Multiple blood gas variables predict AKI survival in an independent manner.

BACKGROUND AND AIM: Acute kidney injury (AKI) is becoming increasingly prevalent among hospitalized patients and carries a poor prognosis. While new biomarkers show promise in identifying early stages of AKI, accurately predicting severe outcomes such as the need for kidney replacement therapy (KRT) or death remains a challenge. However, blood gas analyses (BGA) can be used to diagnose life-threatening complications associated with AKI. The objective of this study was to assess the role of BGA as a biomarker panel in both emerging and established cases of AKI. METHODS: Retrospective observational study examining subjects with newly developed acute kidney injury (AKI). The study will document venous and arterial pH, pCO2, and actual bicarbonate levels upon hospital admission and at the onset of AKI. The primary endpoints include in-hospital mortality, the need for kidney replacement therapy (KRT), and the recovery of kidney function (ROKF). RESULTS: A total of 202 individuals were included in the study. Three variables were found to be independent predictors of in-hospital survival: admission arterial pH, arterial pH at acute kidney injury (AKI) onset, and arterial pCO2 at AKI onset. Additionally, venous pCO2 at AKI onset was identified as an independent predictor for the need of kidney replacement therapy (KRT). CONCLUSIONS: Our study suggests that blood gas analysis may have a potential role in predicting severe outcome variables in acute kidney injury (AKI). The associated costs are minimal.

Hypernatremia: Epidemiology and Predictive Role in Emerging and Established Acute Kidney Injury.

Hypernatremia (plasma sodium > 145 mmol/L) reflects impaired water balance, and affected patients can suffer from severe neurologic symptoms. Hyponatremia, on the other hand, is the most frequent electrolyte disorder in hospitals. It may be diagnosed in acute kidney injury (AKI), but hyponatremia prior to the diagnosis of AKI has also predictive or prognostic value in the short term. Aim of the article was to summarize data on both, epidemiology and outcomes of in-hospital acquired hypernatremia ("In-hospital acquired" refers to the diagnosis of either hypo- or hypernatremia in patients, who did not exhibit any of these electrolyte imbalances upon admission to the hospital). It also aimed to discuss its predictive role in patients with emerging or established AKI. Five databases were searched for references: PubMed, Medline, Google Scholar, Scopus, and Cochrane Library. Studies published between 2000 and 2023 were screened. The following keywords were used: "hypernatremia", "mortality", "pathophysiology", "acute kidney injury", "AKI", "risk prediction", "kidney replacement therapy", "KRT", "renal replacement therapy", "RRT", "hyponatremia", and "heart failure". A total of 16 studies were deemed eligible for inclusion. Among these, 13 studies had a retrospective design, two investigations were published as secondary analyses from prospective trial cohorts, and one study was prospective in nature. Out of the 16 studies, 11 focused on the epidemiology and outcomes of hypernatremia, while five investigations were related to AKI and/or AKI-associated endpoints. The prevalence of hypernatremia diagnosed during hospitalization varied from 1.9% to 6.8%, with one exception where it was 30.8%. All studies demonstrated associations between hypernatremia and mortality, even over extended periods after discharge. In AKI patients, hypernatremia shows potential for predicting in-hospital death. In conclusion, hypernatremic individuals are at higher risk of death during in-hospital therapy. Also, the electrolyte disorder potentially qualifies as a future biomarker for AKI onset and AKI-associated mortality.

The temporal dynamics of visual crowding in letter recognition: Modulating crowding with alternating flicker presentations.

Visual crowding reduces the visibility of a peripherally presented group of stimuli. This is especially challenging for peripheral reading because adjacent letters or characters perceptually crowd one another. We investigated the temporal course of spatial visual crowding by sequentially alternating the visibility of the target and flanking letters within a trigram letter stimulus presented 9° below fixation. We found that alternation rates of roughly 3 Hz released half of the total effect of crowding, whereas 10 Hz alternation rates elicited near-crowded performance. Furthermore, we found a robust performance asymmetry whereby presenting the target first elicited better performance than presenting the flankers first, an effect resembling forward masking. These results held for conditions of high, medium, and low spatial crowding. Future work will determine whether the alternation rates found in the current study can improve peripheral reading.

Increased Serum Sodium at Acute Kidney Injury Onset Predicts In-Hospital Death.

Background: Over the last decades, acute kidney injury (AKI) has been identified as a potentially fatal diagnosis which substantially increases in-hospital mortality in the short term and morbidity/mortality in the long term. However, reliable biomarkers for predicting AKI-associated outcomes are still missing. In this study, we assessed whether serum sodium, measured at different time points during the in-hospital treatment period, provided prognostic information in AKI. Methods: This was a retrospective, observational cohort study. AKI subjects were identified via the in-hospital AKI alert system. Serum sodium and potassium levels were documented at five pre-defined time points: hospital admission, AKI onset, minimum estimated glomerular filtration rate, minimum and maximum of the respective electrolyte during the treatment period. In-hospital death, the need for kidney replacement therapy (KRT) and recovery of kidney function were defined as endpoints. Results: Patients who suffered in-hospital death (n = 37, 23.1%) showed significantly higher serum sodium levels at diagnosis of AKI (survivors: 145.7 ± 2.13 vs. non-survivors: 138.8 ± 0.636 mmol/L, P = 0.003). A logistic regression model was significant for serum sodium levels in patients with in-hospital death (X2, P = 0.003; odds ratio = 1.08 (1.022 - 1.141); R2 = 0.082; d = 0.089). This suggests an increase of the relative risk for in-hospital death by 8% with every unit of serum sodium increase. Patients with a sodium above the upper normal range at AKI diagnosis were also more likely to suffer in-hospital death (P = 0.001). Conclusion: In summary, we present evidence that serum sodium, measured at time of AKI diagnosis, potentially serves as a predictor for in-hospital death in patients with AKI.

Stratification of Acute Kidney Injury Risk, Disease Severity, and Outcomes by Electrolyte Disturbances.

Acute kidney injury (AKI) affects up to 30% of all hospitalized patients in Central Europe and the USA. New biomarker molecules have been identified in recent years; most studies performed so far however aimed to identify markers for diagnostic purposes. Serum electrolytes such as sodium and potassium are quantified in more or less all hospitalized patients. Aim of the article is to review the literature on the AKI predictive role of four distinct serum electrolytes in evolving/progressing AKI. The following databases were searched for references: PubMed, Web of Science, Cochrane Library, and Scopus. The period lasted from 2010 until 2022. The following terms were utilized: "AKI" AND "sodium" OR "potassium" OR "calcium" OR "phosphate" AND "risk" OR "dialysis" OR "recovery of kidney function" OR "renal recovery" OR "kidney recovery" OR "outcome". Finally, 17 references were selected. The included studies were mostly retrospective in nature. Particularly, hyponatremia has been shown to be associated with an overall poor clinical outcome. The association between dysnatremia and AKI is anything but consistent. Hyperkalemia and potassium variability are most likely AKI predictive. Serum calcium and AKI risk are associated in a U-shaped manner. Higher phosphate levels potentially predict AKI in non-coronavirus disease 2019 (COVID-19) patients. The literature suggests that admission electrolytes can offer valuable information about AKI onset during follow-up. Limited data are however available on follow-up characteristics such as the need for dialysis or the chance of renal recovery. These aspects are of particular interest from the nephrologist's perspective.

Therapeutic Targets in Diffuse Midline Gliomas-An Emerging Landscape.

Diffuse midline gliomas (DMGs) are invariably fatal pediatric brain tumours that are inherently resistant to conventional therapy. In recent years our understanding of the underlying molecular mechanisms of DMG tumorigenicity has resulted in the identification of novel targets and the development of a range of potential therapies, with multiple agents now being progressed to clinical translation to test their therapeutic efficacy. Here, we provide an overview of the current therapies aimed at epigenetic and mutational drivers, cellular pathway aberrations and tumor microenvironment mechanisms in DMGs in order to aid therapy development and facilitate a holistic approach to patient treatment.

Impaired neural differentiation of MPS IIIA patient induced pluripotent stem cell-derived neural progenitor cells.

Mucopolysaccharidosis type IIIA (MPS IIIA) is characterised by a progressive neurological decline leading to early death. It is caused by bi-allelic loss-of-function mutations in SGSH encoding sulphamidase, a lysosomal enzyme required for heparan sulphate glycosaminoglycan (HS GAG) degradation, that results in the progressive build-up of HS GAGs in multiple tissues most notably the central nervous system (CNS). Skin fibroblasts from two MPS IIIA patients who presented with an intermediate and a severe clinical phenotype, respectively, were reprogrammed into induced pluripotent stem cells (iPSCs). The intermediate MPS IIIA iPSCs were then differentiated into neural progenitor cells (NPCs) and subsequently neurons. The patient derived fibroblasts, iPSCs, NPCs and neurons all displayed hallmark biochemical characteristics of MPS IIIA including reduced sulphamidase activity and increased accumulation of an MPS IIIA HS GAG biomarker. Proliferation of MPS IIIA iPSC-derived NPCs was reduced compared to control, but could be partially rescued by reintroducing functional sulphamidase enzyme, or by doubling the concentration of the mitogen fibroblast growth factor 2 (FGF2). Whilst both control heparin, and MPS IIIA HS GAGs had a similar binding affinity for FGF2, only the latter inhibited FGF signalling, suggesting accumulated MPS IIIA HS GAGs disrupt the FGF2:FGF2 receptor:HS signalling complex. Neuronal differentiation of MPS IIIA iPSC-derived NPCs was associated with a reduction in the expression of neuronal cell marker genes ßIII-TUBULIN, NF-H and NSE, revealing reduced neurogenesis compared to control. A similar result was achieved by adding MPS IIIA HS GAGs to the culture medium during neuronal differentiation of control iPSC-derived NPCs. This study demonstrates the generation of MPS IIIA iPSCs, and NPCs, the latter of which display reduced proliferation and neurogenic capacity. Reduced NPC proliferation can be explained by a model in which soluble MPS IIIA HS GAGs compete with cell surface HS for FGF2 binding. The mechanism driving reduced neurogenesis remains to be determined but appears downstream of MPS IIIA HS GAG accumulation.

Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.

Subregional brain distribution of simple and complex glycosphingolipids in the mucopolysaccharidosis type I (Hurler syndrome) mouse: impact of diet.

Gangliosides are the most complex oligosaccharide-containing glycosphingolipids defined by the presence of sialic acid and although present in all tissues, predominate in the brain. Considering their importance in neural development, it is unsurprising that ganglioside metabolism is altered in neurodegenerative diseases. The severe form of mucopolysaccharidosis type I, Hurler syndrome (HS), is characterised by progressive loss of neuronal function through largely undefined mechanisms. Here, we sought to interrogate brain gangliosides in a murine model of HS and further, assessed whether dietary modulation of lipid metabolism effected correction of the metabolic abnormalities. The simple gangliosides, GM2 , GM3 , GD2 and GD3 were elevated in the five subregions examined - brain stem, cerebellum, cortex, hippocampus, subcortex - in HS mice as early as 2 months of age compared with their wild type counterparts. Their elevation persisted at 6 months of age, imparting protracted neurological development as these simple gangliosides have usually subsided by this stage of brain development. Their immediate synthetic precursor, lactosylceramide, was also elevated, suggesting that their increase arises at this metabolic intermediary, as dihydroceramide, ceramide and monohexosylceramide were unaffected. Dietary linoleic acid supplementation significantly reduced GM2 and GM3 , and furthermore, improved exploratory behaviour as assessed by the open field test, highlighting the possibility of further exploring dietary intervention as a therapeutic consideration.

Selective normalisation of regional brain bis(monoacylglycero)phosphate in the mucopolysaccharidosis 1 (Hurler) mouse.

Bis(monoacylglycero)phosphate (BMP) is a glycerophospholipid highly enriched in the lysosomal network and elevated in lysosomal diseases. To correct this elevation, BMP synthesis was manipulated by dietary fatty acid supplementation and the impact on subregional brain BMP and pathology assessed in the mouse model of mucopolysaccharidosis 1 (Hurler syndrome (HS)). There was widespread elevation of BMP in HS mice across all six sub-regions - brain stem, cortex, cerebellum, hippocampus, olfactory bulb and the sub-cortex - with 22:6/22:6 the most abundant species. Linoleic acid normalised total BMP in all regions except the cortex and cerebellum, although there were differences in fatty acid species; the major finding a decrease in 22:6- and a concomitant increase in 22:5-containing species. A battery of behaviour assessments showed that in the water cross maze both HS and wild type mice performed less well on the linoleic acid diet, and that both HS and wild type mice on the linoleic acid diet performed similarly and better in the exploratory open field test. This may be a consequence of differential subregional BMP composition in the brain. The effects of high fat and docosahexaenoic/eicosapentaenoic acid enriched diets were generally unremarkable. Although major pathologies were not completely abrogated, much of the neurobehavioural testing was confounded by skeletal pathology that did not resolve. This is the first detailed characterisation of subregional brain BMP species informing on the ability to manipulate this phospholipid in the brain, and as such, may hold promise as an adjunct therapy not only for HS but also for other lysosomal diseases.

Ten signs of a healthy online presence (and symptoms that may indicate it is under the weather).

There is no denying that the Internet has become the marketplace of choice for a vast number of consumers, a number which continues to grow year after year. It is particularly true for the medical community as prospective patients often conduct extensive online research before they even consider picking up a phone to make an appointment. With so much information available online, it's only natural that the Internet is the first stop for so many, and only logical that medical professionals would begin to reach out to searchers online with Web sites, social media, and other online initiatives. How is your practice doing online? The answers to these 10 questions can indicate if your online presence is healthy or in need of an intervention.