A Practice Guide for Physical Therapists Prescribing Physical Exercise for Older Adults.

INTRODUCTION: Physical activity and exercise are protective factors for physical and cognitive decline in older adults, but recent studies reveal that a large percentage of this population do not practice exercise at the levels recommended by international guidelines. The frequency, intensity, type, time, volume, and progression (FITT-VP) principles are a widely used method for prescribing physical exercise, allowing the development of a personalized exercise program that meets the needs of each individual. OBJECTIVES: This masterclass is intended to serve as a professional application tool for physical therapists who prescribe physical exercise for older adults. We present a section for each FITT-VP principle to facilitate handling these principles individually when prescribing exercise for this population. METHODS: Review of the scientific literature and international guidelines on the prescription of physical exercises for older adults. RESULTS: Aerobic, mobility, resistance, balance, and flexibility exercises, as well as functional training, should be included in an exercise program for older adults, which should be progressed using different methods for each of the exercise modalities. CONCLUSIONS: An exercise program for older adults should integrate different exercise modalities. Exercise progression should be performed following the FITT-VP principles and some specific progression factors recommended for each exercise modality. SIGNIFICANCE: Considering the challenge faced by clinicians in designing a viable exercise program for older adults that responds to international recommendations, with this masterclass we hope to help physical therapists to plan an exercise program that is feasible and at the same time, responds to the expected needs of this population.

Percutaneous left stellate ganglion block for refractory ventricular tachycardia in structural heart disease: our single-centre experience.

INTRODUCTION: When electrical storm (ES) is amenable to neither antiarrhythmic drugs, nor deep sedation or catheter ablation, autonomic modulation may be considered. We report our experience with percutaneous left stellate ganglion block (PSGB) to temporarily suppress refractory ventricular arrhythmia (VA) in patients with structural heart disease. METHODS: A retrospective analysis was performed at our institution of patients with structural heart disease and an implantable cardioverter defibrillator (ICD) who had undergone PSGB for refractory VA between January 2018 and October 2021. The number of times antitachycardia pacing (ATP) was delivered and the number of ICD shocks/external cardioversions performed in the week before and after PSGB were evaluated. Charts were checked for potential complications. RESULTS: Twelve patients were identified who underwent a combined total of 15 PSGB and 5 surgical left cardiac sympathetic denervation procedures. Mean age was 73 ± 5.8 years and all patients were male. Nine of 12 (75%) had ischaemic cardiomyopathy, with the remainder having non-ischaemic dilated cardiomyopathy. Mean left ventricular ejection fraction was 35% (±â€¯12.2%). Eight of 12 (66.7%) patients were already being treated with both amiodarone and beta-blockers. The reduction in ATP did not reach statistical significance (p = 0.066); however, ICD shocks (p = 0.028) and ATP/shocks combined were significantly reduced (p = 0.04). At our follow-up electrophysiology meetings PSGB was deemed ineffective in 4 of 12 patients (33%). Temporary anisocoria was seen in 2 of 12 (17%) patients, and temporary hypotension and hoarseness were reported in a single patient. DISCUSSION: In this limited series, PSGB showed promise as a method for temporarily stabilising refractory VA and ES in a cohort of male patients with structural heart disease. The side effects observed were mild and temporary.

LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer.

Lysine-specific demethylase 1 (LSD1 or KDM1A ) has emerged as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Among mCRPC subtypes, neuroendocrine prostate cancer (NEPC) is an exceptionally aggressive variant driven by lineage plasticity, an adaptive resistance mechanism to androgen receptor axis-targeted therapies. Our study shows that LSD1 expression is elevated in NEPC and associated with unfavorable clinical outcomes. Using genetic approaches, we validated the on-target effects of LSD1 inhibition across various models. We investigated the therapeutic potential of bomedemstat, an orally bioavailable, irreversible LSD1 inhibitor with low nanomolar potency. Our findings demonstrate potent antitumor activity against CRPC models, including tumor regressions in NEPC patient-derived xenografts. Mechanistically, our study uncovers that LSD1 inhibition suppresses the neuronal transcriptional program by downregulating ASCL1 through disrupting LSD1:INSM1 interactions and de-repressing YAP1 silencing. Our data support the clinical development of LSD1 inhibitors for treating CRPC - especially the aggressive NE phenotype. Statement of Significance: Neuroendocrine prostate cancer presents a clinical challenge due to the lack of effective treatments. Our research demonstrates that bomedemstat, a potent and selective LSD1 inhibitor, effectively combats neuroendocrine prostate cancer by downregulating the ASCL1- dependent NE transcriptional program and re-expressing YAP1.

Fractional Factorial Design to Evaluate the Synthesis and Electrochemical Transfer Parameters of h-BN Coatings.

In this study, we present a fractional factorial design approach for exploring the effects and interactions of key synthesis and electrochemical transfer parameters on the roughness and wettability of hexagonal boron nitride (h-BN) coatings, due to their essential role in biofilm formation. The studied parameters for the synthesis process include precursor mass, growth time, and substrate conditioning, whereas for the transfer process, applied voltage and aqueous medium concentration were studied. Through this polynomial model, we confirmed the strong influence of precursor mass and medium concentration parameters on h-BN surface roughness and its resulting antibiofilm properties.

Crosstalking interactions between P2X4 and 5-HT3A receptors.

Ionotropic receptors are ligand-gated ion channels triggering fast neurotransmitter responses. Among them, P2X and 5-HT3 receptors have been shown to physically interact each other and functionally inducing cross inhibitory responses. Nevertheless, despite the importance of P2X4 and 5-HT3A receptors that mediate for example neuropathic pain and psychosis respectively, complementary evidence has recently started to move forward in the understanding of this interaction. In this review, we discuss current evidence supporting the mechanism of crosstalking between both receptors, from the structural to the transduction pathway level. We expect this work may guide the design of further experiments to obtain a comprehensive view for the neuropharmacological role of these interacting receptors. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".

Systematic review and meta-analysis on the association between chronic low back pain and cognitive function.

This study aimed to identify and assess the evidence on the association between idiopathic chronic low back pain (LBP) and cognitive function in individuals with LBP. A secondary aim was to explore whether changes in cognitive function are associated with pain characteristics and psychological factors (eg, catastrophizing and fear of movement). Eleven studies were included in this systematic review, and four meta-analyses were conducted. Low to very low-quality evidence suggests impaired cognitive function in individuals with LBP compared to asymptomatic controls for problem solving (k = 5; d = 0.33; CI = 0.16-0.50; z = 3.85 p = 0.0001), speed of information processing (k = 5; d = 0.44; CI = 0.22-0.65; z = 4.02 p < 0.0001), working memory (k = 6; d = 0.50; CI = 0.34-0.66; z = 6.09 p < 0.0001), and delayed memory (k = 3; d = 0.34; CI = 0.07-0.6, z = 2.49 p = 0.02). The association between LBP intensity and psychological factors and cognitive function was inconclusive. More studies are needed to explore these associations and improve evidence in this field. The results of this study suggest that cognitive aspects should be considered during the rehabilitation process of patients with LBP and raise further questions, including whether individuals with LBP are at a greater risk of developing dementia or whether targeting cognitive function will increase the probability of success of LBP treatment. These questions should, also, be considered in future studies.

High species richness in the lichen genus Peltigera (Ascomycota, Lecanoromycetes): 34 species in the dolichorhizoid and scabrosoid clades of section Polydactylon, including 24 new to science.

Applying molecular methods to fungi establishing lichenized associations with green algae or cyanobacteria has repeatedly revealed the existence of numerous phylogenetic taxa overlooked by classical taxonomic approaches. Here, we report taxonomical conclusions based on multiple species delimitation and validation analyses performed on an eight-locus dataset that includes world-wide representatives of the dolichorhizoid and scabrosoid clades in section Polydactylon of the genus Peltigera. Following the recommendations resulting from a consensus species delimitation approach and additional species validation analysis (BPP) performed in this study, we present a total of 25 species in the dolichorhizoid clade and nine in the scabrosoid clade, including respectively 18 and six species that are new to science and formally described. Additionally, one combination and three varieties (including two new to science) are proposed in the dolichorhizoid clade. The following 24 new species are described: P. appalachiensis, P. asiatica, P. borealis, P. borinquensis, P. chabanenkoae, P. clathrata, P. elixii, P. esslingeri, P. flabellae, P. gallowayi, P. hawaiiensis, P. holtanhartwigii, P. itatiaiae, P. hokkaidoensis, P. kukwae, P. massonii, P. mikado, P. nigriventris, P. orientalis, P. rangiferina, P. sipmanii, P. stanleyensis, P. vitikainenii and P. willdenowii; the following new varieties are introduced: P. kukwae var. phyllidiata and P. truculenta var. austroscabrosa; and the following new combination is introduced: P. hymenina var. dissecta. Each species from the dolichorhizoid and scabrosoid clades is morphologically and chemically described, illustrated, and characterised with ITS sequences. Identification keys are provided for the main biogeographic regions where species from the two clades occur. Morphological and chemical characters that are commonly used for species identification in the genus Peltigera cannot be applied to unambiguously recognise most molecularly circumscribed species, due to high variation of thalli formed by individuals within a fungal species, including the presence of distinct morphs in some cases, or low interspecific variation in others. The four commonly recognised morphospecies: P. dolichorhiza, P. neopolydactyla, P. pulverulenta and P. scabrosa in the dolichorhizoid and scabrosoid clades represent species complexes spread across multiple and often phylogenetically distantly related lineages. Geographic origin of specimens is often helpful for species recognition; however, ITS sequences are frequently required for a reliable identification. Citation: Magain N, Miadlikowska J, Goffinet B, et al. 2023. High species richness in the lichen genus Peltigera (Ascomycota, Lecanoromycetes): 34 species in the dolichorhizoid and scabrosoid clades of section Polydactylon, including 24 new to science. Persoonia 51: 1-88. doi: 10.3767/persoonia.2023.51.01.

The Adsorption of P2X2 Receptors Interacting with IgG Antibodies Revealed by Combined AFM Imaging and Mechanical Simulation.

The adsorption of proteins onto surfaces significantly impacts biomaterials, medical devices, and biological processes. This study aims to provide insights into the irreversible adsorption process of multiprotein complexes, particularly focusing on the interaction between anti-His6 IgG antibodies and the His6-tagged P2X2 receptor. Traditional approaches to understanding protein adsorption have centered around kinetic and thermodynamic models, often examining individual proteins and surface coverage, typically through Molecular Dynamics (MD) simulations. In this research, we introduce a computational approach employing Autodesk Maya 3D software for the investigation of multiprotein complexes' adsorption behavior. Utilizing Atomic Force Microscopy (AFM) imaging and Maya 3D-based mechanical simulations, our study yields real-time structural and kinetic observations. Our combined experimental and computational findings reveal that the P2X2 receptor-IgG antibody complex likely undergoes absorption in an 'extended' configuration. Whereas the P2X2 receptor is less adsorbed once is complexed to the IgG antibody compared to its individual state, the opposite is observed for the antibody. This insight enhances our understanding of the role of protein-protein interactions in the process of protein adsorption.

The impact of users' cognitive function on evaluator perceptions of usability.

To explore the association between the user's cognitive function and usability reported by the evaluator. A cross-sectional study was conducted with a community-based sample. Data about participants' age, sex, education, sleep quantity, subjective memory complaints, and cognitive function were collected. A usability session was conducted to evaluate a digital solution called Brain on Track. Independent linear-regression analyses were used to explore univariable and multivariable associations between evaluator-reported usability assessment and the users' cognitive function, age, sex, education, sleep quantity, and subjective memory complaints. A total of 238 participants entered this study, of which 161 (67.6%) were females and the mean age was 42 (SD 12.9) years old. All variables (age, education, sleep quantity, subjective memory complaints and cognitive function) except sex were significantly associated with evaluator-reported usability in the univariable analysis (p < 0.05). Cognitive function, age, education, and subjective memory complaints remained significant in the multivariable model (F = 38.87, p < 0.001) with an adjusted R2 of 0.391. Cognition scores alone showed an adjusted R2 of 0.288. This work suggests that cognitive function impacts evaluator reported usability, alongside other users' characteristics and needs to be considered in the usability evaluation.

Tumor Embolization through Meningohypophyseal and Inferolateral Trunks is Safe and Effective.

BACKGROUND AND PURPOSE: Skull base tumors are commonly supplied by dural branches of the meningohypophyseal and inferolateral trunks. Embolization through these arteries is often avoided due to technical challenges and inherent risks; however, successful embolization can be a valuable surgical adjunct. We aimed to review the success and complications in our series of tumor embolizations through the meningohypophyseal and inferolateral trunks. MATERIALS AND METHODS: We performed a retrospective review of patients with tumor treated with preoperative embolization at our institution between 2010 and 2020. We reviewed the following data: patients' demographics, tumor characteristics, endovascular embolization variables, and surgical results including estimated blood loss, the need for transfusion, and operative time. RESULTS: Among 155 tumor embolization cases, we identified 14 patients in whom tumor embolization was performed using the meningohypophyseal (n = 13) or inferolateral (n = 4) trunk. In this group of patients, on average, 79% of tumors were embolized. No mortality or morbidity from the embolization procedure was observed in this subgroup of patients. The average estimated blood loss in the operation was 395 mL (range, 200-750 mL). None of the patients required a transfusion, and the average operative time was 7.3 hours. CONCLUSIONS: Some skull base tumors necessitate embolization through ICA branches such as the meningohypophyseal and inferolateral trunks. Our series demonstrates that an effective and safe embolization may be performed through these routes.

Ultrastructural characterisation of young and aged dental enamel by atomic force microscopy.

Recent advances in atomic force microscopy (AFM) have allowed the characterisation of dental-associated biomaterials and biological surfaces with high resolution. In this context, the topography of dental enamel - the hardest mineralised tissue in the body - has been explored with AFM-based approaches at the microscale. With age, teeth are known to suffer changes that can impact their structural stability and function; however, changes in enamel structure because of ageing have not yet been explored with nanoscale resolution. Therefore, the aim of this exploratory work was to optimise an approach to characterise the ultrastructure of dental enamel and determine potential differences in topography, hydroxyapatite (HA) crystal size, and surface roughness at the nanoscale associated to ageing. For this, a total of six teeth were collected from human donors from which enamel specimens were prepared. By employing intermittent contact (AC mode) imaging, HA crystals were characterised in both transversal and longitudinal orientation (respect to surface plane) with high resolution in environmental conditions. The external enamel surface displayed the presence of a pellicle-like coating on its surface that was not observable on cleaned specimens. Acid-etching exposed crystals that were imaged and morphologically characterised in high resolution at the nanoscale in both the external and internal regions of enamel in older and younger specimens. Our results demonstrated important individual variations in HA crystal width and roughness parameters across the analysed specimens; however, an increase in surface roughness and decrease in HA width was observed for the pooled older external enamel group compared to younger specimens. Overall, high-resolution AFM was an effective approach for the qualitative and quantitative characterisation of human dental enamel ultrastructure. Future work should focus on exploring the ageing of dental enamel with increased sample sizes to compensate for individual differences as well as other potential confounding factors such as behavioural habits and mechanical forces.

A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk.

A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c-statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a "universal" surrogate end point for cardiovascular risk.

How far are we from predicting multi-drug interactions during treatment for COVID-19 infection?

Seriously ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and hospitalized in intensive care units (ICUs) are commonly given a combination of drugs, a process known as multi-drug treatment. After extracting data on drug-drug interactions with clinical relevance from available online platforms, we hypothesize that an overall interaction map can be generated for all drugs administered. Furthermore, by combining this approach with simulations of cellular biochemical pathways, we may be able to explain the general clinical outcome. Finally, we postulate that by applying this strategy retrospectively to a cohort of patients hospitalized in ICU, a prediction of the timing of developing acute kidney injury (AKI) could be made. Whether or not this approach can be extended to other diseases is uncertain. Still, we believe it represents a valuable pharmacological insight to help improve clinical outcomes for severely ill patients.

Drug-dependent inhibition of nucleotide hydrolysis in the heterodimeric ABC multidrug transporter PatAB from Streptococcus pneumoniae.

The bacterial heterodimeric ATP-binding cassette (ABC) multidrug exporter PatAB has a critical role in conferring antibiotic resistance in multidrug-resistant infections by Streptococcus pneumoniae. As with other heterodimeric ABC exporters, PatAB contains two transmembrane domains that form a drug translocation pathway for efflux and two nucleotide-binding domains that bind ATP, one of which is hydrolysed during transport. The structural and functional elements in heterodimeric ABC multidrug exporters that determine interactions with drugs and couple drug binding to nucleotide hydrolysis are not fully understood. Here, we used mass spectrometry techniques to determine the subunit stoichiometry in PatAB in our lactococcal expression system and investigate locations of drug binding using the fluorescent drug-mimetic azido-ethidium. Surprisingly, our analyses of azido-ethidium-labelled PatAB peptides point to ethidium binding in the PatA nucleotide-binding domain, with the azido moiety crosslinked to residue Q521 in the H-like loop of the degenerate nucleotide-binding site. Investigation into this compound and residue's role in nucleotide hydrolysis pointed to a reduction in the activity for a Q521A mutant and ethidium-dependent inhibition in both mutant and wild type. Most transported drugs did not stimulate or inhibit nucleotide hydrolysis of PatAB in detergent solution or lipidic nanodiscs. However, further examples for ethidium-like inhibition were found with propidium, novobiocin and coumermycin A1, which all inhibit nucleotide hydrolysis by a non-competitive mechanism. These data cast light on potential mechanisms by which drugs can regulate nucleotide hydrolysis by PatAB, which might involve a novel drug binding site near the nucleotide-binding domains.

Pain assessment in cerebral palsy: a systematic review of measurement properties and evaluation using the COSMIN checklist.

PURPOSE: This systematic literature review aims to analyse the methodological quality of instruments available to assess pain in Cerebral Palsy (CP), according to the COSMIN guidelines and checklist. MATERIALS AND METHODS: Electronic literature searches were conducted in PubMed, ScienceDirect, Web of Science, PEdro, Scielo, Scopus and Academic Search Complete (EBSCO host) for articles on measurement properties of self-report, proxy or observational instruments. RESULTS: A total of 14 instruments were identified. Of these, 8 were self-report instruments, 4 were observational instruments and 2 could be used both as self-report or proxy-report. The quality of the manuscripts was inadequate or doubtful in 45.5%, adequate in 15.9% and very good in 38.6% of the cases. No instrument was assessed for all the properties recommended by COSMIN. The quality of the evidence for the measurement properties of the pain assessment instruments ranged from very low to moderate. CONCLUSIONS: There is scarce and low-quality evidence on the measurement properties of instruments used to assess pain in individuals with cerebral palsy. Further research is needed designed in line with the COSMIN recommendations.Implications for rehabilitationThere is scarce and low-quality evidence on the measurement properties of instruments used to assess pain in individuals with cerebral palsy;Clinicians need to carefully choose instruments to assess pain in individuals with cerebral palsy as there is insufficient evidence on the quality of instruments;Self-report pain intensity scales may be a useful instrument for a subgroup of individuals with cerebral palsy.

Cefiderocol Pharmacokinetics in a Patient Receiving Continuous Venovenous Hemodiafiltration.

Antimicrobial dosing in patients receiving continuous renal replacement therapy is a continued clinical challenge. We describe a case of a patient receiving cefiderocol 2 g intravenously every 8 hours as a 3-hour infusion for a multidrug-resistant Pseudomonas aeruginosa pneumonia and bacteremia while undergoing continuous venovenous hemodiafiltration. The clinical course and cefiderocol pharmacokinetics are described.

The sodium iodide symporter (NIS): novel applications for radionuclide imaging and treatment.

Cloning of the sodium iodide symporter (NIS) 25 years ago has opened an exciting chapter in molecular thyroidology with the characterization of NIS as one of the most powerful theranostic genes and the development of a promising gene therapy strategy based on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of 131I or alternative radionuclides, such as 188Re and 211At. Over the past two decades, significant progress has been made in the development of the NIS gene therapy concept, from local NIS gene delivery towards promising new applications in disseminated disease, in particular through the use of oncolytic viruses, non-viral polyplexes, and genetically engineered MSCs as highly effective, highly selective and flexible gene delivery vehicles. In addition to allowing the robust therapeutic application of radioiodine in non-thyroid cancer settings, these studies have also been able to take advantage of NIS as a sensitive reporter gene that allows temporal and spatial monitoring of vector biodistribution, replication, and elimination - critically important issues for preclinical development and clinical translation.

Antibacterial Effect of Honey-Derived Exosomes Containing Antimicrobial Peptides Against Oral Streptococci.

PURPOSE: Recently, our group found exosome-like extracellular vesicles (EVs) in Apis mellifera honey displaying strong antibacterial effects; however, the underlying mechanism is still not understood. Thus, the aim of this investigation was to characterize the molecular and nanomechanical properties of A. mellifera honey-derived EVs in order to elucidate the mechanisms behind their antibacterial effect, as well as to determine differential antibiofilm properties against relevant oral streptococci. METHODS: A. mellifera honey-derived EVs (HEc-EVs) isolated via ultracentrifugation were characterized with Western Blot and ELISA to determine the presence of specific exosomal markers and antibacterial cargo, and atomic force microscopy (AFM) was utilized to explore their ultrastructural and nanomechanical properties via non-destructive immobilization onto poly-L-lysine substrates. Furthermore, the effect of HEc-EVs on growth and biofilm inhibition of S. mutans was explored with microplate assays and compared to S. sanguinis. AFM was utilized to describe ultrastructural and nanomechanical alterations such as cell wall elasticity changes following HEc-EV exposure. RESULTS: Molecular characterization of HEc-EVs identified for the first time important conserved exosome markers such as CD63 and syntenin, and the antibacterial molecules MRJP1, defensin-1 and jellein-3 were found as intravesicular cargo. Nanomechanical characterization revealed that honey-derived EVs were mostly <150nm, with elastic modulus values in the low MPa range, comparable to EVs from other biological sources. Furthermore, incubating oral streptococci with EVs confirmed their antibacterial and antibiofilm capacities, displaying an increased effect on S. mutans compared to S. sanguinis. AFM nanocharacterization showed topographical and nanomechanical alterations consistent with membrane damage on S. mutans. CONCLUSION: Honey is a promising new source of highly active EVs with exosomal origin, containing a number of antibacterial peptides as cargo molecules. Furthermore, the differential effect of HEC-EVs on S. mutans and S. sanguinis may serve as a novel biofilm-modulating strategy in dental caries.

Oral Ferric Maltol for the Treatment of Iron-Deficiency Anemia in Patients With CKD: A Randomized Trial and Open-Label Extension.

RATIONALE & OBJECTIVE: Iron-deficiency anemia is common in patients with chronic kidney disease (CKD) not requiring kidney replacement therapy (KRT). We evaluated effects of oral iron replacement therapy with ferric maltol in these patients. STUDY DESIGN: Phase 3, double-blind, randomized, placebo-controlled trial (AEGIS-CKD) and open-label extension. SETTING & PARTICIPANTS: Adults with stage 3 or 4 CKD and iron-deficiency anemia at 30 US centers. INTERVENTION: Oral ferric maltol at 30mg or placebo twice daily for 16 weeks (2:1 randomization) followed by ferric maltol at 30mg twice daily for up to 36 weeks (all patients). OUTCOME: Change from baseline in hemoglobin (primary end point at week 16), ferritin, transferrin saturation, and serum iron; safety. RESULTS: 167 patients were randomized (ferric maltol, n=111; placebo, n=56). At week 16, hemoglobin had increased significantly with ferric maltol versus placebo (least-squares mean difference: 0.5±0.2 [SE] g/dL; 95% CI, 0.1-0.9; P=0.01). Ferritin, transferrin saturation, and serum iron increased with ferric maltol but declined with placebo (all P<0.05). Hemoglobin levels were sustained up to week 52 in patients continuing ferric maltol and increased in patients switching from placebo to ferric maltol. The most frequent adverse events were gastrointestinal (randomized phase: 41% vs 30% [ferric maltol vs placebo]; open-label phase: 56% vs 46%, respectively). Adverse events led to treatment withdrawal in 7 patients (6%) receiving ferric maltol and 5 patients (9%) receiving placebo during double-blind treatment, and 11 patients (9%) during the open-label extension. LIMITATIONS: Heterogeneity in baseline ferritin levels; high proportion of female participants; single-arm open-label extension. CONCLUSIONS: Ferric maltol was associated with statistically significant (week 16) and sustained (up to week 52) increases in hemoglobin and iron indices in patients with CKD and iron deficiency, and was well tolerated during treatment for up to 52 weeks. FUNDING: Funded by Shield Therapeutics (UK) Ltd. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02968368.