 2-arachidonoylglycerol-d8 revealed a reduced formation of the isotope-labeled MAGL product 2-AG-d8 as compared with vehicle controls, indicating MAGL enzyme inhibition. In vitro MAGL enzyme activity assessment using 2-AG as the substrate revealed an IC50 of 15.8 µM for MAGL inhibition using BCP. These data showed that BCP inhibits MAGL activity in vitro and in vivo, causing 2-AG levels to rise. Since the endocannabinoid 2-AG is a CB1 and CB2 receptor agonist, we propose that 2-AG-mediated cannabinoid receptor activation contributes to BCP's mechanism of analgesia. SIGNIFICANCE STATEMENT: ß-Caryophyllene (BCP) consumption is relatively safe and is approved by the Food and Drug Administration as a flavoring agent, which can be used in cosmetic and food additives. BCP is a potent anti-inflammatory agent that showed substantial antihyperalgesic properties in this study of acute pain suggesting that BCP might be an alternative to opioids. This study shows an additive mechanism (monoacylglycerol lipase inhibition) by which BCP might indirectly alter CB1 and CB2 receptor activity and exhibit its pharmacological properties.

Balloon aortic valvuloplasty with or without percutaneous coronary intervention in the TAVR era.

Introduction The role of balloon aortic valvuloplasty (BAV) amid the era of transcatheter aortic valve replacement (TAVR) remains a topic of debate. We sought to study the safety and feasibility of combined balloon aortic valvuloplasty and percutaneous coronary intervention (BAV-PCI). Methods Between November 2009 and July 2020, all patients undergoing BAV were identified and divided into three groups: combined BAV-PCI (group A), BAV with significant unrevascularised CAD (group B) and BAV without significant CAD (group C). Procedural outcomes, 30-day and one-year mortality were compared. Results A total of 264 patients were studied (n = 84, 93 and 87 patients in group A, B and C, respectively). The STS score was 10.2 ±8, 13.3 ±19 and 8.1 ±7, p = 0.026, in group A, B and C, respectively. VARC-3 adjudicated complications were similar among groups (11%, 13% and 5%, respectively, p = 0.168, respectively). Thirty-day and one-year mortality were 9.8% (n =26) and 32% (n = 86) of the entire cohort. The differences among groups did not reach statistical significance. Using univariate Cox regression analysis, group B were at higher risk of dying compared to group A patients (HR 1.58, 95% CI 1.11 - 2.25, p = 0.010). With multivariate Cox regression analysis, the predictors of mortality were STS score, cardiogenic shock, and mode of presentation and lack of subsequent definitive valve intervention. Conclusion In high-risk patients with aortic valve stenosis, combined BAV-PCI is safe and feasible with comparable outcomes to BAV with and without significant CAD.

Remnants of early Earth differentiation in the deepest mantle-derived lavas.

The noble gas isotope systematics of ocean island basalts suggest the existence of primordial mantle signatures in the deep mantle. Yet, the isotopic compositions of lithophile elements (Sr, Nd, Hf) in these lavas require derivation from a mantle source that is geochemically depleted by melt extraction rather than primitive. Here, this apparent contradiction is resolved by employing a compilation of the Sr, Nd, and Hf isotope composition of kimberlites-volcanic rocks that originate at great depth beneath continents. This compilation includes kimberlites as old as 2.06 billion years and shows that kimberlites do not derive from a primitive mantle source but sample the same geochemically depleted component (where geochemical depletion refers to ancient melt extraction) common to most oceanic island basalts, previously called PREMA (prevalent mantle) or FOZO (focal zone). Extrapolation of the Nd and Hf isotopic compositions of the kimberlite source to the age of Earth formation yields a 143Nd/144Nd-176Hf/177Hf composition within error of chondrite meteorites, which include the likely parent bodies of Earth. This supports a hypothesis where the source of kimberlites and ocean island basalts contains a long-lived component that formed by melt extraction from a domain with chondritic 143Nd/144Nd and 176Hf/177Hf shortly after Earth accretion. The geographic distribution of kimberlites containing the PREMA component suggests that these remnants of early Earth differentiation are located in large seismically anomalous regions corresponding to thermochemical piles above the core-mantle boundary. PREMA could have been stored in these structures for most of Earth's history, partially shielded from convective homogenization.

Belief polarization in a complex world: A learning theory perspective.

We present two models of how people form beliefs that are based on machine learning theory. We illustrate how these models give insight into observed human phenomena by showing how polarized beliefs can arise even when people are exposed to almost identical sources of information. In our first model, people form beliefs that are deterministic functions that best fit their past data (training sets). In that model, their inability to form probabilistic beliefs can lead people to have opposing views even if their data are drawn from distributions that only slightly disagree. In the second model, people pay a cost that is increasing in the complexity of the function that represents their beliefs. In this second model, even with large training sets drawn from exactly the same distribution, agents can disagree substantially because they simplify the world along different dimensions. We discuss what these models of belief formation suggest for improving people's accuracy and agreement.

Interacting regional policies in containing a disease.

Regional quarantine policies, in which a portion of a population surrounding infections is locked down, are an important tool to contain disease. However, jurisdictional governments-such as cities, counties, states, and countries-act with minimal coordination across borders. We show that a regional quarantine policy's effectiveness depends on whether 1) the network of interactions satisfies a growth balance condition, 2) infections have a short delay in detection, and 3) the government has control over and knowledge of the necessary parts of the network (no leakage of behaviors). As these conditions generally fail to be satisfied, especially when interactions cross borders, we show that substantial improvements are possible if governments are outward looking and proactive: triggering quarantines in reaction to neighbors' infection rates, in some cases even before infections are detected internally. We also show that even a few lax governments-those that wait for nontrivial internal infection rates before quarantining-impose substantial costs on the whole system. Our results illustrate the importance of understanding contagion across policy borders and offer a starting point in designing proactive policies for decentralized jurisdictions.

Ancient helium and tungsten isotopic signatures preserved in mantle domains least modified by crustal recycling.

Rare high-3He/4He signatures in ocean island basalts (OIB) erupted at volcanic hotspots derive from deep-seated domains preserved in Earth's interior. Only high-3He/4He OIB exhibit anomalous 182W-an isotopic signature inherited during the earliest history of Earth-supporting an ancient origin of high 3He/4He. However, it is not understood why some OIB host anomalous 182W while others do not. We provide geochemical data for the highest-3He/4He lavas from Iceland (up to 42.9 times atmospheric) with anomalous 182W and examine how Sr-Nd-Hf-Pb isotopic variations-useful for tracing subducted, recycled crust-relate to high 3He/4He and anomalous 182W. These data, together with data on global OIB, show that the highest-3He/4He and the largest-magnitude 182W anomalies are found only in geochemically depleted mantle domains-with high 143Nd/144Nd and low 206Pb/204Pb-lacking strong signatures of recycled materials. In contrast, OIB with the strongest signatures associated with recycled materials have low 3He/4He and lack anomalous 182W. These observations provide important clues regarding the survival of the ancient He and W signatures in Earth's mantle. We show that high-3He/4He mantle domains with anomalous 182W have low W and 4He concentrations compared to recycled materials and are therefore highly susceptible to being overprinted with low 3He/4He and normal (not anomalous) 182W characteristic of subducted crust. Thus, high 3He/4He and anomalous 182W are preserved exclusively in mantle domains least modified by recycled crust. This model places the long-term preservation of ancient high 3He/4He and anomalous 182W in the geodynamic context of crustal subduction and recycling and informs on survival of other early-formed heterogeneities in Earth's interior.

Accommodating clinical trials and other externally manufactured cellular therapy products: challenges, lessons learned and creative solutions.

BACKGROUND AIMS: The Division of Transfusion Medicine and Cellular Therapy at New York-Presbyterian/Columbia University Irving Medical Center (NYPH-CUIMC) comprises the immunohematology laboratory and blood bank (transfusion service), hemotherapy/apheresis and the cellular therapy laboratory (CTL). The CTL processes and stores hematopoietic progenitor cells for bone marrow transplantation from all currently acceptable sources, including bone marrow, peripheral blood and umbilical cord blood. The laboratory provides services for the pediatric and adult blood and marrow transplant programs at both NYPH-CUIMC and the Morgan Stanley Children's Hospital of New York-Presbyterian. The laboratory processes and stores approximately 200 cellular therapy products per year, and the division participates in numerous clinical trials within the institution and with external pharmaceutical manufacturing facilities. As a licensed tissue bank, commercial chimeric antigen receptor T-cell products and other cellular-based therapies that are approved by the US Food and Drug Administration (FDA) are routed through the CTL for storage, processing, coordination of transportation, chain of custody and, eventually, thaw and distribution. Currently, we are distributing four such products from Kite Pharma, Novartis and Bristol Meyers Squid. In comparison to the amount of work, we employ a small staff of only four full-time clinical laboratory technologists, one technical specialist, one quality and operations manager and one medical director. In recent years, the growing use of the hematology/oncology service and the introduction of new immunotherapies have put significant pressure on our division to accommodate and scale up operations. Accompanying this growth is a mounting administrative burden and upsurge in regulatory and protocol-specific oversight. The purpose of this article is to share lessons learned and creative solutions to help better accommodate the surge in development of novel cellular therapies. METHODS: To handle this increase in demand, the CTL worked to standardize administrative procedures, implement comprehensive document control solutions, digitize data collection and implement lean design concepts to increase effectiveness and mitigate risk. RESULTS: Distribution of a standard operating procedure for clinical trial management improved the "on-boarding" process and allowed the laboratory to have more influence in the decision-making process. Implementation of digital workflows and a comprehensive document control system allowed for improved organization of critical documents and proved to be flexible enough to accommodate various protocol-specific requirements. Introduction of visual ques and reorganization of the workspace facilitated better organization, mitigated risk and assisted the laboratory in maintaining regulatory compliance. CONCLUSIONS: Better-defined, structured and controlled laboratory processes helped laboratory management implement new clinical trials and track critical data. Implementing digital solutions using widely available tools like Microsoft SharePoint has proven to be a very secure, low-cost and flexible solution to keeping us "up-to-date" and inspection-ready.

Endocannabinoid System in Polycystic Kidney Disease.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder characterized by renal cyst formation. A major pathological feature of ADPKD is the development of interstitial inflammation. The endocannabinoid (EC) system is present in the kidney and has recently emerged as an important player in inflammation and the pathogenesis of progressive kidney disease. METHODS: Data on ECs were collected using a validated mass spectrometry assay from a well-characterized cohort of 102 ADPKD patients (at baseline and after 2- and 4 years on standard vs. rigorous blood-pressure control) and compared to 100 healthy subjects. RESULTS: Compared to healthy individuals, we found higher interleukins-6 and -1b as well as reduced plasma levels of anandamide (AEA), 2-arachidonoyl-glycerol (2-AG), and their congeners in ADPKD patients. Baseline AEA concentration negatively associated with the progression of ADPKD as expressed by the yearly percent change in height-corrected total kidney volume and positively with the yearly change in renal function (measured as estimated glomerular filtration rate, ΔeGFR). AEA analog palmitoylethanolamide (PEA) is also associated positively with the yearly change in eGFR. DISCUSSION AND CONCLUSION: The results of the present study suggest that ADPKD patients present with lower levels of ECs and that reestablishing the normality of the renal EC system via augmentation of AEA, PEA, and 2-AG levels, either through the increase of their synthesis or through a reduction of their degradation, could be beneficial and may present a promising therapeutic target in said patients.

Endocannabinoid system mediates the association between gut-microbial diversity and anhedonia/amotivation in a general population cohort.

Anhedonia and amotivation are debilitating symptoms and represent unmet therapeutic needs in a range of clinical conditions. The gut-microbiome-endocannabinoid axis might represent a potential modifiable target for interventions. Based on results obtained from animal models, we tested the hypothesis that the endocannabinoid system mediates the association between gut-microbiome diversity and anhedonia/amotivation in a general population cohort. We used longitudinal data collected from 786 volunteer twins recruited as part the TwinsUK register. Our hypothesis was tested with a multilevel mediation model using family structure as random intercept. The model was set using alpha diversity (within-individual gut-microbial diversity) as predictor, serum and faecal levels of the endocannabinoid palmitoylethanolamide (PEA) as mediator, and anhedonia/amotivation as outcome. PEA is considered the endogenous equivalent of cannabidiol, with increased serum levels believed to have anti-depressive effects, while increased stool PEA levels, reflecting increased excretion, are believed to have opposite, detrimental, effects on mental health. We therefore expected that either reduced serum PEA or increased stool PEA would mediate the association between microbial diversity and anhedonia amotivation. Analyses were adjusted for obesity, diet, antidepressant use, sociodemographic and technical covariates. Data were imputed using multiple imputation by chained equations. Mean age was 65.2 ± 7.6; 93% of the sample were females. We found a direct, significant, association between alpha diversity and anhedonia/amotivation (ß = -0.37; 95%CI: -0.71 to -0.03; P = 0.03). Faecal, but not serum, levels of the endocannabinoid palmitoylethanolamide (PEA) mediated this association: the indirect effect was significant (ß = -0.13; 95%CI: -0.24 to -0.01; P = 0.03), as was the total effect (ß = -0.38; 95%CI: -0.72 to -0.04; P = 0.03), whereas the direct effect of alpha diversity on anhedonia/amotivation was attenuated fully (ß = -0.25; 95%CI: -0.60 to 0.09; P = 0.16). Our results suggest that gut-microbial diversity might contribute to anhedonia/amotivation via the endocannabinoid system. These findings shed light on the biological underpinnings of anhedonia/amotivation and suggest the gut microbiota-endocannabinoid axis as a promising therapeutic target in an area of unmet clinical need.

Improvement in walking impairment following surgical and endovascular revascularization: Insights from VOYAGER PAD.

BACKGROUND: Peripheral artery disease (PAD) affects 200 million people worldwide and is associated with impaired quality of life, increased morbidity, and mortality. Supervised exercise therapy (SET) and lower-extremity revascularization (LER) are both proven strategies to improve patient symptoms. Short and long-term functional outcomes after LER for symptomatic PAD in a large, international cohort have not previously been described. METHODS: The VOYAGER PAD trial (ClinicalTrials.gov identifier: NCT02504216) enrolled subjects after LER for symptomatic PAD (Rutherford category 2-6). Participants completed the Walking Impairment Questionnaire (WIQ) at baseline, 1, 3 and 6 months, and every 6 months thereafter. The primary outcome analysis was degree of difficulty walking two blocks at each of the aforementioned time points. Difficulty walking three blocks and climbing one flight of stairs at these time points was also analyzed. Data about supervised and home exercise therapy before or after revascularization were not collected in the VOYAGER PAD trial. RESULTS: Of the 5614 VOYAGER PAD participants completing the WIQ at baseline, three-quarters presented with claudication and one-quarter with critical limb ischemia. Of these, the majority (62% with claudication and 74% with CLI) reported inability or much difficulty walking two blocks prior to LER. Walking improved after LER regardless of revascularization strategy, but one-fifth with claudication and one-third with CLI reported continued inability or much difficulty walking two blocks 1 month after LER. Participants who reported improved walking ability 1 month after LER experienced a durable functional result out to 3 years. Although the proportion of participants reporting significant baseline difficulty climbing one flight of stairs or walking three blocks differed, the trend in immediate and sustained improvement after LER was similar to that observed for walking two blocks. CONCLUSION: In this large, international cohort undergoing LER for symptomatic PAD, nearly two-thirds reported inability or much difficulty walking two blocks at baseline. Although many participants reported improved walking ability after LER, a substantial proportion remained severely disabled. These observations may help motivate providers, patients, and medical systems to improve awareness and engagement in SET referral after LER.

A prospective multicenter study of the efficacy of a fiber-supplemented dietary intervention in dogs with chronic large bowel diarrhea.

BACKGROUND: Chronic large bowel diarrhea is common in dogs and can have a significant impact on their overall health and well being. We evaluated the safety and efficacy of a therapeutic food with select dietary plant fibers known to contain antioxidant and polyphenol compounds on clinical signs in dogs with chronic diarrhea. METHODS: A prospective clinical study was conducted in 31 adult dogs currently experiencing chronic diarrhea from private veterinary practices in the United States. Enrolled dogs were switched to a complete and balanced dry therapeutic food containing whole grains and polyphenol-containing fiber sources for 56 days. Veterinarians evaluated changes from baseline in overall clinical signs, recurrence of clinical signs, and stool parameters at Days 2, 3, 4, 28, and 56. Dog owners evaluated stool consistency daily and nausea/vomiting, quality of life (QoL), and stooling behaviors at Days 1, 14, 28, and 56. Statistical analysis was performed using a mixed-effects model with Day as a fixed-effect. RESULTS: Assessments of overall clinical response and stool parameters indicated that diarrhea improved significantly within 1 day of initiating the therapeutic food. Veterinarians reported that 68% of dogs had complete resolution of their clinical signs by Day 56 and the remaining 32% experienced improvement (P < 0.05), with no cases of recurrence. Veterinarians also reported improvement in stool consistency (P < 0.001) and reductions of blood and mucus in stool (P < 0.001). Significant improvements in nausea/vomiting, stooling behaviors, and quality of life (QoL) were reported by dog owners after 28 days and were sustained through day 56 (P < 0.05). The therapeutic food was safe and well tolerated. CONCLUSIONS: In dogs with chronic large bowel diarrhea, the therapeutic food rapidly improved stool consistency, resolved clinical signs, and improved stooling behaviors and QoL. Therapeutic foods supplemented with fiber sources rich in antioxidant and anti-inflammatory compounds contribute to rapid resolution of chronic diarrhea without recurrence and may contribute to long term health.

Microbiome function underpins the efficacy of a fiber-supplemented dietary intervention in dogs with chronic large bowel diarrhea.

BACKGROUND: Chronic large bowel diarrhea is a common occurrence in pet dogs. While nutritional intervention is considered the primary therapy, the metabolic and gut microfloral effects of fiber and polyphenol-enriched therapeutic foods are poorly understood. METHODS: This prospective clinical study enrolled 31 adult dogs from private veterinary practices with chronic, active large bowel diarrhea. Enrolled dogs received a complete and balanced dry therapeutic food containing a proprietary fiber bundle for 56 days. Metagenomic and metabolomic profiling were performed on fecal samples at Days 1, 2, 3, 14, 28, and 56; metabolomic analysis was conducted on serum samples taken at Days 1, 2, 3, 28, and 56. RESULTS: The dietary intervention improved clinical signs and had a clear effect on the gut microfloral metabolic output of canines with chronic diarrhea, shifting gut metabolism from a predominantly proteolytic to saccharolytic fermentative state. Microbial metabolism of tryptophan to beneficial indole postbiotics and the conversion of plant-derived phenolics into bioavailable postbiotics were observed. The intervention altered the endocannabinoid, polyunsaturated fatty acid, and sphingolipid profiles, suggesting a modulation in gastrointestinal inflammation. Changes in membrane phospholipid and collagen signatures were indicative of improved gut function and possible alleviation of the pathophysiology related to chronic diarrhea. CONCLUSIONS: In dogs with chronic diarrhea, feeding specific dietary fibers increased gut saccharolysis and bioavailable phenolic and indole-related compounds, while suppressing putrefaction. These changes were associated with improved markers of gut inflammation and stool quality.