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Purpose: To propose a new method for quantitatively mapping the renal metabolic rate of oxygen (RMRO 2 ) and to evaluate the proposed method using a caffeine challenge., Theory and Methods: Pseudo-continuous arterial spin labeling (pCASL) and QSM sequences were used to obtain MR images in the kidney. Six healthy volunteers were scanned on caffeine and control days. The pCASL and QSM images were registered using DICOM information and rigid translation. The Fick principle was applied to estimate RMRO 2 . The results on caffeine and control days were compared to evaluate the capability of the proposed method to estimate renal oxygen consumption. A paired t-test was used to assess the statistical significance., Results: Estimated renal blood flow (RBF), QSM, and RMRO 2 maps were consistent with those reported in the literature. RMRO 2 values were higher than the cerebral metabolic rate of oxygen (CMRO 2 ) and were significantly reduced on the caffeine days compared to the control days, consistent with findings from non-MRI literature., Conclusion: The feasibility of measuring renal oxygen consumption using pCASL and QSM images was demonstrated. To the best of our knowledge, this work provides quantitative maps of renal oxygen consumption in humans for the first time. The results were consistent with the literature, including the statistically significant reduction in renal oxygen consumption with caffeine challenge. These findings suggest the potential utility of our technique in measuring renal oxygen consumption noninvasively, especially for patients with complications associated with contrast agents., (© 2024 International Society for Magnetic Resonance in Medicine.)

Amphotericin B (AmB) has been a cornerstone in the treatment of invasive fungal infections for over 6 decades. Compared with conventional amphotericin B deoxycholate (AmB-DOC), liposomal amphotericin B has comparable efficacy but less nephrotoxicity. The main purpose of this study was to investigate the reason why liposomal amphotericin B has similar therapeutic effects but lower toxicity and the differences of distribution in humans between liposomal amphotericin B and AmB-DOC. To compare the distribution of liposomal amphotericin B and AmB-DOC in humans, the physiologically based pharmacokinetic (PBPK) model was established by bottom-up stepwise method. A rat PBPK model was established firstly, then verified in mouse level in consideration of interspecies differences in physiological- and drug-specific parameters, and finally the PBPK model was extrapolated to humans. Based on preclinical and clinical pharmacokinetic (PK) studies, the AmB-DOC and liposomal amphotericin B PBPK model were established, respectively. The simulated results of human PBPK model showed that the liposomal formulation changed the pharmacokinetic characteristics of AmB. Compared with AmB-DOC, the plasma exposure of liposomal formulation was higher, but the renal exposure was significantly reduced., (© 2024 John Wiley & Sons Ltd.)

This work aims to develop and implement a pulse-acquire sequence for three-dimensional (3D) single-voxel localized 13 C MRS in humans at 7 T, in conjunction with bilevel broadband 1 H decoupling, and to test its feasibility in vitro and in vivo in human calf muscle with emphasis on the detection of glycogen C 1 -C 6 . A localization scheme suitable for measuring fast-relaxing 13 C signals in humans at 7 T was developed and implemented using the outer volume suppression (OVS) and one-dimensional image selected in vivo spectroscopy (ISIS-1D) schemes, similar to that which was previously reported in humans at 4 T. The 3D 13 C localization scheme was followed by uniform 13 C adiabatic excitation, all complemented with an option for bilevel broadband 1 H decoupling to improve both 13 C sensitivity and spectral resolution at 7 T. The performance of the pulse-acquire sequence was investigated in vitro on phantoms and in vivo in the human calf muscle of three healthy volunteers, while measuring glycogen C 1 -C 6 . In addition, T 1 and T 2 of glycogen C 1 -C 6 were measured in vitro at 7 T, as well as T 1 of glycogen C 1 in vivo. The glycerol C 2 and C 1,3 lipid resonances were efficiently suppressed in vitro at 7 T using the OVS and ISIS-1D schemes, allowing distinct detection of glycogen C 2 -C 6 . While some glycerol remained in calf muscle in vivo, the intense lipid at 130 ppm was efficiently suppressed. The 13 C sensitivity and spectral resolution of glycogen C 1 -C 6 in vitro and glycogen C 1 in vivo were improved at 7 T using bilevel broadband 1 H decoupling. The T 1 and T 2 of glycogen C 1 -C 6 in vitro at 7 T were consistent compared with those at 8.5 T, while the T 1 of glycogen C 1 in vivo at 7 T resulted similar to that in vitro. Localized 13 C MRS is feasible in human calf muscle in vivo at 7 T, and this will allow further extension of this method for 13 C MRS measurements such as in the brain., (© 2024 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Despite immense interest in biomarker applications of extracellular vesicles (EVs) from blood, our understanding of circulating EVs under physiological conditions in healthy humans remains limited. Using imaging and multiplex bead-based flow cytometry, we comprehensively quantified circulating EVs with respect to their cellular origin in a large cohort of healthy blood donors. We assessed coefficients of variations to characterize their biological variation and explored demographic, clinical, and lifestyle factors contributing to observed variation. Cell-specific circulating EV subsets show a wide range of concentrations that do not correlate with cell-of-origin concentrations in blood, suggesting steady-state EV subset concentrations are regulated by complex mechanisms, which differ even for EV subsets from the same cell type. Interestingly, tetraspanin+ circulating EVs largely originate from platelets and to a lesser extent from lymphocytes. Principal component analysis (PCA) and association analyses demonstrate high biological inter-individual variation in circulating EVs across healthy humans, which are only partly explained by the influence of sex, menopausal status, age and smoking on specific circulating EV and/or tetraspanin+ circulating EV subsets. No global influence of the explored subject's factors on circulating EVs was detected. Our findings provide the first comprehensive, quantitative data towards the cell-origin atlas of plasma EVs, with important implications in the clinical use of EVs as biomarkers., (© 2025 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Objective: There are no criteria for what type of manuscript and to what extent ChatGPT use is permissible in writing manuscripts. I aimed to determine which, human or ChatGPT, writes more readable letters to the editor and whether ChatGPT writes letters mimicking a certain person. I aimed to provide hints as to what makes the difference between humans and ChatGPT., Methods: This is a descriptive pilot study. I tasked ChatGPT (version 3.5) with generating a disagreement letter to my previous article (Letter 0). I wrote a letter involving three weaknesses of the addressed article (Letter 1). I provided ChatGPT with these three weaknesses and tasked it with generating a letter (Letter 2). Then, I supplied my authored letters and tasked ChatGPT with emulating my writing style (Letter 3). Eight professors evaluated the letters' readability and ChatGPT assessed which letter was more likely to be accepted., Results: ChatGPT produced coherent letters (Letters 0 and 2). Professors rated the readability of Letters 1 and 2 similarly, finding Letter 3 less readable. ChatGPT determined that the human-authored Letter 1 had a slightly higher acceptance likelihood than the ChatGPT-generated Letter 2. Although ChatGPT identified personal writing styles, its mimicry did not enhance the letter's quality., Conclusion: This preliminary experiment indicates that human-written letters are perceived to be as readable as, or no less readable than, ChatGPT-generated ones. It suggests that human touch, with its inherent enthusiasm, is essential for effective letter writing. Further comprehensive investigations are warranted to ascertain the extent to which ChatGPT can be used in this domain., (© 2024 International Federation of Gynecology and Obstetrics.)

An over-the-counter product berberine (a major alkaloid in goldenseal) is a substrate of the uptake transporter OCT1 and the metabolizing enzyme CYP2D6. The two genes exhibit common functional polymorphisms. Approximately 9% of Europeans and white Americans are either poor CYP2D6 metabolizers or poor OCT1 transporters. In this study, we investigated the effects of OCT1 and CYP2D6 polymorphisms on berberine pharmacokinetics in humans. We confirmed in vitro that berberine is an OCT1 substrate (K M of 7.0 μM, CL int of 306 ± 29 μL/min/mg). Common OCT1 alleles *3 to *6 showed uptake reduced by at least 65% and Oct1/2 knockout mice showed 3.2-fold higher AUCs in liver perfusion experiments. However, in humans, poor OCT1 transporters did not show any differences in berberine pharmacokinetics compared with reference participants. In contrast, CYP2D6 polymorphisms significantly affected berberine metabolism, but exclusively in females. Females who were poor CYP2D6 metabolizers had an 80% lower M1-to-berberine ratio. General linear model analyses suggest strong synergistic, rather than additive, effects between female sex and CYP2D6 genotype. Overall, berberine displayed low oral bioavailability, yet females had a 2.8-fold higher AUC and a 3.6-fold higher C max than males (P < 0.001). These effects were only partially attributable to the sex-CYP2D6 genotype interaction. In conclusion, despite berberine being an OCT1 substrate, OCT1 deficiency did not affect berberine pharmacokinetics in humans. In contrast, CYP2D6 emerges as a critical enzyme for berberine metabolism in females, but not in males, highlighting sex-specific differences. We suggest that factors beyond CYP2D6 metabolism are determining berberine's systemic exposure, especially in males (NCT05463003)., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The inhibition of renal transport proteins organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1, MATE2-K), and organic anion transporters (OAT1, OAT3) causes clinically relevant drug-drug interactions (DDI). Endogenous biomarkers could be used to improve risk prediction of such renal DDIs. While a number of biomarkers for renal DDIs have been described so far, multiple criteria for valid biomarkers have frequently not been investigated, for example, specificity, metabolism, or food effects. Therefore, there is a need for novel biomarkers of renal DDIs. Here, we investigated the global metabolomic effects following the administration of two classical inhibitors of renal transport proteins [cimetidine (OCT2/MATEs), probenecid (OATs)] in human plasma and urine of healthy volunteers. Additionally, we investigated metabolomic effects of two inhibitors of other transporters [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides)] as controls. This analysis shows that both cimetidine and probenecid affect compounds involved in caffeine metabolism, carnitines, and sulfates. Hierarchical cluster analysis of the effects of all four inhibitors on endogenous compounds identified multiple promising new sensitive and specific biomarker candidates for OCT2/MATE- or OAT-mediated DDIs. For OCT2/MATEs, 5-amino valeric acid betaine (median log 2 -fold change of estimated renal elimination: -3.62) presented itself as a promising candidate. For OATs, estimated renal elimination of 7-methyluric acid and cinnamoylglycine (median log 2 -fold changes -3.10 and -1.92, respectively) was both sensitive and specific. This study provides comprehensive information on metabolomic effects of transport protein inhibition in humans and identifies putative new sensitive and specific biomarkers for renal transporter-mediated DDIs., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Two key series of discoveries about the hippocampus are described. One is the discovery of hippocampal spatial view cells in primates. This discovery opens the way to a much better understanding of human episodic memory, for episodic memory prototypically involves a memory of where people or objects or rewards have been seen in locations "out there" which could never be implemented by the place cells that encode the location of a rat or mouse. Further, spatial view cells are valuable for navigation using vision and viewed landmarks, and provide for much richer, vision-based, navigation than the place to place self-motion update performed by rats and mice who live in dark underground tunnels. Spatial view cells thus offer a revolution in our understanding of the functions of the hippocampus in memory and navigation in humans and other primates with well-developed foveate vision. The second discovery describes a computational theory of the hippocampal-neocortical memory system that includes the only quantitative theory of how information is recalled from the hippocampus to the neocortex. It is shown how foundations for this research were the discovery of reward neurons for food reward, and non-reward, in the primate orbitofrontal cortex, and representations of value including of monetary value in the human orbitofrontal cortex; and the discovery of face identity and face expression cells in the primate inferior temporal visual cortex and how they represent transform-invariant information. This research illustrates how in order to understand a brain computation, a whole series of integrated interdisciplinary discoveries is needed to build a theory of the operation of each neural system., (© 2024 The Author(s). Hippocampus published by Wiley Periodicals LLC.)

Background: Commonly used models for eliciting muscle pain involve the injection of algesic substances or the induction of delayed onset muscle soreness. The former require invasive procedures, and the time frame for pain induction and subsidence in the latter can be inconvenient. This study presents a detailed spatiotemporal characterization of a new experimental model of muscle pain based on short-wave diathermy (SWD), developed to overcome the limitations of existing models., Methods: The shoulder was selected as target site and the effects of the model were tested in two sessions to assess its reliability. Pain intensity profiles were recorded during the application of SWD, and changes in pressure pain threshold (PPT) in the infraspinatus muscle, together with pain intensity, duration, and quality were assessed 30 min after induction., Results: SWD-induced pain intensity scores averaged 4 points on a visual analogue scale, whereas PPT showed a consistent decrease of about 25% relative to baseline values. Pain was localized in the shoulder area, and was described as continuous, dull, well-delimited, heavy, and bearable. Pain lasted for an average of 145 min without requiring reinduction and was reliably elicited in both experimental sessions., Conclusion: SWD can be used to elicit experimental muscle pain in a non-invasive, long-lasting, and reliable way and allows for repeated within- and between-session testing in the shoulder., Significance Statement: SWD produces deep heating in muscles by converting electromagnetic energy to thermal energy. It was previously shown that it can be used to elicit experimental pain in the forearm muscles, and the present study demonstrates that this can be reliably generalized to other body sites, such as the shoulder. Furthermore, SWD application is non-invasive and presents a convenient time frame for pain induction and subsidence, thus overcoming limitations associated with traditional muscle pain models., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Riboflavin (vitamin B 2 ) has been proposed as a biomarker for breast cancer resistance protein (BCRP) activity. In recent studies in mice, cynomolgus monkeys, and humans, BCRP-inhibiting drugs increased the plasma concentration of riboflavin. We showed recently that ticagrelor inhibits BCRP and raises the plasma concentrations of the BCRP substrate rosuvastatin in healthy volunteers. In the same drug-drug interaction study, we now investigated whether ticagrelor affects the plasma concentrations of riboflavin. Intake of 90 mg ticagrelor increased the ratio between the peak plasma riboflavin concentration and the fasting riboflavin concentration before ticagrelor administration by 1.20-fold (90% confidence interval, 1.10-1.32; P = 0.006) compared to placebo. In vitro, riboflavin was transported by BCRP and multidrug-resistance-associated protein 4 (MRP4) but no clear transport was observed by MRP2, MRP3, or the P-glycoprotein. Moreover, ticagrelor inhibited the transport of riboflavin in BCRP- and MRP4-expressing membrane vesicles with unbound 50% inhibitory concentrations of 0.020 and 1.1 μM, respectively. Based on vesicle and tissue protein expression data, the small intestinal MRP4-mediated efflux clearance of riboflavin (1.2-1.4 nL/min/mg) was estimated to be similar to that mediated by BCRP (0.23-1.3 nL/min/mg). As MRP4 is expressed in the basolateral membrane of enterocytes, it may facilitate the absorption of riboflavin and impair the utility of riboflavin as a biomarker of intestinal BCRP. To conclude, ticagrelor modestly raises the plasma concentration of riboflavin probably by inhibiting intestinal BCRP. Inhibition of intestinal MRP4 may have reduced the absorption of riboflavin and limited the effect of ticagrelor on riboflavin levels., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Vaccine efficacy varies globally, often showing reduced immune responses in low- and middle-income countries, possibly due to the immunomodulatory effects of parasitic infections like malaria. This systematic review evaluates the impact of malaria on immune responses to unrelated vaccines in humans and animals. We systematically searched five databases-MEDLINE, Web of Science, Global Health, Scopus and Embase-up to 5th December 2023. Eligible studies compared immune responses to WHO-approved vaccines between malaria-infected and uninfected groups, or between antimalarial-treated and untreated groups. Meta-analysis was performed using random-effects models with standardised mean differences (SMDs) as summary statistics. The study is registered with PROSPERO (CRD42022298053). Twenty-four articles (17 human, 7 animal) met the inclusion criteria, with 13 human articles contributing data for the meta-analysis. Significant heterogeneity was observed. Vaccine responses were higher in malaria uninfected individuals (SMD 0.34, 95% CI 0.07 to 0.60, I 2  = 87.15%) with weaker differences between antimalarial-treated and untreated groups (SMD 0.07, 95% CI -0.01 to 0.16, I 2  = 85.01%). The overall SMD for malaria uninfected/treated vs. infected/untreated was 0.15, 95% CI 0.05-0.26, I 2  = 90.91. Narrative analysis suggested malaria's adverse impact on vaccine responses in animals. Malaria infection may impair vaccines responses; with preventive treatment of malaria partially reversing these effects, highlighting the need for targeted public health interventions., (© 2024 The Author(s). Parasite Immunology published by John Wiley & Sons Ltd.)

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy., (© 2024, The American College of Clinical Pharmacology.)

The aim of this study was to assess the pharmacokinetics of the existing remdesivir intravenous formulation (100 mg dose) against the newly developed oral formulation (20 mg dose) for remdesivir and its active nucleoside metabolite (GS-441524) in beagle dogs followed by healthy human volunteers. A quantification method for remdesivir and its active nucleoside metabolite (GS-441524) in beagle dog and human plasma has been developed and validated using liquid chromatography coupled to triple quadrupole mass spectrometry detection. The analytical methods for beagle dogs and human differ in the calibration curve range, plasma matrix, processing volume, reconstitution volume and injection volume; however all other parameters were same in both methods. A simple protein precipitation extraction was carried out using acetonitrile containing the internal standard remdesivir D5. Remdesivir and GS-441524 were separated on an Endurus C-18P, 100 × 4.6 mm, 3 μm column and detected using a mass spectrometer with electrospray ionization in positive ion mode. The ion transitions used were m/z 603.1 → m/z 200.0 for remdesivir, m/z 292.0 → m/z 202.2 for GS-441524 and m/z 608.2 → m/z 205.1 for remdesivir D5. The calibration curve results were linear in beagle dog plasma (2.0-2,000.8 ng/ml range for remdesivir and 2.0-1,500.4 ng/ml for GS-441524) and human plasma (30.0-4,503.9 ng/ml range for remdesivir and 2.0-200.4 ng/ml for GS-441524). The recovery was >90% in beagle dog and human plasma. These methods were successfully used to determine the pharmacokinetic parameters of the intravenous injection and subcutaneous tablets dosage forms in beagle dogs and healthy humans., (© 2024 John Wiley & Sons, Ltd.)

BI 187004, a selective small-molecule inhibitor of 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β-HSD1 inhibition (50%) was detected in a very low-dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose-dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target-mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high-affinity and low-capacity target 11β-HSD1. The non-intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small-molecule compound. Among the various models explored, the best model was a two-compartment TMDD model with three transit absorption components. The final model provides insights into 11β-HSD1 binding-related parameters for BI 187004, including the total amount of 11β-HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM -1 h -1 ), and the first-order dissociation rate constant (estimated to be 0.11 h -1 ). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004's future clinical trials., (© 2024 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Toxoplasmosis as a zoonotic disease has a worldwide distribution and can infect a wide range of animal hosts, as well as at least one third of the world's human population. The disease is usually mild or asymptomatic in immunocompetent individuals, but dormant tissue cysts survive especially in the brain for the host lifespan, known as latent toxoplasmosis (LT). Recent studies suggest that LT can have certain neurological, immunological psychological and behavioural effects on human including schizophrenia, bipolar disorder, Alzheimer's disease, depression, suicide anxiety and sleeping disorders. LT effects are controversial, and their exact mechanisms of action is not yet fully understood. This review aims to provide an overview of the potential effects, their basic mechanisms including alteration of neurotransmitter levels, immune activation in the central nervous system and induction of oxidative stress. Additionally, beneficial effects of LT, and an explanation of the effects within the framework of manipulation hypothesis, and finally, the challenges and limitations of the current research are discussed., (© 2024 John Wiley & Sons Ltd.)

ABSTRACT Anthropogenic activities often lead to changes in the distribution and behavior of wild species. The mere presence of humans and free‐roaming domestic cats (Felis catus) can affect wildlife communities; however, responses to these disturbances might not be ubiquitous and may vary with local conditions. We investigated European pine marten's (Martes martes) distribution on Elba Island, Italy, where the species is the only wild carnivore. In this system, pine martens act as the top predator, and human presence is mostly driven by seasonal tourism. We evaluated (1) pine marten's occurrence in relation to vegetation type and elevation and the potential effects of proximity to settlements, (2) whether pine marten's distribution was associated with the co‐occurrence of humans and domestic cats, and, if so, (3) whether these co‐occurrence patterns were associated with proximity to anthropogenic infrastructures. Additionally, we explored similarities in activity patterns between pine marten and the other two species. We collected camera‐trap data at 77 locations throughout Elba Island in February–July 2020. Using single‐season multistate occupancy models, we found evidence that pine martens' occupancy was generally high across all vegetation types and elevation, and proximity to settlements was only weakly associated with the species occurrence. Contrary to expectations, we found no evidence of an association between pine martens' distribution and the presence of either humans or free‐roaming domestic cats on Elba Island. Opposing activity patterns might have facilitated pine martens' co‐existence with humans, with pine martens being active at ground level almost exclusively during nighttime. On the contrary, cats and pine martens showed similar activity patterns, and further studies are needed to define the co‐existence mechanisms. These findings have important management implications and suggest that response to direct and indirect anthropogenic pressures can be highly context‐dependent and mediated by the availability of resources and competition mechanisms.

Individuals with low socioeconomic status (SES) are at greater risk of contracting and developing severe disease compared with people with higher SES. Age, sex, host genetics, smoking and cytomegalovirus (CMV) serostatus are known to have a major impact on human immune responses and thus susceptibility to infection. However, the impact of SES on immune variability is not well understood or explored. Here, we used data from the Milieu Intérieur project, a study of 1000 healthy volunteers with extensive demographic and biological data, to examine the effect of SES on immune variability. We developed an Elo-rating system using socioeconomic features such as education, income and home ownership status to objectively rank SES in the 1000 donors. We observed sex-specific SES associations, such as females with a low SES having a significantly higher frequency of CMV seropositivity compared with females with high SES, and males with a low SES having a significantly higher frequency of active smoking compared with males with a high SES. Using random forest models, we identified specific immune genes which were significantly associated with SES in both baseline and immune challenge conditions. Interestingly, many of the SES associations were sex stimuli specific, highlighting the complexity of these interactions. Our study provides a new way of computing SES in human populations that can help identify novel SES associations and reinforces biological evidence for SES-dependent susceptibility to infection. This should serve as a basis for further understanding the molecular mechanisms behind SES effects on immune responses and ultimately disease., (© 2024 The Author(s). Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.)

Cross-species differences in drug transport and metabolism are linked to poor translation of preclinical pharmacokinetic and toxicology data to humans, often resulting in the failure of new chemical entities (NCEs) during clinical drug development. Specifically, inaccurate prediction of renal clearance and renal accumulation of NCEs due to differential abundance of enzymes and transporters in kidneys can lead to differences in pharmacokinetics and toxicity between experimental animals and humans. We carried out liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based protein quantification of 78 membrane drug-metabolizing enzymes and transporters (DMETs) in the kidney membrane fractions of humans, rats, and mice for characterization of cross-species and sex-dependent differences. In general, majority of DMET proteins were higher in rodents than in humans. Significant cross-species differences were observed in 30 out of 33 membrane DMET proteins quantified in all three species. Although no significant sex-dependent differences were observed in humans, the abundance of 28 and 46 membrane proteins showed significant sex dependence in rats and mice, respectively. These cross-species and sex-dependent quantitative abundance data are valuable for gaining a mechanistic understanding of drug renal disposition and accumulation. Further, these data can also be integrated into systems pharmacology tools, such as physiologically based pharmacokinetic models, to enhance the interpretation of preclinical pharmacokinetic and toxicological data., (© 2024 The Authors. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Abstract In muscle, digoxin inhibits Na+,K+‐ATPase (NKA) whereas acute exercise can increase NKA gene expression, consistent with training‐induced increased NKA content. We investigated whether oral digoxin increased NKA isoform mRNA expression (qPCR) in muscle at rest, during and post‐exercise in 10 healthy adults, who received digoxin (DIG, 0.25 mg per day) or placebo (CON) for 14 days, in a randomised, double‐blind and cross‐over design. Muscle was biopsied at rest, after cycling 20 min (10 min each at 33%, then 67% V̇O2peak), then to fatigue at 90% V̇O2peak and 3 h post‐exercise. No differences were found between DIG and CON for NKA α1–3 or β1–3 isoform mRNA. Both α1 (354%, P = 0.001) and β3 mRNA (P = 0.008) were increased 3 h post‐exercise, with α2 and β1–2 mRNA unchanged, whilst α3 mRNA declined at fatigue (−43%, P = 0.045). In resting muscle, total β mRNA (∑(β1+β2+β3)) increased in DIG (60%, P = 0.025) and also when transcripts for each isoform were normalised to CON then either summed (P = 0.030) or pooled (n = 30, P = 0.034). In contrast, total α mRNA (∑(α1+α2+α3), P = 0.348), normalised then summed (P = 0.332), or pooled transcripts (n = 30, P = 0.717) did not differ with DIG. At rest, NKA α1–2 and β1–2 protein abundances were unchanged by DIG. Post‐exercise, α1 and β1–2 proteins were unchanged, but α2 declined at 3 h (19%, P = 0.020). In conclusion, digoxin did not modify gene expression of individual NKA isoforms at rest or with exercise, indicating NKA gene expression was maintained consistent with protein abundances. However, elevated resting muscle total β mRNA with digoxin suggests a possible underlying β gene‐stimulatory effect. Highlights What is the central question of this study? Na+,K+‐ATPase (NKA) in muscle is important for Na+/K+ homeostasis. We investigated whether the NKA‐inhibitor digoxin stimulates increased NKA gene expression in muscle and exacerbates NKA gene responses to exercise in healthy adults. What is the main finding and its importance? Digoxin did not modify exercise effects on muscle NKA α1–3 and β1–3 gene transcripts, which comprised increased post‐exercise α1 and β3 mRNA and reduced α3 mRNA during exercise. However, in resting muscle, digoxin increased NKA total β isoform mRNA expression. Despite inhibitory‐digoxin or acute exercise stressors, NKA gene regulation in muscle is consistent with the maintenance of NKA protein contents.

Abstract Habitual short sleep durations are associated with several cardiovascular diseases. Experimental research generally supports these findings as metrics of arterial function are impaired after complete deprivation of sleep and after longer periods of partial sleep restriction. The acute influence of a single instance of partial sleep restriction (PSR), however, has not been defined. We evaluated arterial structure and function among 32 university‐aged participants on two occasions: once after normal habitual sleep (NS), and again the morning after an acute partial sleep restriction (PSR) intervention involving only 3 h of sleep for a single night. Endothelial function was measured using ultrasonography at the brachial artery via flow‐mediated dilatation (FMD), and a ramp peak oxygen uptake test was used to evaluate cardiorespiratory fitness. Blood samples were collected from a subset of participants to investigate the influence of circulatory factors on cellular mechanisms implicated in endothelial function. Sleep duration was lower after a night of PSR compared to NS (P 0.05). Ex vivo cell culture results aligned with in vivo data, showing that acute PSR does not alter intracellular processes involved in endothelial function. No differences in arterial structure or function were observed between NS and acute PSR in healthy and young participants, and cardiorespiratory fitness does not modulate the arterial response to acute sleep restriction.

Abstract Background: Dogs are the most popular pet animals worldwide, and their frequent and close contact with humans poses an increased risk of zoonotic parasite transmission. Toxocara canis infection is a highly pervasive and economically significant zoonotic infection transmitted by dogs worldwide, commonly in tropical and subtropical regions, particularly in developing countries. Objectives: This study evaluates the epidemiological profile and associated risk factors of T. canis exposure among humans and T. canis infection in domestic dogs in two climatically different governorates in Egypt. Methods: Faecal samples from 360 domiciled dogs were examined using the flotation technique to detect T. canis eggs. In addition, 276 human serum samples were evaluated by enzyme‐linked immunosorbent assay over a period of 10 months from May 2021 to February 2022 in the Alexandria and Qena Governorates, Egypt. Results: Shedding of T. canis was identified in 33.33% (120/360) of dogs and the overall seroprevalence in the human population was 20.65% (57/276). Lower Egypt, represented by the Alexandria Governorate, had higher canine infection (39.47%) and human seropositivity (29.87%) rates than those of Upper Egypt, represented by Qena Governorate (26.47% and 9.02% in dogs and humans, respectively). Statistical analysis of the sociodemographic characteristics of the participants revealed that handwashing, washing of vegetables and fruits and sex were associated with human T. canis exposure. Conclusion: The prevalence rates of confirmed T. canis infection in the Egyptian dogs population and the associated human seropositivity rates reflect its importance as a public health concern and support the call to increase public awareness of this issue. The risk factors identified in this study can contribute to the development of more effective control and prevention strategies.

Abstract Rift Valley fever (RVF) is a severe zoonotic mosquito‐borne disease that represents an important threat to human and animal health, with major public health and socioeconomic impacts. This disease is endemic throughout many African countries and the Arabian Peninsula. This systematic review with meta‐analysis was conducted to determine the RVF prevalence in humans, mosquitoes and other animal species in Africa. The review also provides contemporary data on RVF case fatality rate (CFR) in humans. In this systematic review with meta‐analysis, a comprehensive literature search was conducted on the PubMed, Embase, Web of Science and Global Index Medicus databases from January 2000 to June 2022 to identify relevant studies. Pooled CFR and prevalence estimates were calculated using the random‐effects model. Subgroup analysis and sensitivity analysis were performed, and the I2‐statistic was used to investigate a potential source of heterogeneity. A total of 205 articles were included in the final analysis. The overall RVF CFR in humans was found to be 27.5% [95% CI = 8.0–52.5]. The overall pooled prevalence was 7.8% [95% CI = 6.2–9.6] in humans and 9.3% [95% CI = 8.1–10.6] in animals, respectively. The RVF prevalence in individual mosquitoes ranged from 0.0% to 25%. Subgroup analysis showed substantial heterogeneity with respect to geographical regions and human categories. The study shows that there is a correspondingly similar prevalence of RVF in human and animals; however, human CFR is much higher than the observed prevalence. The lack of a surveillance programme and the fact that this virus has subclinical circulation in animals and humans could explain these observations. The implementation of a One Health approach for RVF surveillance and control would be of great interest for human and animal health.

A review of the use of microdoses and isotopic microtracers for clinical intravenous pharmacokinetic (i.v. PK) data provision is presented. The extent of application of the varied approaches available and the relative merits of each are highlighted with the aim of assisting practitioners in making informed decisions on the most scientifically appropriate design to adopt for any given new drug in development. It is envisaged that significant efficiencies will be realized as i.v. PK data in humans becomes more routinely available for suitable assets in early development, than has been the case prior to the last decade., (© 2023 GSK Research and Development Ltd. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

For a long time, it was believed that new genes arise only from modifications of preexisting genes, but the discovery of de novo protein-coding genes that originated from noncoding DNA regions demonstrates the existence of a "motherless" origination process for new genes. However, the features, distributions, expression profiles, and origin modes of these genes in humans seem to support the notion that their origin is not a purely "motherless" process; rather, these genes arise preferentially from genomic regions encoding preexisting precursors with gene-like features. In such a case, the gene loci are typically not brand new. In this short review, we will summarize the definition and features of human de novo genes and clarify their process of origination from ancestral non-coding genomic regions. In addition, we define the favored precursors, or "hopeful monsters," for the origin of de novo genes and present a discussion of the functional significance of these young genes in brain development and tumorigenesis in humans. This article is categorized under: RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution., (© 2024 Wiley Periodicals LLC.)

Abstract Background Thromboelastography (TEG) is a widely utilized clinical testing method for real‐time monitoring of platelet function and the thrombosis process. Lipid metabolism disorders are crucial risk factors for thrombosis. The lipid metabolism characteristics of hamsters resemble those of humans more closely than mice and rats, and their relatively large blood volume makes them suitable for studying the mechanisms of thrombosis related to plasma lipid mechanisms. Whole blood samples from golden Syrian hamsters and healthy humans were obtained following standard clinical procedures. TEG was employed to evaluate coagulation factor function, fibrinogen (Fib) function, platelet function, and the fibrinolytic system. Methods The whole blood from hamster or healthy human was isolated following the clinical procedure, and TEG was employed to evaluate the coagulation factor function, Fib function, platelet function, and fibrinolytic system. Coagulation analysis used ACLTOP750 automatic coagulation analysis pipeline. Blood routine testing used XN‐2000 automatic blood analyzer. Results TEG parameters revealed that hamsters exhibited stronger coagulation factor function than humans (reaction time [R], p = 0.0117), with stronger Fib function (alpha angle, p

Abstract Background Cryptosporidium infection is one of the major causes of acute gastroenteritis and diarrhoea caused by a protozoan parasite affecting vertebrates and humans. The disease is prevalent in cases of immunocompromised individuals. Despite the impact of the diseases in calf and hospitalized humans, well‐documented studies are not available in the study area. Objectives The objectives of this study were to determine the prevalence of Cryptosporidium infection in calves and hospitalized humans and assess the major associated risk factors associated with Cryptosporidium infection in calves and hospitalized humans. Method A cross‐sectional study was conducted from November 2020 to March 2021 on calf and human Cryptosporidium infection in Libo Kemkem District, North West Ethiopia. A total of 193 calves and 122 human stool samples admitted to the hospital were used for this study. Three kebeles were selected purposely, and individual calves were selected using a simple random sampling method. A number of sampled calves were allocated proportionally to the selected kebeles. Human samples were collected using a systematic random sampling method. Faecal and stool samples were examined using a modified Ziehl–Neelsen staining method. Result The overall prevalence of calf and human Cryptosporidium infection found in this study was 15.5% and 11.5%, respectively. Age of calf, breed, body condition, water source, faecal consistency and hygienic condition were found significantly (p

Abstract Meiosis is a specialized cell division process that generates gametes for sexual reproduction. However, the factors and underlying mechanisms involving meiotic progression remain largely unknown, especially in humans. Here, it is first showed that HSF5 is associated with human spermatogenesis. Patients with a pathogenic variant of HSF5 are completely infertile. Testicular histologic findings in the patients reveal rare postmeiotic germ cells resulting from meiotic prophase I arrest. Hsf5 knockout (KO) mice confirms that the loss of HSF5 causes defects in meiotic recombination, crossover formation, sex chromosome synapsis, and sex chromosome inactivation (MSCI), which may contribute to spermatocyte arrest at the late pachytene stage. Importantly, spermatogenic arrest can be rescued by compensatory HSF5 adeno‐associated virus injection into KO mouse testes. Mechanistically, integrated analysis of RNA sequencing and chromatin immunoprecipitation sequencing data revealed that HSF5 predominantly binds to promoters of key genes involved in crossover formation (e.g., HFM1, MSH5 and MLH3), synapsis (e.g., SYCP1, SYCP2 and SYCE3), recombination (TEX15), and MSCI (MDC1) and further regulates their transcription during meiotic progression. Taken together, the study demonstrates that HSF5 modulates the transcriptome to ensure meiotic progression in humans and mice. These findings will aid in genetic diagnosis of and potential treatments for male infertility.

Abstract Whilst the exercise‐induced myokine interleukin‐6 (IL‐6) plays a beneficial role in cardiac structural adaptations, its influence on exercise‐induced functional cardiac outcomes remains unknown. We hypothesised that IL‐6 activity is required for exercise‐induced improvements in left ventricular global longitudinal strain (LV GLS). In an exploratory study 52 individuals with abdominal obesity were randomised to 12 weeks’ high‐intensity exercise or no exercise in combination with IL‐6 receptor inhibition (IL‐6i) or placebo. LV strain and volume measurements were assessed by cardiac magnetic resonance. Exercise improved LV GLS by −5.4% [95% CI: −9.1% to −1.6%] (P = 0.007). Comparing the change from baseline in LV GLS in the exercise + placebo group (−4.8% [95% CI: −7.4% to −2.2%]; P

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare neurometabolic disorder caused by disruption of the gamma-aminobutyric acid (GABA) pathway. A more detailed understanding of its pathophysiology, beyond the accumulation of GABA and gamma-hydroxybutyric acid (GHB), will increase our understanding of the disease and may support novel therapy development. To this end, we compared biochemical body fluid profiles from SSADHD patients with controls using next-generation metabolic screening (NGMS). Targeted analysis of NGMS data from cerebrospinal fluid (CSF) showed a moderate increase of aspartic acid, glutaric acid, glycolic acid, 4-guanidinobutanoic acid, and 2-hydroxyglutaric acid, and prominent elevations of GHB and 4,5-dihydroxyhexanoic acid (4,5-DHHA) in SSADHD samples. Remarkably, the intensities of 4,5-DHHA and GHB showed a significant positive correlation in control CSF, but not in patient CSF. In an established zebrafish epilepsy model, 4,5-DHHA showed increased mobility that may reflect limited epileptogenesis. Using untargeted metabolomics, we identified 12 features in CSF with high biomarker potential. These had comparable increased fold changes as GHB and 4,5-DHHA. For 10 of these features, a similar increase was found in plasma, urine and/or mouse brain tissue for SSADHD compared to controls. One of these was identified as the novel biomarker 4,5-dihydroxyheptanoic acid. The intensities of selected features in plasma and urine of SSADHD patients positively correlated with the clinical severity score of epilepsy and psychiatric symptoms of those patients, and also showed a high mutual correlation. Our findings provide new insights into the (neuro)metabolic disturbances in SSADHD and give leads for further research concerning SSADHD pathophysiology., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Melatonin exhibits potential for pain relief and long-term safety profile. We examined the analgesic effects of oral melatonin on osteoarthritis (OA) and investigated the underlying mechanism. Using data from a UK primary care database, we conducted a cohort study in individuals with OA to compare the number of oral analgesic prescriptions and the risk of knee/hip replacement between melatonin initiators and hypnotic benzodiazepines (i.e., active comparator) initiators using quantile regression models and Cox-proportional hazard models, respectively. To elucidate causation, we examined the effects of melatonin on pain behaviors and explored several metabolites that may serve as potential regulatory agents of melatonin in the monoiodoacetate rat model of OA. Using data from another community-based cohort study, that is, the Xiangya OA Study, we verified the association between the key serum metabolite and incident symptomatic knee OA. Compared with the hypnotic benzodiazepines cohort (n = 8135), the melatonin cohort (n = 813) had significantly fewer subsequent prescriptions of oral analgesics (50th percentile: 5 vs. 7, 75th percentile: 19 vs. 29, and 99th percentile: 140 vs. 162) and experienced a lower risk of knee/hip replacement (hazard ratio = 0.47, 95% Cl: 0.30-0.73) during the follow-up period. In rats, oral melatonin alleviated pain behaviors and increased serum levels of glycine. There was an inverse association between baseline serum glycine levels and the risk of incident symptomatic knee OA in humans (n = 760). In conclusion, our findings indicate that oral melatonin shows significant potential to be a novel treatment for OA pain. The potential role of glycine in its analgesic mechanism warrants further investigation., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In pre-eclampsia models, nicotinamide (NAM) has protective effects in pre-eclampsia and is being evaluated as a therapeutic nutraceutical in clinical studies. NAM undergoes extensive hepatic metabolism by NAM N-methyltransferase to methylnicotinamide (MNA), which is subsequently metabolized to methyl-2-pyridone-5-carboxamide (M2PY) by aldehyde oxidase. However, the pharmacokinetics of NAM and its major metabolites has never been studied in pregnant individuals. Blood samples were collected before and 1, 2, 4, 8, and 24 hours after single 1 g oral NAM dose in healthy pregnant (gestational age 24-33 weeks) and nonpregnant female volunteers (n = 6/group). Pooled urine was collected from 0 to 8 hours. NAM, MNA, and M2PY area under the concentration-time curve (AUC) data were analyzed by noncompartmental analysis. No difference in the plasma AUC 0→24 of NAM (median (25%-75%): 463 (436-576) vs. 510 (423, 725) μM*hour, P = 0.430) and its intermediate metabolite MNA (89.1 (60.4, 124.4) vs. 83.8 (62.7, 93.7) μM*hour, P = 0.515) was observed in pregnant and nonpregnant volunteers, respectively; however, the terminal metabolite M2PY AUC 0 → 24 was significantly lower in pregnant individuals (218 (188, 254) vs. 597 (460, 653) μM*hour, P < 0.001). NAM renal clearance (CL R ; P = 0.184), MNA CL R (P = 0.180), and total metabolite formation clearance (P = 0.405) did not differ across groups; however, M2PY CL R was significantly higher in pregnant individuals (10.5 (9.3-11.3) vs. 7.5 (6.4-8.5) L/h, P = 0.002). These findings demonstrate that the PK of NAM and systemic exposure to its intermediate metabolite MNA are not significantly altered during pregnancy, and systemic exposure to NAM's major metabolite M2PY was reduced during pregnancy due to increased renal elimination., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Abstract Premise Among the slowest steps in the digitization of natural history collections is converting imaged labels into digital text. We present here a working solution to overcome this long‐recognized efficiency bottleneck that leverages synergies between community science efforts and machine learning approaches. Methods We present two new semi‐automated services. The first detects and classifies typewritten, handwritten, or mixed labels from herbarium sheets. The second uses a workflow tuned for specimen labels to label text using optical character recognition (OCR). The label finder and classifier was built via humans‐in‐the‐loop processes that utilize the community science Notes from Nature platform to develop training and validation data sets to feed into a machine learning pipeline. Results Our results showcase a >93% success rate for finding and classifying main labels. The OCR pipeline optimizes pre‐processing, multiple OCR engines, and post‐processing steps, including an alignment approach borrowed from molecular systematics. This pipeline yields >4‐fold reductions in errors compared to off‐the‐shelf open‐source solutions. The OCR workflow also allows human validation using a custom Notes from Nature tool. Discussion Our work showcases a usable set of tools for herbarium digitization including a custom‐built web application that is freely accessible. Further work to better integrate these services into existing toolkits can support broad community use.

Abstract Background and Aims Alternative therapies, such as zinc supplementation, have been explored as potential interventions for sleep disorders. However, the efficacy of zinc supplementation in improving sleep quality remains uncertain. This systematic review aims to examine the impacts of zinc supplementation on sleep quality in humans. Methods The Web of Science, Medline, Scopus, and Google Scholar databases were comprehensively searched to find studies investigating the effect of zinc supplementation on sleep quality. After identifying relevant studies by screening, relevant data were extracted from them. The quality assessment was conducted using the Cochrane quality assessment tool. Results This systematic review included eight studies. The interventions ranged from 4 to 48 weeks, with a daily dose of zinc supplementation varying between 10 and 73.3 mg. The majority of the evidence examined in this review pointed to the significant improvement effect of zinc supplementation on sleep quality in adults compared to the control groups. Furthermore, zinc supplementation did not have a significant effect on sleep disorders. However, there was no consensus about these findings. Also, the effect of supplementation on sleep duration in nonadults was contradictory. Conclusions This systematic review suggests that zinc supplementation may lead to improvements in sleep quality. However, more research, primarily clinical trials, is needed to clarify the beneficial effects of zinc supplementation on sleep quality with consideration of dietary zinc intake and the Recommended Dietary Allowances of zinc (RDA) in the different populations. It is also recommended to investigate the effect of zinc supplementation on sleep quality in people with zinc deficiency in future studies.

Abstract A growing body of empirical evidence shows that experiences of nature provide people with diverse psychological benefits, including improved cognitive function and mental health. While our understanding of the proximate causes of these positive psychological responses of humans to nature has advanced, the ultimate (evolutionary) drivers behind them remain poorly understood. In this study, we provide a summary of several widely accepted evolutionary hypotheses originating from Biophilia, reviewing their challenges and limitations. Subsequently, we propose a new evolutionary psychological hypothesis—the greenery hypothesis—that integrates recent findings in evolutionary psychiatry with many experimental results unexplained by existing hypotheses/theories. Our proposed hypothesis states that humans have adapted to periodic severe drought and re‐watering cycles by developing both negative and positive psychological responses to the absence or presence of greenery within the landscape as cues to optimise their own behavioural activity. The greenery hypothesis holds the potential to yield several insights into the fundamental understanding of human psychological responses to nature exposure with significant implications for various related fields, including psychiatry, urban planning, and biodiversity conservation and restoration. Read the free Plain Language Summary for this article on the Journal blog.

Abstract The spatial expansion of human populations has increased the overlap between humans and wildlife, leading to the greater tolerance of many wildlife species to humans. However, our current understanding of the consequences of such tolerance is limited. In particular, we lack information on whether reduced behavioural responses to humans are indicative of reduced responses to other potential threats. We made use of a unique natural system comprising geographically adjacent, but nevertheless separate, populations of the threatened Nubian ibex (Capra nubiana) that are exposed to different levels of human disturbance to test the effects of exposure to humans on ibex behavioural responses to other stimuli. We measured flight initiation distance (FID) and alert distance (AD) in males approached by four different stimuli: a human, a human with a dog, a novel object, and a leopard model. Both FID and AD decreased for all stimuli as the human exposure level increased. Ibex in areas that are highly exposed to humans reduced their behavioural responses to humans more strongly compared to other stimuli. These findings suggest that tolerance for humans may be the product of several complementary behavioural mechanisms (such as habituation and non‐random dispersal). Policy implications. Our findings align with the concern that animals highly exposed to human beings may be less capable of surviving in the wild. Our results also emphasize that the interactions between people and wild animals (such as feeding them) determine the behavioural responses of wild animals, shaping patterns of human–wildlife conflict and co‐existence. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Many Asian elephant populations inhabit fragmented human‐dominated landscapes. Human–elephant conflict (HEC) has intensified in such regions, resulting in the deaths of hundreds of people and elephants each year. Controversy between stakeholders then arises as people debate the merits of HEC mitigation approaches, stifling progress. We conducted a survey to evaluate the opinions of experts, farmers and others who have and have not experienced HEC (n = 611), on the causes of HEC, the importance of, conservation of and co‐existence with elephants, and on the acceptability and effectiveness of potential HEC mitigation methods. Analysis of variance and the Potential for Conflict Index showed that all groups agreed with nine of the 10 causes of HEC assessed, on average. All respondent groups had mostly positive attitudes towards the importance and conservation of elephants. However, farmers exposed to HEC disagreed that people should co‐exist with elephants and supported the view that elephants should be removed from human habitats. All groups agreed on the acceptability and effectiveness of electric fencing, early warning systems with infrasonic call detectors, Global Positioning System collars and geophones. However, there was disparity in views between the experts and other stakeholder groups on the acceptability and effectiveness of restricting elephants to protected areas, and translocation of problem elephants to protected areas away from their capture site or to wild elephant holding grounds. While similar views between stakeholders on many subjects are encouraging for elephant conservation, the disparities identified should be given greater attention when planning HEC management programs to minimize conflict between stakeholders.

Abstract Scaring of wildlife is commonly used in attempts to reduce crop damage in agricultural landscapes, but relatively few studies exist on its actual effect. We tracked GPS‐tagged greylag geese (Anser anser) in south‐central Sweden, before and after scaring by approaching them either by walking or by drone. On the field level, we studied the scaring effect by estimating return rate to the field where scared. On the landscape level, we tested if geese were less prone to use agricultural fields after being scared. Geese immediately left the field when scared and 5 min later they were on average 990 m (±56 SE) from the scaring position. The proportion of GPS positions near the scaring position decreased significantly for at least 4 h after scaring. Geese showed a significant shift from agricultural fields to wetland habitats the first 4 h after scaring. However, the effect of scaring soon levelled off; after 24 h the field where scaring had occurred was used to the same extent as any other field in the landscape, and agricultural fields were used to the same extent by scared and undisturbed geese. We did not find any differences in response depending on scaring technique. The probability to return and use agricultural fields after scaring was higher for geese scared in the morning compared to in the afternoon. Moreover, the probability to return and use of agricultural fields were higher in spring than in other seasons. Practical implication. We found that scared geese tend to visit agricultural fields soon after scaring and that scaring alone tends ‘to move the problem around’. This suggests that scaring needs to be repeated across the landscape, but also that accommodation fields where geese do not cause damage may be needed to keep geese off conventional fields. However, our study presents a glimpse of promise as the rather simple drone used covers large areas quickly and minimizes walking in growing crops. With technological advancement and possible autonomous techniques, drones may be capable of providing repeated scaring over large areas in the future.

Abstract Aficamten, a cardiac myosin inhibitor, is being developed for the treatment of patients with symptomatic hypertrophic cardiomyopathy (HCM). The purpose of this study was to determine the absorption, metabolism, and excretion of aficamten. Eight healthy male participants received a single oral dose of 20 mg aficamten (containing approximately 100 μCi of radiocarbon). Blood, urine, and feces samples were collected up to a maximum of Day 26. The pharmacokinetics of aficamten were characterized by moderate absorption, with a median tmax of 2.0 h postdose. The median t1/2 of aficamten was 99.6 h with similar t1/2 observed for metabolites and total radioactivity in plasma and whole blood. The overall total recovery of administered total radioactivity was 89.7% with 57.7% of the dose recovered in feces and 32.0% in urine. The main circulating metabolites in plasma included monohydroxylated metabolites M1a (CK‐3834282) and M1b (CK‐3834283) accounting for 10.5% and 36.4% of the total radioactivity AUC both with a median tmax of 5 h. The other major plasma metabolite was M5 (an oxygen‐linked glucuronide conjugate of M1a), which accounted for 10.3% of the total plasma radioactivity exposure, with a tmax of 24 h. In urine, M5 was the most abundant metabolite with 8.02% total radioactive dose (TRD), followed by M1a and M1b with 6.16% and 2.85% TRD, respectively; however, there were no metabolites in urine observed at >10% of dose. The major metabolite in feces was M18 representing 44.1% of the radioactive dose. These findings indicated that aficamten was eliminated by metabolism, and to a minor extent, by fecal excretion of unchanged aficamten with renal excretion playing a minor role. Feces were the principal route of excretion of the radioactive dose.

Abstract The aim was to examine the acute effects of sprint exercise (SIT) on global gene expression in subcutaneous adipose tissue (AT) in healthy subjects, to enhance understanding of how SIT influences body weight regulation. The hypothesis was that SIT upregulates genes involved in mitochondrial function and fat metabolism. A total of 15 subjects performed three 30‐s all‐out sprints (SIT). Samples were collected from AT, skeletal muscle (SM) and blood (brachial artery and a subcutaneous AT vein) up to 15 min after the last sprint. Results showed that markers of oxidative stress, such as the purines hypoxanthine, xanthine and uric acid, increased markedly by SIT in both the artery and the AT vein. Purines also increased in AT and SM tissue. Differential gene expression analysis indicated a decrease in signaling for mitochondrial‐related pathways, including oxidative phosphorylation, electron transport, ATP synthesis, and heat production by uncoupling proteins, as well as mitochondrial fatty acid beta oxidation. This downregulation of genes related to oxidative metabolism suggests an early‐stage inhibition of the mitochondria, potentially as a protective mechanism against SIT‐induced oxidative stress.

Abstract Raptor‐aircraft collisions (bird strikes) pose a serious safety risk to civil aircraft. Even smaller raptors, such as American kestrels (Falco sparverius), can be problematic within airport environments. Given widespread declines in kestrel populations, public interest, logistical and financial constraints, and other factors, managing kestrels at airports presents some unique challenges. I conducted a study to determine which biological (e.g., age and sex of the bird) and logistical factors (e.g., month and translocation distance) might influence the return of American kestrels live‐captured and translocated from 42 civil airports and military airbases within the contiguous USA during 2016–2021. American kestrels were live‐captured, banded, and translocated various distances from the airfields which were then monitored for returning kestrels. I developed a set of candidate generalized linear mixed models (binomial distribution) involving all possible subsets of 4 factors (age, sex, month, and distance translocated) as well as interactions, and used the location where a kestrel was live‐captured (i.e., airport) as a random factor in all mixed models. The return rate of American kestrels was very low (

Abstract Changes in myonuclear architecture and positioning are associated with exercise adaptations and ageing. However, data on the positioning and number of myonuclei following exercise are inconsistent. Additionally, whether myonuclear domains (MNDs; i.e., the theoretical volume of cytoplasm within which a myonucleus is responsible for transcribing DNA) and myonuclear positioning are altered with age remains unclear. The aim of this investigation was to investigate relationships between age and activity status and myonuclear domains and positioning. Vastus lateralis muscle biopsies from younger endurance‐trained (YT) and older endurance‐trained (OT) individuals were compared with age‐matched untrained counterparts (YU and OU; OU samples were acquired during surgical operation). Serial, optical z‐slices were acquired throughout isolated muscle fibres and analysed to give three‐dimensional coordinates for myonuclei and muscle fibre dimensions. The mean cross‐sectional area (CSA) of muscle fibres from OU individuals was 33%–53% smaller compared with the other groups. The number of nuclei relative to fibre CSA was 90% greater in OU compared with YU muscle fibres. Additionally, scaling of MND volume with fibre size was altered in older untrained individuals. The myonuclear arrangement, in contrast, was similar across groups. Fibre CSA and most myonuclear parameters were significantly associated with age in untrained individuals, but not in trained individuals. These data indicate that regular endurance exercise throughout the lifespan might better preserve the size of muscle fibres in older age and maintain the relationship between fibre size and MND volumes. Inactivity, however, might result in reduced muscle fibre size and altered myonuclear parameters.

Background: Research has highlighted the physical complications of starvation, but there is less research examining the psychological effects of starvation in humans., Aims: This scoping review synthesises literature on the non-physical effects of starvation in humans., Method: Following PRISMA-ScR guidelines, we searched MEDLINE, PsycINFO, and Global Health for studies published between 1946 and 2023 examining the non-physical effects of starvation in individuals aged 2-79 years, including those who were starved, malnourished, stunted, wasted, underweight, had a restrictive eating disorder, or were raised in famine conditions., Results: From 16,555 abstracts, 851 articles on the effects of malnutrition were reviewed, and 318 were included. Among these, 35% focused on children and adolescents, 25.5% on adults with comorbid illnesses, 17% on older adults, 13% on those with eating disorders, 6% on adults without comorbidities, and 3.5% on famine survivors. Cognitive impairments were the most frequently reported effects in children. In adults and older adults, depression and anxiety were common, along with reduced cognitive functioning, reduced quality of life, social withdrawal, impaired sleep and impaired sexual functioning. Individuals with eating disorders experienced depression, anxiety, obsessive-compulsive symptoms, emotion regulation difficulties, and cognitive impairment., Conclusions: There is extensive evidence showing the detrimental non-physical consequences of starvation in children and adults. These findings should inform research, clinical interventions, and educational materials addressing the effects of insufficient nutrition, including in those with restrictive eating disorders., (© 2025 Eating Disorders Association and John Wiley & Sons Ltd.)

Drugs generally used in major depressive disorder are considered inappropriate for the more common milder forms. The efficacy of saffron extracts has been demonstrated in mild to moderate depression and in preclinical models of depression. However, evidence of saffron activity on reduced hedonic responsiveness and motivational anhedonia is limited. Since dopamine transmission dysfunctions are crucially involved in anhedonia and saffron seems to positively modulate dopamine release, we studied the potential antidepressant and anti-anhedonic effects of a standardized formulation of saffron extract in preclinical models of anhedonia-like behaviors, and patients diagnosed with unipolar or bipolar depression. We tested saffron activity in a rat model of stress-induced motivational anhedonia using sucrose self-administration protocols and investigated the molecular underpinnings of this effect focusing on DARPP-32 phosphorylation pattern in response to a reinforcer and BDNF-TrkB signaling, in the nucleus accumbens and medial prefrontal cortex. In parallel, with a pilot double-blind placebo-controlled study we investigated whether saffron add-on therapy reduced symptoms of depression and anhedonia, measured by the Montgomery-Åsberg Depression Rating Scale. Repeated saffron administration restored motivation and reactivity to reward-associated cues in anhedonic rats, likely modulating dopaminergic transmission and BDNF-TrkB signaling. In depressed patients, an 8-week saffron add-on therapy induced a global improvement in depressive symptoms and a significant reduction in anhedonia. The study supports a pro-motivational effect of saffron and suggests a potentially useful saffron-based augmentation strategy in anhedonic patients, albeit with limitations due to small sample size and short trial duration., (© 2025 The Author(s). Phytotherapy Research published by John Wiley & Sons Ltd.)

Objective: Risks and benefits of experimental fetal therapies can remain uncertain after initial clinical studies, especially long-term effects. Nevertheless, pregnant individuals may request them, hoping to benefit their future child. Guidance about offering experimental fetal therapies outside research (as "innovative therapy") is limited, despite their ethical complexity. We propose points for clinicians and reviewers to consider when deciding whether and how to offer experimental fetal therapies as innovative therapies after initial clinical studies., Method: We used conceptual analysis and a current case to develop points for consideration, grounded in broader debates on innovative therapy and the unique challenges associated with experimental fetal therapies., Results: Clinicians should evaluate whether offering experimental fetal therapies as innovative therapy is appropriate for a pregnant individual and their fetus. The anticipated risk-benefit ratio for the fetus should be favorable. For the pregnant individual, risks may outweigh benefits, within reasonable limits. Medical resources should be sufficient to ensure appropriate care. Clinicians should support pregnant individuals in making informed choices. Clinicians offering innovative therapies with more than minimal risk should collect and report data on outcomes. Independent review should take place., Conclusion: Considering these points may advance the interests of fetuses, future children, and their families., (© 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Purpose: To explore the potential of 3T deuterium metabolic imaging (DMI) using a birdcage 2 H radiofrequency (RF) coil in both healthy volunteers and patients with central nervous system (CNS) lesions., Methods: A modified gradient filter, home-built 2 H volume RF coil, and spherical k-space sampling were employed in a three-dimensional chemical shift imaging acquisition to obtain high-quality whole-brain metabolic images of 2 H-labeled water and glucose metabolic products. These images were acquired in a healthy volunteer and three subjects with CNS lesions of varying pathologies. Hardware and pulse sequence experiments were also conducted to improve the signal-to-noise ratio of DMI at 3T., Results: The ability to quantify local glucose metabolism in correspondence to anatomical landmarks across patients with varying CNS lesions is demonstrated, and increased lactate is observed in one patient with the most active disease., Conclusion: DMI offers the potential to examine metabolic activity in human subjects with CNS lesions with DMI at 3T, promising for the potential of the future clinical translation of this metabolic imaging technique., (© 2023 International Society for Magnetic Resonance in Medicine.)

Background: Horses can suffer from gastrointestinal (GI) disease in domestic environments, often precipitated by human-led changes in management. Understanding the consequences of these changes on equine gut microbiota is key to the prevention of such disease episodes., Objective: Profile the faecal microbiota of adult female Exmoor ponies under three management conditions, representing increasing levels of management by humans, encompassing different diets; whilst controlling for age, breed and sex., Study Design: Cross-sectional descriptive., Methods: Faecal samples were collected from three populations of Exmoor ponies kept under contrasting management conditions: 29 adult female ponies in groups with low management (LM) (n = 10), medium management (MM) (n = 10) and high management (HM) (n = 9) levels, based on diet, drug use, handling and exercise. Faecal microbial composition was profiled via high-throughput sequencing of the bacterial 16S rRNA gene, and functional metagenome predictions., Results: We observed profound step-wise changes in microbiome structure in the transition from LM to MM to HM. A relatively high abundance of Proteobacteria and Tenericutes was associated with the HM group; higher abundance of Methanobacteria was observed in the LM group. The MM group had intermediate levels of these taxa and exhibited high 'within group' variation in alpha diversity. Functional predictions revealed increased amino acid and lipid metabolism in HM; energy metabolism in LM and carbohydrate metabolism and immune/metabolic disease pathways in MM., Main Limitations: Low group sizes, incomplete knowledge of bacterial genomes in equine gut microbiota and it was not possible to assess the relative impact of diet, drug use, handling and exercise on the microbiome as variables were confounded., Conclusions: Human-led management factors had profound step-wise effects on faecal microbial composition. Based on functional metagenome predictions, we hypothesise that dietary differences between groups were the major driver of observed differences., (© 2023 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

Abstract The negative impact of large carnivore presence in human‐dominated landscapes manifests as livestock depredation and in extreme cases as attacks on humans. In the case of conflict with leopards in Nepal, attacks resulting in human fatality have become more frequent over time, thus creating an urgent socio‐ecological and management issue. We estimated the occurrence of leopard attacks in Nepal from human‐leopard conflict cases reported in the media. We used occupancy models to analyse data collected from online news reports on incidents of leopard attacks on humans to explore drivers of leopard attacks on a landscape scale. Our results suggest that the probability of occurrence of leopard attack is associated with human population density, terrain ruggedness and livestock density. The human population density effect may be indicative of a density‐dependent relationship, where attacks are more likely in areas where an increased abundance of humans increases encounter rates with leopards. The positive effect of livestock density suggests that livestock may be drawing leopards into human settlements, and consequently increasing the likelihood of attacks on humans. Terrain ruggedness might be offering ideal conditions to facilitate attacks on humans, for example remoteness and high amounts of cover to launch ambush attacks. We provide inference and insights into key determinants of leopard attacks on humans on a landscape scale. These insights can be used to guide future research, inform mitigation measures to reduce leopard attacks and foster a better understanding of the interaction between people and leopards. This study demonstrates the applicability and novelty of using a hierarchical modelling framework applied to freely and publicly available media reports to inform the applied management of human‐wildlife conflict at a national scale. Read the free Plain Language Summary for this article on the Journal blog.