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

Expressions 1992

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Physical rehabilitation interventions for adult patients with critical illness across the continuum of recovery:an overview of systematic reviews protocol

Background: Patients admitted to the intensive care unit with critical illness often experience significant physical\ud impairments, which typically persist for many years following resolution of the original illness. Physical rehabilitation\ud interventions that enhance restoration of physical function have been evaluated across the continuum of recovery\ud following critical illness including within the intensive care unit, following discharge to the ward and beyond hospital\ud discharge. Multiple systematic reviews have been published appraising the expanding evidence investigating these\ud physical rehabilitation interventions, although there appears to be variability in review methodology and quality. We\ud aim to conduct an overview of existing systematic reviews of physical rehabilitation interventions for adult intensive\ud care patients across the continuum of recovery.\ud Methods/design: This protocol has been developed according to the Preferred Reporting Items for Systematic\ud Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines. We will search the Cochrane Systematic Review Database,\ud Database of Abstracts of Reviews of Effectiveness, Cochrane Central Register of Controlled Trials, MEDLINE, Excerpta\ud Medica Database and Cumulative Index to Nursing and Allied Health Literature databases. We will include systematic\ud reviews of randomised controlled trials of adult patients, admitted to the intensive care unit and who have received\ud physical rehabilitation interventions at any time point during their recovery. Data extraction will include systematic\ud review aims and rationale, study types, populations, interventions, comparators, outcomes and quality appraisal\ud method. Primary outcomes of interest will focus on findings reflecting recovery of physical function. Quality of\ud reporting and methodological quality will be appraised using the PRISMA checklist and the Assessment of Multiple\ud Systematic Reviews tool.\ud Discussion: We anticipate the findings from this novel overview of systematic reviews will contribute to the synthesis\ud and interpretation of existing evidence regarding physical rehabilitation interventions and physical recovery in post-critical\ud illness patients across the continuum of recovery

Recovery, rehabilitation and follow-up services following critical illness: an updated UK national cross-sectional survey and progress report

Objective: To comprehensively update and survey the current provision of recovery, rehabilitation and follow-up services for adult critical care patients across the UK. Design: Cross-sectional, self-administered, predominantly closed-question, electronic, online survey. Setting: Institutions providing adult critical care services identified from national databases. Participants: Multiprofessional critical care clinicians delivering services at each site. Results: Responses from 176 UK hospital sites were included (176/242, 72.7%). Inpatient recovery and follow-up services were present at 127/176 (72.2%) sites, adopting multiple formats of delivery and primarily delivered by nurses (n=115/127, 90.6%). Outpatient services ran at 130 sites (73.9%), predominantly as outpatient clinics. Most services (n=108/130, 83.1%) were co-delivered by two or more healthcare professionals, typically nurse/intensive care unit (ICU) physician (n=29/130, 22.3%) or nurse/ICU physician/physiotherapist (n=19/130, 14.6%) teams. Clinical psychology was most frequently lacking from inpatient or outpatient services. Lack of funding was consistently the primary barrier to service provision, with other barriers including logistical and service prioritisation factors indicating that infrastructure and profile for services remain inadequate. Posthospital discharge physical rehabilitation programmes were relatively few (n=31/176, 17.6%), but peer support services were available in nearly half of responding institutions (n=85/176, 48.3%). The effects of the COVID-19 pandemic resulted in either increasing, decreasing or reformatting service provision. Future plans for long-term service transformation focus on expansion of current, and establishment of new, outpatient services. Conclusion: Overall, these data demonstrate a proliferation of recovery, follow-up and rehabilitation services for critically ill adults in the past decade across the UK, although service gaps remain suggesting further work is required for guideline implementation. Findings can be used to enhance survivorship for critically ill adults, inform policymakers and commissioners, and provide comparative data and experiential insights for clinicians designing models of care in international healthcare jurisdictions

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