Molecular basis for the initiation of DNA primer synthesis.

During the initiation of DNA replication, oligonucleotide primers are synthesized de novo by primases and are subsequently extended by replicative polymerases to complete genome duplication. The primase-polymerase (Prim-Pol) superfamily is a diverse grouping of primases, which includes replicative primases and CRISPR-associated primase-polymerases (CAPPs) involved in adaptive immunity1-3. Although much is known about the activities of these enzymes, the precise mechanism used by primases to initiate primer synthesis has not been elucidated. Here we identify the molecular bases for the initiation of primer synthesis by CAPP and show that this mechanism is also conserved in replicative primases. The crystal structure of a primer initiation complex reveals how the incoming nucleotides are positioned within the active site, adjacent to metal cofactors and paired to the templating single-stranded DNA strand, before synthesis of the first phosphodiester bond. Furthermore, the structure of a Prim-Pol complex with double-stranded DNA shows how the enzyme subsequently extends primers in a processive polymerase mode. The structural and mechanistic studies presented here establish how Prim-Pol proteins instigate primer synthesis, revealing the requisite molecular determinants for primer synthesis within the catalytic domain. This work also establishes that the catalytic domain of Prim-Pol enzymes, including replicative primases, is sufficient to catalyse primer formation.

Regulation of intestinal immunity and tissue repair by enteric glia.

Tissue maintenance and repair depend on the integrated activity of multiple cell types1. Whereas the contributions of epithelial2,3, immune4,5 and stromal cells6,7 in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here we uncover important roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus leads to enteric gliosis and the upregulation of an interferon gamma (IFNγ) gene signature. IFNγ-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease8. Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFNγ signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ-EGC signalling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths. Mechanistically, we show that the upregulation of Cxcl10 is an early immediate response of EGCs to IFNγ signalling and provide evidence that this chemokine and the downstream amplification of IFNγ signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFNγ signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFNγ-EGC-CXCL10 axis in immune response and tissue repair after infectious challenge.

Rapid Peptide Cyclization Inspired by the Modular Logic of Nonribosomal Peptide Synthetases.

Nonribosomal cyclic peptides (NRcPs) are structurally complex natural products and a vital pool of therapeutics, particularly antibiotics. Their structural diversity arises from the ability of the multidomain enzyme assembly lines, nonribosomal peptide synthetases (NRPSs), to utilize bespoke nonproteinogenic amino acids, modify the linear peptide during elongation, and catalyze an array of cyclization modes, e.g., head to tail, side chain to tail. The study and drug development of NRcPs are often limited by a lack of easy synthetic access to NRcPs and their analogues, with selective macrolactamization being a major bottleneck. Herein, we report a generally applicable chemical macrocyclization method of unprecedented speed and selectivity. Inspired by biosynthetic cyclization, it combines the deprotected linear biosynthetic precursor peptide sequence with a highly reactive C-terminus to produce NRcPs and analogues in minutes. The method was applied to several NRcPs of varying sequences, ring sizes, and cyclization modes including rufomycin, colistin, and gramicidin S with comparable success. We thus demonstrate that the linear order of modules in NRPS enzymes that determines peptide sequence encodes the key structural information to produce peptides conformationally biased toward macrocyclization. To fully exploit this conformational bias synthetically, a highly reactive C-terminal acyl azide is also required, alongside carefully balanced pH and solvent conditions. This allows for consistent, facile cyclization of exceptional speed, selectivity, and atom efficiency. This exciting macrolactamization method represents a new enabling technology for the biosynthetic study of NRcPs and their development as therapeutics.

Adaptive use of error-prone DNA polymerases provides flexibility in genome replication during tumorigenesis.

Human cells possess many different polymerase enzymes, which collaborate in conducting DNA replication and genome maintenance to ensure faithful duplication of genetic material. Each polymerase performs a specialized role, together providing a balance of accuracy and flexibility to the replication process. Perturbed replication increases the requirement for flexibility to ensure duplication of the entire genome. Flexibility is provided via the use of error-prone polymerases, which maintain the progression of challenged DNA replication at the expense of mutagenesis, an enabling characteristic of cancer. This review describes our recent understanding of mechanisms that alter the usage of polymerases during tumorigenesis and examines the implications of this for cell survival and tumor progression. Although expression levels of polymerases are often misregulated in cancers, this does not necessarily alter polymerase usage since an additional regulatory step may govern the use of these enzymes. We therefore also examine how the regulatory mechanisms of DNA polymerases, such as Rad18-mediated PCNA ubiquitylation, may impact the functionalization of error-prone polymerases to tolerate oncogene-induced replication stress. Crucially, it is becoming increasingly evident that cancer cells utilize error-prone polymerases to sustain ongoing replication in response to oncogenic mutations which inactivate key DNA replication and repair pathways, such as BRCA deficiency. This accelerates mutagenesis and confers chemoresistance, but also presents a dependency that can potentially be exploited by therapeutics.

Risk stratification and treatment goals in pulmonary arterial hypertension.

Risk stratification has gained an increasing role in predicting outcomes and guiding the treatment of patients with pulmonary arterial hypertension (PAH). The most predictive prognostic factors are three noninvasive parameters (World Health Organization functional class, 6-min walk distance and natriuretic peptides) that are included in all currently validated risk stratification tools. However, suffering from limitations mainly related to reduced specificity of PAH severity, these variables may not always be adequate in isolation for guiding individualised treatment decisions. Moreover, with effective combination treatment regimens and emerging PAH therapies, markers associated with pulmonary vascular remodelling are expected to become of increasing relevance in guiding the treatment of patients with PAH. While reaching a low mortality risk, assessed with a validated risk tool, remains an important treatment goal, preliminary data suggest that invasive haemodynamics and cardiac imaging may add incremental value in guiding treatment decisions.

In-Hospital Violence and Its Impact on Critical Care Practitioners.

OBJECTIVES: To provide a narrative review of hospital violence (HV) and its impact on critical care clinicians. DATA SOURCES: Detailed search strategy using PubMed and OVID Medline for English language articles describing HV, risk factors, precipitating events, consequences, and mitigation strategies. STUDY SELECTION: Studies that specifically addressed HV involving critical care medicine clinicians or their practice settings were selected. The time frame was limited to the last 15 years to enhance relevance to current practice. DATA EXTRACTION: Relevant descriptions or studies were reviewed, and abstracted data were parsed by setting, clinician type, location, social media events, impact, outcomes, and responses (agency, facility, health system, individual). DATA SYNTHESIS: HV is globally prevalent, especially in complex care environments, and correlates with a variety of factors including ICU stay duration, conflict, and has recently expanded to out-of-hospital occurrences; online violence as well as stalking is increasingly prevalent. An overlap with violent extremism and terrorism that impacts healthcare facilities and clinicians is similarly relevant. A number of approaches can reduce HV occurrence including, most notably, conflict management training, communication initiatives, and visitor flow and access management practices. Rescue training for HV occurrences seems prudent. CONCLUSIONS: HV is a global problem that impacts clinicians and imperils patient care. Specific initiatives to reduce HV drivers include individual training and system-wide adaptations. Future methods to identify potential perpetrators may leverage machine learning/augmented intelligence approaches.

Feasible Route to High-Temperature Ambient-Pressure Hydride Superconductivity.

A key challenge in materials discovery is to find high-temperature superconductors. Hydrogen and hydride materials have long been considered promising materials displaying conventional phonon-mediated superconductivity. However, the high pressures required to stabilize these materials have restricted their application. Here, we present results from high-throughput computation, considering a wide range of high-symmetry ternary hydrides from across the periodic table at ambient pressure. This large composition space is then reduced by considering thermodynamic, dynamic, and magnetic stability before direct estimations of the superconducting critical temperature. This approach has revealed a metastable ambient-pressure hydride superconductor, Mg_{2}IrH_{6}, with a predicted critical temperature of 160 K, comparable to the highest temperature superconducting cuprates. We propose a synthesis route via a structurally related insulator, Mg_{2}IrH_{7}, which is thermodynamically stable above 15 GPa, and discuss the potential challenges in doing so.

Myths and Methodologies: Standardisation in human physiology research-should we control the controllables?

The premise of research in human physiology is to explore a multifaceted system whilst identifying one or a few outcomes of interest. Therefore, the control of potentially confounding variables requires careful thought regarding the extent of control and complexity of standardisation. One common factor to control prior to testing is diet, as food and fluid provision may deviate from participants' habitual diets, yet a self-report and replication method can be flawed by under-reporting. Researchers may also need to consider standardisation of physical activity, whether it be through familiarisation trials, wash-out periods, or guidance on levels of physical activity to be achieved before trials. In terms of pharmacological agents, the ethical implications of standardisation require researchers to carefully consider how medications, caffeine consumption and oral contraceptive prescriptions may affect the study. For research in females, it should be considered whether standardisation between- or within-participants in regards to menstrual cycle phase is most relevant. The timing of measurements relative to various other daily events is relevant to all physiological research and so it can be important to standardise when measurements are made. This review summarises the areas of standardisation which we hope will be considered useful to anyone involved in human physiology research, including when and how one can apply standardisation to various contexts.

What's new in whole blood resuscitation? In the trauma bay and beyond.

PURPOSE OF REVIEW: Transfusion therapy commonly supports patient care during life-threatening injury and critical illness. Herein we examine the recent resurgence of whole blood (WB) resuscitation for patients in hemorrhagic shock following trauma and other causes of severe bleeding. RECENT FINDINGS: A growing body of literature supports the use of various forms of WB for hemostatic resuscitation in military and civilian trauma practice. Different types of WB include warm fresh whole blood (FWB) principally used in the military and low titer O cold stored whole blood (LTOWB) used in a variety of military and civilian settings. Incorporating WB initial resuscitation alongside subsequent component therapy reduces aggregate blood product utilization and improves early mortality without adversely impacting intensive care unit length of stay or infection rate. Applications outside the trauma bay include prehospital WB and use in patients with nontraumatic hemorrhagic shock. SUMMARY: Whole blood may be transfused as FWB or LTOWB to support a hemostatic approach to hemorrhagic shock management. Although the bulk of WB resuscitation literature has appropriately focused on hemorrhagic shock following injury, extension to other etiologies of severe hemorrhage will benefit from focused inquiry to address cost, efficacy, approach, and patient-centered outcomes.

Substrate-induced strain in molybdenum disulfide grown by aerosol-assisted chemical vapor deposition.

Transition metal dichalcogenides have been extensively studied in recent years because of their fascinating optical, electrical, and catalytic properties. However, low-cost, scalable production remains a challenge. Aerosol-assisted chemical vapor deposition (AACVD) provides a new method for scalable thin film growth. In this study, we demonstrate the growth of molybdenum disulfide (MoS2) thin films using AACVD method. This method proves its suitability for low-temperature growth of MoS2thin films on various substrates, such as glass, silicon dioxide, quartz, silicon, hexagonal boron nitride, and highly ordered pyrolytic graphite. The as-grown MoS2shows evidence of substrate-induced strain. The type of strain and the morphology of the as-grown MoS2highly depend on the growth substrate's surface roughness, crystallinity, and chemical reactivity. Moreover, the as-grown MoS2shows the presence of both direct and indirect band gaps, suitable for exploitation in future electronics and optoelectronics.

Iterative assessment of a sports rehydration beverage containing a novel amino acid formula on water uptake kinetics.

PURPOSE: Rapid gastric emptying and intestinal absorption of beverages is essential for rapid rehydration, and certain amino acids (AA) may augment fluid delivery. Three sugar-free beverages, containing differing AA concentrations (AA + PZ), were assessed for fluid absorption kinetics against commercial sugar-free (PZ, GZ) and carbohydrate-containing (GTQ) beverages. METHODS: Healthy individuals (n = 15-17 per study) completed three randomised trials. Three beverages (550-600 mL) were ingested in each study (Study 1: AA + PZ [17.51 g/L AA], PZ, GZ; Study 2: AA + PZ [6.96 g/L AA], PZ, GZ; Study 3: AA + PZ [3.48 g/L AA], PZ, GTQ), containing 3.000 g deuterium oxide (D2O). Blood samples were collected pre-, 2-min, 5-min, and every 5-min until 60-min post-ingestion to quantify maximal D2O enrichment (Cmax), time Cmax occurred (Tmax) and area under the curve (AUC). RESULTS: Study 1: AUC (AA + PZ: 15,184 ± 3532 δ‰ vs. VSMOW; PZ: 17,328 ± 3153 δ‰ vs. VSMOW; GZ: 17,749 ± 4204 δ‰ vs. VSMOW; P ≤ 0.006) and Tmax (P ≤ 0.005) were lower for AA + PZ vs. PZ/GZ. Study 2: D2O enrichment characteristics were not different amongst beverages (P ≥ 0.338). Study 3: Cmax (AA + PZ: 440 ± 94 δ‰ vs. VSMOW; PZ: 429 ± 83 δ‰ vs. VSMOW; GTQ: 398 ± 81 δ‰ vs. VSMOW) was greater (P = 0.046) for AA + PZ than GTQ, with no other differences (P ≥ 0.106). CONCLUSION: The addition of small amounts of AA (3.48 g/L) to a sugar-free beverage increased fluid delivery to the circulation compared to a carbohydrate-based beverage, but greater amounts (17.51 g/L) delayed delivery.

Towards a unified carbon accounting landscape.

The overarching purpose of carbon accounting is to reduce carbon emissions to meet net-zero targets and minimize the impact of climate change. However, the plethora of methods and approaches used means that products and systems sometimes cannot easily be compared. The mix of regional and life cycle-based systems can mean that we lack global oversight of our emissions and impact. In some situations where a regional approach is used, industry/business/regions are incentivized to reduce their own/territorial emissions, which can mean that an optimal global solution is not adopted. Countries where grid emissions are higher can be selected for production because it reduces regional (not global) carbon levels. Furthermore, these can be areas where the climate impact may be felt the most: not the just transition we aspire to. Our work provides an analysis of the current system together with its challenges and limitations, paving the way towards a more unified framework to create climate justice together with transparent and comparable accounting methodology for industry and regions alike. This article is part of the discussion meeting issue 'Green carbon for the chemical industry of the future'.

Observation of metastable structures of the ethylene glycol-water dimer in helium nanodroplets.

Ethylene glycol (EG) is the simplest organic diol. Here we measure infrared spectra of the EG monomer and its dimer with water, the complex, EG(H2O), embedded in superfluid helium nanodroplets. For the monomer, only a single, gauche, conformation is observed. For EG(H2O), no trace of the global energy minimum is seen, a structure that would maximize the hydrogen bonding contacts. Instead, only metastable structures are formed, suggesting that dimerization in a superfluid environment leads to kinetic trapping in local energy minima. In addition, we obtain evidence for a dimer where the conformation of EG switches from gauche to trans on account of dimerization with a water molecule. This observation is assumed to be driven over an energy barrier by utilizing the energy released as hydrogen bonding occurs.

Diagnostic Approach to Interstitial Lung Diseases Associated with Connective Tissue Diseases.

Interstitial lung disorders are a group of respiratory diseases characterized by interstitial compartment infiltration, varying degrees of infiltration, and fibrosis, with or without small airway involvement. Although some are idiopathic (e.g., idiopathic pulmonary fibrosis, idiopathic interstitial pneumonias, and sarcoidosis), the great majority have an underlying etiology, such as systemic autoimmune rheumatic disease (SARD, also called Connective Tissue Diseases or CTD), inhalational exposure to organic matter, medications, and rarely, genetic disorders. This review focuses on diagnostic approaches in interstitial lung diseases associated with SARDs. To make an accurate diagnosis, a multidisciplinary, personalized approach is required, with input from various specialties, including pulmonary, rheumatology, radiology, and pathology, to reach a consensus. In a minority of patients, a definitive diagnosis cannot be established. Their clinical presentations and prognosis can be variable even within subsets of SARDs.

Teaching Airway Management Using Virtual Reality: A Scoping Review.

Airway management, a defined procedural and cognitive skillset embracing routine tracheal intubation and emergency airway rescue, is most often acquired through an apprenticeship model of opportunistic learning during anesthesia or acute care residency training. This training engages a host of modalities to teach and embed skill sets but is generally time- and location-constrained. Virtual reality (VR)-based simulation training offers the potential for reproducible and asynchronous skill acquisition and maintenance, an advantage that may be important with restricted trainee work hours and low frequency but high-risk events. In the absence of a formal curriculum from training bodies-or expert guidance from medical professional societies-local initiatives have filled the VR training void in an unstructured fashion. We undertook a scoping review to explore current VR-based airway management training programs to assess their approach, outcomes, and technologies to discover programming gaps. English-language publications addressing any aspect of VR simulation training for airway management were identified across PubMed, Embase, and Scopus. Relevant articles were used to craft a scoping review conforming to the Scale for quality Assessment of Narrative Review Articles (SANRA) best-practice guidance. Fifteen studies described VR simulation programs to teach airway management skills, including flexible fibreoptic bronchoscopic intubation (n = 10), direct laryngoscopy (n = 2), and emergency cricothyroidotomy (n = 1). All studies were single institution initiatives and all reported different protocols and end points using bespoke applications of commercial technology or homegrown technologic solutions. VR-based simulation for airway management currently occurs outside of a formal curriculum structure, only for specific skill sets, and without a training pathway for educators. Medical educators with simulation training and medical professional societies with content expertise have the opportunity to develop consensus guidelines that inform training curricula as well as specialty technology use.

Circulating microRNAs associated with bronchodilator response in childhood asthma.

BACKGROUND: Bronchodilator response (BDR) is a measure of improvement in airway smooth muscle tone, inhibition of liquid accumulation and mucus section into the lumen in response to short-acting beta-2 agonists that varies among asthmatic patients. MicroRNAs (miRNAs) are well-known post-translational regulators. Identifying miRNAs associated with BDR could lead to a better understanding of the underlying complex pathophysiology. OBJECTIVE: The purpose of this study is to identify circulating miRNAs associated with bronchodilator response in asthma and decipher possible mechanism of bronchodilator response variation. METHODS: We used available small RNA sequencing on blood serum from 1,134 asthmatic children aged 6 to 14 years who participated in the Genetics of Asthma in Costa Rica Study (GACRS). We filtered the participants into the highest and lowest bronchodilator response (BDR) quartiles and used DeSeq2 to identify miRNAs with differential expression (DE) in high (N = 277) vs. low (N = 278) BDR group. Replication was carried out in the Leukotriene modifier Or Corticosteroids or Corticosteroid-Salmeterol trial (LOCCS), an adult asthma cohort. The putative target genes of DE miRNAs were identified, and pathway enrichment analysis was performed. RESULTS: We identified 10 down-regulated miRNAs having odds ratios (OR) between 0.37 and 0.76 for a doubling of miRNA counts and one up-regulated miRNA (OR = 2.26) between high and low BDR group. These were assessed for replication in the LOCCS cohort, where two miRNAs (miR-200b-3p and miR-1246) were associated. Further, functional annotation of 11 DE miRNAs were performed as well as of two replicated miRs. Target genes of these miRs were enriched in regulation of cholesterol biosynthesis by SREBPs, ESR-mediated signaling, G1/S transition, RHO GTPase cycle, and signaling by TGFB family pathways. CONCLUSION: MiRNAs miR-1246 and miR-200b-3p are associated with both childhood and adult asthma BDR. Our findings add to the growing body of evidence that miRNAs play a significant role in the difference of asthma treatment response among patients as it points to genomic regulatory machinery underlying difference in bronchodilator response among patients. TRIAL REGISTRATION: LOCCS cohort [ClinicalTrials.gov number NCT00156819, Registration date 20050912], GACRS cohort [ClinicalTrials.gov number NCT00021840].

Hypohydration induced by prolonged cycling in the heat increases biomarkers of renal injury in males.

PURPOSE: Recent studies have shown that hypohydration can increase renal injury. However, the contribution of hypohydration to the extent of renal injury is often confounded by exercise induced muscle damage. Therefore, the aim of the present study was to investigate the effect of manipulating hydration status during moderate-intensity cycling in the heat on biomarkers of renal injury. METHODS: Following familiarisation, fourteen active males (age: 21 [20-22] y; BMI: 22.1 ± 1.9 kg/m2; V ˙ O2peak: 55 ± 9 mL/kg/min) completed two experimental trials, in a randomised cross-over design. Experimental trials consisted of up to 120 min of intermittent cycling (~ 50% Wpeak) in the heat (~ 35 °C, ~ 50% relative humidity). During exercise, subjects consumed either a water volume equal to 100% body mass losses (EU) or minimal water (HYP; 75-100 mL) to induce ~ 3% body mass loss. Blood and urine samples were collected at baseline, 30 min post-exercise and 24 h post-baseline, with an additional urine sample collected immediately post-exercise. RESULTS: Thirty minutes post-exercise, body mass and plasma volume were lower in HYP than EU (P < 0.001), whereas serum and urine osmolality (P < 0.001), osmolality-corrected urinary kidney injury molecule-1 concentrations (HYP: 2.74 [1.87-5.44] ng/mOsm, EU: 1.15 [0.84-2.37] ng/mOsm; P = 0.024), and percentage change in osmolality-corrected urinary neutrophil gelatinase-associated lipocalin concentrations (HYP: 61 [17-141] %, EU: 7.1 [- 4 to 24] %; P = 0.033) were greater in HYP than EU. CONCLUSION: Hypohydration produced by cycling in the heat increased renal tubular injury, compared to maintaining euhydration with water ingestion.

Fluid and electrolyte balance following consumption of skimmed milk and a plant-based soya beverage at rest in euhydrated males.

PURPOSE: Cow's milk is one of the most hydrating beverages, but many individuals choose not to consume dairy in their diet due to intolerance, allergy, or dietary preference. Milk is commonly replaced with plant-based beverages, including soya which has the most comparable protein content, but little is known about their hydration potential. This study compared fluid and electrolyte balance responses between a soya beverage and skimmed cow's milk. METHODS: Ten healthy males [age 27 (6) y; body mass index 24.6 (2.3) kg/m2] completed two randomised counterbalanced trials, involving consuming 1000 mL water from approximately isocaloric amounts of skimmed cow's milk (MILK) or a sweetened soya beverage (SOYA), in four aliquots over 30 min in a euhydrated fasted state. Volume, specific gravity, and electrolyte (sodium, potassium, chloride) concentrations were determined in total-void urine samples collected pre-/post-beverage ingestion, and hourly for 180 min thereafter. Hunger, thirst, nausea and stomach fullness were rated proximal to urine samples. RESULTS: Total urine mass (MILK, 986 ± 254 g; SOYA, 950 ± 248 g; P = 0.435) and urine specific gravity (P = 0.156) did not differ between trials. Potassium balance was greater in SOYA 0-180 min post-beverage (P ≤ 0.013), whilst chloride balance was greater in MILK 0-120 min post-beverage (P ≤ 0.036). Sodium balance (P = 0.258), total electrolyte balance (P = 0.258), and subjective measures (P ≥ 0.139) were not different between trials. CONCLUSION: Replacing cow's milk with a soya beverage did not negatively impact fluid balance in healthy young males, making it a viable option for those who choose not to consume dairy in their diet.

Rules of formation of H-C-N-O compounds at high pressure and the fates of planetary ices.

The solar system's outer planets, and many of their moons, are dominated by matter from the H-C-N-O chemical space, based on solar system abundances of hydrogen and the planetary ices [Formula: see text]O, [Formula: see text], and [Formula: see text] In the planetary interiors, these ices will experience extreme pressure conditions, around 5 Mbar at the Neptune mantle-core boundary, and it is expected that they undergo phase transitions, decompose, and form entirely new compounds. While temperature will dictate the formation of compounds, ground-state density functional theory allows us to probe the chemical effects resulting from pressure alone. These structural developments in turn determine the planets' interior structures, thermal evolution, and magnetic field generation, among others. Despite its importance, the H-C-N-O system has not been surveyed systematically to explore which compounds emerge at high-pressure conditions, and what governs their stability. Here, we report on and analyze an unbiased crystal structure search among H-C-N-O compounds between 1 and 5 Mbar. We demonstrate that simple chemical rules drive stability in this composition space, which explains why the simplest possible quaternary mixture HCNO-isoelectronic to diamond-emerges as a stable compound and discuss dominant decomposition products of planetary ice mixtures.

Environmental challenges facing athletes, stakeholders and spectators at Paris 2024 Olympic and Paralympic Games: an evidence-based review of mitigation strategies and recommendations.

The upcoming Paris 2024 Olympic and Paralympic Games could face environmental challenges related to heat, air quality and water quality. These challenges will pose potential threats to athletes and impact thousands of stakeholders and millions of spectators. Recognising the multifaceted nature of these challenges, a range of strategies will be essential for mitigating adverse effects on participants, stakeholders and spectators alike. From personalised interventions for athletes and attendees to comprehensive measures implemented by organisers, a holistic approach is crucial to address these challenges and the possible interplay of heat, air and water quality factors during the event. This evidence-based review highlights various environmental challenges anticipated at Paris 2024, offering strategies applicable to athletes, stakeholders and spectators. Additionally, it provides recommendations for Local Organising Committees and the International Olympic Committee that may be applicable to future Games. In summary, the review offers solutions for consideration by the stakeholders responsible for and affected by the anticipated environmental challenges at Paris 2024.