Plasma Catecholamines in Patients Undergoing Invasive Cardiopulmonary Exercise Test for Exercise Intolerance.

BACKGROUND: Invasive cardiopulmonary exercise testing (iCPET) combines traditional cardiopulmonary exercise testing with invasive hemodynamic measurements to assess exercise intolerance, which can be caused by preload insufficiency (PI), characterized by low ventricular filling pressures and reduced cardiac output during exertion. We hypothesize that plasma catecholamine levels at rest and during exercise correlate with hemodynamic parameters in PI. METHODS: We included adult patients who underwent iCPET for exercise intolerance and had plasma catecholamines measured at rest and peak exercise. RESULTS: Among 84 patients, PI was identified in 57 (67.8%). Compared to patients without PI, those with PI were younger [median (IQR) 37 (28, 46) vs 47 (39,55) years, p=0.005] and had lower workload at peak exercise [81 (66, 96) vs 95 (83.5, 110.50) Watts, p=0.006]. Patients with PI had higher heart rates at rest and peak exercise [87 (78, 97) vs 79 (74, 87) bpm, p=0.04; and 167 (154, 183) vs 156 (136, 168) bpm, p=0.01, respectively]. In all patients, epinephrine and norepinephrine at peak exercise directly correlated with peak workload (r:0.41, p<0.001 and r:0.47, p<0.001, respectively). Resting epinephrine was higher in patients with PI [136 (60, 210) vs 77 (41, 110) pg/mL, p=0.02]. There was no significant difference in the change in catecholamines from rest to peak exercise between patients with or without PI. CONCLUSION: PI patients exhibited elevated heart rate and epinephrine at rest, indicating increased sympathetic activity. We did not find strong associations between catecholamines and cardiac filling pressures, suggesting that catecholamine levels are predominantly influenced by peak workload.

Outcomes and Practices of Endotracheal Intubation Using the Glasgow Coma Scale in Acute Non-Traumatic Poisoning: A Systematic Review and Meta-Analysis of Proportions.

BACKGROUND: Acute poisoning often results in decreased consciousness, necessitating airway assessment and management. Existing literature in the trauma setting suggests the importance of airway protection in unconscious patients to prevent complications, including aspiration. Practices for endotracheal intubation in non-traumatic acute poisoning are poorly described and variable, particularly regarding the use of a Glasgow Coma Scale (GCS) ≤ 8 threshold for intubation. METHODS: A systematic review and meta-analysis of proportions was conducted to evaluate intubation rates and outcomes in patients presenting for acute non-traumatic poisoning. Studies were excluded if the primary indication for intubation was not airway protection. We analyzed rates of intubation, mortality, and aspiration by subgrouping patients into GCS ≤ 8, GCS 9-15, or mixed GCS. Common and random-effects analysis were used, supplemented by subgroup analyses. RESULTS: 39 studies were included in the analysis, involving 15,959 patients. Random-effects pooled intubation rates varied significantly across GCS categories: GCS ≤ 8 (30.0%, I2 = 92%, p < 0.01), GCS 9-15 (1.0%, I2 = 0%, p = 0.91), and mixed GCS (11.0%, I2 = 94%, p < 0.01), p-value <0.01 for subgroup difference. Aspiration rates also varied: GCS ≤ 8 (19.0%, I2 = 84%, p < 0.01), GCS 9-15 (4.0%, I2 = 78%, p < 0.01), and mixed group (5.0%, I2 = 72%, p < 0.01), p-value <0.01 for subgroup difference. Mortality rates remained low across all groups: GCS ≤ 8 (1.0%, I2 = 0%, p = 0.62), GCS 9-15 (1.0%, I2 = 0%, p = 0.99), and mixed group (2.0%, I2 = 68%, p < 0.01). CONCLUSION: The conventional "less than 8, intubate" approach may not be directly applicable to acute poisoning patients due to heterogeneity in patient presentation, intubation practices, and low mortality. Therefore, a nuanced approach is warranted to optimize airway management strategies tailored to individual patient needs.

Smooth operator(s): dialing up and down neurotransmitter responses by G-protein regulators.

G-protein-coupled receptors (GPCRs) are essential mediators of neuromodulation and prominent pharmacological targets. While activation of heterotrimeric G-proteins (GαßÉ£) by GPCRs is essential in this process, much less is known about the postreceptor mechanisms that influence G-protein activity. Neurons express G-protein regulators that shape the amplitude and kinetics of GPCR-mediated synaptic responses. Although many of these operate by directly altering how G-proteins handle guanine-nucleotides enzymatically, recent discoveries have revealed alternative mechanisms by which GPCR-stimulated G-protein responses are modulated at the synapse. In this review, we cover the molecular basis for, and consequences of, the action of two G-protein regulators that do not affect the enzymatic activity of G-proteins directly: Gα inhibitory interacting protein (GINIP), which binds active Gα subunits, and potassium channel tetramerization domain-containing 12 (KCTD12), which binds active Gßγ subunits.

The Early Appearance of Asthma and Its Relationship with Gut Microbiota: A Narrative Review.

Asthma is, worldwide, the most frequent non-communicable disease affecting both children and adults, with high morbidity and relatively low mortality, compared to other chronic diseases. In recent decades, the prevalence of asthma has increased in the pediatric population, and, in general, the risk of developing asthma and asthma-like symptoms is higher in children during the first years of life. The "gut-lung axis" concept explains how the gut microbiota influences lung immune function, acting both directly, by stimulating the innate immune system, and indirectly, through the metabolites it generates. Thus, the process of intestinal microbial colonization of the newborn is crucial for his/her future health, and the alterations that might generate dysbiosis during the first 100 days of life are most influential in promoting hypersensitivity diseases. That is why this period is termed the "critical window". This paper reviews the published evidence on the numerous factors that can act by modifying the profile of the intestinal microbiota of the infant, thereby promoting or inhibiting the risk of asthma later in life. The following factors are specifically addressed in depth here: diet during pregnancy, maternal adherence to a Mediterranean diet, mode of delivery, exposure to antibiotics, and type of infant feeding during the first three months of life.

Predictors of outcomes after internal fixation of periprosthetic femoral hip fractures Subgroup analysis of the peri-implant and peri-prosthetic fractures Spanish registry (PIPPAS).

PURPOSE: To identify risk factors predisposing patients to poor outcomes after fixation of periprosthetic hip fractures around femoral stems. METHODS: Prospective multicentre cohort study of fractures around a hip replacement stem managed by internal fixation. The primary outcome was one-year mortality, while secondary outcomes were local complications and healthcare burden-related outcomes (nursing facility utilization and hospital length of stay). RESULTS: One-year mortality was 16.2%. Age-adjusted Charlson Comorbidity Index score (OR=1.17; 95%CI=1.03-1.33)), Pfeiffer Short Portable Mental Status Questionnaire (SPMSQ) score (OR=1.16; 1.06-1.28), prosthetic dysfunction (OR=1.90; 1.00-3.61), and postoperative medical complications (OR=1.97; 1.06-3.68) were predictors of mortality. Patients with prior prosthetic dysfunction, lower Pfeiffer SPMSQ scores, Vancouver A fractures, and fractures fixed only using cerclages were at higher risk of local complications, which occurred in 9.3% of cases. Medical (OR=1.81; 1.05-3.13) and local complications (OR=5.56; 2.42-3.13) emerged as consistent risk factors for new institutionalization. Average hospitalization time was 13.9±9.2 days. Each day of fixation delay led to an average 1.4-day increase in total hospitalization. CONCLUSION: Frail periprosthetic hip-fracture patients with poorer functional status, dysfunctional replacements, and postoperative complications are at increased risk of mortality. Postoperative complications are more common in patients with dysfunctional arthroplasties, Vancouver A fractures, and fixation using cerclages alone. Postoperative complications were the most consistent predictor of higher healthcare resource utilization.

Effect of Rapid Response Order Panels on Resident and Nurse Satisfaction.

Background: Hospitals are required to have rapid response (RR) systems in place to respond to acute changes in a patient's condition. In high-stress situations like RR, medical residents face decision-making challenges due to time constraints and perceived pressure. Instituting order panels (OPs) can facilitate clinical decision making and improve residents' and nurses' satisfaction and patient safety. Objective: This quality improvement (QI) project aimed to create and institute standardized OPs for common RR clinical scenarios to improve satisfaction of internal medicine residents and nurses with the RR process. Methods: This was a single tertiary care center QI project that developed OPs for 10 common RR scenarios. Resident and nursing satisfaction with RR was assessed before and after OP implementation via survey and qualitative data collection. Results: Residents and nurses expressed high levels of satisfaction across various aspects of the RR process before and after OP implementation in both quantitative and qualitative analysis. Increased satisfaction was observed among residents regarding time spent placing orders (94%; P = 0.02) and time spent correcting wrong orders (87%; P = 0.03) after OP implementation. The nurses' survey revealed no statistically significant differences in satisfaction before and after the implementation of OPs regarding communication, collaboration, efficiency, and organization of the team. Conclusion: The introduction of standardized OPs for RRs resulted in increased satisfaction among internal medicine residents in terms of order placement and correcting wrong orders. Nurse satisfaction based on survey responses remained neutral. Qualitative data from both groups demonstrated a positive impact on communication, efficiency, and teamwork.

Role of body mass index in unbalanced (dysanaptic) lung growth of healthy infants.

RATIONALE: Imbalance between forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) (dysanapsis) has been reported in children who are obese. This dysanaptic growth might begin at an early age, although there are no data on children younger than 6 years. OBJETIVES: To assess whether body mass index (BMI) and early weight gain, in healthy infants born at term, plays a significant role in the imbalance between FEV1 and FVC, even in the absence of obesity. METHODS: Lung function was measured by means of raised volume rapid thoracic compression in 69 healthy infants born at term from the Nutrition in Early Life and Asthma cohort. Dysanapsis was defined as zFVC >0.674, zFEV0 .5 ≥-1.645, and FEV0 .5/FVC ≤-1.645. Weight gain (g/day) and growth rate (cm/year) were calculated as the difference between weight and length on the test date and those at birth. To assess the relationship between zBMI and dysanapsis, a receiver operating characteristic curve was performed. Multivariable analysis was carried out by means of linear regressions (one for each lung function index) and by logistic regression for dysanapsis (yes/no). RESULTS: Higher zBMI was associated with risk of dysanapsis (odds ratio: 3.53, [95% confidence interval: 1.30; 9.66]; p = .014): Each additional zBMI unit was associated with ~10 mL higher FVC and with ~3.5% lower FEV0.5/FVC. Weight gain was associated with lower FEV0.5/FVC ratio. CONCLUSION: Dysanaptic development of lung function begins very early in infancy and is related with weight gain and body mass index, even in the absence of obesity.

Get Ready to Sharpen Your Tools: A Short Guide to Heterotrimeric G Protein Activity Biosensors.

G protein-coupled receptors (GPCRs) are the largest class of transmembrane receptors encoded in the human genome, and they initiate cellular responses triggered by a plethora of extracellular stimuli ranging from neurotransmitters and hormones to photons. Upon stimulation, GPCRs activate heterotrimeric G proteins (Gαßγ) in the cytoplasm, which then convey signals to their effectors to elicit cellular responses. Given the broad biological and biomedical relevance of GPCRs and G proteins in physiology and disease, there is great interest in developing and optimizing approaches to measure their signaling activity with high accuracy and across experimental systems pertinent to their functions in cellular communication. This review provides a historical perspective on approaches to measure GPCR-G protein signaling, from quantification of second messengers and other indirect readouts of activity to biosensors that directly detect the activity of G proteins. The latter is the focus of a more detailed overview of the evolution of design principles for various optical biosensors of G protein activity with different experimental capabilities. We will highlight advantages and limitations of biosensors that detect different G protein activation hallmarks, like dissociation of Gα and Gßγ or nucleotide exchange on Gα, as well as their suitability to detect signaling mediated by endogenous versus exogenous signaling components or in physiologically relevant systems like primary cells. Overall, this review intends to provide an assessment of the state-of-the-art for biosensors that directly measure G protein activity to allow readers to make informed decisions on the selection and implementation of currently available tools. SIGNIFICANCE STATEMENT: G protein activity biosensors have become essential and widespread tools to assess GPCR signaling and pharmacology. Yet, investigators face the challenge of choosing from a growing list of G protein activity biosensors. This review provides an overview of the features and capabilities of different optical biosensor designs for the direct detection of G protein activity in cells, with the aim of facilitating the rational selection of systems that align with the specific scientific questions and needs of investigators.

Profile of cattle breed sensitivity to the tick Rhipicephalus microplus.

Among cattle, Bos taurus breeds and their crosses are more sensitive to tick infestations than Bos indicus breeds that are more resistant to infestation and more adaptable to tropical climates. The presence of susceptible individuals in herds and inadequate tick control lead to direct and indirect losses in the meat production chain, in addition to increased mortality due to cattle tick fever. The objective of this study was to describe, compare and rank the sensitivity of different breeds of stabled cattle to the tick Rhipicephalus microplus and to present, as an innovative result, a scale called the Tick Ruler. Secondary data on the number of retrieved engorged females, engorged female ticks' weight, egg mass weight and number of larvae were extracted from research reports of experiments conducted over 18 years with eight breeds to describe and report the sensitivity of the breeds to artificial infestation by R. microplus larvae. For analyses, the recovery rate of engorged female ticks and the percentile of dispersion of individuals in their respective races were calculated, and comparison of these percentiles between races was performed. The ranking of the percentiles resulted in the organization of the breeds by their susceptibility to R. microplus; we call this scale the "Tick Ruler." The ruler is a simple, easy-to-understand tool that can be used by technicians and producers to evaluate the tick sensitivity of a breed of interest and can assist producers in decision-making to find a balance between increased production gains and the risk of economic losses depending on the breed composition in a cattle herd.

Babesia bigemina (smith and Kilbourne, 1893) detection in Amblyomma sculptum (Berlese, 1888) ticks in the Mato Grosso do Sul state, Brazil.

Ticks parasitize various hosts, including humans, and are known to transmit pathogens that can be harmful not only to animals but also to humans. To evaluate the possible presence of pathogens in ticks, we aimed to collect and identify tick fauna specimens in Lagoa Comprida Municipal Natural Park, an anthropogenic urban area located in Aquidauana, Mato Grosso do Sul, Brazil. A total of 1216 ticks, of which 51.2% were Amblyomma sculptum, 1.2% were Amblyomma dubitatum, and 41% were Amblyomma spp. were collected. These results show that the prevalence of A. sculptum is significantly higher than that of A. dubitatum across all four seasons. Molecular analyses revealed positive samples for the genus Babesia, including the confirmation of Babesia bigemina in an A. sculptum specimen, marking the first record of this relationship. This unexpected finding demands greater attention and deeper analysis in the context of the epidemiology of tick-borne diseases.

Plasma polyamines during pregnancy and their relationships with maternal allergies and the immune response of the neonates.

BACKGROUND: Some studies have reported that polyamine levels may influence immune system programming. The aim of this study was to evaluate the polyamine profile during gestation and its associations with maternal allergy and cytokine production in cord blood cells in response to different allergenic stimuli. METHODS: Polyamines were determined in plasma of pregnant women (24 weeks, N = 674) and in umbilical cord samples (N = 353 vein and N = 160 artery) from the Mediterranean NELA birth cohort. Immune cell populations were quantified, and the production of cytokines in response to different allergic and mitogenic stimuli was assessed in cord blood. RESULTS: Spermidine and spermine were the most prevalent polyamines in maternal, cord venous, and cord arterial plasma. Maternal allergies, especially allergic conjunctivitis, were associated with lower spermine in umbilical cord vein. Higher levels of polyamines were associated with higher lymphocyte number but lower Th2-related cells in cord venous blood. Those subjects with higher levels of circulating polyamines in cord showed lower production of inflammatory cytokines, especially IFN-α, and lower production of Th2-related cytokines, mainly IL-4 and IL-5. The effects of polyamines on Th1-related cytokines production were uncertain. CONCLUSIONS: Spermidine and spermine are the predominant polyamines in plasma of pregnant women at mid-pregnancy and also in umbilical cord. Maternal allergic diseases like allergic conjunctivitis are related to lower levels of polyamines in cord vein, which could influence the immune response of the newborn. Cord polyamine content is related to a decreased Th2 response and inflammatory cytokines production, which might be important to reduce an allergenic phenotype in the neonate.

Role of Atomicity and Interface on InOx-TiO2 Composites: Thermo-Photo Valorization of CO2.

The synthesis, physicochemical, and functional properties of composite solids resulting from the surface spread of oxidized indium species onto nanoplatelets of anatase were investigated. Both the size and the interaction between the indium- and titanium-containing components control the functional properties. In the reduction of CO2 to CO, the best samples have an indium content between ca. 2 and 5 mol % and showed an excess rate over the photo and thermo-alone processes above 33% and an energy efficiency of 1.3%. Subnanometric (monomeric and dimeric) indium species present relatively weak thermal catalytic response but strong thermo-photo promotion of the activity. A gradual change in functional properties was observed with the growth of the indium content of the solids, leading to a progressive increase of thermal activity but lower thermo-photo promotion. The study provides a well-defined structure-activity relationship rationalizing the dual thermo-photo properties of the catalysts and establishes a guide for the development of highly active and stable composite solids for the elimination and valorization of CO2.

Multimodal Quality Initiatives in Sepsis Care: Assessing Impact on Core Measures and Outcomes.

ABSTRACT: Providing timely and effective care for patients with sepsis is challenging due to delays in recognition and intervention. The Surviving Sepsis Campaign has developed bundles that have been shown to reduce sepsis mortality. However, hospitals have not consistently adhered to these bundles, resulting in suboptimal outcomes. To address this, a multimodal quality improvement sepsis program was implemented from 2017 to 2022 in a large urban tertiary hospital. The aim of this program was to enhance the Severe Sepsis and Septic Shock Management Bundle compliance and reduce sepsis mortality. At baseline, the Severe Sepsis and Septic Shock Management Bundle compliance rates were low, at 25%, with a sepsis observed/expected mortality ratio of 1.14. Our interventions included the formation of a multidisciplinary committee, the appointment of sepsis champions, the implementation of sepsis alerts and order sets, the formation of a Code Sepsis team, real-time audits, and peer-to-peer education. By 2022, compliance rose to 62%, and the observed/expected mortality ratio decreased to 0.73. Our approach led to improved outcomes and hospital rankings. These findings underscore the efficacy of a comprehensive sepsis care initiative, emphasizing the importance of interdisciplinary collaboration. A multimodal hospital-wide sepsis performance program is feasible and can contribute to improved outcomes. However, further research is necessary to determine the specific impact of individual strategies on sepsis outcomes.

Atomic and Electronic Structures of Co-Doped In2O3 from Experiment and Theory.

The synthesis and properties of stoichiometric, reduced, and Co-doped In2O3 are described in the light of several experimental techniques, including X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), ultraviolet (UV)-visible spectroscopy, porosimetry, and density functional theory (DFT) methods on appropriate models. DFT-based calculations provide an accurate prediction of the atomic and electronic structure of these systems. The computed lattice parameter is linearly correlated with the experimental result in the Co concentration ranging from 1.0 to 5.0%. For higher Co concentrations, the theoretical-experimental analysis of the results indicates that the dopant is likely to be preferentially present at surface sites. The analysis of the electronic structure supports the experimental assignment of Co2+ for the doped material. Experiments and theory find that the presence of Co has a limited effect on the material band gap.

Local environment in biomolecular condensates modulates enzymatic activity across length scales.

The mechanisms that underlie the regulation of enzymatic reactions by biomolecular condensates and how they scale with compartment size remain poorly understood. Here we use intrinsically disordered domains as building blocks to generate programmable enzymatic condensates of NADH-oxidase (NOX) with different sizes spanning from nanometers to microns. These disordered domains, derived from three distinct RNA-binding proteins, each possessing different net charge, result in the formation of condensates characterized by a comparable high local concentration of the enzyme yet within distinct environments. We show that only condensates with the highest recruitment of substrate and cofactor exhibit an increase in enzymatic activity. Notably, we observe an enhancement in enzymatic rate across a wide range of condensate sizes, from nanometers to microns, indicating that emergent properties of condensates can arise within assemblies as small as nanometers. Furthermore, we show a larger rate enhancement in smaller condensates. Our findings demonstrate the ability of condensates to modulate enzymatic reactions by creating distinct effective solvent environments compared to the surrounding solution, with implications for the design of protein-based heterogeneous biocatalysts.

Ongoing CPR with an onboard physician.

Introduction: Recent data are not available on ongoing CPR for emergency services with an onboard physician. The aim of the present study was to identify factors associated with the decision to transport patients to hospital with ongoing CPR and examine their survival to hospital discharge with good neurological status. Methods: An observational study based on a registry of out-of-hospital cardiac arrests attended to by emergency services with an onboard physician. All OHCA cases occurring between the 1st of January and the 31st of December 2022 were included. Patients receiving ongoing CPR during transport to the hospital were compared with patients pronounced dead at the scene following arrival of the care team. The dependent variable was ongoing CPR during transport to the hospital. The main characteristics and the neurological status of patients surviving to discharge were described. Results: A total of 9321 cases were included, of which 350 (3.7%) were transported to hospital with ongoing CPR. Such patients were young (59.9 ± 20.1 years vs 64.6 ± 16.9 years; p < 0.001; 95%CI: 0.98 [0.98; 0.99]) with arrest taking place outside of the home (151 [44.5%] vs 4045 [68.01%]; p < 0.001; 95%CI: 0.41 [0.31; 0.54]) and being witnessed by EMS (126 [36.0%] vs 667 [11.0%]; p < 0.001; 95%CI: 4.31 [3.19; 5.80]), whilst initial rhythm differed from asystole (164 [47.6%] vs 4325 [73.0%]; p < 0.01; 95%CI: 0.44 [0.33; 0.60]) and a mechanical device was more often employed during resuscitation and transport to hospital (199 [56.9%] vs 2050 [33.8%]; p < 0.001; 95%CI: 2.75 [2.10; 3.59]). Seven patients (2%) were discharged alive from hospital, five with ad integrum neurological recovery (CPC1) and two with minimally impaired neurological function (CPC2). Conclusions: The strategy of ongoing CPR is uncommon in EMS with an onboard physician. Despite their limited efficacy, the availability of mechanical chest compression devices, together with the possibility of specific hospital treatments, mainly ICP and ECMO, opens up the possibility of this approach with determined patients.

Recommendations for asthma monitoring in children: A PeARL document endorsed by APAPARI, EAACI, INTERASMA, REG, and WAO.

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

Maternal non-compliance with recommended folic acid supplement use alters global DNA methylation in cord blood of newborns: A cohort study.

BACKGROUND & AIMS: Prenatal folate exposure may alter epigenetic marks in the offspring. We aimed to evaluate associations between prenatal exposure to folic acid (FA) in preconception and in utero with cord blood DNA methylation in long interspersed nuclear element 1 (LINE-1) and Alu short interspersed nuclear elements (SINEs) as markers of global DNA methylation levels. METHODS: Data come from 325 mother-child pairs participating in the Nutrition in Early Life and Asthma (NELA) birth cohort (2015-2018). Pregnant women were asked about supplement use, including brand name and dose, one month before pregnancy (preconception) and through the trimesters of pregnancy. Maternal dietary folate intake was assessed using a validated food frequency questionnaire with additional questions for FA supplement use. Folate serum levels were measured in mothers at 24 weeks of gestation and in cord blood of newborns. DNA methylation was quantitatively assessed by bisulfite pyrosequencing on 5 LINE-1 and 3 Alu different elements. Associations were estimated using multivariable linear regression models. RESULTS: A reduction in methylation levels of LINE-1 in newborns was associated with the use of FA supplements below the recommended doses (<400 ug/day) during preconception (-0.50; 95% CI: -0.91, -0.09; P = 0.016), and from preconception up to 12 weeks of gestation (-0.48; 95% CI: -0.88, -0.08; P = 0.018). Maternal use of FA supplements above the tolerable upper intake level of 1000 ug/day from preconception until 12 weeks of gestation was also related to lower methylation in LINE-1 at birth (-0.77; 95% CI: -1.52, -0.02; P = 0.044). Neither FA supplement use after 12 weeks of gestation nor maternal total folate intake (diet plus supplements) were associated with global DNA methylation levels at birth. CONCLUSIONS: Maternal non-compliance with the use of FA supplement recommendations from preconception up to 12 weeks of gestation reduces offspring global DNA methylation levels at birth.

Host-Guest Stimuli-Responsive Click Chemistry.

Click chemistry has reached its maturity as the weapon of choice for the irreversible ligation of molecular fragments, with over 20 years of research resulting in the development or improvement of highly efficient kinetically controlled conjugation reactions. Nevertheless, traditional click reactions can be disadvantageous not only in terms of efficiency (side products, slow kinetics, air/water tolerance, etc.), but also because they completely avoid the possibility to reversibly produce and control bound/unbound states. Recently, non-covalent click chemistry has appeared as a more efficient alternative, in particular by using host-guest self-assembled systems of high thermodynamic stability and kinetic lability. This review discusses the implementation of molecular switches in the development of such non-covalent ligation processes, resulting in what we have termed stimuli-responsive click chemistry, in which the bound/unbound constitutional states of the system can be favored by external stimulation, in particular using host-guest complexes. As we exemplify with handpicked selected examples, these supramolecular systems are well suited for the development of human-controlled molecular conjugation, by coupling thermodynamically regulated processes with appropriate temporally resolved extrinsic control mechanisms, thus mimicking nature and advancing our efforts to develop a more function-oriented chemical synthesis.