Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response.

Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory with emerging cellular roles, including its ability to elicit anti-tumour immunity. Nonetheless, how MOMP triggers inflammation and how the cell regulates this remains poorly defined. We find that upon MOMP, many proteins localised either to inner or outer mitochondrial membranes are ubiquitylated in a promiscuous manner. This extensive ubiquitylation serves to recruit the essential adaptor molecule NEMO, leading to the activation of pro-inflammatory NF-κB signalling. We show that disruption of mitochondrial outer membrane integrity through different means leads to the engagement of a similar pro-inflammatory signalling platform. Therefore, mitochondrial integrity directly controls inflammation, such that permeabilised mitochondria initiate NF-κB signalling.

A joint NCBI and EMBL-EBI transcript set for clinical genomics and research.

Comprehensive genome annotation is essential to understand the impact of clinically relevant variants. However, the absence of a standard for clinical reporting and browser display complicates the process of consistent interpretation and reporting. To address these challenges, Ensembl/GENCODE1 and RefSeq2 launched a joint initiative, the Matched Annotation from NCBI and EMBL-EBI (MANE) collaboration, to converge on human gene and transcript annotation and to jointly define a high-value set of transcripts and corresponding proteins. Here, we describe the MANE transcript sets for use as universal standards for variant reporting and browser display. The MANE Select set identifies a representative transcript for each human protein-coding gene, whereas the MANE Plus Clinical set provides additional transcripts at loci where the Select transcripts alone are not sufficient to report all currently known clinical variants. Each MANE transcript represents an exact match between the exonic sequences of an Ensembl/GENCODE transcript and its counterpart in RefSeq such that the identifiers can be used synonymously. We have now released MANE Select transcripts for 97% of human protein-coding genes, including all American College of Medical Genetics and Genomics Secondary Findings list v3.0 (ref. 3) genes. MANE transcripts are accessible from major genome browsers and key resources. Widespread adoption of these transcript sets will increase the consistency of reporting, facilitate the exchange of data regardless of the annotation source and help to streamline clinical interpretation.

Germline knockout of Nr2e3 protects photoreceptors in three distinct mouse models of retinal degeneration.

Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting Nr2e3, a transcription factor required for the normal differentiation of rod photoreceptors. Nr2e3 knockout results in hybrid rod photoreceptors that express the full complement of rod genes, but also a subset of cone genes. We show that germline deletion of Nr2e3 potently protects rods in three mechanistically diverse mouse models of retinal degeneration caused by bright-light exposure (light damage), structural deficiency (rhodopsin-deficient Rho-/- mice), or abnormal phototransduction (phosphodiesterase-deficient rd10 mice). Nr2e3 knockout confers strong neuroprotective effects on rods without adverse effects on their gene expression, structure, or function. Furthermore, in all three degeneration models, prolongation of rod survival by Nr2e3 knockout leads to lasting preservation of cone morphology and function. These findings raise the possibility that upregulation of one or more cone genes in Nr2e3-deficient rods may be responsible for the neuroprotective effects we observe.

Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA.

Despite whole-genome sequencing (WGS), many cases of single-gene disorders remain unsolved, impeding diagnosis and preventative care for people whose disease-causing variants escape detection. Since early WGS data analytic steps prioritize protein-coding sequences, to simultaneously prioritize variants in non-coding regions rich in transcribed and critical regulatory sequences, we developed GROFFFY, an analytic tool that integrates coordinates for regions with experimental evidence of functionality. Applied to WGS data from solved and unsolved hereditary hemorrhagic telangiectasia (HHT) recruits to the 100,000 Genomes Project, GROFFFY-based filtration reduced the mean number of variants/DNA from 4,867,167 to 21,486, without deleting disease-causal variants. In three unsolved cases (two related), GROFFFY identified ultra-rare deletions within the 3' untranslated region (UTR) of the tumor suppressor SMAD4, where germline loss-of-function alleles cause combined HHT and colonic polyposis (MIM: 175050). Sited >5.4 kb distal to coding DNA, the deletions did not modify or generate microRNA binding sites, but instead disrupted the sequence context of the final cleavage and polyadenylation site necessary for protein production: By iFoldRNA, an AAUAAA-adjacent 16-nucleotide deletion brought the cleavage site into inaccessible neighboring secondary structures, while a 4-nucleotide deletion unfolded the downstream RNA polymerase II roadblock. SMAD4 RNA expression differed to control-derived RNA from resting and cycloheximide-stressed peripheral blood mononuclear cells. Patterns predicted the mutational site for an unrelated HHT/polyposis-affected individual, where a complex insertion was subsequently identified. In conclusion, we describe a functional rare variant type that impacts regulatory systems based on RNA polyadenylation. Extension of coding sequence-focused gene panels is required to capture these variants.

Complementing model species with model clades.

Model species continue to underpin groundbreaking plant science research. At the same time, the phylogenetic resolution of the land plant Tree of Life continues to improve. The intersection of these two research paths creates a unique opportunity to further extend the usefulness of model species across larger taxonomic groups. Here we promote the utility of the Arabidopsis thaliana model species, especially the ability to connect its genetic and functional resources, to species across the entire Brassicales order. We focus on the utility of using genomics and phylogenomics to bridge the evolution and diversification of several traits across the Brassicales to the resources in Arabidopsis, thereby extending scope from a model species by establishing a "model clade". These Brassicales-wide traits are discussed in the context of both the model species Arabidopsis thaliana and the family Brassicaceae. We promote the utility of such a "model clade" and make suggestions for building global networks to support future studies in the model order Brassicales.

Metals from spacecraft reentry in stratospheric aerosol particles.

Large increases in the number of low earth orbit satellites are projected in the coming decades [L. Schulz, K.-H. Glassmeier, Adv. Space Res. 67, 1002-1025 (2021)] with perhaps 50,000 additional satellites in orbit by 2030 [GAO, Large constellations of satellites: Mitigating environmental and other effects (2022)]. When spent rocket bodies and defunct satellites reenter the atmosphere, they produce metal vapors that condense into aerosol particles that descend into the stratosphere. So far, models of spacecraft reentry have focused on understanding the hazard presented by objects that survive to the surface rather than on the fate of the metals that vaporize. Here, we show that metals that vaporized during spacecraft reentries can be clearly measured in stratospheric sulfuric acid particles. Over 20 elements from reentry were detected and were present in ratios consistent with alloys used in spacecraft. The mass of lithium, aluminum, copper, and lead from the reentry of spacecraft was found to exceed the cosmic dust influx of those metals. About 10% of stratospheric sulfuric acid particles larger than 120 nm in diameter contain aluminum and other elements from spacecraft reentry. Planned increases in the number of low earth orbit satellites within the next few decades could cause up to half of stratospheric sulfuric acid particles to contain metals from reentry. The influence of this level of metallic content on the properties of stratospheric aerosol is unknown.

Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer.

Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine from glutamate and ammonia is essential for neurotransmission and ammonia detoxification. Here, we show that mammalian GS uses glutamate and methylamine to produce a methylated glutamine analog, N5-methylglutamine. Untargeted metabolomics revealed that liver-specific GS deletion and its pharmacological inhibition in mice suppress hepatic and circulating levels of N5-methylglutamine. This alternative activity of GS was confirmed in human recombinant enzyme and cells, where a pathogenic mutation in the active site (R324C) promoted the synthesis of N5-methylglutamine over glutamine. N5-methylglutamine is detected in the circulation, and its levels are sustained by the microbiome, as demonstrated by using germ-free mice. Finally, we show that urine levels of N5-methylglutamine correlate with tumor burden and GS expression in a ß-catenin-driven model of liver cancer, highlighting the translational potential of this uncharacterized metabolite.

A large source of cloud condensation nuclei from new particle formation in the tropics.

Cloud condensation nuclei (CCN) can affect cloud properties and therefore Earth's radiative balance1-3. New particle formation (NPF) from condensable vapours in the free troposphere has been suggested to contribute to CCN, especially in remote, pristine atmospheric regions4, but direct evidence is sparse, and the magnitude of this contribution is uncertain5-7. Here we use in situ aircraft measurements of vertical profiles of aerosol size distributions to present a global-scale survey of NPF occurrence. We observe intense NPF at high altitudes in tropical convective regions over both Pacific and Atlantic oceans. Together with the results of chemical-transport models, our findings indicate that NPF persists at all longitudes as a global-scale band in the tropical upper troposphere, covering about 40 per cent of Earth's surface. Furthermore, we find that this NPF in the tropical upper troposphere is a globally important source of CCN in the lower troposphere, where CCN can affect cloud properties. Our findings suggest that the production of CCN as new particles descend towards the surface is not adequately captured in global models, which tend to underestimate both the magnitude of tropical upper tropospheric NPF and the subsequent growth of new particles to CCN sizes.

A cohort study of sodium-glucose cotransporter-2 inhibitors after acute kidney injury among Veterans with diabetic kidney disease.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk for several adverse outcomes among patients with diabetic kidney disease. Yet, optimal timing for SGLT2i after acute kidney injury (AKI) is uncertain, as are the providers responsible for post-AKI SGLT2i initiation. Using a retrospective cohort of United States Veterans with diabetes mellitus type 2 and proteinuria, we examined encounters by provider specialty before SGLT2i initiation and subsequent all-cause mortality after hospitalization with AKI, defined by a 50% or more rise in serum creatinine. Covariates included recovery, defined by return to a 110% or less of baseline creatinine, and time since AKI hospitalization. Among 21,330 eligible Veterans, 7,798 died (37%) and 6,562 received a SGLT2i (31%) over median follow-up of 2.1 years. Post-AKI SGLT2i use was associated with lower mortality risk [adjusted hazard ratio 0.63 (95% confidence interval 0.58-0.68)]. Compared with neither SGLT2i use nor recovery, mortality risk was similar with recovery without SGLT2i use [0.97 (0.91-1.02)] but was lower without recovery prior to SGLT2i use [0.62 (0.55-0.71)] and with SGLT2i use after recovery [0.60 (0.54-0.67)]. Finally, the effect of SGLT2i was stable over time (P for time-interaction 0.19). Thus, we observed reduced mortality with SGLT2i use after AKI among Veterans with diabetic kidney disease whether started earlier or later or before or after observed recovery. Hence, patients with diabetic kidney disease who receive a SGLT2i earlier after AKI experience no significant harm impacting mortality and experience a lower mortality risk than those who do not.

Pharmacist-driven outreach initiative to increase prescribing of sodium-glucose cotransporter-2 inhibitors in eligible VHA patients with chronic kidney disease: a study protocol.

BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk for multiple adverse events, several of which have been proven to be less likely with the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i). As a result, guidelines now recommend SGLT2i be given to those with mild to moderate CKD and type 2 diabetes. The objective of this study is to evaluate if a pharmacist-driven SGLT2i prescribing initiative among eligible patients with CKD and diabetes within the VA could more rapidly improve the adoption of SGLT2i via a pragmatic approach aligned with learning health systems. METHODS: Eligible patients will be identified through an established VA diabetes dashboard. Veterans with an odd social security number (SSN), which is effectively a random number, will be the intervention group. Those with even SSNs will serve as the control while awaiting a second iteration of the same interventional program. The intervention will be implemented in a rolling fashion across one Veterans Integrated Service Network. Our primary outcome is initiation of an SGLT2i. Secondary outcomes will include medication adherence and safety-related outcomes. DISCUSSION: This project tests the impact of a pharmacist-driven medication outreach initiative as a strategy to accelerate initiation of SGLT2i. The results of this work will not only illustrate the effectiveness of this strategy for SGLT2is but may also have implications for increasing other guideline-concordant care. Furthermore, the utilization of SSNs to select Veterans for the first wave of this program has created a pseudo-randomized interventional trial supporting a pragmatic learning health system approach. TRIAL REGISTRATION: ISRCTN12374636.

Sea spray aerosol concentration modulated by sea surface temperature.

Natural aerosols in pristine regions form the baseline used to evaluate the impact of anthropogenic aerosols on climate. Sea spray aerosol (SSA) is a major component of natural aerosols. Despite its importance, the abundance of SSA is poorly constrained. It is generally accepted that wind-driven wave breaking is the principle governing SSA production. This mechanism alone, however, is insufficient to explain the variability of SSA concentration at given wind speed. The role of other parameters, such as sea surface temperature (SST), remains controversial. Here, we show that higher SST promotes SSA mass generation at a wide range of wind speed levels over the remote Pacific and Atlantic Oceans, in addition to demonstrating the wind-driven SSA production mechanism. The results are from a global scale dataset of airborne SSA measurements at 150 to 200 m above the ocean surface during the NASA Atmospheric Tomography Mission. Statistical analysis suggests that accounting for SST greatly enhances the predictability of the observed SSA concentration compared to using wind speed alone. Our results support implementing SST into SSA source functions in global models to better understand the atmospheric burdens of SSA.

Renin-Angiotensin-Aldosterone System Blockade after AKI with or without Recovery among US Veterans with Diabetic Kidney Disease.

SIGNIFICANCE STATEMENT: Among patients with CKD, optimal use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers after AKI is uncertain. Despite these medications' ability to reduce risk of mortality and other adverse outcomes, there is concern that ACEi/ARB use may delay recovery of kidney function or precipitate recurrent AKI. Prior studies have provided conflicting data regarding the optimal timing of these medications after AKI and have not addressed the role of kidney recovery in determining appropriate timing. This study in US Veterans with diabetes mellitus and proteinuria demonstrated an association between ACEi/ARB use and lower mortality. This association was more pronounced with earlier post-AKI ACEi/ARB use and was not meaningfully affected by initiating ACEis/ARBs before versus after recovery from AKI. BACKGROUND: Optimal use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) after AKI is uncertain. METHODS: Using data derived from electronic medical records, we sought to estimate the association between ACEi/ARB use after AKI and mortality in US military Veterans with indications for such treatment (diabetes and proteinuria) while accounting for AKI recovery. We used ACEi/ARB treatment after hospitalization with AKI (defined as serum creatinine ≥50% above baseline concentration) as a time-varying exposure in Cox models. The outcome was all-cause mortality. Recovery was defined as return to ≤110% of baseline creatinine. A secondary analysis focused on ACEi/ARB use relative to AKI recovery (before versus after). RESULTS: Among 54,735 Veterans with AKI, 31,146 deaths occurred over a median follow-up period of 2.3 years. Approximately 57% received an ACEi/ARB <3 months after hospitalization. In multivariate analysis with time-varying recovery, post-AKI ACEi/ARB use was associated with lower risk of mortality (adjusted hazard ratio [aHR], 0.74; 95% confidence interval [CI], 0.72 to 0.77). The association between ACEi/ARB use and mortality varied over time, with lower mortality risk associated with earlier initiation ( P for interaction with time <0.001). In secondary analysis, compared with those with neither recovery nor ACEi/ARB use, risk of mortality was lower in those with recovery without ACEi/ARB use (aHR, 0.90; 95% CI, 0.87 to 0.94), those without recovery with ACEi/ARB use (aHR, 0.69; 95% CI, 0.66 to 0.72), and those with ACEi/ARB use after recovery (aHR, 0.70; 95% CI, 0.67 to 0.73). CONCLUSIONS: This study demonstrated lower mortality associated with ACEi/ARB use in Veterans with diabetes, proteinuria, and AKI, regardless of recovery. Results favored earlier ACEi/ARB initiation.

Phylogenomics reveals extreme gene tree discordance in a lineage of dominant trees: hybridization, introgression, and incomplete lineage sorting blur deep evolutionary relationships despite clear species groupings in Eucalyptus subgenus Eudesmia.

Eucalypts are a large and ecologically important group of plants on the Australian continent, and understanding their evolution is important in understanding evolution of the unique Australian flora. Previous phylogenies using plastome DNA, nuclear-ribosomal DNA, or random genome-wide SNPs, have been confounded by limited genetic sampling or by idiosyncratic biological features of the eucalypts, including widespread plastome introgression. Here we present phylogenetic analyses of Eucalyptus subgenus Eudesmia (22 species from western, northern, central and eastern Australia), in the first study to apply a target-capture sequencing approach using custom, eucalypt-specific baits (of 568 genes) to a lineage of Eucalyptus. Multiple accessions of all species were included, and target-capture data were supplemented by separate analyses of plastome genes (average of 63 genes per sample). Analyses revealed a complex evolutionary history likely shaped by incomplete lineage sorting and hybridization. Gene tree discordance generally increased with phylogenetic depth. Species, or groups of species, toward the tips of the tree are mostly supported, and three major clades are identified, but the branching order of these clades cannot be confirmed with confidence. Multiple approaches to filtering the nuclear dataset, by removing genes or samples, could not reduce gene tree conflict or resolve these relationships. Despite inherent complexities in eucalypt evolution, the custom bait kit devised for this research will be a powerful tool for investigating the evolutionary history of eucalypts more broadly.

Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death.

During apoptosis, the mitochondrial outer membrane is permeabilized, leading to the release of cytochrome c that activates downstream caspases. Mitochondrial outer membrane permeabilization (MOMP) has historically been thought to occur synchronously and completely throughout a cell, leading to rapid caspase activation and apoptosis. Using a new imaging approach, we demonstrate that MOMP is not an all-or-nothing event. Rather, we find that a minority of mitochondria can undergo MOMP in a stress-regulated manner, a phenomenon we term "minority MOMP." Crucially, minority MOMP leads to limited caspase activation, which is insufficient to trigger cell death. Instead, this caspase activity leads to DNA damage that, in turn, promotes genomic instability, cellular transformation, and tumorigenesis. Our data demonstrate that, in contrast to its well-established tumor suppressor function, apoptosis also has oncogenic potential that is regulated by the extent of MOMP. These findings have important implications for oncogenesis following either physiological or therapeutic engagement of apoptosis.

Electronic Health Records' Support for Primary Care Physicians' Situation Awareness: A Metanarrative Review.

OBJECTIVE: Situation awareness (SA) refers to people's perception and understanding of their dynamic environment. In primary care, reduced SA among physicians increases errors in clinical decision-making and, correspondingly, patients' risk of experiencing adverse outcomes. Our objective was to understand the extent to which electronic health records (EHRs) support primary care physicians (PCPs)' SA during clinical decision-making. METHOD: We conducted a metanarrative review of papers in selected academic databases, including CINAHL and MEDLINE. Eligible studies included original peer-reviewed research published between January 2012 and August 2020 on PCP-EHR interactions. We iteratively queried, screened, and summarized literature focused on EHRs supporting PCPs' clinical decision-making and care management for adults. Then, we mapped findings to an established SA framework to classify external factors (individual, task, and system) affecting PCPs' levels of SA (1-Perception, 2-Comprehension, and 3-Projection) and identified SA barriers. RESULTS: From 1504 articles identified, we included and synthesized 19 studies. Study designs were largely noninterventional. Studies described EHR workflow misalignments, usability issues, and communication challenges. EHR information, including lab results and care plans, was characterized as incomplete, untimely, or irrelevant. Unmet information needs made it difficult for PCPs to obtain even basic SA, Level 1 SA. Prevalent barriers to PCPs developing SA with EHRs were errant mental models, attentional tunneling, and data overload. CONCLUSION: Based on our review, EHRs do not support the development of higher levels of SA among PCPs. Review findings suggest SA-oriented design processes for health information technology could improve PCPs' SA, satisfaction, and decision-making.

Blending bauxite residues with multiple byproducts improves capping materials for tailings storage facilities.

Amelioration and management of large volumes of tailings resulting from alumina refining is a major challenge owing to the high alkalinity and salinity of residues. Blended byproduct caps are a potential new and more cost-effective approach to tailings management, where tailings are blended with other local byproducts in order to reduce pH, salinity and toxic elements. Here, alkaline bauxite residue was blended with four byproducts (waste acid, sewage water, fly ash and eucalypt mulch) to create a range of potential capping materials. We leached and weathered materials in the glasshouse with deionized water over nine weeks to investigate if byproducts on their own or in combination improved cap conditions. Combining all four byproducts (10 wt % waste acid, 5 wt % sewage water, 20 wt % fly ash and 10 wt % eucalypt mulch) achieved lower pH (9.60) compared to any byproduct applied individually, or un-remediated bauxite residue (pH 10.7). Leaching decreased EC by dissolving and exporting salts and minerals from the bauxite residue. Fly ash addition increased organic carbon (likely from non-combusted organic material) and nitrogen, while eucalypt mulch increased inorganic phosphorus. Addition of byproducts also decreased the concentration of potentially toxic elements (e.g., Al, Na, Mo and V) and enhanced pH neutralisation. Initial pH with single byproduct treatments was 10.4-10.5, which decreased to between 9.9-10.0. Further lowering of pH and salinity as well as increased nutrient concentrations may be possible through higher addition rates of byproducts, incorporation of other materials such as gypsum, and increasing leaching/weathering time of tailings in situ.

Navigating through chemical space and evolutionary time across the Australian continent in plant genus Eremophila.

Eremophila is the largest genus in the plant tribe Myoporeae (Scrophulariaceae) and exhibits incredible morphological diversity across the Australian continent. The Australian Aboriginal Peoples recognize many Eremophila species as important sources of traditional medicine, the most frequently used plant parts being the leaves. Recent phylogenetic studies have revealed complex evolutionary relationships between Eremophila and related genera in the tribe. Unique and structurally diverse metabolites, particularly diterpenoids, are also a feature of plants in this group. To assess the full dimension of the chemical space of the tribe Myoporeae, we investigated the metabolite diversity in a chemo-evolutionary framework applying a combination of molecular phylogenetic and state-of-the-art computational metabolomics tools to build a dataset involving leaf samples from a total of 291 specimens of Eremophila and allied genera. The chemo-evolutionary relationships are expounded into a systematic context by integration of information about leaf morphology (resin and hairiness), environmental factors (pollination and geographical distribution), and medicinal properties (traditional medicinal uses and antibacterial studies), augmenting our understanding of complex interactions in biological systems.

Effectiveness of BNT162b2 and mRNA-1273 Second Doses and Boosters for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection and SARS-CoV-2-Related Hospitalizations: A Statewide Report From the Minnesota Electronic Health Record Consortium.

Using vaccine data combined with electronic health records, we report that mRNA boosters provide greater protection than a 2-dose regimen against SARS-CoV-2 infection and related hospitalizations. The benefit of a booster was more evident in the elderly and those with comorbidities.

Why Test Results Are Still Getting "Lost" to Follow-up: a Qualitative Study of Implementation Gaps.

BACKGROUND: Lack of timely follow-up of abnormal test results is common and has been implicated in missed or delayed diagnosis, resulting in potential for patient harm. OBJECTIVE: As part of a larger project to implement change strategies to improve follow-up of diagnostic test results, this study sought to identify specifically where implementation gaps exist, as well as possible solutions identified by front-line staff. DESIGN: We used a semi-structured interview guide to collect qualitative data from Veterans Affairs (VA) facility staff who had experience with test results management and patient safety. SETTING: Twelve VA facilities across the USA. PARTICIPANTS: Facility staff members (n = 27), including clinicians, lab and imaging professionals, nursing staff, patient safety professionals, and leadership. APPROACH: We conducted a content analysis of interview transcripts to identify perceived barriers and high-risk areas for effective test result management, as well as recommendations for improvement. RESULTS: We identified seven themes to guide further development of interventions to improve test result follow-up. Themes related to trainees, incidental findings, tracking systems for electronic health record notifications, outdated contact information, referrals, backup or covering providers, and responsibility for test results pending at discharge. Participants provided recommendations for improvement within each theme. CONCLUSIONS: Perceived barriers and recommendations for improving test result follow-up often reflected previously known problems and their corresponding solutions, which have not been consistently implemented in practice. Better policy solutions and improvement methods, such as quality improvement collaboratives, may bridge the implementation gaps between knowledge and practice.

Hyperkalaemia in Heart Failure: Consequences for Outcome and Sequencing of Therapy.

PURPOSE OF REVIEW: Heart failure (HF), in conjunction with common comorbidities such as chronic kidney disease and diabetes and medical therapies such as RAASi, predisposes to hyperkalaemia which may lead to hospitalisation and death. This paper aims to review the most current evidence surrounding the risks and management of hyperkalaemia in HF, with particular focus on recent research into RAASi including novel selective mineralocorticoid receptor blockers and novel potassium binders. RECENT FINDINGS: The most recent evidence shows that even moderate hyperkalaemia may predispose to adverse outcomes such as hospitalisation and death. Furthermore, it may prevent patients from receiving optimal medical therapy for HF by reducing prescription of RAASi therapy. Novel potassium binders such as sodium zirconium cyclosilicate (SZC) and patiromer present potential options to reduce and prevent hyperkalaemia as well as maintain optimal RAASi dosing in HF. Management of hyperkalaemia in HF has advanced in recent years. New therapies such as SZC and patiromer are contributing to the management of acute hyperkalaemia and also access to life-saving RAASi therapies by tackling and preventing hyperkalaemia in the community.