AIM. Right ventricular (RV) function plays an important role in determining symptom burden and clinical outcomes in pulmonary hypertension (PH). Global Wasted Work (GWW) quantifies mechanical inefficiencies in RV performance associated with elevated afterload but remains understudied in precapillary PH. We evaluated the relationship between GWW and echocardiographic indices of RV failure, RV remodelling, RV-PA coupling and invasive hemodynamics, and studied its prognostic significance in precapillary PH. METHODS AND RESULTS. Myocardial work indices were assessed using 3D echocardiography in patients with well-defined precapillary PH and simultaneously performed right heart catheterization. Patients with poor image quality, significant valvular lesions and associated left heart disease were excluded. Among 61 patients, those with GWW≥38mmHg/% (n=31) exhibited larger RV end-systolic volume (60 [42 - 71] vs. 42 [35 – 46] ml/m 2, p=0.009), lower TAPSE (17 [16 – 20] vs. 20 [17 – 23] mm, p = 0.04), higher E a (1.32[0.98 – 1.57] vs. 0.92 [0.64– 1.29] mmHg/ml, p= 0.02) and higher pulmonary vascular resistance (11.1 [8.1 – 14.2] vs. 5.4 [3.4 – 8.7]WU, p=0.002) compared with GWW<38mmHg/%. GWW progressively decreased as RV longitudinal strain and RV-PA coupling improved and increased concomitant to decreasing cardiac index and increasing pulmonary vascular resistance. GWW was associated with increased risk of death or transplantation (HR: 2.5 [1.1 - 5.7]). CONCLUSIONS. Elevated GWW is associated with RV remodelling, worsening RV function and reduced survival in precapillary PH. Further studies are warranted in larger populations to explore potential utility of GWW in risk stratification, treatment monitoring and PH management.

A new approximation function is introduced to fit the solution of a fractional differential equation of order one-half. The analyzed case includes a nonhomogeneous term defined by a modified Bessel function of the first kind. The analytical solution of this equation corresponds to the product of two modified Bessel functions. The new fitting function is developed using the multipoint quasi-rational method, which uses both the series expansion of the Bessel function and its asymptotic expansion. Additionally, a significant modification is introduced to the structure of the fitting function to capture two terms of the asymptotic expansion of the Bessel functions. We show an example for fixed values, and the maximum relative error of the fitting function for the solution of the fractional differential equation of order one-half is 0 .18%, a remarkably low value considering that only six fitting parameters are used.

Purpose: To determine the positive predictive values (PPVs) of ICD-9 and ICD-10-based diagnostic coding algorithms to identify periprosthetic joint infection (PJI) following total hip arthroplasty (THA) within the United States (US) Veterans Health Administration (VHA). Methods: We selected patients with: (1) any position hospital discharge ICD-9 or ICD-10 diagnosis of PJI, (2) ICD-9, ICD-10, or Current Procedural Terminology (CPT) procedure codes for THA any time prior to PJI diagnosis, (3) CPT code for hip X-ray within ±90 days of the PJI diagnosis, and (4) 1 or more CPT codes for arthrocentesis, arthrotomy, or revision arthroplasty all occurring within ±90 days of the PJI diagnosis date. We obtained separate samples of patients for ICD-9 and ICD-10-based PJI diagnoses. These samples were stratified by THA medical center volume. Infectious disease physicians adjudicated each identified PJI event. The PPV (95% confidence interval [CI]) for the ICD-9 and ICD-10 PJI algorithms were calculated. Results: Among the 90 sampled hip PJI events for the ICD-9 era, 79 were confirmed PJIs (PPV, 87.8%; 95% CI, 79.2%-93.7%). For the 90 sampled hip PJI events for the ICD-10 era, 72 were confirmed PJIs (PPV, 80.0%; 95% CI, 70.3%-87.7%). Conclusion: These algorithms yielded a PPV of 87.8% (ICD-9) and 80.0% (ICD-10), for confirmed PJI events and could be considered for use in future pharmacoepidemiologic studies.

Obtaining genome‐wide data from complex samples, such as environmental material or bulk species collections, is increasingly feasible, yet inferring species presence and population genomic insights remains challenging. We applied metagenomic sequencing to 40 arthropod bulk samples collected with Malaise traps across Sweden and compared results with metabarcoding of the same material. Using a custom genome database, we achieved genus-level classification largely consistent with metabarcoding. While metagenomics detected all genera identified by metabarcoding, conservative filtering thresholds designed to minimize false positives also excluded some true signals, particularly for low-abundance taxa. Taxonomic overlap between methods was further constrained by limited reference database representation. Beyond taxonomic assignment, metagenomic sequencing yielded genome-level information: we inferred haplotype diversity, heterozygosity, and geographic population structure for several abundant species, including variable degrees of hybrid origin in red wood ants and the genetic distinctiveness of Gotland bumblebees. Finally, by-catch plant DNA present in the bulk samples revealed plausible arthropod–plant interactions, several of which align with known ecological associations. Together, these results demonstrate the potential of metagenomics for biodiversity monitoring and population genomics, while underscoring the importance of filtering criteria and comprehensive reference databases.

Title: Penile Fracture; An Emergency Managed Successfully In A Rural Setting : A Case Report

Children with asthma account for a large share of pediatric pulmonology patients, with global pediatric asthma prevalence estimated at 9.1%. In this Pediatric Pulmonology Year in Review, we aim to highlight and summarize publications on pediatric asthma that were published in the year 2024. Our aim was to focus on publications that may impact clinical practice, although we recognize that all publications may not apply to every practitioner. We also acknowledge that we as authors are unable to properly highlight every publication of clinical relevance on pediatric asthma. Any exclusions do not necessarily indicate a lack of relevance but rather a limitation of space. Articles on pediatric asthma were reviewed if they were published in 2024. After articles were collected, the authors reviewed the selections to determine if they had potential to impact the clinical care of pediatric patients with asthma. The final selection of publications was then grouped into themes to help orient the readers to areas of interest. In this review, we will highlight publications on Diagnosis and Monitoring, Treatment and Management, Environmental and Social Factors, Genetics and Biomarkers, and Innovative Programs and Health Policy. We hope this review will spark discussions on current clinical practices, as well as inspire future work on relevant topics.

Heat stress is a major abiotic stress that limits alfalfa ( Medicago sativa L.) productivity. To test whether cytokinin-overexpressing engineered rhizobia could enhance heat tolerance, we inoculated alfalfa with modified rhizobia and evaluated their physiological and molecular responses. We found that inoculation with engineered rhizobia significantly increased trans-Zeatin content in alfalfa. Compared with control rhizobia-inoculated plants, engineered rhizobia-inoculated plants exhibited increased plant height, fresh/dry weight, relative water content, and photosynthetic efficiency (total chlorophyll and carotenoids), alongside reduced hydrogen peroxide (H 2O 2) and superoxide (O 2 .-) levels under heat stress. RNA-seq analysis revealed that engineered rhizobia upregulated heat stress-responsive genes in alfalfa, which was further verified by qRT-PCR. Metabolomics analyses showed significant alterations in phenylpropanoid, flavonoid, phenolic acid, and salicylic acid metabolic pathways in engineered rhizobia-inoculated plants under heat stress. Contrary to conventional approaches, our results demonstrate that cytokinin-overexpressing rhizobia not only enhance alfalfa heat tolerance but also activate multi-pathway stress responses. Collectively, these findings propose a novel strategy for developing heat-tolerant alfalfa through engineered rhizobia-mediated cytokinin biosynthesis, which helps to promote the development of sustainable alfalfa breeding for heat-tolerant varieties.

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) has been associated with improvements in physical health and well-being. However, there are growing concerns about side-effects related to sleep, cognition and new or worsening mental health in a subset. This study assessed healthcare providers’ perceptions of the positive and negative impacts of ETI and compared provider ratings in Europe to the United States (US). Methods: The European CF Society’s Mental Health Working Group adapted and distributed the survey developed by the CF Foundation’s Mental Health Advisory Committee. It assessed healthcare providers’ observations of the impacts of ETI in these domains: 1) positive and negative physical and psychological effects, 2) sleep difficulties, 3) cognitive difficulties, 4) worsening mental health, and 5) concerns about the future and finances. Results: Seventy-eight healthcare providers across 21 European (EU) countries responded, endorsing similar percentages of positive physical and psychological effects as US providers. However, in Europe lower percentages of MH side-effects (e.g., increased depression/anxiety, suicidal ideation, body image), and concerns about the future (e.g., copays, food insecurity). Conclusions: Across international providers similar positive results were reported. A substantial proportion of PWCF across EU and US experienced ETI side-effects related to sleep, cognition, and new or worsening mental health. However, EU providers reported significantly fewer side-effects related to mental health, negative body image, planning for the future and finances. MH side-effects led to dosing changes in ETI and in the US, they led to changes in MH medications. These international data document the importance of systematically assessing and managing these side-effects.

Generalist species that benefit from human impacts on terrestrial ecosystems and expand their distribution range can threaten biodiversity by outcompeting or predating on native specialists. This is exemplified by the northward expansion of the red fox onto the arctic tundra where this mesopredator threatens endemic arctic fox and ground nesting bird populations. Here, effective management efforts to control the expansion depend on understanding the spatiotemporal scales of red fox movement within the tundra, and on identifying habitats that provide food resources to red foxes. We addressed these needs by studying the geographic space use and habitat selection of 14 red foxes on the low Arctic tundra of Varanger Peninsula in Norway by means of GPS telemetry. Red foxes used large home ranges and were especially mobile during winter, partly owing to occasional movements beyond home range boundaries. Home ranges were significantly smaller near the marine coastline and at higher human land use intensities, likely owing to higher food availability. These habitat features were also selected for within individual home ranges, confirming the importance of these habitats to red foxes on the tundra. High mobility necessitates large-scale culling efforts aimed at achieving long-term reductions in red fox densities. However, localized and temporary effects may be achieved by aligning culling with periods of reduced red fox movement and breeding of vulnerable species in late spring and summer. Additionally, reducing food subsidies associated with human land use could mitigate the underlying drivers of red fox expansion, offering a more sustainable approach to management.

The alteration of the hydrological regime caused by damming remains a critical challenge for river systems. The Rio Chama, a highly regulated river, has undergone severe alterations in its hydrological regime due to a series of dams that impact sediment transport mechanisms and riparian vegetation dynamics. This study employs remote sensing to assess reach-scale changes in riparian vegetation and geomorphology and field-informed 2D hydrodynamic modeling to determine sediment transport processes. We used a random forest classifier within Google Earth Engine and high-resolution NAIP imagery (2011 to 2022) to assess changes in riparian vegetation and channel planform. We evaluated the impact of different flows on sediment transport mechanisms, along with field-data-informed sediment distribution at the sub-reach scale. Following a 2009 high flow release, channel width remained relatively stable, although planform changes were observed, including shifts in the channel centerline and localized bank erosion, especially in the sinuous sections. Vegetation expanded over time and encroached along bars, linked to reduced overbank flooding and sustained baseflow year-round. Furthermore, results indicated that even smaller flows can lead to fine sediment displacement, while higher flows are necessary to mobilize coarse sediments. This study offers valuable insights for ecological flow recommendations, particularly for the Rio Chama, and supports improved restoration strategies and long-term river management in other dam-regulated systems across arid and semi-arid regions.

Cardiac contractility modulation – Making it workNiraj Varma MA, MD, PhD, FRCP

Navigating the Pre- and Post-AlphaFold Divide: CAPRI 8th evaluation meeting, February 12-14, Grenoble, FRAlexandre M.J.J. Bonvin1 and M. F. Lensink21 Bijvoet Centre for Biomolecular Research, Faculty of Science - Chemistry, Utrecht University, The Netherlands2 University of Lille, CNRS UMR8576 UGSF, Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France* Corresponding authors: marc.lensink@univ-lille.fr and a.m.j.j.bonvin@uu.nlBiomolecular interactions govern a broad spectrum of cellular and intercellular processes. Characterising these interactions at atomic resolution is fundamental for elucidating molecular mechanisms in health and disease and for guiding the development of novel therapeutics. In addition to classical structural biology methods—including X-ray crystallography, NMR, cryo-electron microscopy and tomography—as well as a wide array of complementary experimental techniques, computational approaches for predicting the structures of protein complexes have long played an essential and synergistic role. Over time, these computational methods have advanced to model increasingly large and intricate assemblies, often integrating diverse experimental and bioinformatics data within the framework of integrative structural biology. More recently, the advent of artificial intelligence (AI) has introduced powerful new predictive strategies, further expanding the toolkit of computational structural biology.Progress in this field has been closely monitored and continues to be catalysed by the Critical Assessment of Predicted Interactions (CAPRI) initiative (capri-docking.org ; https://www.ebi.ac.uk/pdbe/complex-pred/capri/ ), established in 2001. CAPRI provides a community-wide platform for blind assessment of modelling algorithms on experimentally determined protein complexes (called “targets”), made available to the organisers prior to publication. Prediction Rounds are launched as new targets arise and typically last 3–6 weeks. Registered participants are invited to predict the three-dimensional structure of target assemblies, using either sequence information alone or, when available, the structures of unbound components. CAPRI Rounds also include a Scoring challenge, in which participants must discriminate near-native solutions from ensembles of models gathered from all submissions. Groups may participate as Predictors, Scorers, or both. Comprehensive details on the organisation of CAPRI Rounds, evaluation procedures, and group performance rankings are available at the CAPRI websites.To date, 59 CAPRI Rounds have been completed, comprising more than 300 targets. Results from Rounds 1–45 were presented at seven assessment meetings between 2002 and 2018. Initially centred on homo- and hetero-protein complexes, CAPRI has progressively expanded its scope to encompass protein–peptide, protein–nucleic acid, and protein–carbohydrate assemblies. Several Rounds have further explored the prediction of binding affinities and the explicit modelling of interfacial water molecules. Since 2014, CAPRI has also conducted joint experiments with the Critical Assessment of Structure Prediction (CASP), fostering deeper integration across modelling methodologies and research communities. While CASP originally focused on the prediction of individual protein structures (http://predictioncenter.org/ ), it has since broadened its scope to include protein assemblies, protein–nucleic acid, and protein–ligand complexes. Outcomes from joint CAPRI–CASP challenges have been published in dedicated Special Issues ofProteins .1–7This CAPRI Special Issue reports on the prediction results for 16 targets from Rounds 47–55 (2020–2024). The extended evaluation period reflects both a scarcity of suitable targets and the disruption caused by the COVID-19 pandemic. During this period, the CAPRI community also contributed to the urgent modelling of SARS-CoV-2 complexes (the COVID effort, Round 51), which is not included in the present analysis. The current evaluation also excludes the CASP-linked Rounds 50 and 54, described elsewhere.8,9A total of 64 groups participated in these six Rounds, including 61 predictor and 53 scorer groups. Results were presented at the eighth CAPRI evaluation meeting, held jointly with the Integrative Computational Biology Workshop in February 2024 at the Institut de Biologie Structurale (IBS) in Grenoble, France (https://workshops.ill.fr/event/392/ ; http://www.capri-docking.org/events/ ). The meeting was organised by Dr. Martin Blackledge (IBS, Grenoble), Dr. Frédéric Cazals (INRIA, Sophia Antipolis), Dr. Sergei Grudinin (Université Grenoble Alpes), Dr. Anne Martel (Institut Laue-Langevin, European Neutron Source), Dr. Sylvain Prévost (Institut Laue-Langevin, European Neutron Source), Dr. Guy Schoehn (IBS, Grenoble), Dr. Mark Tully (ESRF, Grenoble), Dr. Martin Weik (IBS, Grenoble), Dr. Alexandre Bonvin (Utrecht University), and Dr. Shoshana Wodak (VIB-VUB Center for Structural Biology, Brussels).

Accurate prediction of community assembly is a central goal in ecology but is challenging because assembly could be governed by numerous mechanisms. Few theoretical models explicitly incorporate or test multiple mechanisms at once. We empirically tested the predictive performance of a plant community assembly model built using all possible combinations of four mechanisms (resource competition, spatiotemporal niche differentiation, dispersal and colonization, population growth rates) and 11 underlying attributes based on measured plant traits (e.g. fecundity, phenology). The full model accurately predicted out-of-sample observations of five grasses sown in mixture along a soil nitrogen gradient (overall R2 = 0.65). Alternative model variants, parameterized using subsets of the mechanisms and their nested attributes, still retained high explanatory power if the model included at least three of the four mechanisms. Our results suggest that plant community composition is determined by simultaneous effects of multiple mechanisms, and simpler theories have much lower predictive abilities.

Aim: Appropriate drug exposure is as crucial as proper selection and timely antibiotic administration in sepsis treatment. However, evidence is lacking regarding the current dosing regimen to achieve pharmacodynamic targets in patients with sepsis. This study aimed to describe ceftriaxone pharmacokinetic (PK) parameters and establish optimal dosing regimens for sepsis patients. Methods: This study investigated the pharmacokinetics of ceftriaxone in sepsis patients receiving ceftriaxone 2 g every 12 or 24 h. Blood samples (11–14 samples per patient) were collected within the first 24 h post-administration. PK parameters were estimated from unbound plasma concentrations using a non-linear mixed-effects modelling approach (NONMEM® software). Monte Carlo simulations were conducted to evaluate the probability of target attainment of standard and high-dose ceftriaxone at various minimum inhibitory concentrations (MICs). Results: Population PK analysis of 238 concentration-time data points from 20 patients revealed that a two-compartment model best described ceftriaxone PK. Glomerular filtration rate (GFR), serum albumin, and body weight significantly affected clearance, volume of distribution, and intercompartmental clearance, respectively. Simulation results demonstrated that the standard dose of 2 g every 24 h was adequate for pathogens with MIC ≤1 mg L -1. For pathogens with higher MICs (2–8 mg L -1), particularly in patients with GFR >130 mL min -1, a dose of 2 g every 12 h may be more appropriate. Conclusion: Standard ceftriaxone (2 g intravenous q 24 h, 30-min infusion) was adequate for susceptible pathogens, whereas modified regimens were warranted for patients infected with less susceptible organisms with augmented renal clearance.

BosR, the sole member of the ferric uptake regulator (FUR) family in Borrelia burgdorferi ( Bb), is essential for the spirochete’s transcriptional adaptation to the mammalian host environment. Although best known for activating rpoS and establishing the mammalian-phase RpoS regulon, BosR originally was linked to regulation of genes involved in Bb’s oxidative stress response. Here, we show that BosR governs gene expression through both RpoS-dependent and RpoS-independent mechanisms under in vitro and mammalian host-adapted conditions. Using RNA-seq and a DNA-binding-defective BosR-R39A mutant, we demonstrate that DNA binding is essential for BosR’s global regulatory functions. BosR activates rpoS, promotes RpoS-dependent gene regulation, and independently modulates a distinct set of genes involved in a variety of cellular functions, including genome maintenance, chemotaxis, and virulence. Notably, canonical oxidative stress response genes previously attributed to BosR were not differentially expressed in Δ bosR strains in vitro or in mammals. Despite its broad regulatory scope, BosR does not recognize a single, conserved DNA-binding motif, suggesting that DNA occupancy is influenced by local sequence context or DNA topology. Our findings support a bifunctional model in which BosR collaborates with RNA polymerase (RNAP)-RpoS holoenzyme to activate and repress RpoS-regulated genes, while functioning as a canonical FUR-like regulator to control RpoD-dependent genes independently of RNAP interaction.

When an action does not yield the sensory action effect associated with it, prediction error (PE) signals are generated. The present study investigates auditory event-related potential (ERP) markers of PE for violations of strong action-effect couplings as a function of whether the participants’ intention focuses on a particular action or a particular action effect. Participants produced high- and low-pitched tones by left and right button presses according to a pattern of visual stimuli. While the instruction as well as the action and tone sequences produced by the participants were identical, the type of intention induced by the visual symbols differed (in a between-subject design): In the action-effect intention group, the pattern consisted of “notes” (for high/low pitch), in the action intention group it consisted of “letters” (for left/right button-press). Occasionally, a button-press did not produce the associated sensory action effect. These incongruent sounds elicited an enhanced auditory N1 compared to congruent sounds in the “notes” but not the “letters” group which we interpret as PE signal. Actions selected by the intended action effect in the “notes” group presumably induced a predictive sensory representation of the action outcome, its violation resulting in an early PE at the level of the auditory N1. N2b and P3 were elicited in both groups. This suggests that the respective action-effect couplings were represented, and their violation processed at a conceptual level also in the “letters” group. These results support theories postulating that event representations bind together features of stimuli, actions, and associated outcomes.

Freezing of gait, a disabling symptom in Parkinson’s disease, presents a major challenge for wearable classification algorithms that struggle to distinguish pathological freezes from voluntary stops. To address this ambiguity, we evaluated whether incorporating eye-gaze kinematics could improve classification accuracy compared to using ankle-mounted inertial measurement units (IMUs) alone. We analyzed data from 10 participants performing standardized walking tasks and compared two deep learning classifiers differing only in their inputs: an IMU‑only model (bilateral ankle accelerometer and gyroscope) and an IMU+Gaze model that fuses IMU channels with 3D fixation‑velocity from the headset eye tracker. With subject‑independent five‑fold cross‑validation, the IMU+Gaze model improved macro‑averaged performance – precision 0.758 vs 0.675, recall 0.867 vs 0.701, and F1 0.801 vs 0.683 – relative to IMU‑only. Gains were largest for intentional standing (F1 0.679 vs 0.390), reducing the proportion of standing windows misclassified as freezing from 63.6% (14/22) to 9.1% (2/22). These findings show that gaze kinematics complement ankle kinematics for disambiguating voluntary stopping from FOG and potentially strengthen automated monitoring, clinician‑facing assessment, and patient‑facing assistive technologies.

IntroductionLateral meningocele is a rare form of spinal dysraphism where meningeal diverticula herniate through the neural foramina. While most meningoceles are dorsal and lumbosacral, lateral meningoceles typically occur in the thoracic region. The etiology is incompletely understood but is thought to involve failed caudal neural tube closure, influenced by folate deficiency, genetic factors, and environmental exposures [1, 2]. Associations with neurofibromatosis type 1 (NF-1) and connective tissue disorders like Marfan syndrome have been described [3].In rare instances, lateral meningoceles are a cardinal feature of Lehman syndrome, an autosomal dominant disorder caused by NOTCH3 gene mutations [4]. This syndrome’s phenotype includes distinct craniofacial dysmorphisms, growth deficiency, congenital heart defects, and feeding difficulties [2, 5]. While cognitive impairment and hearing loss have been documented, fewer than half of the 22 reported patients with Lehman syndrome had confirmed loss-of-function NOTCH3 mutations. [5, 6, 7]Here, we report a unique case of bilateral thoracic lateral meningoceles in a 6-month-old infant who presented without clinically apparent syndromic features. This case highlights the importance of including rare spinal anomalies in the differential diagnosis for infants with unexplained recurrent chest infections.