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This paper is concerned with five integral inequalities considered as generalisations of an inequality first discovered by G.H. Hardy and J.E. Littlewood in 1932. Subsequently the inequality was considered in greater detail in the now classic text Inequalities of 1934, written by Hardy and Littlewood together with G. Pólya. All these inequalities involve Lebesgue square-integrable functions, together with their first two derivatives, integrated over the positive half-line of the real field. The method to discuss the analytical properties of these inequalities is based on the Sturm–Liouville theory of the underlying second-order differential equation, and the associated Titchmarsh–Weyl -coefficient. The five examples are specially chosen so that the corresponding Sturm–Liouville differential equations have solutions in the domain of special functions; in the case of these examples the functions involved are those named as the Airy, Bessel, Gamma and the Weber parabolic cylinder functions. The extensive range of known properties of these functions enables explicit analysis of some of the analytical problems to give definite results in the examples of this paper. The analytical problems are "hard" in the technical sense and some of them remain unsolved; this position leads to the statement in the paper of a number of conjectures. In recent years the difficulties involved in the analysis of these problems led to a numerical approach and this method has been remarkably successful. Although such methods, involving standard error analysis and the inevitable introduction of round-off error, cannot by their nature provide analytical proofs; nevertheless the now established record of success of these numerical methods in predicting correct analytical results lends authority to the correctness of the conjectures made in this paper.

Field epidemiology training programs have been successful models to address a country's needs for a skilled public health workforce, partly due to their responsiveness to the countries' unique needs. The Centers for Disease Control and Prevention has partnered with ministries of health to strengthen their workforce through customized competency-based training programs. While desirable, emphasis on program flexibility can result in redundancy and inconsistency. To address this challenge, the ADDIE model (analysis, design, development, implementation, and evaluation) of instructional design was used by a cross-functional team to guide completion of a standard curriculum based on 15 competencies. The standard curriculum has supported the development and expansion of programs while still allowing for adaptation. This article describes the process that was used to develop the curriculum, which, together with needs assessment and evaluation, is crucial for successful training programs. [ABSTRACT FROM AUTHOR]

A theory is developed for the scattering of electromagnetic waves by a perfectly conducting axisymmetric body. It is illustrated by investigating the scatter due to a circular rod with tapered ends, the taper being conical. For a half-wavelength scatterer it is found that the maximum of the scattering coefficient is transferred to an appreciably higher frequency by an increase in taper. When the obstacle is long the pattern of back scatter indicates the presence of a travelling wave for a substantial range of cross-sections provided that the angle of taper is sharp enough. [ABSTRACT FROM AUTHOR]

Determines the electromagnetic field produced by a magnetic dipole in the presence of a perfectly conducting cone of arbitrary cross-section. Electric intensity; Magnetic field; Reflection on a circular cone; Reflection coefficient; Cone behavior during its nearly flat plate condition.

Antiphospholipid syndrome is characterized by a prothrombotic state and the presence of β2 glycoprotein I (β 2-GPI)-dependent antiphospholipid antibodies. The feasibility of a B cell tolerance-based approach for specific reduction of anti-β2 -GPI antibodies was investigated. Anti- β2GPI antibodies isolated from a patient with antiphospholipid syndrome were used to screen peptide libraries expressed in phage, resulting in the identification of a phage that specifically bound anti-β 2-GPI antibodies. The phage-displayed peptide was identified and chemically optimized to generate a synthetic 14-mer peptide with an internal thioether linkage (LJP 685) that retained the binding profile of the original phage. LJP 685 was conjugated to a defined, non-immunogenic organic platform to generate a tetravalent presentation of LJP 685 for use as a toleragen. Tetravalent LJP 685 induced a dose-dependent reduction in antibody levels in mice previously immunized and boosted with LJP 685 coupled to the carrier keyhole limpet hemocyanin. These experiments support the technical feasibility of a tolerance-based approach for reducing anti-β2GPI antibodies in vivo. [ABSTRACT FROM PUBLISHER]

There has been a significant volume of work investigating the design and synthesis of new crystalline multicomponent systems via examining complementary functional groups that can reliably interact through the formation of noncovalent bonds, such as hydrogen bonds (H-bonds). Crystalline multicomponent molecular adducts formed using this approach, such as cocrystals, salts, and eutectics, have emerged as drug product intermediates that can lead to effective drug property modifications. Recent advancement in the production for these multicomponent molecular adducts has moved from batch techniques that rely upon intensive solvent use to those that are solvent-free, continuous, and industry-ready, such as reactive extrusion. In this study, a novel eutectic system was found when processing albendazole and maleic acid at a 1:2 molar ratio and successfully prepared using mechanochemical methods including liquid-assisted grinding and hot-melt reactive extrusion. The produced eutectic was characterized to exhibit a 100 °C reduction in melting temperature and enhanced dissolution performance (>12-fold increase at 2 h point), when compared to the native drug compound. To remove handling of the eutectic as a formulation intermediate, an end-to-end continuous-manufacturing-ready process enables feeding of the raw parent reagents in their respective natural forms along with a chosen polymeric excipient, Eudragit EPO. The formation of the eutectic was confirmed to have taken place in situ in the presence of the polymer, with the reaction yield determined using a multivariate calibration model constructed by combining spectroscopic analysis with partial least-squares regression modeling. The ternary extrudates exhibited a dissolution profile similar to that of the 1:2 prepared eutectic, suggesting a physical distribution (or suspension) of the in situ synthesized eutectic contents within the polymeric matrix.

Therapeutic deep eutectic solvents (THEDES) have been attracting increasing attention in the pharmaceutical literature as a promising enabling technology capable of improving physicochemical and biopharmaceutical properties for difficult-to-deliver drug compounds. The current literature has explored amide local anaesthetics and carboxylic acid nonsteroidal anti-inflammatories (NSAIDs) as commonly used THEDES formers for their active hydrogen-bonding functionality. However, little is known about what happens within the "deep eutectic" region where a range of binary compositions present simply as a liquid with no melting events detectable across experimentally achievable conditions. There is also very limited understanding of how parent compounds' physicochemical properties could impact upon the formation, interaction mechanism, and stability of the formed liquid systems, despite the significance of these information in dose adjustment, industrial handling, and scaling-up of these liquids. In the current work, we probed the "deep eutectic" phenomenon by investigating the formation and physicochemical behaviours of some chosen lidocaine-NSAID systems across a wide range of composition ratios. Our data revealed that successfully formed THEDES exhibited composition dependent T g variations with strong positive deviations from predicted T g values using the Gordon-Taylor theory, suggesting substantial interactions within the formed supramolecular structure. Interestingly, it was found that the parent compound's glass forming ability had a noticeable impact upon such profound interaction and hence could dictate the success of THEDES formation. It has also been confirmed that all successful systems were formed based on charge-assisted hydrogen bonding within their THEDES network, affirming the significant role of partial protonisation on achieving a profound melting point depression. More importantly, the work found that within the "deep eutectic" region there was still an ideal, or thermodynamically preferrable "THEDES point", which would exhibit excellent stability upon exposure to stress storage conditions. The discoveries of this study bring the literature one step closer to fully understanding the "therapeutic deep eutectic" phenomenon. Through correlation between parent reagents' physicochemical properties and the synthesised products' characteristics, we establish a more educated process for the prediction and engineering of THEDES., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Inflorescence architecture is highly variable across plant lineages yet is critical for facilitating reproductive success. The capitulum-type inflorescence of the Asteraceae is marked as a key morphological innovation that preceded the family's diversification and expansion. Despite its evolutionary significance, our understanding of capitulum development and evolution is limited. This review highlights our current perspective on capitulum evolution through the lens of both its molecular and developmental underpinnings. We attempt to summarize our understanding of the capitulum by focusing on two key characteristics: patterning (arrangement of florets on a capitulum) and floret identity specification. Note that these two features are interconnected such that the identity of florets depends on their position along the inflorescence axis. Phytohormones such as auxin seemingly determine both pattern progression and floret identity specification through unknown mechanisms. Floret morphology in a head is controlled by differential expression of floral symmetry genes regulating floret identity specification. We briefly summarize the applicability of the ABCE quartet model of flower development in regulating the floret organ identity of a capitulum in Asteraceae. Overall, there have been promising advancements in our understanding of capitula; however, comprehensive functional genetic analyses are necessary to fully dissect the molecular pathways and mechanisms involved in capitulum development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Understanding the interplay between kinetics and thermodynamics of polymer-mediated liquid-liquid phase separation is crucial for designing and implementing an amorphous solid dispersion formulation strategy for poorly water-soluble drugs. This work investigates the phase behaviors of a poorly water-soluble model drug, celecoxib (CXB), in a supersaturated aqueous solution with and without polymeric additives (PVP, PVPVA, HPMCAS, and HPMCP). Drug-polymer-water ternary phase diagrams were also constructed to estimate the thermodynamic behaviors of the mixtures at room temperature. The liquid-liquid phase separation onset point for CXB was detected using an inline UV/vis spectrometer equipped with a fiber optic probe. Varying CXB concentrations were achieved using an accurate syringe pump throughout this study. The appearance of the transient nanodroplets was verified by cryo-EM and total internal reflection fluoresence microscopic techniques. The impacts of various factors, such as polymer composition, drug stock solution pumping rates, and the types of drug-polymer interactions, are tested against the onset points of the CXB liquid-liquid phase separation (LLPS). It was found that the types of drug-polymer interactions, i.e., hydrogen bonding and hydrophobic interactions, are vital to the position and shapes of LLPS in the supersaturation drug solution. A relation between the behaviors of LLPS and its location in the CXB-polymer-water ternary phase diagram was drawn from the findings.

In 1950, the leaders of independent India celebrated the contributions that surgeons could make to modernising India. Surgeons, however, faced a difficult choice. Some wanted to invest in generalist surgeons to make basic surgical care available to all Indians. Others wanted to invest in specialists to ensure that India participated in cutting-edge surgical research and care. These debates shaped the emergence of cardiac surgery at two centres: the Christian Medical College in Vellore and the King Edward Memorial Hospital in Bombay. CMC invested in thoracic surgery in the 1940s to offer new treatments for tuberculosis. This gave surgeons the opportunity to explore new techniques of cardiac surgery. Debate quickly emerged about whether investments in cardiology and cardiac surgery made sense. In the end, the specialities were supported in order to attract paying patients. A parallel controversy took place at KEM, where the dean debated the Bombay Municipal Corporation about the role of surgical research at a public hospital. The Rockefeller Foundation influenced both sites, offering financial support if they adopted an American model of full-time faculty clinician-researchers. The two case studies reveal how unusual dynamics could contribute to the establishment of new medical specialities in India., (© 2023 Foundation for the Sociology of Health & Illness.)

This introduction to a special section brings together three papers first presented at a panel, 'Medical Professions in South Asia: Historical and Contemporary Analyses', at the 26th European Conference on South Asian Studies, held in Vienna, Austria and online, in July 2021. All three papers deal with aspects of the professionalisation of biomedical doctors in India since its independence in 1947. The authors bring together historical and sociological approaches to illuminate the growth of specialisms, patterns of practitioner-patient interactions and efforts to maintain occupational closure and maintain status in the face of growing challenges. The introduction concludes with a discussion of the relevance of these papers for the sociology of health and illness in India and beyond., (© 2023 The Author. Journal compilation © 2023 Foundation for the Sociology of Health & Illness/Blackwell Publishing Ltd.)

Objectives: To identify and internally validate metabolites predictive of spontaneous preterm birth (sPTB) using multiple machine learning methods and sequential maternal serum samples, and to predict spontaneous early term birth (sETB) using these metabolites., Design: Case-cohort design within a prospective cohort study., Setting: Cambridge, UK., Population or Sample: A total of 399 Pregnancy Outcome Prediction study participants, including 98 cases of sPTB., Methods: An untargeted metabolomic analysis of maternal serum samples at 12, 20, 28 and 36 weeks of gestation was performed. We applied six supervised machine learning methods and a weighted Cox model to measurements at 28 weeks of gestation and sPTB, followed by feature selection. We used logistic regression with elastic net penalty, followed by best subset selection, to reduce the number of predictive metabolites further. We applied coefficients from the chosen models to measurements from different gestational ages to predict sPTB and sETB., Main Outcome Measures: sPTB and sETB., Results: We identified 47 metabolites, mostly lipids, as important predictors of sPTB by two or more methods and 22 were identified by three or more methods. The best 4-predictor model had an optimism-corrected area under the receiver operating characteristics curve (AUC) of 0.703 at 28 weeks of gestation. The model also predicted sPTB in 12-week samples (0.606, 95% CI 0.544-0.667) and 20-week samples (0.657, 95% CI 0.597-0.717) and it predicted sETB in 36-week samples (0.727, 95% CI 0.606-0.849). A lysolipid, 1-palmitoleoyl-GPE (16:1)*, was the strongest predictor of sPTB at 12 weeks of gestation (0.609, 95% CI 0.548-0.670), 20 weeks (0.630, 95% CI 0.569-0.690) and 28 weeks (0.660, 95% CI 0.599-0.722), and of sETB at 36 weeks (0.739, 95% CI 0.618-0.860)., Conclusions: We identified and internally validated maternal serum metabolites predictive of sPTB. A lysolipid, 1-palmitoleoyl-GPE (16:1)*, is a novel predictor of sPTB and sETB. Further validation in external populations is required., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Lehman Caves is an extensively decorated high desert cave that represents one of the main tourist attractions in Great Basin National Park, Nevada. Although traditionally considered a water table cave, recent studies identified abundant speleogenetic features consistent with a hypogenic and, potentially, sulfuric acid origin. Here, we characterized white mineral deposits in the Gypsum Annex (GA) passage to determine whether these secondary deposits represent biogenic minerals formed during sulfuric acid corrosion and explored microbial communities associated with these and other mineral deposits throughout the cave. Powder X-ray diffraction (pXRD), scanning electron microscopy with electron dispersive spectroscopy (SEM-EDS), and electron microprobe analyses (EPMA) showed that, while most white mineral deposits from the GA contain gypsum, they also contain abundant calcite, silica, and other phases. Gypsum and carbonate-associated sulfate isotopic values of these deposits are variable, with δ 34 S V-CDT between +9.7‰ and +26.1‰, and do not reflect depleted values typically associated with replacement gypsum formed during sulfuric acid speleogenesis. Petrographic observations show that the sulfates likely co-precipitated with carbonate and SiO 2 phases. Taken together, these data suggest that the deposits resulted from later-stage meteoric events and not during an initial episode of sulfuric acid speleogenesis. Most sedimentary and mineral deposits in Lehman Caves have very low microbial biomass, with the exception of select areas along the main tour route that have been impacted by tourist traffic. High-throughput 16S rRNA gene amplicon sequencing showed that microbial communities in GA sediments are distinct from those in other parts of the cave. The microbial communities that inhabit these oligotrophic secondary mineral deposits include OTUs related to known ammonia-oxidizing Nitrosococcales and Thaumarchaeota, as well as common soil taxa such as Acidobacteriota and Proteobacteria. This study reveals microbial and mineralogical diversity in a previously understudied cave and expands our understanding of the geomicrobiology of desert hypogene cave systems., (© 2024 John Wiley & Sons Ltd.)

Objective: To determine the inter-relationships between five first-trimester biomarkers (pregnancy associated plasma protein A [PAPP-A], alpha-fetoprotein [AFP], beta human chorionic gonadotrophin [beta-hCG], placenta growth factor [PlGF] and soluble fms-like tyrosine kinase receptor-1 [sFlt-1]) and a range of adverse pregnancy outcomes (APOs)., Design: Prospective cohort study of nulliparous singleton pregnancy., Setting: Cambridge, UK., Population or Sample: 4056 pregnancy outcome prediction study participants., Methods: The biomarker concentrations were measured in maternal serum at ~12 weeks of gestation. Univariable analysis of APOs was performed using logistic regression. Multivariable analysis used best subsets logistic regression with cross-validation., Main Outcome Measures: Pre-eclampsia (PE), small for gestational age (SGA), including severe SGA (birthweight <3rd), fetal growth restriction (FGR), preterm birth (PTB, both induced and spontaneous [iPTB and sPTB, respectively]), pre-viable loss and stillbirth, plus combinations of outcomes., Results: Lower values of PAPP-A, PlGF and sFlt-1 and higher values of AFP were associated with FGR (OR for 1 SD higher value 0.59 [95% CI 0.48-0.74], OR 0.56 [95% CI 0.44-0.70], OR 0.68 [95% CI 0.54-0.87] and OR 1.53 [95% CI 1.25-1.88]), severe SGA (OR 0.59 [95% CI 0.49-0.72], OR 0.71 [95% CI 0.57-0.87], OR 0.74 [95% CI 0.60-0.91] and OR 1.41 [95% CI 1.17-1.71]), sPTB (OR  0.61 [95% CI 0.50-0.73], OR 0.79 [95% CI 0.66-0.96], OR 0.57 [95% CI 0.47-0.70] and OR 1.41 [95% CI 1.18-1.67]) and iPTB (OR  0.72 [95% CI 0.57-0.91], OR 0.62 [95% CI 0.49-0.78], OR 0.71 [95% CI 0.56-0.90] and OR 1.44 [95% CI 1.16-1.78]), respectively. When combinations of biomarkers were assessed, PAPP-A and AFP were independently associated with severe SGA; PAPP-A alone with PE + PTB; PlGF alone with severe PE; PlGF, beta-hCG, AFP and PAPP-A with the combination of PE and SGA; AFP and sFlt-1 with sPTB; and AFP and PlGF with iPTB., Conclusions: Combinations of first-trimester placental biomarkers are associated with APOs. However, the patterns vary for different types of APO, indicating heterogeneity in the underlying pathophysiological pathways., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Fusobacterium nucleatum (Fn), a bacterium present in the human oral cavity and rarely found in the lower gastrointestinal tract of healthy individuals 1 , is enriched in human colorectal cancer (CRC) tumours 2-5 . High intratumoural Fn loads are associated with recurrence, metastases and poorer patient prognosis 5-8 . Here, to delineate Fn genetic factors facilitating tumour colonization, we generated closed genomes for 135 Fn strains; 80 oral strains from individuals without cancer and 55 unique cancer strains cultured from tumours from 51 patients with CRC. Pangenomic analyses identified 483 CRC-enriched genetic factors. Tumour-isolated strains predominantly belong to Fn subspecies animalis (Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (Fna C1 and Fna C2). Of these, only Fna C2 dominates the CRC tumour niche. Inter-Fna analyses identified 195 Fna C2-associated genetic factors consistent with increased metabolic potential and colonization of the gastrointestinal tract. In support of this, Fna C2-treated mice had an increased number of intestinal adenomas and altered metabolites. Microbiome analysis of human tumour tissue from 116 patients with CRC demonstrated Fna C2 enrichment. Comparison of 62 paired specimens showed that only Fna C2 is tumour enriched compared to normal adjacent tissue. This was further supported by metagenomic analysis of stool samples from 627 patients with CRC and 619 healthy individuals. Collectively, our results identify the Fna clade bifurcation, show that specifically Fna C2 drives the reported Fn enrichment in human CRC and reveal the genetic underpinnings of pathoadaptation of Fna C2 to the CRC niche., (© 2024. The Author(s).)

Objective: To improve patient outcomes and promote health equity, medical students must be taught not only biomedicine, but also the social sciences to understand the larger contexts in which patients live and health care operates. Yet, most undergraduate medical education does not explicitly cover these topics in a required, longitudinal curriculum., Methods: In January 2015 at Harvard Medical School, we created a two-part sequence (pre- and post-clerkship) of required, 4-week multidisciplinary courses-"Essentials of the Profession I and II"-to fill this gap. "Essentials of the Profession II (EOP2)" is an advanced social sciences course anchored in patient narratives and the lived experiences of students and includes clinical epidemiology and population health, healthcare delivery and leadership, health policy, medical ethics and professionalism, and social medicine that engages students to conduct structural analyses to be effective healers, advocates, and leaders., Results: Per student course evaluations, the overall course rating was 1.7 (SD 0.9, 1 = excellent and 5 = poor); its overall rating has improved over time; and it has scored well even when run virtually. It was rated highly in application of critical thinking, integration of the disciplines, and relevance for clinical work. Qualitative analyses of student responses revealed the following key course strengths: breadth of topics, teaching faculty and guest speakers, and small group discussions. The weaknesses included workload, lack of diversity of opinions, repetition, and time spent in lectures., Conclusions: We argue that EOP2 is "essential" for post-clerkship medical education. It offers an opportunity to re-ignite and enhance humanism and activism; remind students why they chose the medical profession; equip them with frameworks and toolkits to help them to overcome challenges; and devise solutions to improve health care and patient outcomes that are applicable to their future training and ongoing practice of medicine., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

The study objective was to design and characterise herein unreported polyologels composed of a range of diol and triol solvents and polyvinyl methyl ether-co-maleic acid (PVM/MA) and, determine their potential suitability for the treatment of periodontal and related diseases in the oral cavity using suitable in vitro methodologies. Polyologel flow and viscoelastic properties were controlled by the choice of solvent and the concentration of polymer. At equivalent polymer concentrations, polyologels prepared with glycerol (a triol) exhibited the greatest elasticity and resistance to deformation. Within the diol solvents (PEG 400, pentane 1,5-diol, propane 1,2-diol, propane 1,3-diol, and ethylene glycol), PEG 400 polyologels possessed the greatest elasticity and resistance to deformation, suggesting the importance of distance of separation between the diol groups. Using Raman spectroscopy bond formation between the polymer carbonyl group and the diol hydroxyl groups was observed. Polyologel mucoadhesion was influenced by viscoelasticity; maximum mucoadhesion was shown by glycerol polyologels at the highest polymer concentration (20% w / w ). Similarly, the choice of solvent and concentration of PVM/MA affected the release of tetracycline from the polyologels. The controlled release of tetracycline for at least 10 h was observed for several polyologels, which, in combination with their excellent mucoadhesion and flow properties, offer possibilities for the clinical use of these systems to treat diseases within the oral cavity.

Premise: A family-specific probe set for sunflowers, Compositae-1061, enables family-wide phylogenomic studies and investigations at lower taxonomic levels, but may lack resolution at genus to species levels, especially in groups complicated by polyploidy and hybridization., Methods: We developed a Hyb-Seq probe set, Compositae-ParaLoss-1272, that targets orthologous loci in Asteraceae. We tested its efficiency across the family by simulating target enrichment sequencing in silico. Additionally, we tested its effectiveness at lower taxonomic levels in the historically complex genus Packera . We performed Hyb-Seq with Compositae-ParaLoss-1272 for 19 Packera taxa that were previously studied using Compositae-1061. The resulting sequences from each probe set, plus a combination of both, were used to generate phylogenies, compare topologies, and assess node support., Results: We report that Compositae-ParaLoss-1272 captured loci across all tested Asteraceae members, had less gene tree discordance, and retained longer loci than Compositae-1061. Most notably, Compositae-ParaLoss-1272 recovered substantially fewer paralogous sequences than Compositae-1061, with only ~5% of the recovered loci reporting as paralogous, compared to ~59% with Compositae-1061., Discussion: Given the complexity of plant evolutionary histories, assigning orthology for phylogenomic analyses will continue to be challenging. However, we anticipate Compositae-ParaLoss-1272 will provide improved resolution and utility for studies of complex groups and lower taxonomic levels in the sunflower family., (© 2024 The Authors. Applications in Plant Sciences published by Wiley Periodicals LLC on behalf of Botanical Society of America.)

As global warming became a cause of concern in the 1980s, researchers and climate activists initially paid little attention to the possible health effects of a warmer world. This changed quickly between 1985 and 1989, when scientists working on contracts with the US Department of Energy and the Environmental Protection Agency extrapolated from existing knowledge about the impact of weather on health to speculate about how global warming would impact health. However, they downplayed the impact of their contributions by highlighting the uncertainty in their models and the adaptability of human societies. Since that time, physicians and other health scientists have maintained a steady drumbeat of warnings about the health effects of global warming. They have published widely in the medical literature and participated actively in international scientific collaborations. Their research has significantly increased the breadth and depth of climate-health science and shown that measurable impacts of global warming have already begun. But as the many climate crises of 2023 show, action against global warming remains inadequate. Is it still reasonable to hope that health advocacy will incite communities and politicians to act? The history of climate and health advocacy reveals many obstacles that must be overcome.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking 1-4 . Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with β-thalassaemia, a condition in which GDF15 levels are chronically high 5 , report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG., (© 2023. The Author(s).)

Background: In pregnancy, women are encouraged to cease smoking and limit caffeine intake. We employed objective definitions of smoking and caffeine exposure to assess their association with adverse outcomes., Methods: We conducted a case cohort study within the Pregnancy Outcome Prediction study to analyse maternal serum metabolomics in samples from 12, 20, 28 and 36 weeks of gestational age. Objective smoking status was defined based on detectable cotinine levels at each time point and objective caffeine exposure was based on tertiles of paraxanthine levels at each time point. We used logistic and linear regression to examine the association between cotinine, paraxanthine and the risk of pre-eclampsia, spontaneous pre-term birth (sPTB), fetal growth restriction (FGR), gestational diabetes mellitus and birthweight., Results: There were 914 and 915 women in the smoking and caffeine analyses, respectively. Compared with no exposure to smoking, consistent exposure to smoking was associated with an increased risk of sPTB [adjusted odds ratio (aOR) = 2.58, 95% CI: 1.14 to 5.85)] and FGR (aOR = 4.07, 95% CI: 2.14 to 7.74) and lower birthweight (β = -387 g, 95% CI: -622 g to -153 g). On univariate analysis, consistently high levels of paraxanthine were associated with an increased risk of FGR but that association attenuated when adjusting for maternal characteristics and objective-but not self-reported-smoking status., Conclusions: Based on objective data, consistent exposure to smoking throughout pregnancy was strongly associated with sPTB and FGR. High levels of paraxanthine were not independently associated with any of the studied outcomes and were confounded by smoking., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Epidemiological Association.)