Fluid Management for Critically Ill Patients with Acute Kidney Injury Receiving Kidney Replacement Therapy: An International Survey.

BACKGROUND: In critically ill patients receiving KRT, high ultrafiltration rates and persistent fluid accumulation are associated with adverse outcomes. The purpose of this international survey was to evaluate current practices and evidence gaps related to fluid removal with KRT in critically ill patients. METHODS: This was a multinational, web-based survey distributed by seven networks comprising nephrologists and intensivists. Physicians involved in the care of critically ill patients were invited to complete a 39-question survey about fluid management practices on KRT. The survey was distributed from September 2021 to December 2021. RESULTS: There were 757 respondents from 96 countries (response rate of 65%). Most respondents practiced adult medicine (89%) and worked in an academic center (69%). The majority (91%) reported aiming for a 0.5- to 2-L negative fluid balance per day when fluid removal is indicated, although there was important variability in what respondents considered a safe maximal target. Intensivists were more likely than nephrologists to use adjunct volume status assessment methods ( i.e. , ultrasound, hemodynamic markers, and intra-abdominal pressure), while nephrologists were more likely to deploy cointerventions aimed at improving tolerance to fluid removal ( i.e. , osmotic agents and low-temperature dialysate). There was a broad consensus that rapid decongestion should be prioritized when fluid accumulation is present, but the prevention of hypotension was also reported as a competing priority. A majority (77%) agreed that performing trials that compare fluid management strategies would be ethical and clinically relevant. CONCLUSIONS: We have identified multiple areas of variability in current practice of fluid management for patients receiving KRT. Most nephrologists and intensivists agreed that several knowledge gaps related to fluid removal strategies should be investigated in future randomized controlled trials.

Venous Doppler to Assess Congestion: A Comprehensive Review of Current Evidence and Nomenclature.

Organ congestion from venous hypertension is an important pathophysiological mechanism mediating organ injury in several clinical contexts including critical illness, congestive heart failure and end-stage chronic kidney disease. However, the practical evaluation of venous congestion is often challenging at the bedside because of the limitations of traditional methods. Point-of-care ultrasound (POCUS) enables the clinician to assess venous velocity profiles during the cardiac cycle using Doppler modalities. Venous Doppler profile abnormalities at multiple sites are detected when elevated venous pressure results in hemodynamic changes within the systemic venous circulation. The detection of these abnormal Doppler profiles may identify patients with clinically significant systemic venous congestion. These patients have been reported to be at increased risk of medical complications. Improving the evaluation of venous congestion may lead to individualized treatment and improved patient outcomes. In this review, we describe the physiologic principles necessary to understand venous Doppler assessment. We also propose a nomenclature for the description of venous Doppler profiles. Finally, we provide a narrative review of the current clinical evidence related to use of venous Doppler assessment in various clinical contexts.

Prevalence of Bipolar Symptoms or Disorder in Epilepsy: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: This systematic review with meta-analysis (PROSPERO: CRD42021249336) was performed to estimate the pooled lifetime prevalence of bipolar symptoms (BS) and bipolar disorder (BD) in people with epilepsy (PWE). METHODS: A search was performed on June 5, 2021, in 4 databases (MEDLINE/PubMed, Ovid EMBASE, Ovid APA PsycInfo, and Web of Science) for original research reporting on BS/BD in PWE, with no restriction on language or time of publication. Inclusion criteria were as follows: (1) original research, (2) cross-sectional study design component, (3) reported lifetime prevalence of BS/BD or enough information to calculate an estimate, and (4) reported the method by which participants were deemed bipolar. Studies based on an exclusively pediatric population were excluded. To calculate pooled lifetime prevalence of BS/BD, 2 meta-analytic random-effects models were fitted, one for BS and the other for BD. Risk of bias was assessed using a standardized appraisal tool for studies reporting prevalence. Certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. RESULTS: A total of 750 records were screened and 17 studies were included for analysis: 7 provided prevalence estimates for only BS, 8 for only BD, and 2 for both BS and BD. After outlier exclusion and subgroup analysis using screening method as a moderator, the pooled prevalence of BS in PWE was 12.3% (95% CI 10.6%-14.1%) (7,506 PWE). The pooled prevalence of BD in PWE was 4.5% (95% CI 2.2%-7.4%) (48,334 PWE). Considerable heterogeneity was present, more so for BD than for BS, and could be explained through differences in population demographics and study methodology. DISCUSSION: This study's main limitation was regarding the certainty of evidence. However, our estimates of prevalence should prompt further research on BS/BD in PWE. Given the significant morbidity associated with BD, clinicians should carefully screen PWE for BS.

Clinical Correlates Identify ProBDNF and Thrombo-Inflammatory Markers as Key Predictors of Circulating p75NTR Extracellular Domain Levels in Older Adults.

The p75NTR receptor binds all neurotrophins and is mostly known for its role in neuronal survival and apoptosis. Recently, the extracellular domain (ECD) of p75NTR has been reported in plasma, its levels being dysregulated in numerous neurological diseases. However, the factors associated with p75NTR ECD levels remain unknown. We investigated clinical correlates of plasma p75NTR ECD levels in older adults without clinically manifested neurological disorders. Circulating p75NTR levels were measured by enzyme-linked immunosorbent assay in plasma obtained from participants in the BEL-AGE cohort (n = 1,280). Determinants of plasma p75NTR ECD levels were explored using linear and non-linear statistical models. Plasma p75NTR ECD levels were higher in male participants; were positively correlated with circulating concentrations of pro-brain-derived neurotrophic factor, and inflammatory markers interleukin-6 and CD40 Ligand; and were negatively correlated with the platelet activation marker P-selectin. While most individuals had p75NTR levels ranging from 43 to 358 pg/ml, high p75NTR levels reaching up to 9,000 pg/ml were detectable in a subgroup representing 15% of the individuals studied. In this cohort of older adults without clinically manifested neurological disorders, there was no association between plasma p75NTR ECD levels and cognitive performance, as assessed by the Montreal Cognitive Assessment score. The physiological relevance of high p75NTR ECD levels in plasma warrants further investigation. Further research assessing the source of circulating p75NTR is needed for a deeper understanding of the direction of effect, and to investigate whether high p75NTR ECD levels are predictive biomarkers or consequences of neuropathology.

Pro-inflammatory role of Wnt/ß-catenin signaling in endothelial dysfunction.

Background: Endothelial dysfunction is a critical component of both atherosclerotic plaque formation and saphenous vein graft failure. Crosstalk between the pro-inflammatory TNF-α-NFκB signaling axis and the canonical Wnt/ß-catenin signaling pathway potentially plays an important role in regulating endothelial dysfunction, though the exact nature of this is not defined. Results: In this study, cultured endothelial cells were challenged with TNF-α and the potential of a Wnt/ß-catenin signaling inhibitor, iCRT-14, in reversing the adverse effects of TNF-α on endothelial physiology was evaluated. Treatment with iCRT-14 lowered nuclear and total NFκB protein levels, as well as expression of NFκB target genes, IL-8 and MCP-1. Inhibition of ß-catenin activity with iCRT-14 suppressed TNF-α-induced monocyte adhesion and decreased VCAM-1 protein levels. Treatment with iCRT-14 also restored endothelial barrier function and increased levels of ZO-1 and focal adhesion-associated phospho-paxillin (Tyr118). Interestingly, inhibition of ß-catenin with iCRT-14 enhanced platelet adhesion in cultured TNF-α-stimulated endothelial cells and in an ex vivo human saphenous vein model, most likely via elevating levels of membrane-tethered vWF. Wound healing was moderately retarded by iCRT-14; hence, inhibition of Wnt/ß-catenin signaling may interfere with re-endothelialisation in grafted saphenous vein conduits. Conclusion: Inhibition of the Wnt/ß-catenin signaling pathway with iCRT-14 significantly recovered normal endothelial function by decreasing inflammatory cytokine production, monocyte adhesion and endothelial permeability. However, treatment of cultured endothelial cells with iCRT-14 also exerted a pro-coagulatory and moderate anti-wound healing effect: these factors may affect the suitability of Wnt/ß-catenin inhibition as a therapy for atherosclerosis and vein graft failure.

Tourniquet application by schoolchildren-a randomized crossover study of three commercially available models.

BACKGROUND: Life-threatening hemorrhage is a major cause of preventable mortality in trauma. Studies have demonstrated the effectiveness and safety of commercial tourniquets when used by adult civilians. However, there are no data about tourniquet application by children.This study's goal is to determine which of three commercially available tourniquets is most effective when used by children. METHODS: A randomized crossover study was conducted in four elementary schools in Montreal to compare three commercially available tourniquets. The study population is primary school children aged 10 to 12 years (5th-6th grade). A total of 181 students were invited to participate; 96 obtained parental approval and were recruited. Participants underwent a short 7-minute video training on the use of three commercial tourniquets and were subsequently given a 2-minute practice period. Students were evaluated on their ability to successfully apply the tourniquet and the time to complete application. After applying all three tourniquets, the students selected their favorite model. The primary outcome is the proportion of successful applications per tourniquet model. Secondary outcomes include time to successful application for each tourniquet model and tourniquet model preference. RESULTS: The mechanical advantage tourniquet (MAT) outperformed the combat application tourniquet (CAT) and the stretch wrap and tuck tourniquet (SWATT) in terms of success rate (MAT, 67%; CAT, 44%; SWATT, 24%; p < 0.0001), time to application (MAT, 57 seconds; CAT, 80 seconds; SWATT, 90 seconds; p < 0.0001), and preference (MAT, 64%; CAT, 30%; SWATT, 6%; p < 0.0001). CONCLUSION: In this study, the MAT performs better in terms of success rate, time to application, and preference when used by school-aged children. This study can be helpful when facilities are purchasing tourniquets for use by students.

Androgen-Induced Relaxation of Uterine Myocytes Is Mediated by Blockade of Both Ca(2+) Flux and MLC Phosphorylation.

CONTEXT: Uterine quiescence must be maintained until pregnancy reaches term. Premature activation of myometrial contractility leads to preterm labor and delivery. OBJECTIVE: To scrutinize the potential of androgens to relax the myometrium and the mechanism of their action. SAMPLES: A pregnancy-derived myometrial smooth muscle cell line (PHM1-41) and myometrial strips prepared from tissues obtained from pregnant women (lean, n = 9; obese, n = 6) undergoing elective cesarean section at term and from nonpregnant C57BL/6 mice (n=5) were each utilized. DESIGN: The contraction of collagen-embedded PHM1-41s and the stretch-induced contraction of human and murine myometrial strips were assessed after incubation with Testosterone (T), dihydrotestosterone (DHT), and T conjugated to BSA. Intracellular calcium ([Ca(2+)]) and phosphorylated myosin light chain concentrations were quantified in PHM1-41s using a Fluo-4 Ca(2+) assay and in-cell Westerns, respectively. SETTING: University research institute. RESULTS: DHT and T, but not T conjugated to BSA, impaired the contractile function of PHM1-41s and of human and murine myometrial strips. The response was rapid (observed within minutes), was sustainable for up to 48 hours, and was not abolished on knockdown of the androgen receptor. DHT (100 µm) reduced the amplitude of lean strip contraction to 2 ± 2% of the pretreatment value and T (100 µm) to 3.3 ± 1%. These values for obese strips were 15 ± 6.7% and 11 ± 6.7%, respectively. At the same doses, in murine strips, DHT reduced the amplitude to 4.8 ± 3% and T to 4.9 ± 3%. DHT (50 µm) pretreatment reduced the oxytocin-stimulated increase in [Ca(2+)] (P < .0001; n = 6) and phosphorylated myosin light chain (P < .05; n = 5) in PHM1-41s. CONCLUSION: Lipid-soluble androgens could be developed as tocolytic agents for the treatment of preterm labor.