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Cardio-Renal-Metabolic (CaReMe) diseases, in the form of heart failure, chronic kidney disease and diabetes mellitus, justify prescription of multiple prognostically beneficial medications, specifically renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter-2 inhibitors. Use of these medications is complicated by association with adverse effects, particularly acute kidney injury and hyperkalaemia. Balancing risk and benefit is a common dilemma in acute medicine, with increasingly frequent and complex treatment decisions. Physicians should contemplate adjustments to medications within the context of not just acute illness but also long-term benefit. In the setting of hyperkalaemia, potassium-binding medications can be utilised. At hospital discharge optimisation of therapy can be achieved through clear safety netting advice, scheduled biochemical follow-up, and planned clinical review.
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Lesión Renal Aguda , Hiperpotasemia , Humanos , Hiperpotasemia/tratamiento farmacológico , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/terapia , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/terapia , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
INTRODUCTION: The prevalence of heart failure (HF) is more common in people with advanced non-dialysis chronic kidney disease (ND-CKD) compared to the general population. It is well known that HF with reduced ejection fraction (HFrEF) is associated with a higher risk of mortality in people with ND-CKD. However, the impact of HFrEF on progression into end-stage kidney disease (ESKD) is not well studied. Our study aimed to examine the independent association of HFrEF on progression to ESKD after correcting for confounding factors using two methods of propensity scoring. METHODS: This study used data from the Salford Kidney Study, a longitudinal study which has recruited more than 3,000 patients with ND-CKD since 2002. Patients without a history of HF during the recruitment questionnaire were included in the control group. Patients with a reported history of HF and echo showing left ventricular ejection fraction <40% at enrolment were included in the HFrEF group. Two propensity score methods were used to attenuate the effects of confounding factors between the two groups - propensity score matching (PSM) and inverse probability weighting (IPW). Univariate and multivariate Cox-regression analyses were performed. RESULTS: A total of 2,383 patients were included in the analysis. Patients with HFrEF had significantly higher median age and a higher percentage of male gender compared to patients with no HF (72.5 vs. 66.6 years and 71.8 vs. 61.1%, respectively). Univariate and 5 models of multivariate Cox-regression analysis showed that HFrEF in people with CKD was a strong predictor for a higher incidence of ESKD (model 5: hazard ratio 1.38; 95% confidence interval = 1.01-1.90; p = 0.044). The association between HFrEF and the risk of ESKD remained significant after using the PSM and the IPW methods. CONCLUSION: Patients with concomitant advanced ND-CKD and prevalent HFrEF were found to have a higher risk of ESKD when compared to patients with no HF. This risk persists despite the adjustment of confounding factors using PSM and IPW.
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Progresión de la Enfermedad , Insuficiencia Cardíaca , Fallo Renal Crónico , Puntaje de Propensión , Insuficiencia Renal Crónica , Volumen Sistólico , Humanos , Masculino , Femenino , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/epidemiología , Volumen Sistólico/fisiología , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/complicaciones , Anciano , Persona de Mediana Edad , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Factores de Riesgo , Estudios Longitudinales , Prevalencia , Tasa de Filtración Glomerular/fisiologíaRESUMEN
The design of compounds during hit-to-lead often seeks to explore a vector from a core scaffold to form additional interactions with the target protein. A rational approach to this is to probe the region of a protein accessed by a vector with a systematic placement of pharmacophore features in 3D, particularly when bound structures are not available. Herein, we present bbSelect, an open-source tool built to map the placements of pharmacophore features in 3D Euclidean space from a library of R-groups, employing partitioning to drive a diverse and systematic selection to a user-defined size. An evaluation of bbSelect against established methods exemplified the superiority of bbSelect in its ability to perform diverse selections, achieving high levels of pharmacophore feature placement coverage with selection sizes of a fraction of the total set and without the introduction of excess complexity. bbSelect also reports visualizations and rationale to enable users to understand and interrogate results. This provides a tool for the drug discovery community to guide their hit-to-lead activities.
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Descubrimiento de Drogas , Programas Informáticos , Descubrimiento de Drogas/métodos , Modelos Moleculares , Diseño de Fármacos , Proteínas/química , FarmacóforoRESUMEN
BACKGROUND: Patients with chronic intestinal failure (CIF) are at increased risk of developing renal impairment. The aim of this study was to evaluate the occurrence of chronic kidney disease (CKD) in patients dependent on home parenteral nutrition (HPN) and assess risk factors for renal impairment, including patients with all mechanisms of CIF. METHODS: This was a cohort study of patients initiated on HPN between March 1, 2015, and March 1, 2020, at a national UK IF Reference Centre. Patients were followed from their first discharge with HPN until HPN cessation or the end of follow-up on December 31, 2021. RESULTS: There were 357 patients included in the analysis. Median follow-up time was 4.7 years. At baseline, >40% of patients had renal impairment, with 15.4% fulfilling the criteria for CKD. Mean estimated glomerular filtration rate (eGFR) decreased significantly during the first year after initiation of HPN from 93.32 ml/min/1.73 m2 to 86.30 ml/min/1.73 m2 at the first year of follow-up (P = 0.002), with sequential stabilization of renal function. Increased age at HPN initiation and renal impairment at baseline were associated with decreased eGFR. By the end of follow-up, 6.7% patients developed renal calculi and 26.1% fulfilled the criteria for CKD. CONCLUSION: This is the largest study of renal function in patients receiving long-term HPN. After the first year following HPN initiation, the rate of decline in eGFR was similar to that expected in the general population. These findings should reassure patients and clinicians that close monitoring of renal function can lead to good outcomes.
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Tasa de Filtración Glomerular , Insuficiencia Intestinal , Nutrición Parenteral en el Domicilio , Insuficiencia Renal Crónica , Humanos , Nutrición Parenteral en el Domicilio/efectos adversos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Estudios Longitudinales , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/complicaciones , Anciano , Adulto , Factores de Riesgo , Insuficiencia Intestinal/terapia , Enfermedad Crónica , Estudios de CohortesRESUMEN
BACKGROUND AND OBJECTIVES: Atherosclerotic renal artery stenosis may cause hypertension, chronic kidney disease and heart failure, but large randomized control trials to date have shown no major additional benefit of renal revascularization over optimal medical management. However, these trials did not consider outcomes specifically in relation to clinical presentations. Given that atherosclerotic renal artery stenosis is a heterogenous condition, measures of success likely differ according to the clinical presentation. Our retrospective study objectives were to determine the effects of revascularization when applied to specific clinical presentations and after careful multi-disciplinary team review. METHODS: All patients presenting to our centre and its referring hospitals with radiological findings of at least one renal artery stenosis > 50% between January 2015 and January 2020 were reviewed at the renovascular multi-disciplinary team meeting with revascularization considered in accordance with international guidelines, notably for patients with anatomically significant renal artery stenosis, adequately sized kidney and presentations with any of; deteriorating kidney function, heart failure syndrome, or uncontrollable hypertension. Optimal medical management was recommended for all patients which included lipid lowering agents, anti-platelets and anti-hypertensives targeting blood pressure ≤ 130/80 mmHg. The effect of revascularization was assessed according to the clinical presentation; blood pressure and number of agents in those with renovascular hypertension, delta glomerular filtration rate in those with ischaemic nephropathy and heart failure re-admissions in those with heart failure syndromes. RESULTS: During this 5-year period, 127 patients with stenosis ≥ 50% were considered by the multidisciplinary team, with 57 undergoing revascularization (17 primarily for severe hypertension, 25 deteriorating kidney function, 6 heart failure syndrome and 9 for very severe anatomical stenosis). Seventy-nine percent of all revascularized patients had a positive outcome specific to their clinical presentation, with 82% of those with severe hypertension improving blood pressure control, 72% with progressive ischaemic nephropathy having attenuated GFR decline, and no further heart failure admissions in those with heart failure. Seventy-eight percent of patients revascularized for high grade stenosis alone had better blood pressure control with 55% also manifesting renal functional benefits. CONCLUSIONS: Multi-disciplinary team discussion successfully identified a group of patients more likely to benefit from revascularization based on 3 key factors: clinical presentation, severity of the renal artery lesion and the state of the kidney beyond the stenotic lesion. In this way, a large proportion of patients can clinically improve after revascularization if their outcomes are considered according to the nature of their clinical presentation.
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Hipertensión Renovascular , Obstrucción de la Arteria Renal , Humanos , Obstrucción de la Arteria Renal/terapia , Obstrucción de la Arteria Renal/complicaciones , Obstrucción de la Arteria Renal/fisiopatología , Estudios Retrospectivos , Anciano , Femenino , Masculino , Hipertensión Renovascular/terapia , Hipertensión Renovascular/etiología , Hipertensión Renovascular/fisiopatología , Hipertensión Renovascular/diagnóstico , Resultado del Tratamiento , Persona de Mediana Edad , Aterosclerosis/complicaciones , Tasa de Filtración Glomerular , Grupo de Atención al Paciente , Antihipertensivos/uso terapéuticoRESUMEN
The mussel industry faces challenges such as low and inconsistent levels of larvae settlement and poor-quality spat, leading to variable production. However, mussel farming remains a vital sustainable and environmentally responsible method for producing protein, fostering ecological responsibility in the aquaculture sector. We investigate the population connectivity and larval dispersion of blue mussels (Mytilus edulis) in Scottish waters, as a case study, using a multidisciplinary approach that combined genetic data and particle modelling. This research allows us to develop a thorough understanding of blue mussel population dynamics in mid-latitude fjord regions, to infer gene-flow patterns, and to estimate population divergence. Our findings reveal a primary south-to-north particle transport direction and the presence of five genetic clusters. We discover a significant and continuous genetic material exchange among populations within the study area, with our biophysical model's outcomes aligning with our genetic observations. Additionally, our model reveals a robust connection between the southwest coast and the rest of the west coast. This study will guide the preservation of mussel farming regions, ensuring sustainable populations that contribute to marine ecosystem health and resilience.
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Mytilus edulis , Animales , Mytilus edulis/genética , Estuarios , Ecosistema , Acuicultura , Larva/genéticaRESUMEN
Federated multipartner machine learning has been touted as an appealing and efficient method to increase the effective training data volume and thereby the predictivity of models, particularly when the generation of training data is resource-intensive. In the landmark MELLODDY project, indeed, each of ten pharmaceutical companies realized aggregated improvements on its own classification or regression models through federated learning. To this end, they leveraged a novel implementation extending multitask learning across partners, on a platform audited for privacy and security. The experiments involved an unprecedented cross-pharma data set of 2.6+ billion confidential experimental activity data points, documenting 21+ million physical small molecules and 40+ thousand assays in on-target and secondary pharmacodynamics and pharmacokinetics. Appropriate complementary metrics were developed to evaluate the predictive performance in the federated setting. In addition to predictive performance increases in labeled space, the results point toward an extended applicability domain in federated learning. Increases in collective training data volume, including by means of auxiliary data resulting from single concentration high-throughput and imaging assays, continued to boost predictive performance, albeit with a saturating return. Markedly higher improvements were observed for the pharmacokinetics and safety panel assay-based task subsets.
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Benchmarking , Relación Estructura-Actividad Cuantitativa , Bioensayo , Aprendizaje AutomáticoRESUMEN
The emergency department (ED) is a fast-paced environment responsible for large volumes of patients with varied disease acuity. Operational pressures on EDs are increasing, which creates the imperative to efficiently identify patients at imminent risk of acute deterioration. The aim of this study is to systematically compare the performance of machine learning algorithms based on logistic regression, gradient boosted decision trees, and support vector machines for predicting imminent clinical deterioration for patients based on cross-sectional patient data extracted from electronic patient records (EPR) at the point of entry to the hospital. We apply state-of-the-art machine learning methods to predict early patient deterioration, based on their first recorded vital signs, observations, laboratory results, and other predictors documented in the EPR. Clinical deterioration in this study is measured by in-hospital mortality and/or admission to critical care. We build on prior work by incorporating interpretable machine learning and fairness-aware modelling, and use a dataset comprising 118, 886 unplanned admissions to Salford Royal Hospital, UK, to systematically compare model variations for predicting mortality and critical care utilisation within 24 hours of admission. We compare model performance to the National Early Warning Score 2 (NEWS2) and yield up to a 0.366 increase in average precision, up to a [Formula: see text] reduction in daily alert rate, and a median 0.599 reduction in differential bias amplification across the protected demographics of age and sex. We use Shapely Additive exPlanations to justify the models' outputs, verify that the captured data associations align with domain knowledge, and pair predictions with the causal context of each patient's most influential characteristics. Introducing our modelling to clinical practice has the potential to reduce alert fatigue and identify high-risk patients with a lower NEWS2 that might be missed currently, but further work is needed to trial the models in clinical practice. We encourage future research to follow a systematised approach to data-driven risk modelling to obtain clinically applicable support tools.
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Deterioro Clínico , Servicios Médicos de Urgencia , Humanos , Estudios Transversales , Aprendizaje Automático , Toma de DecisionesRESUMEN
BACKGROUND: Chronic kidney disease (CKD) is estimated to affect more than 2.5 million adults in England, and this is expected to rise to 4.2 million by 2036 (1). Population-level digital healthcare systems have the potential to enable earlier detection of CKD providing an opportunity to introduce interventions that attenuate progression and reduce the risk of end-stage kidney disease (ESKD) and cardiovascular diseases (CVD). Services that can support patients with CKD, CVD, and diabetes mellitus (DM) have the potential to reduce fragmented clinical care and optimise pharmaceutical management. METHODS AND RESULTS: The Salford renal service has established an outpatient improvement programme which aims to address these issues via two projects. Firstly, the development of a CKD dashboard that can stratify patients by their kidney failure risk equation (KFRE) risk. High-risk patients would be invited to attend an outpatient clinic if appropriate. Specialist advice and guidance would be offered to primary care providers looking after patients with medium risk. Patients with lower risk would continue with standard care via their primary care provider unless there was another indication for a nephrology referral. The CKD dashboard identified 11546 patients (4.4% of the total adult population in Salford) with T2DM and CKD. The second project is the establishment of the Metabolic CardioRenal (MRC) clinic. It provided care for 209 patients in the first 8 months of its establishment with a total of 450 patient visits. Initial analysis showed clustering of cardiorenal metabolic diseases with 85% having CKD stages 3 and 4 and 73.2% having DM. In addition, patients had a significant burden of CVD with 50.2% having hypertension and 47.8% having heart failure. CONCLUSION: There is a pressing need to create new outpatient models of care to tackle the rising epidemic of cardio-renal metabolic diseases. This model of service has potential benefits at both organisational and patient levels including improving patient management via risk stratification, increased care capacity and reduction of variation of care. Patients will benefit from earlier intervention, appropriate referral for care, reduction in CKD-related complications, and reduction in hospital visits and cardiovascular events. In addition, this combined digital and patient-facing model of care will allow rapid translation of advances in cardio-renal metabolic diseases into clinical practice.
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Enfermedades Cardiovasculares , Insuficiencia Renal Crónica , Adulto , Humanos , Multimorbilidad , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/complicaciones , Inglaterra/epidemiología , Instituciones de Atención Ambulatoria , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/terapiaRESUMEN
Recent events have made it apparent that the creatinine based estimating equations for glomerular filtration have their flaws. Some flaws have been known for some time; others have prompted radical modification of the equations themselves. These issues persist in part owing to the behaviour of the creatinine molecule itself, particularly in acute and critical illness. There are significant implications for patient treatment decisions, including drug and fluid therapies and choice of imaging modality (contrast vs. non-contrast CT scan for example). An alternative biomarker, Cystatin C, has been used with some success both alone and in combination with creatinine to help improve the accuracy of particular estimating equations. Problems remain in certain circumstances and costs may limit the more widespread use of the alternative assay. This review will explore both the historical and more recent evidence for glomerular filtration estimation, including options to directly measure glomerular filtration (rather than estimate), perhaps the holy grail for both Biochemistry and Nephrology.
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Enfermedad Crítica , Insuficiencia Renal Crónica , Humanos , Tasa de Filtración Glomerular , Creatinina , BiomarcadoresRESUMEN
Purpose: To develop and validate a deep learning model for detection of nasogastric tube (NGT) malposition on chest radiographs and assess model impact as a clinical decision support tool for junior physicians to help determine whether feeding can be safely performed in patients (feed/do not feed). Materials and Methods: A neural network ensemble was pretrained on 1 132 142 retrospectively collected (June 2007-August 2019) frontal chest radiographs and further fine-tuned on 7081 chest radiographs labeled by three radiologists. Clinical relevance was assessed on an independent set of 335 images. Five junior emergency medicine physicians assessed chest radiographs and made feed/do not feed decisions without and with artificial intelligence (AI)-generated NGT malposition probabilities placed above chest radiographs. Decisions from the radiologists served as ground truths. Model performance was evaluated using receiver operating characteristic analysis. Agreement between junior physician and radiologist decision was determined using the Cohen κ coefficient. Results: In the testing set, the ensemble achieved area under the receiver operating characteristic curve values of 0.82 (95% CI: 0.78, 0.86), 0.77 (95% CI: 0.71, 0.83), and 0.98 (95% CI: 0.96, 1.00) for satisfactory, malpositioned, and bronchial positions, respectively. In the clinical evaluation set, mean interreader agreement for feed/do not feed decisions among junior physicians was 0.65 ± 0.03 (SD) and 0.77 ± 0.13 without and with AI support, respectively. Mean agreement between junior physicians and radiologists was 0.53 ± 0.05 (unaided) and 0.65 ± 0.09 (AI-aided). Conclusion: A simple classifier for NGT malposition may help junior physicians determine the safety of feeding in patients with NGTs.Keywords: Neural Networks, Feature Detection, Supervised Learning, Machine Learning Supplemental material is available for this article. Published under a CC BY 4.0 license.
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We previously reported a study of features of emergency healthcare response to COVID-19 that could be modified to mitigate against future excess deaths. Here we determined what themes persisted in later waves. This was an expert panel review of all components of care delivered to COVID-19 patients who died (primary and secondary care, community services, NHS 111 and 999, COVID oximetry at home, virtual wards). 174 deaths were included. 5% were deemed >50% avoidable, 75% included avoidability themes. Contact with primary care remains mostly via telephone, creating diagnostic risk. Patient decision to avoid healthcare contact was common. Recommendations include: better utilisation of home monitoring in future pandemics; improved avoidance of nosocomial spread; patients be encouraged to seek medical advice earlier.
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COVID-19 , Pandemias , Humanos , Hospitales , Oximetría , Atención a la SaludRESUMEN
BACKGROUND: Hypertension is commonly observed in patients living with chronic kidney disease (CKD). Finding an optimal treatment regime remains challenging due to the complex bidirectional cause-and-effect relationship between hypertension and CKD. There remains variability in antihypertensive treatment practices. AIM: To analyze data from the Salford Kidney Study database in relation to antihypertensive prescribing patterns amongst CKD patients. METHODS: The Salford Kidney Study is an ongoing prospective study that has been recruiting CKD patients since 2002. All patients are followed up annually, and their medical records including the list of medications are updated until they reach study endpoints [starting on renal replacement therapy or reaching estimated glomerular filtration rate (eGFR) expressed as mL/min/1.73 m2 ≤ 10 mL/min/1.73 m2, or the last follow-up date, or data lock on December 31, 2021, or death]. Data on antihypertensive prescription practices in correspondence to baseline eGFR, urine albumin-creatinine ratio, primary CKD aetiology, and cardiovascular disease were evaluated. Associations between patients who were prescribed three or more antihypertensive agents and their clinical outcomes were studied by Cox regression analysis. Kaplan-Meier analysis demonstrated differences in survival probabilities. RESULTS: Three thousand two hundred and thirty non-dialysis-dependent CKD patients with data collected between October 2002 and December 2019 were included. The median age was 65 years. A greater proportion of patients were taking three or more antihypertensive agents with advancing CKD stages (53% of eGFR ≤ 15 mL/min/1.73 m2 vs 26% of eGFR ≥ 60 mL/min/1.73 m2, P < 0.001). An increased number of patients receiving more classes of antihypertensive agents was observed as the urine albumin-creatinine ratio category increased (category A3: 62% vs category A1: 40%, P < 0.001), with the upward trends particularly noticeable in the number of individuals prescribed renin angiotensin system blockers. The prescription of three or more antihypertensive agents was associated with all-cause mortality, independent of blood pressure control (hazard ratio: 1.15; 95% confidence interval: 1.04-1.27, P = 0.006). Kaplan-Meier analysis illustrated significant differences in survival outcomes between patients with three or more and those with less than three antihypertensive agents prescribed (log-rank, P < 0.001). CONCLUSION: Antihypertensive prescribing patterns in the Salford Kidney Study based on CKD stage were consistent with expectations from the current United Kingdom National Institute of Health and Care Excellence guideline algorithm. Outcomes were poorer in patients with poor blood pressure control despite being on multiple antihypertensive agents. Continued research is required to bridge remaining variations in hypertension treatment practices worldwide.
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BACKGROUND: Renin-angiotensin-aldosterone system inhibitors (RAASi) improve prognosis in patients with heart failure with reduced ejection fraction (HFrEF), but suboptimal dosing or discontinuation of these medications often occurs due to RAASi-associated hyperkalaemia. We established a nephrology-led hyperkalaemia clinic to oversee prescribing of patiromer, an oral potassium binder, to facilitate RAASi optimization. METHODS: The clinic was established in July 2019 at a nephrology tertiary centre in the UK. Patients with HFrEF who were unable to increase RAASi dosage due to hyperkalaemia were referred to the clinic, where all patients commenced patiromer 8.4 g daily. RAASi adjustments were deferred to the referring teams. Study outcomes included the percentage of patients who achieved a RAASi dose increase and the proportion of patients with normokalaemia at follow-up. Outcomes were evaluated until 1 May 2021. RESULTS: A total of 34 patients were reviewed in the clinic between July 2019 and December 2020. Mean age was 71.6 years (±10.6 years), 56% had diabetes, and 71% had chronic kidney disease stages 3a-5; mean estimated glomerular filtration rate was 56 mL/min/1.73 m2 (±21 mL/min/1.73 m2). During follow-up, 13 patients discontinued patiromer (6 of whom did so due to gastrointestinal side effects) and were discharged; 2 patients died from non-hyperkalaemia-related illness; one switched to an alternative potassium binder. Over a mean follow-up of 13.4 months (±5.8 months), 17 of the 20 patients (85%) who continued with a potassium binder achieved a RAASi dose increase, with 4 patients (20%) receiving maximal dosages. This was attained by achieving normokalaemia during follow-up. No patients required magnesium supplementation. Of the 19 patients on patiromer, 12 continued this therapy for more than 12 months and 4 received it safely for 20 months. DISCUSSION/CONCLUSION: Patiromer prescribing in a nephrology-led hyperkalaemia clinic facilitated RAASi up-titration in patients with HFrEF by controlling potassium levels.
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Insuficiencia Cardíaca , Hiperpotasemia , Humanos , Anciano , Sistema Renina-Angiotensina , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Potasio , Volumen Sistólico , Hiperpotasemia/inducido químicamente , Hiperpotasemia/tratamiento farmacológicoRESUMEN
BACKGROUND: Atherosclerotic renovascular disease (ARVD) often follows an asymptomatic chronic course which may be undetected for many years. However, there are certain critical acute presentations associated with ARVD and these require a high index of suspicion for underlying high-grade RAS (renal artery stenosis) to improve patient outcomes. These acute presentations, which include decompensated heart failure syndromes, accelerated hypertension, rapidly declining renal function, and acute kidney injury (AKI), are usually associated with bilateral high-grade RAS (> 70% stenosis), or high-grade RAS in a solitary functioning kidney in which case the contralateral kidney is supplied by a vessel demonstrating renal artery occlusion (RAO). These presentations are typically underrepresented in large, randomized control trials which to date have been largely negative in terms of the conferred benefit of revascularization. CASE PRESENTATION: Here we describe 9 individual patients with 3 classical presentations including accelerated phase hypertension, heart failure syndromes, AKI and a fourth category of patients who suffered recurrent presentations. We describe their response to renal revascularization. The predominant presentation was that consistent with ischaemic nephropathy all of whom had a positive outcome with revascularization. CONCLUSION: A high index of suspicion is required for the diagnosis of RAS in these instances so that timely revascularization can be undertaken to restore or preserve renal function and reduce the incidence of hospital admissions for heart failure syndromes.
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Lesión Renal Aguda , Aterosclerosis , Insuficiencia Cardíaca , Hipertensión Renovascular , Hipertensión , Placa Aterosclerótica , Obstrucción de la Arteria Renal , Lesión Renal Aguda/complicaciones , Aterosclerosis/complicaciones , Aterosclerosis/diagnóstico por imagen , Insuficiencia Cardíaca/complicaciones , Humanos , Hipertensión/complicaciones , Obstrucción de la Arteria Renal/complicaciones , Obstrucción de la Arteria Renal/diagnóstico por imagen , Obstrucción de la Arteria Renal/cirugía , SíndromeRESUMEN
Optimization of binding affinities for ligands to their target protein is a primary objective in rational drug discovery. Herein, we report on a collaborative study that evaluates various compounds designed to bind to the SET and MYND domain-containing protein 3 (SMYD3). SMYD3 is a histone methyltransferase and plays an important role in transcriptional regulation in cell proliferation, cell cycle, and human carcinogenesis. Experimental measurements using the scintillation proximity assay show that the distributions of binding free energies from a large number of independent measurements exhibit non-normal properties. We use ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling) protocols to predict the binding free energies and to provide a detailed chemical insight into the nature of ligand-protein binding. Our results show that the 1-trajectory ESMACS protocol works well for the set of ligands studied here. Although one unexplained outlier exists, we obtain excellent statistical ranking across the set of compounds from the ESMACS protocol and good agreement between calculations and experiments for the relative binding free energies from the TIES protocol. ESMACS and TIES are again found to be powerful protocols for the accurate comparison of the binding free energies.
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Amidas , Isoxazoles , Amidas/farmacología , N-Metiltransferasa de Histona-Lisina/química , Humanos , Ligandos , Unión Proteica , Proteínas/metabolismo , TermodinámicaRESUMEN
The diagnosis and management of atherosclerotic renovascular disease (ARVD) is complex and controversial. Despite evidence from the ASTRAL (2009) and CORAL (2013) randomized controlled trials showing that percutaneous renal artery revascularization did not improve major outcomes compared with best medical therapy alone over 3-5 years, several areas of uncertainty remain. Medical therapy, including statin and antihypertensive medications, has evolved in recent years, and the use of renin-angiotensin-aldosterone system blockers is now considered the primary means to treat hypertension in the setting of ARVD. However, the criteria to identify kidneys with renal artery stenosis that have potentially salvageable function are evolving. There are also data suggesting that certain high-risk populations with specific clinical manifestations may benefit from revascularization. Here, we provide an overview of the epidemiology, diagnosis, and treatment of ARVD based on consensus recommendations from a panel of physician experts who attended the recent KDIGO (Kidney Disease: Improving Global Outcomes) Controversies Conference on central and peripheral arterial diseases in chronic kidney disease. Most focus is provided for contentious issues, and we also outline aspects of investigation and management of ARVD that require further research.
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Aterosclerosis , Hipertensión Renovascular , Obstrucción de la Arteria Renal , Aterosclerosis/diagnóstico , Aterosclerosis/epidemiología , Aterosclerosis/terapia , Humanos , Hipertensión Renovascular/diagnóstico , Hipertensión Renovascular/epidemiología , Hipertensión Renovascular/etiología , Riñón , Arteria Renal , Obstrucción de la Arteria Renal/diagnóstico , Obstrucción de la Arteria Renal/epidemiología , Obstrucción de la Arteria Renal/terapia , Sistema Renina-AngiotensinaRESUMEN
Variants of the susceptible-infected-removed (SIR) model of Kermack & McKendrick (1927) enjoy wide application in epidemiology, offering simple yet powerful inferential and predictive tools in the study of diverse infectious diseases across human, animal and plant populations. Direct transmission models (DTM) are a subset of these that treat the processes of disease transmission as comprising a series of discrete instantaneous events. Infections transmitted indirectly by persistent environmental pathogens, however, are examples where a DTM description might fail and are perhaps better described by models that comprise explicit environmental transmission routes, so-called environmental transmission models (ETM). In this paper we discuss the stochastic susceptible-exposed-infected-removed (SEIR) DTM and susceptible-exposed-infected-removed-pathogen (SEIR-P) ETM and we show that the former is the timescale separation limit of the latter, with ETM host-disease dynamics increasingly resembling those of a DTM when the pathogen's characteristic timescale is shortened, relative to that of the host population. Using graphical posterior predictive checks (GPPC), we investigate the validity of the SEIR model when fitted to simulated SEIR-P host infection and removal times. Such analyses demonstrate how, in many cases, the SEIR model is robust to departure from direct transmission. Finally, we present a case study of white spot disease (WSD) in penaeid shrimp with rates of environmental transmission and pathogen decay (SEIR-P model parameters) estimated using published results of experiments. Using SEIR and SEIR-P simulations of a hypothetical WSD outbreak management scenario, we demonstrate how relative shortening of the pathogen timescale comes about in practice. With atttempts to remove diseased shrimp from the population every 24h, we see SEIR and SEIR-P model outputs closely conincide. However, when removals are 6-hourly, the two models' mean outputs diverge, with distinct predictions of outbreak size and duration.
Asunto(s)
Enfermedades Transmisibles/transmisión , Brotes de Enfermedades , Enfermedades Endémicas , Epidemias , Animales , Teorema de Bayes , Enfermedades Transmisibles/fisiopatología , Biología Computacional/métodos , Simulación por Computador , Ambiente , Modelos Epidemiológicos , Humanos , Modelos Biológicos , Modelos Teóricos , Método de Montecarlo , Probabilidad , Procesos EstocásticosRESUMEN
BACKGROUND: Acute kidney injury (AKI) is a recognised complication of coronavirus disease 2019 (COVID-19), yet the reported incidence varies widely and the associated risk factors are poorly understood. METHODS: Data was collected on all adult patients who returned a positive COVID-19 swab while hospitalised at a large UK teaching hospital between 1st March 2020 and 3rd June 2020. Patients were stratified into community- and hospital-acquired AKI based on the timing of AKI onset. RESULTS: Out of the 448 eligible patients with COVID-19, 118 (26.3 %) recorded an AKI during their admission. Significant independent risk factors for community-acquired AKI were chronic kidney disease (CKD), diabetes, clinical frailty score and admission C-reactive protein (CRP), systolic blood pressure and respiratory rate. Similar risk factors were significant for hospital-acquired AKI including CKD and trough systolic blood pressure, peak heart rate, peak CRP and trough lymphocytes during admission. In addition, invasive mechanical ventilation was the most significant risk factor for hospital-acquired AKI (adjusted odds ratio 9.1, p < 0.0001) while atrial fibrillation conferred a protective effect (adjusted odds ratio 0.29, p < 0.0209). Mortality was significantly higher for patients who had an AKI compared to those who didn't have an AKI (54.3 % vs. 29.4 % respectively, p < 0.0001). On Cox regression, hospital-acquired AKI was significantly associated with mortality (adjusted hazard ratio 4.64, p < 0.0001) while community-acquired AKI was not. CONCLUSIONS: AKI occurred in over a quarter of our hospitalised COVID-19 patients. Community- and hospital-acquired AKI have many shared risk factors which appear to converge on a pre-renal mechanism of injury. Hospital- but not community acquired AKI was a significant risk factor for death.