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There is growing evidence that reef-building corals can acclimate to novel and challenging thermal conditions. However, potential trade-offs that accompany acclimation remain largely unexplored. We investigated physiological trade-offs in colonies of a globally abundant coral species (Pocillopora acuta) that were acclimated ex situ to an elevated temperature of 31 °C (i.e., 1 °C above their bleaching threshold) for six years. By comparing them to conspecifics maintained at a cooler temperature, we found that the energy storage of corals was prioritized over skeletal growth at the elevated temperature. This was associated with the formation of higher density skeletons, lower calcification rates and consequently lower skeletal extension rates, which entails ramifications for future reef-building processes, structural complexity and reef community composition. Furthermore, symbionts were physiologically compromised at 31 °C and had overall lower energy reserves, likely due to increased exploitation by their host, resulting in an overall lower stress resilience of the holobiont. Our study shows how biological trade-offs of thermal acclimation unfold, helping to refine our picture of future coral reef trajectories. Importantly, our observations in this six-year study do not align with observations of short-term studies, where elevated temperatures were often associated with the depletion of energy reserves, highlighting the importance of studying acclimation of organisms at relevant biological scales.
Subject(s)
Acclimatization , Anthozoa , Coral Reefs , Anthozoa/physiology , Animals , Acclimatization/physiology , TemperatureABSTRACT
The parenting literature has established the coparenting relationship as central to the parenting behaviors and outcomes of men. The construct of coparenting encompasses supportive efforts among individuals that facilitate the rearing of children and unsupportive actions that can undermine parenting efforts (Merrifield & Gamble, 2013). Few studies have examined undermining coparenting as an experience that shapes Black men's health outcomes. In this study, we apply the social determinants of health framework to examine the impact of Black fathers' perceptions of undermining coparenting on their self-reported ratings of mental and physical health. Using a nationally representative sample of Black men (n = 255), correlational analyses revealed perceptions of undermining coparenting to be a significant predictor of higher levels of anger and poorer perceptions of physical health. These relationships were found to be mediated by depressive symptoms and moderated by restrictive emotionality. It is recommended that the negative impact of undermining coparenting on health be considered as a potential comorbidity contributing to negative health outcomes for Black men. This study adds to the literature on coparenting, Black men's health, and Black fatherhood more generally and urges policymakers and practitioners to consider undermining as an often overlooked, but significant, social determinant of health impacting the well-being of Black men. We also offer recommendations for promoting Black men's health by educating families on the effects of undermining and offering the supports necessary for achieving positive coparenting dynamics.
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The field of microbial pathogenesis seeks to identify the agents and mechanisms responsible for disease causation. Since Robert Koch introduced postulates that were used to guide the characterization of microbial pathogens, technological advances have substantially increased the capacity to rapidly identify a causative infectious agent. Research efforts currently focus on causation at the molecular level with a search for virulence factors (VFs) that contribute to different stages of the infectious process. We note that the quest to identify and characterize VFs sometimes lacks scientific rigor, and this suggests a need to examine the epistemology of VF characterization. We took this premise as an opportunity to explore the epistemology of VF characterization. In this perspective, we discuss how the characterization of various gene products that evolved to facilitate bacterial survival in the broader environment have potentially been prematurely mischaracterized as VFs that contribute to pathogenesis in the context of human biology. Examples of the reasoning that can affect misinterpretation, or at least a premature assignment of mechanistic causation, are provided. Our aim is to refine the categorization of VFs by emphasizing a broader biological view of their origin.
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The effect of dietary macronutrients on fasting and postprandial responses was examined. Thirty-six healthy dogs were fed a high-carbohydrate (HiCHO) food once daily for 5 weeks, followed by randomization to either a high-protein, low-carbohydrate (PROT_LoCHO) or high-fat, low-carbohydrate (FAT_LoCHO) food for 5 weeks, then crossed over to the other LoCHO food for 5 weeks. Plasma samples were obtained at the end of each feeding period at timepoints before (0 h) and 2 h post-feeding. Apparent total circulating energy availability was assessed as a summation of the energetic contributions of measured glucose, ß-hydroxybutyrate, triglycerides (TGs), non-esterified fatty acids (NEFAs), and fatty acids not from TGs or NEFAs. In both the fed and fasted states, there were increases in circulating apparent total energy availability after feeding the FAT_LoCHO food compared with the HiCHO or PROT_LoCHO foods. Changes from the postabsorptive to postprandial points in catabolic, anabolic, and signaling lipids all exhibited food effects. Consumption of either LoCHO food led to lower leptin/ghrelin ratios in the fasted state relative to the HiCHO food. The FAT_LoCHO food led to the highest postprandial levels of the incretins gastric inhibitory peptide and glucagon-like peptide-1, yet the lowest increases in insulin relative to the other foods. These findings provide information on how macronutrients can influence dietary energy processing and metabolic health.
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INTRODUCTION: With the rise of ambulatory surgery centers (ASCs), rapid motor and sensory recovery after anesthesia is crucial. The purpose of this study was to evaluate the safety and efficacy of low-dose single-shot hyperbaric bupivacaine for spinal anesthesia (SA) for patients undergoing outpatient arthroplasty. METHODS: Data were reviewed from a single ASC from 2018 to 2020 for two arthroplasty-trained surgeons for all patients with primary arthroplasties that had administration of low-dose hyperbaric bupivacaine. Data collected from the ASC records were then further evaluated for total spinal block time, length of blockade, time to discharge criteria, visual analog scale (VAS) scores, and time to discharge. RESULTS: Two hundred twenty-seven patients undergoing 244 primary arthroplasties received SA with low-dose hyperbaric bupivacaine. The volume of 0.75% bupivacaine varied: 115 patients received 0.8 mL (6 mg), 111 patients received 1.0 mL (7.5 mg), and 17 patients received 1.2 mL (9 mg). Total SA time averaged 144 minutes with a mean of 30 minutes from post anesthesia care unit arrival to motor recovery. The mean time from post anesthesia care unit arrival to discharge criteria was 89 minutes. The average VAS at discharge was 1.44; the average VAS on POD1 was 3.0. No episodes of urinary retention and no reports of transient neurologic symptoms were noted in the study population. CONCLUSION: Low-dose, single-shot hyperbaric bupivacaine SA is an effective option in the ASC for arthroplasty, providing a fast return of motor function, facilitating rapid discharge, and is safe with a relatively low-risk profile.
Subject(s)
Ambulatory Surgical Procedures , Anesthesia, Spinal , Anesthetics, Local , Bupivacaine , Humans , Bupivacaine/administration & dosage , Anesthesia, Spinal/methods , Anesthetics, Local/administration & dosage , Anesthetics, Local/therapeutic use , Male , Female , Middle Aged , Aged , Arthroplasty , Retrospective Studies , Anesthesia Recovery Period , AdultABSTRACT
Large-scale, explosive volcanic eruptions are one of the Earth's most hazardous natural phenomena. We demonstrate that their size, frequency, and composition can be explained by processes in long-lived, high-crystallinity source reservoirs that control the episodic creation of large volumes of eruptible silicic magma and its delivery to the subvolcanic chamber where it is stored before eruption. Melt percolates upward through the reservoir and accumulates a large volume of low-crystallinity silicic magma which remains trapped until buoyancy causes magma-driven fractures to propagate into the overlying crust, allowing rapid magma transfer from the reservoir into the chamber. Ongoing melt percolation in the reservoir accumulates a new magma layer and the process repeats. Our results suggest that buoyancy, rather than crystallinity, is the key control on magma delivery from the source reservoir. They identify an optimum reservoir size for the largest silicic eruptions that is consistent with data from natural systems and explain why larger magnitude eruptions are not observed on Earth.
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Background: Ketogenic foods limit digestible carbohydrates but contain high fat, and have antioxidant and anti-inflammatory effects as well as improving mitochondrial function. ß-Hydroxybutyrate (BHB), 1 of the ketone bodies, reduces the proinflammatory NLR family pyrin domain containing 3 inflammasomes, as well as chemokines in cultures. Objectives: We assessed the immune-modulating effects of 2 low-carbohydrate (LoCHO) foods varying in protein and fat and compared their effects with a food replete with high-carbohydrate (HiCHO) in healthy canines. Methods: Dogs were fed control food [HiCHO; ketogenic ratio (KR: 0.46) followed by LoCHO_PROT (KR: 0.97), then LoCHO_FAT (KR: 1.63) or LoCHO_FAT followed by LoCHO_PROT. Each food was fed for 5 wk, with collections in the 5th wk; 15 wk feeding total. Gene expression for circulating inflammatory cytokines from 10 dogs was assessed using the Canine RT2 Profiler polymerase chain reaction array, and fold changes were calculated using the ΔΔCt method. Results: LoCHO_FAT significantly increased circulating ß-hydroxybutyrate compared with both HiCHO and LoCHO_PROT. When compared with HiCHO, there was a significant decrease in several proinflammatory cytokines/chemokines in LoCHO_PROT and LoCHO_FAT groups, including chemokine (C-C motif) ligand (CCL)1, CCL8, CCL13, CCL17, CCL24, chemokine (C-X3-C motif) ligand 1, chemokine (C-X-C motif) receptor 1, Interleukin-10 receptor alpha ((IL)-10RA), IL-1 receptor antagonist, IL-5, and secreted phosphoprotein 1 (all P < 0.05). Interestingly, a subset of inflammatory proteins that decreased in LoCHO_PROT but not in LoCHO_FAT included IL-33, IL-6 receptor, IL-7, IL-8, Nicotinamide phosphoribosyltransferase, and tumor necrosis factor (TNF) receptor superfamily member 11B. In contrast, the decrease in inflammatory markers in LoCHO_FAT, but not in LoCHO_PROT, included complement component 5, granulocyte colony-stimulating factor or G-CSF, interferon-γ, IL-3, IL-10RB, IL-17C, Tumor necrosis factor superfamily (TNFSF)13, TNFSF13B, and TNFSF14. Decreased concentrations of selected cytokines indicate that both low-carbohydrate foods exert an anti-inflammatory effect and provide a strong rationale for testing their efficacy in dogs with inflammatory conditions. Conclusions: Both LoCHO_PROT and LoCHO_FAT foods might be important as part of immune-modulating therapeutic nutritional strategies to reduce inflammation to maintain health in canines. Our study identifies several inflammatory genes that are reduced when fed ketogenic food that were not previously reported.
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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.
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OBJECTIVES: Pharmaceutical innovation can contribute to reducing the burden of disease in human populations. This research asks whether products approved by the US Food and Drug Administration (FDA) from 2010 to 2019 and expedited review programmes incentivising development of products for serious disease were aligned with the US or global burden of disease. DESIGN: Cross-sectional study. OUTCOME MEASURES: Association of FDA product approvals (2010-2019), first approved indications, designations for expedited review with the burden of disease (disability-adjusted life years (DALYs)), years of life lost (YLL) and years of life lived with disability (YLD) for 122 WHO Global Health Estimates (GHE) conditions in US and global (ex-US) populations. RESULTS: The FDA approved 387 drugs in 2010-2019 with lead indications associated with 59/122 GHE conditions. Conditions with at least one new drug had greater US DALYs (p=0.001), US YLL (p<0.001), global DALYs (p=0.030) and global YLL (p=0.004) but not US YLD (p=0.158) or global YLD (p=0.676). Most approvals were for conditions in the top quartile of US DALYs or YLL, but <27% were for conditions in the top quartile of global DALYs or YLL. The likelihood of a drug having one or more designations for expedited review programmes was negatively associated (OR<1) with US DALYs, US YLD and global YLD. There was a weak negative association with global DALYs and a weak positive association (OR>1) with US and global YLL. CONCLUSIONS: FDA drug approvals from 2010 to 2019 were more strongly aligned with US than global disease burden. Designations for expedited review were not aligned with either the US or global burdens of disease and may inadvertently disincentivise development of products addressing global disease burdens. These results may inform policies to better align pharmaceutical innovation with the burdens of disease.
Subject(s)
Disabled Persons , Global Burden of Disease , United States , Humans , Cross-Sectional Studies , Quality-Adjusted Life Years , Pharmaceutical Preparations , United States Food and Drug AdministrationABSTRACT
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.
Subject(s)
Artificial Intelligence , Behavior , Humans , Altruism , TrustABSTRACT
A middle-aged man with no previous cardiac history was admitted to the hospital being treated for thigh cellulitis, during his stay he developed palpitations and tachycardia which on initial ECG showed atrial flutter with a 2:1 AV block and evidence of an accessory pathway. He was subsequently given AV nodal blocking agents in the form of beta-blockers (bisoprolol) to slow his heart rate down; unfortunately, this led to hemodynamic instability due to 1:1 conduction of the atrial flutter down the accessory pathway. This case report demonstrates the importance of recognising pre-excitation on an ECG and the potential adverse effect of administering AV nodal blockade.
Subject(s)
Atrial Flutter , Drug-Related Side Effects and Adverse Reactions , Male , Middle Aged , Humans , Atrial Flutter/drug therapy , Heart , Bisoprolol , CellulitisABSTRACT
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.
Subject(s)
Analgesia , Arachidonic Acids , Endocannabinoids , Glycerides , Polycyclic Sesquiterpenes , Animals , Rats , Endocannabinoids/pharmacology , Glycerol , Isotopes , Monoacylglycerol Lipases , Receptor, Cannabinoid, CB2ABSTRACT
Emotional well-being has a known relationship with a person's direct social ties, including friendships; but do ambient social and emotional features of the local community also play a role? This work takes advantage of university students' assignment to different local networks-or "social microclimates"-to probe this question. Using Least Absolute Shrinkage and Selection Operator (LASSO) regression, we quantify the collective impact of individual, social network, and microclimate factors on the emotional well-being of a cohort of first-year college students. Results indicate that well-being tracks individual factors but also myriad social and microclimate factors, reflecting one's peers and social surroundings. Students who belonged to emotionally stable and tight-knit microclimates (i.e., had emotionally stable friends or resided in densely connected residence halls) reported lower levels of psychological distress and higher levels of life satisfaction, even when controlling for factors such as personality and social network size. Although rarely discussed or acknowledged in the policies that create them, social microclimates are consequential to well-being, especially during life transitions. The effects of microclimate factors are small relative to some individual factors; however, they explain unique variance in well-being that is not directly captured by emotional stability or other individual factors. These findings are novel, but preliminary, and should be replicated in new samples and contexts. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Subject(s)
Friends , Microclimate , Humans , Friends/psychology , Personality , Peer GroupABSTRACT
Organ function emerges from the interactions between their constituent cells. The investigation of cellular organization can provide insight into organ function following structure-function relationships. Here, we investigate the extent to which properties in cellular organization can arise "for free" as an emergent property of embedding cells in space versus those that are actively generated by patterning processes. Default cellular configurations were established using three-dimensional (3D) digital tissue models. Network-based analysis of these synthetic cellular assemblies established a quantitative topological baseline of cellular organization, granted by virtue of passive spatial packing and the minimal amount of order that emerges for free in tessellated tissues. A 3D cellular-resolution digital tissue atlas for the model plant species Arabidopsis was generated, and the extent to which the organs in this organism conform to the default configurations was established through statistical comparisons with digital tissue models. Cells in different tissues of Arabidopsis do not conform to random packing arrangements to varying degrees. Most closely matching the random models was the undifferentiated shoot apical meristem (SAM) from which aerial organs emanate. By contrast, leaf and sepal tissue showed the greatest deviation from this baseline, suggesting these to be the most "complex" tissues in Arabidopsis. Investigation of the patterning principles responsible for the gap between these tissues and default patterns revealed cell elongation and the introduction of air spaces to contribute toward additional organ patterning complexity. This work establishes a quantitative morphospace to understand the principles of organ construction and its diversity within a single organism.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis/metabolism , Meristem/metabolism , Arabidopsis Proteins/metabolism , Morphogenesis , Plant Leaves/metabolism , Gene Expression Regulation, PlantABSTRACT
Introduction: The effect of medium-chain fatty acid-containing triglycerides (MCT), long-chain polyunsaturated fatty acid-containing triglycerides from fish oil (FO), and their combination (FO+MCT) on the serum metabolome of dogs (Canis familiaris) was evaluated. Methods: Dogs (N = 64) were randomized to either a control food, one with 7% MCT, one with FO (0.18% eicosapentaenoate and 1.3% docosahexaenoate), or one with FO+MCT for 28 days following a 14-day washout period on the control food. Serum metabolites were analyzed via chromatography followed by mass spectrometry. Results: Additive effects of serum metabolites were observed for a number of metabolite classes, including fatty acids, phospholipids, acylated amines including endocannabinoids, alpha-oxidized fatty acids, and methyl donors. Some effects of the addition of FO+MCT were different when the oils were combined compared with when each oil was fed separately, namely for acylcarnitines, omega-oxidized dicarboxylic acids, and amino acids. Several potentially beneficial effects on health were observed, including decreased circulating triglycerides and total cholesterol with the addition of FO (with or without MCT) and decreases in N-acyl taurines with the addition of MCT, FO, or FO+MCT. Discussion: Overall, the results of this study provide a phenotypic characterization of the serum lipidomic response to dietary supplementation of long-chain n3-polyunsaturated and medium-chain saturated fats in canines.
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Despite the broad range of interest and applications, controls on the surface charge of crude oil in aqueous solution remain poorly understood. The primary data source to understand the surface charge on crude oil comprises measurements of zeta potential on individual drops or emulsions obtained using the electrophoretic method (EPM). Here we (i) collate and review previous measurements of zeta potential on crude oil, (ii) compare and contrast the results, and (iii) report new measurements of zeta potential on crude oil wetting films and layers relevant to oil-saturated porous media, obtained using the streaming potential method (SPM). Results show that the zeta potential depends on electrolyte pH and the concentration of divalent ions Ca2+ and Mg2+. Lower pH and higher concentration of these divalent ions yields more positive zeta potential. The isoelectric point (IEP) in simple NaCl electrolytes lies in the pH range 3-5. The IEP in simple CaCl2 and MgCl2 electrolytes can be expressed as pCa or pMg, respectively, and lies in the range 0-1. Close to the IEP, the zeta potential varies linearly with pH, pCa or pMg, suggesting simple Nernstian behaviour of the crude oil surface. The sensitivity of the zeta potential to pH, pCa and pMg decreases with increasing total ionic strength. The impact of pH, pCa and pMg on zeta potential varies significantly across different crude oils and differs from non-polar hydrocarbons. The potential for other multivalent ions to modify crude oil zeta potential has not been tested. Data for crude oil wetting films and layers, obtained using the SPM and strongly oil-wet porous substrates in which the solid surfaces are coated with the crude oil of interest, are comparable to those obtained using emulsions and the EPM, suggesting that the controls on zeta potential on crude oil are the same irrespective of whether the oil forms droplets or wetting layers. The literature data reviewed here, along with new measured data, provide important insight into the effect of pH, and the concentration of divalent ions, on the zeta potential of crude oil in aqueous solution. They demonstrate relationships between ion concentration and zeta potential that are observed irrespective of crude oil composition. They also show that the crude oil composition plays a role, yet no consistent trends are observed between zeta potential and commonly measured bulk oil properties, possibly because bulk properties do not reflect the concentrations of interfacially active species in crude oil that may impact the development of surface charge. Moreover, data are extremely scarce for complex, high ionic strength electrolytes or at elevated temperature. The data reviewed and reported here have broad relevance to many engineering and industrial activities involving crude oil.
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Importance: The launch of the Advanced Research Projects Agency for Health to advance new cures and address public concern regarding drug prices has raised questions about the roles of government and industry in drug development. Objectives: To compare National Institutes of Health (NIH) spending on phased clinical development of approved drugs with that by industry. Design: This cross-sectional study examined NIH funding for published research reporting the results of phased clinical trials of drugs approved between 2010 and 2019 and compared the findings with reported industry spending estimates. Data analysis was performed between May 2021 and August 2022 using PubMed data from January 1999 through October 2021 and NIH Research Portfolio Online Reporting Tools Expenditures and Results data from January 1999 through December 2020. Exposures: Drugs approved between 2010 and 2019. Main Outcome and Measures: National Institutes of Health funding for published research describing applied research on approved drugs, basic research on their biological targets, and phased clinical trials related to drugs approved between 2010 and 2019 were evaluated using Mann-Whitney U tests. All costs were inflation adjusted to 2018. Results: National Institutes of Health funding for basic or applied research related to 386 of 387 drugs approved between 2010 and 2019 totaled $247.3 billion. Of this amount, $8.1 billion (3.3%) was related to phased clinical development. This funding contributed to 12â¯340 publications on phased clinical trial results involving 240 of 387 (62.0%) drugs. Average NIH spending was $33.8 million per drug, including $13.9 million per drug for phase 1, $22.2 million per drug for phase 2, and $12.9 million per drug for phase 3 trials. Spending by NIH on phased development represented 9.8% to 10.7% of estimated industry spending, including 24.6% to 25.3% of estimated phase 1, 21.4% to 23.2% of phase 2, and 3.7% to 4.3% of phase 3 costs. Considering 60 products for which estimated industry costs were publicly available, NIH spending on clinical trials was significantly lower than estimated industry spending (sum of averages, $54.9 million per drug; mean difference, $326.0 million; 95% CI, $235.6-$416.4 million; 2-tailed paired t test P < .001). More than 90% of NIH funding came through cooperative agreements or program projects and centers, while 3.3% of NIH funding came through investigator-initiated research projects. Conclusions and Relevance: In this cross-sectional study, NIH funding for phased clinical development of drugs approved between 2010 and 2019 represented a small fraction of NIH spending on pharmaceutical innovation. This spending focused primarily on early-phase clinical trials and research capacity and was significantly less than estimated industry spending on clinical development. These results may inform the efficient allocation of government funding to advance pharmaceutical innovation.
Subject(s)
Drug Development , National Institutes of Health (U.S.) , United States , Humans , Cross-Sectional Studies , Research Personnel , Pharmaceutical PreparationsABSTRACT
Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis.
Subject(s)
Arthritis, Rheumatoid , Gastrointestinal Microbiome , Microbiota , Humans , Gastrointestinal Microbiome/genetics , Inflammation , Phenotype , Metabolic Networks and PathwaysABSTRACT
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.
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Importance: Government and the pharmaceutical industry make substantive contributions to pharmaceutical innovation. This study compared the investments by the National Institutes of Health (NIH) and industry and estimated the cost basis for assessing the balance of social and private returns. Objectives: To compare NIH and industry investments in recent drug approvals. Design, Setting, and Participants: This cross-sectional study of NIH funding associated with drugs approved by the FDA from 2010 to 2019 was conducted from May 2020 to July 2022 and accounted for basic and applied research, failed clinical candidates, and discount rates for government spending compared with analogous estimates of industry investment. Main Outcomes and Measures: Costs from the NIH for research associated with drug approvals. Results: Funding from the NIH was contributed to 354 of 356 drugs (99.4%) approved from 2010 to 2019 totaling $187 billion, with a mean (SD) $1344.6 ($1433.1) million per target for basic research on drug targets and $51.8 ($96.8) million per drug for applied research on products. Including costs for failed clinical candidates, mean (SD) NIH costs were $1441.5 ($1372.0) million per approval or $1730.3 ($1657.6) million per approval, estimated with a 3% discount rate. The mean (SD) NIH spending was $2956.0 ($3106.3) million per approval with a 10.5% cost of capital, which estimates the cost savings to industry from NIH spending. Spending and approval by NIH for 81 first-to-target drugs was greater than reported industry spending on 63 drugs approved from 2010 to 2019 (difference, -$1998.4 million; 95% CI, -$3302.1 million to -$694.6 million; P = .003). Spending from the NIH was not less than industry spending considering clinical failures, a 3% discount rate for NIH spending, and a 10.5% cost of capital for the industry (difference, -$1435.3 million; 95% CI, -$3114.6 million to $244.0 million; P = .09) or when industry spending included prehuman research (difference, -$1394.8 million; 95% CI, -$3774.8 million to $985.2 million; P = .25). Accounting for spillovers of NIH-funded basic research on drug targets to multiple products, NIH costs were $711.3 million with a 3% discount rate, which was less than the range of reported industry costs with 10.5% cost of capital. Conclusions and Relevance: The results of this cross-sectional study found that NIH investment in drugs approved from 2010 to 2019 was not less than investment by the pharmaceutical industry, with comparable accounting for basic and applied research, failed clinical trials, and cost of capital or discount rates. The relative scale of NIH and industry investment may provide a cost basis for calibrating the balance of social and private returns from investments in pharmaceutical innovation.