Impact of physical activity on surrogate markers of cardiovascular disease in the haemodialysis population.

Background: The haemodialysis (HD) population is sedentary, with substantial cardiovascular disease risk. In the general population, small increases in daily step count associate with significant reductions in cardiovascular mortality. This study explores the relationship between daily step count and surrogate markers of cardiovascular disease, including left ventricular ejection fraction (LVEF) and native T1 (a marker of diffuse myocardial fibrosis), within the HD population. Methods: This was a post hoc analysis of the association between daily step count and metabolic equivalent of task (MET) and prognostically important cardiac magnetic resonance imaging parameters from the CYCLE-HD study (ISRCTN11299707). Unadjusted linear regression and multiple linear regression adjusted for age, body mass index, dialysis vintage, haemoglobin, hypertension and ultrafiltration volume were performed. Significant relationships were explored with natural cubic spline models with four degrees of freedom (five knots). Results: A total of 107 participants were included [age 56.3 ± 14.1 years, 79 (73.8%) males]. The median daily step count was 2558 (interquartile range 1054-4352). There were significant associations between steps and LVEF (ß = 0.292; P = .009) and steps and native T1 (ß = -0.245; P = .035). Further modelling demonstrated most of the increase in LVEF occurred at up to 2000 steps/day and there was an inverse dose-response relationship between steps and native T1, with the most pronounced reduction in native T1 between ≈2500 and 6000 steps/day. Conclusions: The results suggest an association between daily step count and parameters of cardiovascular health in the HD population. These findings support the recommendations for encouraging physical activity but are not the justification. Further research should evaluate whether a simple physical activity intervention improves cardiovascular outcomes in individuals receiving maintenance HD.

Incorporating Noncovalent Interactions in Transfer Learning Gaussian Process Regression Models for Molecular Simulations.

FFLUX is a quantum chemical topology-based multipolar force field that uses Gaussian process regression machine learning models to predict atomic energies and multipole moments on the fly for fast and accurate molecular dynamics simulations. These models have previously been trained on monomers, meaning that many-body effects, for example, intermolecular charge transfer, are missed in simulations. Moreover, dispersion and repulsion have been modeled using Lennard-Jones potentials, necessitating careful parametrization. In this work, we take an important step toward addressing these shortcomings and show that models trained on clusters, in this case, a dimer, can be used in FFLUX simulations by preparing and benchmarking a formamide dimer model. To mitigate the computational costs associated with training higher-dimensional models, we rely on the transfer of hyperparameters from a smaller source model to a larger target model, enabling an order of magnitude faster training than with a direct learning approach. The dimer model allows for simulations that account for two-body effects, including intermolecular polarization and charge penetration, and that do not require nonbonded potentials. We show that addressing these limitations allows for simulations that are closer to quantum mechanics than previously possible with the monomeric models.

Assessment of Posttransplant Bacteremia Caused by Extended-Spectrum Beta-Lactamase-Producing Gram-Negative Bacteria Among Kidney Transplant Recipients.

BACKGROUND: Extended-spectrum beta-lactamase-producing gram-negative rods (ESBL-GNR) are a rising cause of bacteremia in kidney transplant recipients (KT). The study purpose was to examine patient mortality, allograft survival, estimated glomerular filtration rate (eGFR) at the end of 1 year, and readmission rates while looking at treatment strategies among KTs with ESBL-GNR and non-ESBL-GNR bacteremia at our institution. METHODS: This study was a retrospective, cohort analysis of KTs with gram-negative bacteremia from January 1, 2020, to December 31, 2021. The primary outcome of the study was mortality. Patient outcomes were assessed for 365 days after positive blood cultures. RESULTS: The study included 63 patients. Of these, 18 (29%) patients had bacteremia caused by an ESBL-GNR and 45 (71%) patients had bacteremia caused by a non-ESBL-GNR. Patient survival at 90 days was 94% in the ESBL-GNR group and 96% in the non-ESBL-GNR group. Ciprofloxacin was the most common antimicrobial therapy at discharge (68.9%) in the non-ESBL-GNR group whereas ertapenem was the most common in the ESBL-GNR group (44.5%). Median eGFR at discharge was 41 mL/min/1.73 m2 in the ESBL-GNR group and 48 mL/min/1.73 m2 in the non-ESBL-GNR group. Ninety-day readmission occurred in 9 (50%) ESBL-GNR patients and 14 (32%) non-ESBL-GNR patients. None of the above comparisons are statistically significant (p > 0.05). Eleven (61%) ESBL-GNR and 2 (4%) non-ESBL-GNR patients used outpatient parenteral antimicrobial therapy (p < 0.001). CONCLUSIONS: Among KTs with ESBL-GNR bacteremia, no significant difference was detected in mortality or allograft function compared to non-ESBL-GNR bacteremia.

NHS-Reimbursed Cannabis Flowers for Cancer Palliative Care and the Management of Chemotherapy-Induced Nausea and Vomiting: An Autobiographical Case Report.

Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect of cancer treatment, affecting many patients. Cannabinoid agonists, such as nabilone and Δ9-tetrahydrocannabinol (THC), the main psychoactive component of Cannabis sativa L., have shown efficacy as antiemetics. Here, we report the case of Michael Roberts (MR), who we believe is the first British patient reimbursed by the National Health Service (NHS) England for the cost of medicinal cannabis flowers to manage CINV. Medical data were obtained from NHS records and individual funding request (IFR) forms. Patient-reported outcome measures (PROMs) were collected using validated questionnaires as part of the standard of care at the specialized private clinics where the prescription of medicinal cannabis was initiated. The patient presented with rectosigmoid adenocarcinoma with lung metastases. He received FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy and underwent an emergency Hartmann's procedure with subsequent second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy and lung ablation. MR reported severe nausea and vomiting associated with the initial FOLFIRI treatment. Antiemetics metoclopramide and aprepitant demonstrated moderated efficacy. Antiemetics ondansetron, levomepromazine, and nabilone were associated with intolerable side effects. Inhalation of THC-predominant cannabis flowers in association with standard medication improved CINV, anxiety, sleep quality, appetite, overall mood, and quality of life. Our results add to the available evidence suggesting that medicinal cannabis flowers may offer valuable support in cancer palliative care integrated with standard-of-care oncology treatment. The successful individual funding request in this case demonstrates a pathway for other patients to gain access to these treatments, advocating for broader awareness and integration of cannabis-based medicinal products in national healthcare services.

Low uveitis rates in patients with axial spondyloarthritis treated with bimekizumab: pooled results from phase 2b/3 trials.

OBJECTIVES: Acute anterior uveitis ('uveitis') is a common axial spondyloarthritis (axSpA) extramusculoskeletal manifestation. Interleukin (IL)-17 is implicated in its pathogenesis, however, there is conflicting evidence for IL-17A inhibition in uveitis management. We report pooled analyses of uveitis incidence in patients receiving bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, from phase 2b/3 trials. METHODS: Data were pooled for patients receiving BKZ 160 mg or placebo in the double-blind treatment period of the phase 3 BE MOBILE 1 (NCT03928704; non-radiographic axSpA) and BE MOBILE 2 (NCT03928743; radiographic axSpA) trials. Data were separately pooled for patients treated with at least one BKZ dose in the BE MOBILE trials and their ongoing open-label extension (OLE; NCT04436640), and the phase 2b BE AGILE trial (NCT02963506; radiographic axSpA) and its ongoing OLE (NCT03355573). Uveitis rates and exposure-adjusted incidence rates (EAIR)/100 patient-years (PYs) are reported. RESULTS: In the BE MOBILE 1 and 2 double-blind treatment period, 0.6% (2/349) of patients receiving BKZ experienced uveitis vs 4.6% (11/237) receiving placebo (nominal p=0.001; EAIR (95% CI): 1.8/100 PYs (0.2 to 6.7) vs 15.4/100 PYs (95% CI 7.7 to 27.5)). In patients with history of uveitis, EAIR was lower in patients receiving BKZ (6.2/100 PYs (95% CI 0.2 to 34.8); 1.9%) vs placebo (70.4/100 PYs (95% CI 32.2 to 133.7); 20.0%; nominal p=0.004). In the phase 2b/3 pool (N=848; BKZ exposure: 2034.4 PYs), EAIR remained low (1.2/100 PYs (95% CI 0.8 to 1.8)). CONCLUSIONS: Bimekizumab, a dual-IL-17A/F inhibitor, may confer protective effects for uveitis in patients with axSpA.

Amoebozoan testate amoebae illuminate the diversity of heterotrophs and the complexity of ecosystems throughout geological time.

Heterotrophic protists are vital in Earth's ecosystems, influencing carbon and nutrient cycles and occupying key positions in food webs as microbial predators. Fossils and molecular data suggest the emergence of predatory microeukaryotes and the transition to a eukaryote-rich marine environment by 800 million years ago (Ma). Neoproterozoic vase-shaped microfossils (VSMs) linked to Arcellinida testate amoebae represent the oldest evidence of heterotrophic microeukaryotes. This study explores the phylogenetic relationship and divergence times of modern Arcellinida and related taxa using a relaxed molecular clock approach. We estimate the origin of nodes leading to extant members of the Arcellinida Order to have happened during the latest Mesoproterozoic and Neoproterozoic (1054 to 661 Ma), while the divergence of extant infraorders postdates the Silurian. Our results demonstrate that at least one major heterotrophic eukaryote lineage originated during the Neoproterozoic. A putative radiation of eukaryotic groups (e.g., Arcellinida) during the early-Neoproterozoic sustained by favorable ecological and environmental conditions may have contributed to eukaryotic life endurance during the Cryogenian severe ice ages. Moreover, we infer that Arcellinida most likely already inhabited terrestrial habitats during the Neoproterozoic, coexisting with terrestrial Fungi and green algae, before land plant radiation. The most recent extant Arcellinida groups diverged during the Silurian Period, alongside other taxa within Fungi and flowering plants. These findings shed light on heterotrophic microeukaryotes' evolutionary history and ecological significance in Earth's ecosystems, using testate amoebae as a proxy.

Inhibition of CD226 Co-Stimulation Suppresses Diabetes Development in the NOD Mouse by Augmenting Tregs and Diminishing Effector T Cell Function.

Aims/hypothesis: Immunotherapeutics targeting T cells are crucial for inhibiting autoimmune disease progression proximal to disease onset in type 1 diabetes. A growing number of T cell-directed therapeutics have demonstrated partial therapeutic efficacy, with anti-CD3 (α-CD3) representing the only regulatory agency-approved drug capable of slowing disease progression through a mechanism involving the induction of partial T cell exhaustion. There is an outstanding need to augment the durability and effectiveness of T cell targeting by directly restraining proinflammatory T helper type 1 (Th1) and type 1 cytotoxic CD8+ T cell (Tc1) subsets, while simultaneously augmenting regulatory T cell (Treg) activity. Here, we present a novel strategy for reducing diabetes incidence in the NOD mouse model using a blocking monoclonal antibody targeting the type 1 diabetes-risk associated T cell co-stimulatory receptor, CD226. Methods: Female NOD mice were treated with anti-CD226 between 7-8 weeks of age and then monitored for diabetes incidence and therapeutic mechanism of action. Results: Compared to isotype-treated controls, anti-CD226 treated NOD mice showed reduced insulitis severity at 12 weeks and decreased disease incidence at 30 weeks. Flow cytometric analysis performed five weeks post-treatment demonstrated reduced proliferation of CD4+ and CD8+ effector memory T cells in spleens of anti-CD226 treated mice. Phenotyping of pancreatic Tregs revealed increased CD25 expression and STAT5 phosphorylation following anti-CD226, with splenic Tregs displaying augmented suppression of CD4+ T cell responders in vitro. Anti-CD226 treated mice exhibited reduced frequencies of islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP)-reactive CD8+ T cells in the pancreas, using both ex vivo tetramer staining and single-cell T cell receptor sequencing (scTCR-seq) approaches. 51Cr-release assays demonstrated reduced cell-mediated lysis of beta-cells by anti-CD226-treated autoreactive cytotoxic T lymphocytes. Conclusions/interpretation: CD226 blockade reduces T cell cytotoxicity and improves Treg function, representing a targeted and rational approach for restoring immune regulation in type 1 diabetes.

Diminished Immune Cell Adhesion in Hypoimmune ICAM-1 Knockout Pluripotent Stem Cells.

Hypoimmune gene edited human pluripotent stem cells (hPSCs) are a promising platform for developing reparative cellular therapies that evade immune rejection. Existing first-generation hypoimmune strategies have used CRISPR/Cas9 editing to modulate genes associated with adaptive (e.g., T cell) immune responses, but have largely not addressed the innate immune cells (e.g., monocytes, neutrophils) that mediate inflammation and rejection processes occurring early after graft transplantation. We identified the adhesion molecule ICAM-1 as a novel hypoimmune target that plays multiple critical roles in both adaptive and innate immune responses post-transplantation. In a series of studies, we found that ICAM-1 blocking or knock-out (KO) in hPSC-derived cardiovascular therapies imparted significantly diminished binding of multiple immune cell types. ICAM-1 KO resulted in diminished T cell proliferation responses in vitro and in longer in vivo retention/protection of KO grafts following immune cell encounter in NeoThy humanized mice. The ICAM-1 KO edit was also introduced into existing first-generation hypoimmune hPSCs and prevented immune cell binding, thereby enhancing the overall hypoimmune capacity of the cells. This novel hypoimmune editing strategy has the potential to improve the long-term efficacy and safety profiles of regenerative therapies for cardiovascular pathologies and a number of other diseases.

Design and Synthesis of Clinical Candidate PF-06852231 (CVL-231): A Brain Penetrant, Selective, Positive Allosteric Modulator of the M4 Muscarinic Acetylcholine Receptor.

Selective activation of the M4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M4 selective positive allosteric modulators (PAMs), ultimately culminating in the identification of 21 (PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia.

Analysis of PM2.5, black carbon, and trace metals measurements from the Kansas City Transportation and Local-Scale Air Quality Study (KC-TRAQS).

Communities near transportation sources can be impacted by higher concentrations of particulate matter (PM) and other air pollutants. Few studies have reported on air quality in complex urban environments with multiple transportation sources. To better understand these environments, the Kansas City Transportation and Local-Scale Air Quality Study (KC-TRAQS) was conducted in three neighborhoods in Southeast Kansas City, Kansas. This area has several emissions sources including transportation (railyards, vehicles, diesel trucks), light industry, commercial facilities, and residential areas. Stationary samples were collected for 1-year (October 24, 2017, to October 31, 2018) at six sites using traditional sampling methods and lower-cost air sensor packages. This work examines PM less than 2.5 µm in diameter (PM2.5), black carbon (BC), and trace metals data collected during KC-TRAQS. PM2.5 filter samples showed the highest 24-h mean concentrations (9.34 µg/m3) at the sites located within 20-50 m of the railyard. Mean 24-h PM2.5 concentrations, ranging from 7.96 to 9.34 µg/m3, at all sites were lower than that of the nearby regulatory site (9.83 µg/m3). Daily maximum PM2.5 concentrations were higher at the KC-TRAQS sites (ranging from 25.31 to 43.76 µg/m3) compared to the regulatory site (20.50 µg/m3), suggesting short-duration impacts of localized emissions sources. Across the KC-TRAQS sites, 24-h averaged PM2.5 concentrations from the sensor package (P-POD) ranged from 3.24 to 5.69 µg/m3 showing that, out-of-the-box, the PM sensor underestimated the reference concentrations. KC-TRAQS was supplemented by elemental and organic carbon (EC/OC) and trace metal analysis of filter samples. The EC/OC data suggested the presence of secondary organic aerosol formation, with the highest mean concentrations observed at the site within 20 m of the railyard. Trace metals data showed daily, monthly, and seasonal variations for iron, copper, zinc, chromium, and nickel, with elevated concentrations occurring during the summer at most of the sites.Implications: This work reports on findings from a year-long air quality study in Southeast Kansas City, Kansas to understand micro-scale air quality in neighborhoods impacted by multiple emissions sources such as transportation sources (including a large railyard operation), light industry, commercial facilities, and residential areas. While dozens of studies have reported on air quality near roadways, this work will provide more information on PM2.5, black carbon, and trace metals concentrations near other transportation sources in particular railyards. This work can also inform additional field studies near railyards.

Ancient Plasmodium genomes shed light on the history of human malaria.

Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species1. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia BCE, respectively; for P. vivax, this evidence pre-dates textual references by several millennia3. Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.

Transferability of Buckingham Parameters for Short-Range Repulsion between Topological Atoms.

The repulsive part of the Buckingham potential, with parameters A and B, can be used to model deformation energies and steric energies. Both are calculated using the interacting quantum atom energy decomposition scheme where the latter is obtained from the former by a charge-transfer-based energy correction. These energies relate to short-range interactions, specifically the deformation of electron density and steric hindrance, respectively, when topological atoms approach each other. In this work, we calculate and fit the energies of carbonyl carbon, carbonyl oxygen, and, where possible, amine nitrogen atoms to the repulsive part of the Buckingham potential for 26 molecules. We find that while the steric energies of all atom pairs studied display exponential behavior with respect to distance, some deformation energy data do not. The obtained parameters are shown to be transferable by calculating root-mean-square errors of fitted potentials with respect to energy data of the same atom in, as far as possible, all other molecules from our data set. We observed that 36% and 10% of these errors were smaller than 4 kJ mol-1 for steric and deformation energy, respectively. Thus, we find that steric energy parameters are more transferable than deformation energy parameters. Finally, we speculate about the physical meaning of the A and B parameters and the implications of the strong exponential and exponential-linear piecewise relationships that we observe between them.

Who Benefits from Manipulation under Anesthesia Following Total Knee Arthroplasty?

Arthrofibrosis is a multifactorial process that results in decreased knee range of motion (ROM). Manipulation under anesthesia (MUA) is commonly regarded as the preferred initial treatment of arthrofibrosis following total knee arthroplasty (TKA). There have been no well-controlled studies demonstrating that MUA effectively increases ROM in patients who develop arthrofibrosis after TKA when compared with routine care. The purpose of this study was to determine whether MUA had any advantage over routine care in the treatment of patients who developed arthrofibrosis following TKA. The authors identified patients who underwent primary TKA at the authors' institution between 2010 and 2014 and had flexion ≤ 100 degrees at early follow-up. Knees were grouped based on how the arthrofibrosis was treated: those who underwent MUA and those who received routine care. Knee flexion was captured preoperatively (prior to TKA), at early follow-up (prior to MUA or routine care), and at 1-year follow up. Flexion change from early follow-up to 1 year was calculated. The average flexion at 1-year follow-up was not significantly different between the two groups (106.1 ± 11.7 degrees in the routine care group versus 106.3 ± 12.8 degrees in the MUA group). The MUA group had a greater proportion of patients with flexion gains > 20 degrees at final follow-up when compared with patients who underwent routine care (56% vs. 8%, p < 0.0001). This study demonstrates that patients with decreased ROM at early follow-up after primary TKA can expect greater ROM increase at 1-year follow-up if they undergo MUA compared with patients who undergo routine care. (Journal of Surgical Orthopaedic Advances 33(1):033-036, 2024).

Skeletal Muscle Texture Assessment Using Ultrasonography: Comparison with Magnetic Resonance Imaging in Chronic Kidney Disease.

Skeletal muscle dysfunction is common in chronic kidney disease (CKD). Of interest is the concept of "muscle quality," of which measures include ultrasound-derived echo intensity (EI). Alternative parameters of muscle texture, for example, gray level of co-occurrence matrix (GCLM), are available and may circumvent limitations in EI. The validity of EI is limited in humans, particularly in chronic diseases. This study aimed to investigate the associations between ultrasound-derived parameters of muscle texture with MRI. Images of the thigh were acquired using a 3 Tesla MRI scanner. Quantification of muscle (contractile), fat (non-contractile), and miscellaneous (connective tissue, fascia) components were estimated. Anatomical rectus femoris cross-sectional area was measured using B-mode 2D ultrasonography. To assess muscle texture, first (i.e., EI)- and second (i.e., GLCM)-order statistical analyses were performed. Fourteen participants with CKD were included (age: 58.0 ± 11.9 years, 50% male, eGFR: 27.0 ± 7.4 ml/min/1.73m2, 55% Stage 4). Higher EI was associated with lower muscle % (quadriceps: ß = -.568, p = .034; hamstrings: ß = -.644, p = .010). Higher EI was associated with a higher fat % in the hamstrings (ß = -.626, p = .017). A higher angular second moment from GLCM analysis was associated with greater muscle % (ß = .570, p = .033) and lower fat % (ß = -.534, p = .049). A higher inverse difference moment was associated with greater muscle % (ß = .610, p = .021 and lower fat % (ß = -.599, p = .024). This is the first study to investigate the associations between ultrasound-derived parameters of muscle texture with MRI. Our preliminary findings suggest ultrasound-derived texture analysis provides a novel indicator of reduced skeletal muscle % and thus increased intramuscular fat.

Quantifying lung fissure integrity using a three-dimensional patch-based convolutional neural network on CT images for emphysema treatment planning.

Purpose: Evaluation of lung fissure integrity is required to determine whether emphysema patients have complete fissures and are candidates for endobronchial valve (EBV) therapy. We propose a deep learning (DL) approach to segment fissures using a three-dimensional patch-based convolutional neural network (CNN) and quantitatively assess fissure integrity on CT to evaluate it in subjects with severe emphysema. Approach: From an anonymized image database of patients with severe emphysema, 129 CT scans were used. Lung lobe segmentations were performed to identify lobar regions, and the boundaries among these regions were used to construct approximate interlobar regions of interest (ROIs). The interlobar ROIs were annotated by expert image analysts to identify voxels where the fissure was present and create a reference ROI that excluded non-fissure voxels (where the fissure is incomplete). A CNN configured by nnU-Net was trained using 86 CT scans and their corresponding reference ROIs to segment the ROIs of left oblique fissure (LOF), right oblique fissure (ROF), and right horizontal fissure (RHF). For an independent test set of 43 cases, fissure integrity was quantified by mapping the segmented fissure ROI along the interlobar ROI. A fissure integrity score (FIS) was then calculated as the percentage of labeled fissure voxels divided by total voxels in the interlobar ROI. Predicted FIS (p-FIS) was quantified from the CNN output, and statistical analyses were performed comparing p-FIS and reference FIS (r-FIS). Results: The absolute percent error mean (±SD) between r-FIS and p-FIS for the test set was 4.0% (±4.1%), 6.0% (±9.3%), and 12.2% (±12.5%) for the LOF, ROF, and RHF, respectively. Conclusions: A DL approach was developed to segment lung fissures on CT images and accurately quantify FIS. It has potential to assist in the identification of emphysema patients who would benefit from EBV treatment.

A subclass of evening cells promotes the switch from arousal to sleep at dusk.

Animals exhibit rhythmic patterns of behavior that are shaped by an internal circadian clock and the external environment. Although light intensity varies across the day, there are particularly robust differences at twilight (dawn/dusk). These periods are also associated with major changes in behavioral states, such as the transition from arousal to sleep. However, the neural mechanisms by which time and environmental conditions promote these behavioral transitions are poorly defined. Here, we show that the E1 subclass of Drosophila evening clock neurons promotes the transition from arousal to sleep at dusk. We first demonstrate that the cell-autonomous clocks of E2 neurons primarily drive and adjust the phase of evening anticipation, the canonical behavior associated with "evening" clock neurons. We next show that conditionally silencing E1 neurons causes a significant delay in sleep onset after dusk. However, rather than simply promoting sleep, activating E1 neurons produces time- and light-dependent effects on behavior. Activation of E1 neurons has no effect early in the day but then triggers arousal before dusk and induces sleep after dusk. Strikingly, these activation-induced phenotypes depend on the presence of light during the day. Despite their influence on behavior around dusk, in vivo voltage imaging of E1 neurons reveals that their spiking rate and pattern do not significantly change throughout the day. Moreover, E1-specific clock ablation has no effect on arousal or sleep. Thus, we suggest that, rather than specifying "evening" time, E1 neurons act, in concert with other rhythmic neurons, to promote behavioral transitions at dusk.

High above the rest: standing behaviors in the amoebae of Sappinia and Thecamoeba.

Many terrestrial microbes have evolved cell behaviors that help them rise above their substrate, often to facilitate dispersal. One example of these behaviors is found in the amoebae of Sappinia pedata, which actively lift most of their cell mass above the substrate, known as standing. This standing behavior was first described in S. pedata in the 1890s from horse dung isolates but never molecularly characterized from dung. Our study expands this understanding, revealing the first molecularly confirmed S. pedata from herbivore dung in Mississippi, USA, and describing a new species, Sappinia dangeardi n. sp., with larger trophozoite cells. Additionally, we isolated another standing amoeba, Thecamoeba homeri n. sp., from soil, exhibiting a previously unreported "doughnut shape" transient behavior. In S. dangeardi n. sp., we discovered that standing is likely triggered by substrate drying, and that actin filaments actively localize in the "stalk" to support the standing cells, as observed through confocal microscopy. While the purpose of standing behaviors has not been investigated, we hypothesize it is energetically expensive and therefore a significant evolutionary strategy in these organisms. Overall, this study emphasizes behavioral adaptations to terrestrial environments within Amoebozoa, stressing the importance of diverse laboratory conditions that replicate natural habitats.

Isolation of Naegleria lustrarea n. sp. (Excavata, Discoba, Heterolobosea) from the feces of Ambystoma annulatum (Ringed Salamander) in Northwest Arkansas.

The salamander, Ambystoma annulatum, is considered a "species of special concern" in the state of Arkansas, USA, due to its limited geographic range, specialized habitat requirements and low population size. Although metazoan parasites have been documented in this salamander species, neither its native protists nor microbiome have yet been evaluated. This is likely due to the elusive nature and under-sampling of the animal. Here, we initiate the cataloguing of microbial associates with the identification of a new heterlobosean species, Naegleria lustrarea n. sp. (Excavata, Discoba, Heterolobosea), isolated from feces of an adult A. annulatum.

What to do with foundation therapies for heart failure for patients with end-stage kidney disease on haemodialysis.

There is a significant burden of cardiovascular disease morbidity and mortality in the end-stage kidney disease population, driven by traditional and non-traditional risk factors. Despite its prevalence, heart failure is difficult to diagnose in the dialysis population due to overlapping clinical presentations, limitations of investigations, and the impact on the cardiorenal axis. 'Foundation therapies' are the key medications which improve patient outcomes in heart failure with reduced ejection fraction and include beta-blockers, renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter-2 inhibitors. They are underutilised in the dialysis population due to the exclusion of chronic kidney disease patients from major trials and legitimate clinical concerns e.g. hyperkalaemia, intradialytic hypotension and residual kidney function preservation. A coordinated cardiorenal multidisciplinary approach can guide appropriate diagnostic considerations (biomarkers interpretation, imaging, addressing unique complications of kidney disease), optimise dialysis management (prescription length, frequency and ultrafiltration targets) and when at euvolaemia facilitate the stepwise introduction of appropriate foundation therapies.