Clopidogrel-Mediated P2Y12 Inhibition According to Renal Function in Patients With Diabetes Mellitus and CAD.

This prospective ex vivo and in vitro pharmacodynamic (PD)/pharmacokinetic investigation was conducted in patients with diabetes mellitus with (n = 31) and without chronic kidney disease (n = 30). PD assessments included platelet reactivity index, maximum platelet aggregation, and P2Y12 reaction units. Ex vivo pharmacokinetic assessments included plasma levels of clopidogrel and its active metabolite. In vitro PD assessments were conducted on baseline samples incubated with escalating concentrations of clopidogrel and its active metabolite. Among patients with diabetes mellitus treated with clopidogrel, impaired renal function was associated with increased maximum platelet aggregation. This finding could be attributed partially to upregulation of the P2Y12 activity without differences in drug absorption or metabolism. (Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus; NCT03774394).

Agricultural practices and biodiversity: Conservation policies for semi-natural grasslands in Europe.

Europe's semi-natural grasslands support notably high levels of temperate biodiversity across multiple taxonomic groups. However, these ecosystems face unique conservation challenges. Contemporary agricultural practices have replaced historical traditional low-intensity agriculture in many regions, resulting in a spectrum of management intensities within these ecosystems, ranging from highly intensive methods to complete abandonment. Paradoxically, both extremes along this spectrum of management intensity can be detrimental to biodiversity of semi-natural grasslands. Moreover, while anthropogenic climate change is an overarching threat to these ecosystems, rapid changes in land use and its intensity often present more immediate pressures. Often occurring at a faster rate than climate change itself, these land-use changes have the potential to rapidly impact the biodiversity of these grasslands. Here, we divide the ecological processes, threats, and developments to semi-natural grasslands into three sections. First, we examine the different impacts of agricultural intensification and abandonment on these ecosystems, considering their different consequences for biodiversity. Second, we review seminal works on various evidence-based management practices and offer a concise summary that provides support for various conservation and management strategies. However, the socio-economic factors that drive both abandonment and intensification in semi-natural grasslands can also be used to develop solutions through strategic governmental and non-governmental interventions. Accordingly, we conclude with a way forward by providing several key policy recommendations. By synthesizing existing knowledge and identifying research gaps, this essay aims to provide valuable insights for advancing the sustainable management of semi-natural grasslands.

Dynamic Anthropometrics in Pancreatic Cancer: Associations Between Body Composition Changes During Neoadjuvant Therapy and Survival Outcomes After Resection.

BACKGROUND: Assessment of individual tumor biology and response to systemic therapy in pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge. The significance of anthropometric (body composition) changes during chemotherapy as a surrogate for tumor biology in the setting of localized PDAC is unknown. METHODS: A retrospective, single-institution analysis of patients with PDAC who received neoadjuvant therapy (NAT) and pancreatectomy from 2017 to 2021 was performed. Radiologic anthropometric analysis used artificial intelligence-driven software to segment and compute total and sub-compartment muscle area, adipose tissue area, and attenuation values at the level of the L3 vertebra. Kaplan-Meier survival estimates, log-rank tests, and multivariable Cox regression models were used in survival analyses. RESULTS: The inclusion criteria were met by 138 patients. Although decreases in muscle and adipose tissue areas during NAT were predominant, a subset of patients experienced an increase in these compartments. Increases in muscle greater than 5% (hazard ratio [HR], 0.352; 95% confidence interval [CI] 0.135-0.918; p = 0.033) and increases in adipose tissue greater than 15% (HR, 0.375; 95% CI 0.144-0.978; p = 0.045), were significantly associated with improved survival, whereas loss of visceral fat greater than 15% was detrimental (HR 1.853; CI 1.099-3.124; p = 0.021). No significant associations with single time-point anthropometrics were observed. Gains in total muscle and adipose mass were associated with improved pathologic response to systemic therapy and less advanced pathologic tumor stage. CONCLUSIONS: Dynamic anthropometric analysis during NAT for PDAC is a stronger prognostic indicator than measurements taken at a single point in time. Repeated anthropometric analysis during preoperative chemotherapy may serve as a biomarker for individual tumor biology and response to therapy.

Multimodal neuroimaging to characterize symptom-specific networks in movement disorders.

Movement disorders, such as Parkinson's disease, essential tremor, and dystonia, are characterized by their predominant motor symptoms, yet diseases causing abnormal movement also encompass several other symptoms, including non-motor symptoms. Here we review recent advances from studies of brain lesions, neuroimaging, and neuromodulation that provide converging evidence on symptom-specific brain networks in movement disorders. Although movement disorders have traditionally been conceptualized as disorders of the basal ganglia, cumulative data from brain lesions causing parkinsonism, tremor and dystonia have now demonstrated that this view is incomplete. Several recent studies have shown that lesions causing a given movement disorder occur in heterogeneous brain locations, but disrupt common brain networks, which appear to be specific to each motor phenotype. In addition, findings from structural and functional neuroimaging in movement disorders have demonstrated that brain abnormalities extend far beyond the brain networks associated with the motor symptoms. In fact, neuroimaging findings in each movement disorder are strongly influenced by the constellation of patients' symptoms that also seem to map to specific networks rather than individual anatomical structures or single neurotransmitters. Finally, observations from deep brain stimulation have demonstrated that clinical changes, including both symptom improvement and side effects, are dependent on the modulation of large-scale networks instead of purely local effects of the neuromodulation. Combined, this multimodal evidence suggests that symptoms in movement disorders arise from distinct brain networks, encouraging multimodal imaging studies to better characterize the underlying symptom-specific mechanisms and individually tailor treatment approaches.

Correction: Real-time structural dynamics of the ultrafast solvation process around photo-excited aqueous halides.

[This corrects the article DOI: 10.1039/D4SC01912A.].

The association between sleep, mental health, and health behaviours: a Danish population-based cross-sectional study.

AIMS: Sleep problems constitute a significant public health problem due to their high prevalence and impact on mental health and health behaviours, with major consequences for individuals and society. Therefore, the aim of this study was to investigate the association between sleep problems (duration and quality), mental health and health behaviours. METHODS: Cross-sectional data was derived from the 2021 health survey 'How are you?' from the Central Denmark Region. The study population was a stratified random sample of 33,925 respondents aged 16 years or older. We used logistic regression models to analyse the associations between sleep problems and indicators of mental health and health behaviour. The models were adjusted for sex, age, educational attainment, labour market attachment, cohabitation, and indicators of mental health and health behaviour. RESULTS: A prevalence of around 10% for both short- and long sleep duration and poor sleep quality was found. All were associated with poor mental health-related quality of life, depression, stress, perceived stressors and obesity. In addition, short sleep duration was associated with daily smoking, and long sleep duration was associated with physical inactivity and daily smoking. CONCLUSIONS: Our findings revealed a stronger association between sleep problems and mental health indicators in comparison to health behaviours. We found that sleep duration and sleep quality in broad terms were associated with similar variables within mental health and health behaviour. These findings underline the importance of adopting a comprehensive approach to addressing sleep problems in the context of health promotion, disease prevention, treatment and rehabilitation.

Transcranial Focused Ultrasound Targeting the Amygdala May Increase Psychophysiological and Subjective Negative Emotional Reactivity in Healthy Older Adults.

Background: The amygdala is highly implicated in an array of psychiatric disorders but is not accessible using currently available noninvasive neuromodulatory techniques. Low-intensity transcranial focused ultrasound (TFUS) is a neuromodulatory technique that has the capability of reaching subcortical regions noninvasively. Methods: We studied healthy older adult participants (N = 21, ages 48-79 years) who received TFUS targeting the right amygdala and left entorhinal cortex (active control region) using a 2-visit within-participant crossover design. Before and after TFUS, behavioral measures were collected via the State-Trait Anxiety Inventory and an emotional reactivity and regulation task utilizing neutral and negatively valenced images from the International Affective Picture System. Heart rate and self-reported emotional valence and arousal were measured during the emotional reactivity and regulation task to investigate subjective and physiological responses to the task. Results: Significant increases in both self-reported arousal in response to negative images and heart rate during emotional reactivity and regulation task intertrial intervals were observed when TFUS targeted the amygdala; these changes were not evident when the entorhinal cortex was targeted. No significant changes were found for state anxiety, self-reported valence to the negative images, cardiac response to the negative images, or emotion regulation. Conclusions: The results of this study provide preliminary evidence that a single session of TFUS targeting the amygdala may alter psychophysiological and subjective emotional responses, indicating some potential for future neuropsychiatric applications. However, more work on TFUS parameters and targeting optimization is necessary to determine how to elicit changes in a more clinically advantageous way.

Transcranial focused ultrasound (TFUS) is an emerging brain stimulation technique with the ability to noninvasively alter the activity of deep brain regions. Studying the potential for TFUS to alter behavioral response and processing, this study employed MRI-guided TFUS targeting the right amygdala in older adults. We found that TFUS targeting the right amygdala increased self-reported arousal in response to negative images, providing preliminary evidence that a single session of TFUS may be capable of affecting emotional reactivity.

The day after mowing: Time and type of mowing influence grassland arthropods.

Recent losses in the abundance and diversity of arthropods have been documented in many regions and ecosystems. In grasslands, such insect declines are largely attributed to land use, including modern machinery and mowing regimes. However, the effects of different mowing techniques on arthropods remain poorly understood. Using 11 years of data from 111 agricultural grassland plots across Germany, we analyzed the influence of various grassland management variables on the abundance and abundance-accounted species richness of four arthropod orders: Araneae, Coleoptera, Hemiptera, and Orthoptera. The analysis focused on detailed mowing information, for example, days after mowing and mower type, and compared their effect with other aspects of grassland management, that is, rolling, leveling, fertilization, and grazing. We found strong negative effects of mowing on all four arthropod orders, with arthropod abundance being lowest directly after mowing and steadily increasing to three to seven times the abundance after 100 days post-mowing. Likewise, Hemiptera and Coleoptera species richness was 30% higher 100 days after mowing. Mower width showed a positive effect on Orthoptera abundance, but not on the other arthropods. Arthropod abundance and Coleoptera species richness were lowest when a mulcher was used compared to rotary or bar mowers. In addition to mowing, intensive grazing negatively affected Orthoptera abundance but not the other orders. Mowing represents a highly disturbing and iterative stressor with negative effects on arthropod abundance and diversity, likely contributed by mowing-induced mortality and habitat alteration. While modifications of mowing techniques such as mower type or mowing height and width may help to reduce the negative impact of mowing on arthropods, our results show that mowing itself has the most substantial negative effect. Based on our results, we suggest that reduced mowing frequency, omission of mowing in parts of the grassland (refuges), or extensive grazing instead of mowing have the greatest potential to promote arthropod populations.

Mapping of flumioxazin tolerance in a snap bean diversity panel leads to the discovery of a master genomic region controlling multiple stress resistance genes.

Introduction: Effective weed management tools are crucial for maintaining the profitable production of snap bean (Phaseolus vulgaris L.). Preemergence herbicides help the crop to gain a size advantage over the weeds, but the few preemergence herbicides registered in snap bean have poor waterhemp (Amaranthus tuberculatus) control, a major pest in snap bean production. Waterhemp and other difficult-to-control weeds can be managed by flumioxazin, an herbicide that inhibits protoporphyrinogen oxidase (PPO). However, there is limited knowledge about crop tolerance to this herbicide. We aimed to quantify the degree of snap bean tolerance to flumioxazin and explore the underlying mechanisms. Methods: We investigated the genetic basis of herbicide tolerance using genome-wide association mapping approach utilizing field-collected data from a snap bean diversity panel, combined with gene expression data of cultivars with contrasting response. The response to a preemergence application of flumioxazin was measured by assessing plant population density and shoot biomass variables. Results: Snap bean tolerance to flumioxazin is associated with a single genomic location in chromosome 02. Tolerance is influenced by several factors, including those that are indirectly affected by seed size/weight and those that directly impact the herbicide's metabolism and protect the cell from reactive oxygen species-induced damage. Transcriptional profiling and co-expression network analysis identified biological pathways likely involved in flumioxazin tolerance, including oxidoreductase processes and programmed cell death. Transcriptional regulation of genes involved in those processes is possibly orchestrated by a transcription factor located in the region identified in the GWAS analysis. Several entries belonging to the Romano class, including Bush Romano 350, Roma II, and Romano Purpiat presented high levels of tolerance in this study. The alleles identified in the diversity panel that condition snap bean tolerance to flumioxazin shed light on a novel mechanism of herbicide tolerance and can be used in crop improvement.

3DMOUSEneST: a volumetric, label-free imaging method evaluating embryo-uterine interaction and decidualization efficacy.

Effective interplay between the uterus and the embryo is essential for pregnancy establishment, however, convenient methods to screen embryo implantation success and maternal uterine response in experimental mouse models are currently lacking. Here we report 3DMOUSEneST, a groundbreaking method for analyzing mouse implantation sites based on label-free higher harmonic generation microscopy, providing unprecedented insights into the embryo-uterine dynamics during early pregnancy. The 3DMOUSEneST method incorporates second-harmonic generation microscopy to image the three-dimensional structure formed by decidual fibrillar collagen, named 'decidual nest', and third-harmonic generation microscopy to evaluate early conceptus (defined as the embryo and extraembryonic tissues) growth. We demonstrate that decidual nest volume is a measurable indicator of decidualization efficacy and correlates with the probability of early pregnancy progression based on a logistic regression analysis using Smad1/5 and Smad2/3 conditional knockout mice with known implantation defects. 3DMOUSEneST has great potential to become a principal method for studying decidual fibrillar collagen and characterizing mouse models associated with early embryonic lethality and fertility issues.

Correcting Edge Defects in Self-Assembled Monolayers through Thermal Annealing.

Self-assembled monolayers (SAMs) are emerging as platform technology for a myriad of applications, yet they still possess varied spatial stability and predictability issues as their properties are heavily dependent on subtle structural features. Reducing entropy within such a system serves as one of many potential solutions to increase order and therefore coherence/precision in measured properties. Here we explore controlled thermal annealing to improve edge disorders in SAMs and significantly reduce data variance. Using both odd- and even-numbered n-alkanethiol SAMs on Au, we observe statistically significant difference in the contact angles between edge and center. Thermal annealing at 40°C significantly narrows differences between edges and centre of the SAM, albeit with significant reduction in the parity dependent odd-even effect. This study provides a pathway to improve SAMs consistency through minimal external perturbation as reflected by the minimization of odd-even effect as SAMs become increasingly ordered.

International consensus on fasting terminology.

Although fasting is increasingly applied for disease prevention and treatment, consensus on terminology is lacking. Using Delphi methodology, an international, multidisciplinary panel of researchers and clinicians standardized definitions of various fasting approaches in humans. Five online surveys and a live online conference were conducted with 38 experts, 25 of whom completed all 5 surveys. Consensus was achieved for the following terms: "fasting" (voluntary abstinence from some or all foods or foods and beverages), "modified fasting" (restriction of energy intake to max. 25% of energy needs), "fluid-only fasting," "alternate-day fasting," "short-term fasting" (lasting 2-3 days), "prolonged fasting" (≥4 consecutive days), and "religious fasting." "Intermittent fasting" (repetitive fasting periods lasting ≤48 h), "time-restricted eating," and "fasting-mimicking diet" were discussed most. This study provides expert recommendations on fasting terminology for future research and clinical applications, facilitating communication and cross-referencing in the field.

[Pulmonary Embolism]. / Tromboembolia de pulmón.

Pulmonary embolism (PE), the most severe form of presentation of venous thromboembolic disease (VTE), currently represents a foremost healthcare issue due to its high impact in terms of morbidity, mortality, costs, and resource consumption. Early mortality associated with PE is primarily due to hemodynamic instability, exacerbation of pre-existing conditions, or major complications of antithrombotic therapies. Beyond the risk of death, there are relevant complications related to PE, such as bleedings, VTE recurrences, and persistence of residual respiratory symptoms; the latter complication related to PE is mainly characterized by two entities, chronic thromboembolic pulmonary hypertension and chronic thromboembolic disease. Significant scientific advances made in recent years have allowed for the improvement of both diagnostic and therapeutic management of the disease, as outlined in this document through a series of relevant issues about PE that are answered with the most up-to-date scientific evidence.

Real-time structural dynamics of the ultrafast solvation process around photo-excited aqueous halides.

This work investigates and describes the structural dynamics taking place following charge-transfer-to-solvent photo-abstraction of electrons from I- and Br- ions in aqueous solution following single- and 2-photon excitation at 202 nm and 400 nm, respectively. A Time-Resolved X-ray Solution Scattering (TR-XSS) approach with direct sensitivity to the structure of the surrounding solvent as the water molecules adopt a new equilibrium configuration following the electron-abstraction process is utilized to investigate the structural dynamics of solvent shell expansion and restructuring in real-time. The structural sensitivity of the scattering data enables a quantitative evaluation of competing models for the interaction between the nascent neutral species and surrounding water molecules. Taking the I0-O distance as the reaction coordinate, we find that the structural reorganization is delayed by 0.1 ps with respect to the photoexcitation and completes on a time scale of 0.5-1 ps. On longer time scales we determine from the evolution of the TR-XSS difference signal that I0: e- recombination takes place on two distinct time scales of ∼20 ps and 100 s of picoseconds. These dynamics are well captured by a simple model of diffusive evolution of the initial photo-abstracted electron population where the charge-transfer-to-solvent process gives rise to a broad distribution of electron ejection distances, a significant fraction of which are in the close vicinity of the nascent halogen atoms and recombine on short time scales.

Evaluation of the surgical management strategy for acute cholecystitis in patients over 75years old.

INTRODUCTION: Acute cholecystitis occurs frequently in the elderly. According to the current recommendations specific to the characteristics of each case, these patients are most often treated by delayed cholecystectomy after medical treatment. Our study aimed to compare the success rate of this strategy in patients over and under 75years of age. PATIENTS AND METHODS: This was a retrospective single-center analytic observational study that included patients who were hospitalized for acute cholecystitis in a geriatric postoperative unit (unité postopératoire gériatrique [UPOG]) and gastrointestinal surgery unit between 2021 and 2022. The main endpoint was the failure rate of deferred cholecystectomy. Secondary endpoints included: respect for the recommended operative delay, loss of the patient's functional independence during hospitalization, and the reason for surgical abstention. RESULTS: In total, 290 patients were included. The strategy of delayed elective cholecystectomy was not achieved in 31 (44%) patients 75years old or older vs. eight (18%) patients younger than 75years old (P=0.005). The main reason was the decision not to operate after medical treatment. In both groups, the recommended operative interval was equitably respected and the loss of autonomy during hospitalization was minor. More than one-third of the elderly patients scheduled for elective surgery finally refused to undergo surgery. CONCLUSION: The strategy of routine elective cholecystectomy should not be strict in the elderly with acute cholecystitis; the indication for this procedure should take into account the wishes as well as the physiological status of the patient.

IL-17 is associated with disease severity and targetable inflammatory processes in heart failure.

AIMS: Heart failure (HF) is recognized as an inflammatory disease in which cytokines play an important role. In animal HF models, interleukin-17A (IL-17) has been linked to deterioration of cardiac function and fibrosis, whereas knock-out of IL-17 showed beneficial cardiac effects. However, there is limited evidence of IL-17 involvement in patients with HF. This study aims to investigate the clinical characteristics, outcomes, and pathophysiological processes associated with circulating IL-17 concentrations in patients with HF. METHODS AND RESULTS: IL-17 was measured by ELISA in 2082 patients diagnosed with HF along with 363 circulating proteins using proximity extension assay technology for differential expression and pathway analysis. Data were validated in an independent cohort of 1737 patients with HF. Patients with elevated IL-17 concentrations had more severe HF, as reflected by more frequent current or previous hospitalizations for HF, higher New York Heart Association functional class (NYHA) and higher levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP). High IL-17 concentrations were independently associated with an increased risk of hospitalization for HF and mortality. In both cohorts, the most strongly up-regulated proteins in patients with high IL-17 were fibroblast growth factor 21 (FGF-21), interleukin-6 (IL-6), C-X-C motif chemokine ligand 13 (CXCL13), tumour necrosis factor receptor superfamily member 6B (TNFRSF6B) and interleukin-1 receptor antagonist (IL-1RA). Pathway over-representation analysis showed increased activity of pathways related to lymphocyte-mediated immunity, leukocyte activation and regulation of the immune response. CONCLUSIONS: In patients with HF, elevated IL-17 concentrations indicate more severe HF and increased activity of inflammatory processes known to be involved in the pathophysiology of HF. IL-17 might hold potential for identifying and targeting inflammation in HF.

Alcohol consumption in elderly people. What is the real magnitude of the problem?

The harmful effects of alcohol consumption have been well studied in the general population, but in the group of people over 80 years of age there is not much information regarding its relevance. It is estimated than 30%-40% of this population consumes alcohol regularly and around 10% engage in high-risk consumption. Furthermore, potential interactions between this substance and commonly consumed drugs in this age group, like oral antidiabetics, anticoagulants and antibiotics, may pose a risk of serious complications. In this sense, the aim of the present work was to analyze the magnitude of alcohol consumption within people over 80 years of age and the impact it has on their health. A narrative review of the available literature on the topic was carried out, which showed that alcohol consumption in people over 80 years of age is common in our environment and is associated with multiple complications and the development of different pathologies. The correct quantification of alcohol consumption in very elderly people must be integrated into the daily clinical practice of Medicine in general and Internal Medicine in particular.

Genomic insights into the 2022-2023Vibrio cholerae outbreak in Malawi.

Malawi experienced its deadliest Vibrio cholerae (Vc) outbreak following devastating cyclones, with >58,000 cases and >1700 deaths reported between March 2022 and May 2023. Here, we use population genomics to investigate the attributes and origin of the Malawi 2022-2023 Vc outbreak isolates. Our results demonstrate the predominance of ST69 clone, also known as the seventh cholera pandemic El Tor (7PET) lineage, expressing O1 Ogawa (~ 80%) serotype followed by Inaba (~ 16%) and sporadic non-O1/non-7PET serogroups (~ 4%). Phylogenetic reconstruction revealed that the Malawi outbreak strains correspond to a recent importation from Asia into Africa (sublineage AFR15). These isolates harboured known antimicrobial resistance and virulence elements, notably the ICEGEN/ICEVchHai1/ICEVchind5 SXT/R391-like integrative conjugative elements and a CTXφ prophage with the ctxB7 genotype compared to historical Malawian Vc isolates. These data suggest that the devastating cyclones coupled with the recent importation of 7PET serogroup O1 strains, may explain the magnitude of the 2022-2023 cholera outbreak in Malawi.