Chronic Hyponatremia and Brain Structure and Function Before and After Treatment.

RATIONALE & OBJECTIVE: Hyponatremia is the most common electrolyte disorder and is associated with significant morbidity and mortality. This study investigated neurocognitive impairment, brain volume, and alterations in magnetic resonance imaging (MRI)-based measures of cerebral function in patients before and after treatment for hyponatremia. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients with presumed chronic hyponatremia without signs of hypo- or hypervolemia treated in the emergency department of a German tertiary-care hospital. EXPOSURE: Hyponatremia (ie, plasma sodium concentration [Na+]<125mmol/L) before and after treatment leading to [Na+]>130mmol/L. OUTCOMES: Standardized neuropsychological testing (Mini-Mental State Examination, DemTect, Trail Making Test A/B, Beck Depression Inventory, Timed Up and Go) and resting-state MRI were performed before and after treatment of hyponatremia to assess total brain and white and gray matter volumes as well as neuronal activity and its synchronization. ANALYTICAL APPROACH: Changes in outcomes after treatment for hyponatremia assessed using bootstrapped confidence intervals and Cohen d statistic. Associations between parameters were assessed using correlation analyses. RESULTS: During a 3.7-year period, 26 patients were enrolled. Complete data were available for 21 patients. Mean [Na+]s were 118.4mmol/L before treatment and 135.5mmol/L after treatment. Most measures of cognition improved significantly. Comparison of MRI studies showed a decrease in brain tissue volumes, neuronal activity, and synchronization across all gray matter after normalization of [Na+]. Volume effects were particularly prominent in the hippocampus. During hyponatremia, synchronization of neuronal activity was negatively correlated with [Na+] (r=-0.836; 95% CI, -0.979 to-0.446) and cognitive function (Mini-Mental State Examination, r=-0.523; 95% CI, -0.805 to-0.069; DemTect, r=-0.744; 95% CI, -0.951 to-0.385; and Trail Making Test A, r=0.692; 95% CI, 0.255-0.922). LIMITATIONS: Small sample size, insufficient quality of several MRI scans as a result of motion artifact. CONCLUSIONS: Resolution of hyponatremia was associated with improved cognition and reductions in brain volumes and neuronal activity. Impaired cognition during hyponatremia is closely linked to increased neuronal activity rather than to tissue volumes. Furthermore, the hippocampus appears to be particularly susceptible to hyponatremia, exhibiting pronounced changes in tissue volume. PLAIN-LANGUAGE SUMMARY: Hyponatremia is a common clinical problem, and patients often present with neurologic symptoms that are at least partially reversible. This study used neuropsychological testing and magnetic resonance imaging to examine patients during and after correction of hyponatremia. Treatment led to an improvement in patients' cognition as well as a decrease in their brain volumes, spontaneous neuronal activity, and synchronized neuronal activity between remote brain regions. Volume effects were particularly prominent in the hippocampus, an area of the brain that is important for the modulation of memory. During hyponatremia, patients with the lowest sodium concentrations had the highest levels of synchronized neuronal activity and the poorest cognitive test results.

Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway.

SIGNIFICANCE STATEMENT: AKI is a major clinical complication leading to high mortality, but intensive research over the past decades has not led to targeted preventive or therapeutic measures. In rodent models, caloric restriction (CR) and transient hypoxia significantly prevent AKI and a recent comparative transcriptome analysis of murine kidneys identified kynureninase (KYNU) as a shared downstream target. The present work shows that KYNU strongly contributes to CR-mediated protection as a key player in the de novo nicotinamide adenine dinucleotide biosynthesis pathway. Importantly, the link between CR and NAD+ biosynthesis could be recapitulated in a human cohort. BACKGROUND: Clinical practice lacks strategies to treat AKI. Interestingly, preconditioning by hypoxia and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. METHODS: Kynureninase (KYNU) knockout mice were generated by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and comparative transcriptome, proteome and metabolite analyses of murine kidneys pre- and post-ischemia-reperfusion injury in the context of CR or ad libitum diet were performed. In addition, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation. RESULTS: We identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the effect of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans. CONCLUSIONS: CR induces the de novo NAD+ synthesis pathway in the context of IRI and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.

The impact of the SARS-CoV-2 pandemic-related lockdowns on orthopedic trauma emergencies at a level-one trauma center.

INTRODUCTION: The SARS-CoV-2 pandemic and its associated lockdowns had a profound effect on orthopedic trauma emergencies. This study aimed to investigate the patient volume and injury patterns at a level-one trauma center during the SARS-CoV-2 pandemic and compare them to the pre-pandemic conditions. MATERIALS AND METHODS: A retrospective chart review of all patients who presented to the orthopedic trauma emergency department of a level-one trauma center in Cologne, Germany within a 2 year period from March 16th, 2019 to March 15th, 2020 (pre-pandemic control) and from March 16th, 2020 and March 15th, 2021 (pandemic) was performed. The pandemic year was separated into three periods: (1) first lockdown, (2) between lockdowns and (3) second lockdown. The absolute numbers of patient presentations, the Manchester triage score (MTS) and the relative proportion of patients with structural organ injuries, fractures and dislocations, of polytraumatized patients, of hospital admissions, of subsequent emergency or semi-elective surgeries and of work-related accidents were evaluated in comparison to the pre-pandemic control. RESULTS: A total of 21,642 patient presentations were included in this study. Significantly less weekly orthopedic trauma emergency patient presentations were recorded during the pandemic (p < 0.01). The MTS was significantly lower during the first lockdown and between lockdowns (p < 0.01). The proportional incidence of overall structural organ injuries, fractures and dislocations, of upper limb fractures/dislocations, of hospital admissions and of patients requiring surgery was significantly increased during the pandemic (p ≤ 0.03). The proportional incidence of work-related injuries was significantly decreased during the pandemic (p < 0.01). CONCLUSIONS: Orthopedic trauma emergency presentations were reduced during the SARS-CoV-2 pandemic. Due to the reluctancy of patients to visit the emergency department during the pandemic, the proportions of relevant injuries in general and of upper limb injuries in particular as well as of patients requiring hospital admission and trauma-related surgery were significantly increased.

Caloric restriction reduces the pro-inflammatory eicosanoid 20-hydroxyeicosatetraenoic acid to protect from acute kidney injury.

Acute kidney injury is a frequent complication in the clinical setting and associated with significant morbidity and mortality. Preconditioning with short-term caloric restriction is highly protective against kidney injury in rodent ischemia reperfusion injury models. However, the underlying mechanisms are unknown hampering clinical translation. Here, we examined the molecular basis of caloric restriction-mediated protection to elucidate the principles of kidney stress resistance. Analysis of an RNAseq dataset after caloric restriction identified Cyp4a12a, a cytochrome exclusively expressed in male mice, to be strongly downregulated after caloric restriction. Kidney ischemia reperfusion injury robustly induced acute kidney injury in male mice and this damage could be markedly attenuated by pretreatment with caloric restriction. In females, damage was significantly less pronounced and preconditioning with caloric restriction had only little effect. Tissue concentrations of the metabolic product of Cyp4a12a, 20-hydroxyeicosatetraenoic acid (20-HETE), were found to be significantly reduced by caloric restriction. Conversely, intraperitoneal supplementation of 20-HETE in preconditioned males partly abrogated the protective potential of caloric restriction. Interestingly, this effect was accompanied by a partial reversal of caloric restriction--induced changes in protein but not RNA expression pointing towards inflammation, endoplasmic reticulum stress and lipid metabolism. Thus, our findings provide an insight into the mechanisms underlying kidney protection by caloric restriction. Hence, understanding the mediators of preconditioning is an important prerequisite for moving towards translation to the clinical setting.

Clinical course and predictive risk factors for fatal outcome of SARS-CoV-2 infection in patients with chronic kidney disease.

PURPOSE: The ongoing pandemic caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) has stressed health systems worldwide. Patients with chronic kidney disease (CKD) seem to be more prone to a severe course of coronavirus disease (COVID-19) due to comorbidities and an altered immune system. The study's aim was to identify factors predicting mortality among SARS-CoV-2-infected patients with CKD. METHODS: We analyzed 2817 SARS-CoV-2-infected patients enrolled in the Lean European Open Survey on SARS-CoV-2-infected patients and identified 426 patients with pre-existing CKD. Group comparisons were performed via Chi-squared test. Using univariate and multivariable logistic regression, predictive factors for mortality were identified. RESULTS: Comparative analyses to patients without CKD revealed a higher mortality (140/426, 32.9% versus 354/2391, 14.8%). Higher age could be confirmed as a demographic predictor for mortality in CKD patients (> 85 years compared to 15-65 years, adjusted odds ratio (aOR) 6.49, 95% CI 1.27-33.20, p = 0.025). We further identified markedly elevated lactate dehydrogenase (> 2 × upper limit of normal, aOR 23.21, 95% CI 3.66-147.11, p < 0.001), thrombocytopenia (< 120,000/µl, aOR 11.66, 95% CI 2.49-54.70, p = 0.002), anemia (Hb < 10 g/dl, aOR 3.21, 95% CI 1.17-8.82, p = 0.024), and C-reactive protein (≥ 30 mg/l, aOR 3.44, 95% CI 1.13-10.45, p = 0.029) as predictors, while renal replacement therapy was not related to mortality (aOR 1.15, 95% CI 0.68-1.93, p = 0.611). CONCLUSION: The identified predictors include routinely measured and universally available parameters. Their assessment might facilitate risk stratification in this highly vulnerable cohort as early as at initial medical evaluation for SARS-CoV-2.

The prognostic signature of health-related quality of life in older patients admitted to the emergency department: a 6-month follow-up study.

BACKGROUND: The management of older and multimorbid patients with complex care requires a personalised and comprehensive approach. The main diagnosis is often registered as the cause of hospitalisation, yet poor health-related quality of life (HRQoL) as well as multimorbidity may represent the underlying cause and markedly influence prognosis. AIMS: To analyse the association of HRQoL and clinical prognosis over time as assessed by a Comprehensive Geriatric Assessment (CGA)-based Multidimensional Prognostic Index (MPI) in older patients admitted to the emergency department (ED). METHODS: We used data from the prospective MPI-HOPE (Influence of the MPI on the Hospitalisation of Older Patients admitted to the Emergency department) study. Data from 165 patients (≥ 75 years) admitted to the ED of the University Hospital of Cologne, Germany, between Oct 2017 and Jan 2018 were included. Clinical prognosis was calculated by the MPI and HRQoL by the EQ5D-5L. Follow-up interviews assessed HRQoL up to 6 months after discharge. RESULTS: Most patients were multimorbid and presented with several geriatric syndromes. At admission, HRQoL was highest in patients with the best clinical prognosis. The MPI showed a negative correlation with the EQ-Index at admission (rs(86) = - 0.50, p < 0.0001) and follow-up assessments after 3 and 6 months (rs(86) = - 0.55 and rs(86) = - 0.47, p < 0.0001). DISCUSSION: Our results suggest that patients' self-perceived HRQoL in the ED is related to functional health status and clinical prognosis. CONCLUSION: The MPI as a multidimensional snapshot provides information on clinical health indicators and informs about subjective HRQoL, thereby helping in identifying patients who would benefit from a specific treatment within the frame of a patient-centered, value-based care strategy geriatric treatment.

The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury.

BACKGROUND: Although AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized that these preconditioning strategies use similar pathways to augment cellular stress resistance. METHODS: To identify genes and pathways shared by caloric restriction and hypoxic preconditioning, we used RNA-sequencing transcriptome profiling to compare the transcriptional response with both modes of preconditioning in mice before and after renal ischemia-reperfusion injury. RESULTS: The gene expression signatures induced by both preconditioning strategies involve distinct common genes and pathways that overlap significantly with the transcriptional changes observed after ischemia-reperfusion injury. These changes primarily affect oxidation-reduction processes and have a major effect on mitochondrial processes. We found that 16 of the genes differentially regulated by both modes of preconditioning were strongly correlated with clinical outcome; most of these genes had not previously been directly linked to AKI. CONCLUSIONS: This comparative analysis of the gene expression signatures in preconditioning strategies shows overlapping patterns in caloric restriction and hypoxic preconditioning, pointing toward common molecular mechanisms. Our analysis identified a limited set of target genes not previously known to be associated with AKI; further study of their potential to provide the basis for novel preventive strategies is warranted. To allow for optimal interactive usability of the data by the kidney research community, we provide an online interface for user-defined interrogation of the gene expression datasets (http://shiny.cecad.uni-koeln.de:3838/IRaP/).

Modulation of Endocannabinoids by Caloric Restriction Is Conserved in Mice but Is Not Required for Protection from Acute Kidney Injury.

Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents, AKI can be effectively prevented through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans), longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, particularly arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.

Rapid response infrastructure for pandemic preparedness in a tertiary care hospital: lessons learned from the COVID-19 outbreak in Cologne, Germany, February to March 2020.

The coronavirus disease (COVID-19) pandemic has caused tremendous pressure on hospital infrastructures such as emergency rooms (ER) and outpatient departments. To avoid malfunctioning of critical services because of large numbers of potentially infected patients seeking consultation, we established a COVID-19 rapid response infrastructure (CRRI), which instantly restored ER functionality. The CRRI was also used for testing of hospital personnel, provided epidemiological data and was a highly effective response to increasing numbers of suspected COVID-19 cases.

The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) leads to significant morbidity and mortality; unfortunately, strategies to prevent or treat AKI are lacking. In recent years, several preconditioning protocols have been shown to be effective in inducing organ protection in rodent models. Here, we characterized two of these interventions-caloric restriction and hypoxic preconditioning-in a mouse model of cisplatin-induced AKI and investigated the underlying mechanisms by acquisition of multi-layered omic data (transcriptome, proteome, N-degradome) and functional parameters in the same animals. Both preconditioning protocols markedly ameliorated cisplatin-induced loss of kidney function, and caloric restriction also induced lipid synthesis. Bioinformatic analysis revealed mRNA-independent proteome alterations affecting the extracellular space, mitochondria, and transporters. Interestingly, our analyses revealed a strong dissociation of protein and RNA expression after cisplatin treatment that showed a strong correlation with the degree of damage. N-degradomic analysis revealed that most posttranscriptional changes were determined by arginine-specific proteolytic processing. This included a characteristic cisplatin-activated complement signature that was prevented by preconditioning. Amyloid and acute-phase proteins within the cortical parenchyma showed a similar response. Extensive analysis of disease-associated molecular patterns suggested that transcription-independent deposition of amyloid P-component serum protein may be a key component in the microenvironmental contribution to kidney damage. This proof-of-principle study provides new insights into the pathogenesis of cisplatin-induced AKI and the molecular mechanisms underlying organ protection by correlating phenotypic and multi-layered omics data.

Prevalence of hyponatremia in inpatients with incurable and life-limiting diseases and its association with physical symptoms-a retrospective descriptive study.

PURPOSE: Hyponatremia is a common electrolyte abnormality seen in hospitalized patients. It may cause a variety of symptoms and is associated with longer hospitalizations and higher mortality. However, to date, only little is known about the extent of hyponatremia in patients with incurable diseases and whether it is associated with physical symptoms in this patient group. This study aims to describe the prevalence of hyponatremia, associated symptoms, and symptom intensity in inpatients with hyponatremia receiving specialist palliative care (SPC). METHODS: This is a retrospective study. Demographic and clinical data as well as symptoms, scored symptom intensity, and laboratory values were collected. All inpatients of a large German University Hospital receiving SPC in 2013 with documented sodium values were included. RESULTS: In 2013, 789 inpatients received SPC of which 710 had documented sodium values. The prevalence of hyponatremia was 38.7% (275/710). A mild degree showed 220 (31,0%), 44 (6.2%) had a moderate, and 11 (1.6%) a severe form. Hyponatremia patients experienced significantly more symptoms than normonatremic patients (mean = 7.71 vs 6.63; p < 0.001). Breathlessness, depressiveness, nausea, vomiting, poor appetite, constipation, and weakness were significantly more frequent in patients with hyponatremia. Furthermore, hyponatremia severity was associated with higher symptom intensity (mean = 13.29 vs 11.28; p < 0.001). CONCLUSIONS: More than one third of all SPC patients showed a hyponatremia, and the hyponatremia grade was associated with symptom burden and symptom intensity. A prospective analysis is needed to further examine this association and the possible influence of hyponatremia correction on symptom burden reduction.

Assessing renal changes after remote ischemic preconditioning (RIPC) of the upper extremity using BOLD imaging at 3T.

OBJECTIVE: Acute kidney injury (AKI) is an important risk factor for a number of adverse outcomes including end-stage renal disease and cardiovascular morbidity and mortality. Whilst many clinical situations that can induce AKI are known-e.g. drug toxicity, contrast agent exposure or ischemia during surgery-targeted preventive or therapeutic measures are still lacking. As to renoprotective strategies, remote ischemic preconditioning (RIPC) is one of the most promising novel approaches and has been examined by a number of clinical trials. The aim of this study was to use blood oxygenation level-dependent (BOLD) MRI as a surrogate parameter to assess the effect of RIPC in healthy volunteers. MATERIALS AND METHODS: In this IRB-approved, prospective study, 40 healthy volunteers were stratified with 20 undergoing an RIPC procedure (i.e. RIPC group) with a transient ischemia of the right arm, and 20 undergoing a sham procedure. Before and after the procedure, both kidneys of all participants were scanned using a 12-echo mGRE sequence for functional BOLD imaging at 3T. For each volunteer, 180 ROIs were placed in the cortex and the medulla of the kidneys. Ultimately, R2* values, which have an inverse correlation with the oxygenation level of tissue, were averaged for the RIPC and control groups. RESULTS: Following intervention, mean R2* values significantly decreased in the RIPC group in both the cortex (18.6 ± 2.3 vs. 17.5 ± 1.7 Hz; p = 0.0047) and medulla (34 ± 5.2 vs. 32.2 ± 4.2 Hz; p = 0.0001). However, no significant differences were observed in the control group. CONCLUSION: RIPC can be non-invasively assessed in healthy volunteers using BOLD MRI at 3T, demonstrating a higher oxygen content in kidney tissue. This study presents a first-in-man trial establishing a quantifiable readout of RIPC and its effects on kidney physiology. BOLD measurements may advance clinical trials in further evaluating RIPC for future clinical care.

Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis.

Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.

Thiazide-Associated Hyponatremia, Report of the Hyponatremia Registry: An Observational Multicenter International Study.

BACKGROUND: Hyponatremia is a frequent and potentially life-threatening adverse side effect of thiazide diuretics. This sub-analysis of the Hyponatremia Registry database focuses on current management practices of thiazide-associated hyponatremia (TAH) and compares differences between TAH and syndrome of inappropriate antidiuretic hormone secretion (SIADH). METHODS: We analyzed 477 patients from 225 US and EU sites with euvolemic hyponatremia ([Na+] ≤130 mEq/L) who were receiving a thiazide diuretic. Of these, 118 met criteria for true thiazide-induced hyponatremia (TIH). RESULTS: Thiazide was withdrawn immediately after hyponatremia was diagnosed only in 57% of TAH; in these patients, the median rate of [Na+] change (Δdaily[Na+]) was significantly higher than those with continued thiazide treatment (3.8 [interquartile range: 4.0] vs. 1.7 [3.8] mEq/L/day). The most frequently employed therapies were isotonic saline (29.6%), fluid restriction (19.9%), the combination of these two (8.2%), and hypertonic saline (5.2%). Hypertonic saline produced the greatest Δdaily[Na+] (8.0[6.4] mEq/L/day) followed by a combination of fluid restriction and normal saline (4.5 [3.8] mEq/L/day) and normal saline alone (3.6 [3.5] mEq/L/day). Fluid restriction was markedly less effective (2.7 [2.7] mEq/L/day). Overly rapid correction of hyponatremia occurred in 3.1% overall, but in up to 21.4% given hypertonic saline. Although there are highly significant differences in the biochemical profiles between TIH and SIADH, no predictive diagnostic test could be derived. CONCLUSIONS: Despite its high incidence and potential risks, the management of TAH is often poor. Immediate withdrawal of the thiazide is crucial for treatment success. Hypertonic saline is most effective in correcting hyponatremia but associated with a high rate of overly rapid correction. We could not establish a diagnostic laboratory-based test to differentiate TIH from SIADH.

Euvolemic hyponatremia in cancer patients. Report of the Hyponatremia Registry: an observational multicenter international study.

PURPOSE: Hyponatremia secondary to SIADH is frequent in cancer patients and potentially deleterious. The aim of this sub-analysis of the Hyponatremia Registry database is to analyze current diagnostic and therapeutic management practices in cancer patients with SIADH. METHODS: We analyzed 358 cancer patients who had serum sodium concentration ([Na+]) ≤ 130 mEq/L and a clinical diagnosis of SIADH from 225 sites in the USA and EU. RESULTS: Precise diagnostic testing was performed in only 46%. Almost 12% of all patients did not receive any hyponatremia treatment. The most frequent therapies were fluid restriction (20%), isotonic saline (14%), fluid restriction/isotonic saline (7%), tolvaptan (8%), and salt tablets (7%). Hypertonic saline was used in less than 3%. Tolvaptan produced the greatest median rate of [Na+] change (IQR) (3.0 (4.7) mEq/L/day), followed by hypertonic saline (2.0(7.0) mEq/L/day), and fluid restriction/isotonic saline (1.9(3.2) mEq/L/day). Both fluid restriction and isotonic saline monotherapies were significantly less effective (0.8(2.0) mEq/L/day and 1.3(3.0) mEq/L/day, respectively) and were associated with clinically relevant rates of treatment failure. Only 46% of patients were discharged with [Na+] ≥ 130 mEq/L. Overly rapid correction of hyponatremia occurred in 11.7%. CONCLUSIONS: Although essential for successful hyponatremia management, appropriate diagnostic testing is not routinely performed in current practice. The most frequently employed monotherapies were often ineffective and sometimes even aggravated hyponatremia. Tolvaptan was used less often but showed significantly greater effectiveness. Despite clear evidence that hyponatremia is associated with poor outcome in oncology patients, most patients were discharged still hyponatremic. Further studies are needed to assess the beneficial impact of hyponatremia correction with effective therapies.

Current treatment practice and outcomes. Report of the hyponatremia registry.

Current management practices for hyponatremia (HN) are incompletely understood. The HN Registry has recorded diagnostic measures, utilization, efficacy, and outcomes of therapy for eu- or hypervolemic HN. To better understand current practices, we analyzed data from 3087 adjudicated adult patients in the registry with serum sodium concentration of 130 mEq/l or less from 225 sites in the United States and European Union. Common initial monotherapy treatments were fluid restriction (35%), administration of isotonic (15%) or hypertonic saline (2%), and tolvaptan (5%); 17% received no active agent. Median (interquartile range) mEq/l serum sodium increases during the first day were as follows: no treatment, 1.0 (0.0-4.0); fluid restriction, 2.0 (0.0-4.0); isotonic saline, 3.0 (0.0-5.0); hypertonic saline, 5.0 (1.0-9.0); and tolvaptan, 4.0 (2.0-9.0). Adjusting for initial serum sodium concentration with logistic regression, the relative likelihoods for correction by 5 mEq/l or more (referent, fluid restriction) were 1.60 for hypertonic saline and 2.55 for tolvaptan. At discharge, serum sodium concentration was under 135 mEq/l in 78% of patients and 130 mEq/l or less in 49%. Overly rapid correction occurred in 7.9%. Thus, initial HN treatment often uses maneuvers of limited efficacy. Despite an association with poor outcomes and availability of effective therapy, most patients with HN are discharged from hospital still hyponatremic. Studies to assess short- and long-term benefits of correction of HN with effective therapies are needed.

The ciliopathy disease protein NPHP9 promotes nuclear delivery and activation of the oncogenic transcriptional regulator TAZ.

Nephronophthisis (NPH) is a genetically heterogenous kidney disease and represents the most common genetic cause for end-stage renal disease in children. It is caused by the mutation of genes encoding for the nephrocystin proteins (NPHPs) which localize to primary cilia or centrosomes, classifying this disease as a 'ciliopathy'. Recently, it has been shown that NPHP4 acts as a potent negative regulator of mammalian Hippo signalling by interacting with the Lats protein kinase and controlling the phosphorylation of the oncogenic transcriptional activator TAZ. Here, we demonstrate that NPHP9, another NPH family member, also controls TAZ activity by a distinct mechanism. NPHP9, which is also called NEK8, directly interacted with TAZ and induced nuclear translocation of the TAZ/NPHP9 protein complex. Binding of NPHP9 to TAZ was enhanced in a TAZ mutant that lost its ability to bind 14-3-3, suggesting that 14-3-3 and NPHP9 may compete for TAZ binding, with 14-3-3 favouring cytoplasmic retention and NPHP9 mediating nuclear delivery. Consistently, co-expression of NPHP4, which inhibits TAZ phosphorylation at the 14-3-3 binding site through the inhibition of Lats kinase activity, induced efficient nuclear delivery of the TAZ/NPHP9 protein pair. Consistent with a role for TAZ in controlling proliferation and tumorigenesis, the downregulation of NPHP9 inhibited the TAZ-dependent proliferation of hippo-responsive normal epithelial and also breast cancer cells. As NPHP9 has been shown to be upregulated in breast cancer, these data do not only support a critical role for TAZ/hippo signalling in the pathogenesis of NPH but may also imply a possible role for NPHP9 in TAZ-mediated tumorigenesis.

Personalized, interdisciplinary patient pathway for cross-sector care of multimorbid patients (eliPfad trial): study protocol for a randomized controlled trial.

BACKGROUND: Multimorbid and frail elderly patients often carry a high burden of treatment. Hospitalization due to the onset of an acute illness can disrupt the fragile balance, resulting in further readmissions after hospital discharge. Current models of care in Germany do not meet the needs of this patient group. Rather lack of coordination and integration of care combined with a lack of interdisciplinary approaches result in fragmented and inadequate care and increase the burden of treatment even more. METHODS: eliPfad is a randomized controlled trial conducted in 6 hospitals in Germany. Multimorbid elderly patients aged 55 or older are randomly assigned to the intervention or control group. Patients in the intervention group receive the eliPfad intervention additional to standard care. The core components of eliPfad are: Early assessment of patients' individual treatment burden and support through a specially trained case manager Involvement of the patient's general practitioner (GP) right from the beginning of the hospital stay Preparation of an individual, cross-sectoral treatment plan through the interdisciplinary hospital team with the involvement of the patient's GP Establishment of a cross-sectoral electronic patient record (e-ePA) for documentation and cross-sectoral exchange Support/Promote patient adherence Tailored early rehabilitation during the hospital stay, which is continued at home Close-tele-monitoring of medically meaningful vital parameters through the use of tablets, digital devices, and personal contacts in the home environment The intervention period begins in the hospital and continues 6 weeks after discharge. Patients in the control group will be treated according to standard clinical care and discharged according to current discharge management. The primary aim is the prevention/reduction of readmissions in the first 6 months after discharge. In addition, the impact on health-related quality of life, the burden of treatment, survival, self-management, medication prescription, health literacy, patient-centered care, cost-effectiveness, and process evaluation will be examined. Nine hundred forty-eight patients will be randomized 1:1 to intervention and control group. DISCUSSION: If eliPfad leads to fewer readmissions, proves (cost-)effective, and lowers the treatment burden, it should be introduced as a new standard of care in the German healthcare system. TRIAL REGISTRATION: The trial was registered in the German Clinical Trials Registry (Deutsches Register Klinischer Studien (DRKS)) on 08/14/2023 under the ID DRKS00031500 .

[Clinical acute and emergency medicine curriculum-focus on internal medicine : Recommendations for advanced training in internal medicine in the emergency department]. / Curriculum Klinische Akut- und Notfallmedizin ­ Schwerpunkt Innere Medizin : Empfehlung zu Weiterbildungsinhalten der Inneren Medizin in der Notaufnahme.

In Germany, physicians qualify for emergency medicine by combining a specialty medical training-e.g. internal medicine-with advanced training in emergency medicine according to the statutes of the State Chambers of Physicians largely based upon the Guideline Regulations on Specialty Training of the German Medical Association. Internal medicine and their associated subspecialities represent an important column of emergency medicine. For the internal medicine aspects of emergency medicine, this curriculum presents an overview of knowledge, skills (competence levels I-III) as well as behaviours and attitudes allowing for the best treatment of patients. These include general aspects (structure and process quality, primary diagnostics and therapy as well as indication for subsequent treatment; resuscitation room management; diagnostics and monitoring; general therapeutic measures; hygiene measures; and pharmacotherapy) and also specific aspects concerning angiology, endocrinology, diabetology and metabolism, gastroenterology, geriatric medicine, hematology and oncology, infectiology, cardiology, nephrology, palliative care, pneumology, rheumatology and toxicology. Publications focussing on contents of advanced training are quoted in order to support this concept. The curriculum has primarily been written for internists for their advanced emergency training, but it may generally show practising emergency physicians the broad spectrum of internal medicine diseases or comorbidities presented by patients attending the emergency department.