Designing nutrition-based interventional trials for the future: addressing the known knowns

Abstract The consistent decline in critical illness mortality has a significant effect on trial design, whereby either an improbable effect sizes or large number of patients are required. The signal-to-noise ratio is of particular interest for the critically ill. When considering the potential signal, interventions need to match outcomes in regard to biological plausibility. Provision of nutrition is a complex decision with many underappreciated aspects of noise. However, a fundamental interaction is often not accounted for time. Working as a community to evolve trial design will be our challenge for nutrition interventions in the critically ill for the future

Populations of planets in multiple star systems

Astronomers have discovered that both planets and binaries are abundant throughout the Galaxy. In combination, we know of over 100 planets in binary and higher-order multi-star systems, in both circumbinary and circumstellar configurations. In this chapter we review these findings and some of their implications for the formation of both stars and planets. Most of the planets found have been circumstellar, where there is seemingly a ruinous influence of the second star if sufficiently close (<50 AU). Hosts of hot Jupiters have been a particularly popular target for binary star studies, showing an enhanced rate of stellar multiplicity for moderately wide binaries (>100 AU). This was thought to be a sign of Kozai-Lidov migration, however recent studies have shown this mechanism to be too inefficient to account for the majority of hot Jupiters. A couple of dozen circumbinary planets have been proposed around both main sequence and evolved binaries. Around main sequence binaries there are preliminary indications that the frequency of gas giants is as high as those around single stars. There is however a conspicuous absence of circumbinary planets around the tightest main sequence binaries with periods of just a few days, suggesting a unique, more disruptive formation history of such close stellar pairs.Comment: Invited review chapter, accepted for publication in "Handbook of Exoplanets", ed. H. Deeg & J. A. Belmont

CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation

The CYFIP1/SRA1 gene is located in a chromosomal region linked to various neurological disorders, including intellectual disability, autism, and schizophrenia. CYFIP1 plays a dual role in two apparently unrelated processes, inhibiting local protein synthesis and favoring actin remodeling. Here, we show that brain-derived neurotrophic factor (BDNF)-driven synaptic signaling releases CYFIP1 from the translational inhibitory complex, triggering translation of target mRNAs and shifting CYFIP1 into the WAVE regulatory complex. Active Rac1 alters the CYFIP1 conformation, as demonstrated by intramolecular FRET, and is key in changing the equilibrium of the two complexes. CYFIP1 thus orchestrates the two molecular cascades, protein translation and actin polymerization, each of which is necessary for correct spine morphology in neurons. The CYFIP1 interactome reveals many interactors associated with brain disorders, opening new perspectives to define regulatory pathways shared by neurological disabilities characterized by spine dysmorphogenesis.status: publishe

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice

IMPORTANCE: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. OBJECTIVE: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. EXPOSURES: Genetic test results. MAIN OUTCOMES AND MEASURES: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. RESULTS: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). CONCLUSIONS AND RELEVANCE: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes

suPAR as a marker of infection in acute kidney injury – a prospective observational study

Abstract Background Soluble urokinase-type plasminogen activator receptor (suPAR) has emerged as a new sepsis biomarker. It is not known whether suPAR has a role in critically ill patients with severe acute kidney injury (AKI). Methods Our main aims were to describe serial serum suPAR concentrations in patients with severe AKI, to investigate a potential association between suPAR and C-reactive protein (CRP), and to compare suPAR and CRP as diagnostic markers of infection in patients with AKI. Between April 2013 – April 2014, we recruited adult patients (≥18 years) with AKI KDIGO stage 2/3 admitted to a multidisciplinary Intensive Care Unit (ICU) in a University Hospital in UK. Serial serum suPAR and CRP concentrations were measured for 6 days. We compared the characteristics and serial suPAR and CRP concentrations of patients with and without an infection using Chi-squared, Fisher’s exact, t-test and Mann-Whitney tests as appropriate, and calculated the area under the receiver operating characteristics curve (AUC). Results Data of 55 patients with AKI stage 2/3 were analysed (62% male; mean age 60.5) of whom 43 patients received continuous renal replacement therapy. suPAR was not detectable in effluent fluid. There was no significant correlation between daily suPAR and CRP concentrations. In patients with an infection, suPAR results were significantly higher than in those without an infection across all time points; there was no significant difference in CRP levels between both groups. After exclusion of patients with an infection before or on day of admission to ICU, the AUC of suPAR for predicting an infection later was 0.62 (95% CI 0.43–0.80) compared to 0.50 (95% CI 0.29–0.71) for CRP. Conclusions In critically ill patients with AKI stage 2/3, suPAR is a better marker of infection than CRP. Trial registration The study was retrospectively registered on the ISRCTN registry on 25 November 2012 (ISRCTN88354940)

Micronutrient use in critical care: survey of clinical practice

Background &amp; aims: micronutrients, principally vitamins and minerals, play an important role both in health and in disease. Parenteral micronutrient products are commonly prescribed for critically ill patients both in line with the terms of the product's license, and for other indications where there is an underpinning physiological rationale, or precedent, for their use but little evidence. This survey sought to understand United Kingdom (UK) prescribing practice in this area.Methods: a 12-question survey was circulated to healthcare professionals working in UK critical care units. The survey was designed to explore several aspects of micronutrient prescribing or recommendation practice by the critical care multidisciplinary team, including indications and underpinning clinical rationale for using these products, dosing, and considerations with respect to micronutrients delivered as part of nutrition. Results were analysed, exploring indications, considerations relating to diagnoses, therapies including renal replacement therapies, and method of nutrition. Results: 217 responses were included in the analysis, with 58% from physicians and the remaining 42% from nurses, pharmacists, dietitians and other healthcare disciplines. Vitamins were most commonly prescribed or recommended for Wernicke's encephalopathy (prescribed or recommended by 76% of respondents), treatment of refeeding syndrome (64.5%), and for patients with unknown or uncertain alcohol intake history (63.6%). These clinically suspected or confirmed indications were cited more frequently as a reason to prescribe than laboratory identified deficiency states. 20% of respondents indicated that they would prescribe or recommend parenteral vitamins for patients requiring renal replacement therapy. The practice of vitamin C prescribing was heterogeneous, including dose and indication. Trace elements were prescribed or recommended less often than vitamins, with the most frequently reported indications being for patients requiring parenteral nutrition (42.9%), biochemically confirmed deficiency states (35.9%), and for treatment of refeeding syndrome (26.3%). Conclusions: micronutrient prescribing in ICUs in the UK is heterogeneous, with clinical scenarios where there is an evidence base or an established precedent for their use often guiding decisions to use micronutrient products. Further work to examine the potential benefits and harms on patient-oriented outcomes of micronutrient product administration should be undertaken, to facilitate their judicious and cost-effective use, with a focus on areas where they have a theoretical benefit.</p