May I have your consent? Informed consent in clinical trials- feasibility in emergency situations

Clinical researchers in acute emergency settings are commonly faced with the difficulty of satisfying the conventional ethical requirement of obtaining informed consent, whilst ensuring a representative group of patients is recruited into studies. We discuss our own experience in addressing institutional ethical requirements to obtain informed consent in a multi-centre trial, recruiting highly agitated patients in the emergency setting in Melbourne, Australia. We suggest that, through the application of existing ethical and legal frameworks and pre-emptive communication with the key stakeholders in ethics committees, hospital insurers and legal representatives, a balance can be struck between ethical and legal requirements on the one hand, and the integrity of the research question, on the other.published_or_final_versio

Settlement of blue crab postlarvae in western North Atlantic estuaries

We quantified variability in daily settlement of blue crab postlarvae (megalopae) on identical artificial settlement substrates at up to 6 sites concurrently over a broad geographic expanse (similar to 1300 km) of the western North Atlantic (Delaware-South Carolina, USA). The 4-year study encompassed the blue crab recruitment season (generally July-November) from 1989-1992. Regional settlement was characterized by: (1) constant low levels of daily settlement punctuated by significantly non-random, episodic peaks of variable duration and intensity with peaks collectively accounting for at least half the total annual settlement at a site; (2) spatial and temporal variability leading to a general lack of coherence between sites in a given year and across years within a site; (3) occasional coherence in patterns between sites during a given year, suggesting linkages in regional processes affecting settlement; and, (4) significant semilunar patterns of episodic settlement pulses at the York River and Charleston-Harbor sites over a 4-year period. Thus, regional settlement patterns exhibit both consistent (i.e., semilunar periodicity, episodic pulses) and variable (i.e., temporal and spatial variation) elements, which are likely due to a combination of stochastic and deterministic processes. Such patterns may impart an ecological advantage to crabs settling en masse (i.e., reduced encounter rate with predators through predator swamping) or at continuous low levels (i.e., below a density-dependent threshold) during the recruitment season. An identical study illustrated that settlement in Gulf of Mexico estuaries exhibited similarly episodic and highly variable patterns. Daily mean and total annual settlement were up to a hundred-fold greater for gulf than Atlantic Coast estuaries implying population limitation by post-settlement processes in the gulf and greater recruitment limitation in the Atlantic. These studies emphasize the merit of conducting research over a broad geographic range using standardized techniques to attempt meaningful ecological comparisons

Structural basis of dimerization and nucleic acid binding of human DBHS proteins NONO and PSPC1.

The Drosophila behaviour/human splicing (DBHS) proteins are a family of RNA/DNA binding cofactors liable for a range of cellular processes. DBHS proteins include the non-POU domain-containing octamer-binding protein (NONO) and paraspeckle protein component 1 (PSPC1), proteins capable of forming combinatorial dimers. Here, we describe the crystal structures of the human NONO and PSPC1 homodimers, representing uncharacterized DBHS dimerization states. The structures reveal a set of conserved contacts and structural plasticity within the dimerization interface that provide a rationale for dimer selectivity between DBHS paralogues. In addition, solution X-ray scattering and accompanying biochemical experiments describe a mechanism of cooperative RNA recognition by the NONO homodimer. Nucleic acid binding is reliant on RRM1, and appears to be affected by the orientation of RRM1, influenced by a newly identified 'β-clasp' structure. Our structures shed light on the molecular determinants for DBHS homo- and heterodimerization and provide a basis for understanding how DBHS proteins cooperatively recognize a broad spectrum of RNA targets

Relation of substance use disorders to mortality, accident and emergency department attendances, and hospital admissions: A 13-year population-based cohort study in Hong Kong

BACKGROUND: The impact of substance use disorders (SUD) in an Asian population has not been fully explored. We aimed to assess the risk of mortality, accident and emergency (A&E) department attendances, and hospital admissions associated with SUD in a population-based cohort study. METHOD: Patients diagnosed with SUD in public A&E departments from 2004 to 2016 (N = 8,423) were identified in the Clinical Database Analysis and Reporting System of the Hong Kong Hospital Authority and 1:1 matched to patients without SUD by propensity score (N = 6,074 in each group). Relative risks of mortality, A&E attendances and hospital admissions were assessed using Cox regression and Hurdle negative binomial regression. RESULTS: Patients with SUD had higher mortality (hazard ratio=1.43; 95% confidence interval [CI]=1.26-1.62) and more often died from poisoning or toxicity and injuries. The odds ratio (OR) for A&E attendances and all-cause hospital admissions associated with SUD were 2.80 (95% CI=2.58-3.04) and 3.54 (95% CI=3.26-3.83), respectively. The impact of SUD on the above outcomes was greatest among school-aged individuals (≤ 21 years) and decreased with age. The relative risk of mental disorder-related hospital admissions was much higher than that for infections, respiratory diseases, and cardiovascular diseases. In patients with SUD, ketamine and amphetamine use were associated with increased A&E attendances than opioid use. CONCLUSIONS: SUD was associated with increased mortality, A&E attendances and hospital admissions, especially in school-aged individuals. Our findings suggest prioritising early treatment and preventive interventions for school-aged individuals and focusing on the management of comorbid mental disorders and the use of ketamine and amphetamine

Economic evaluation of midazolam–droperidol combination, versus droperidol or olanzapine for the management of acute agitation in the emergency department: A within-trial analysis

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Intramuscular midazolam, olanzapine, or haloperidol for the management of acute agitation: A multi-centre, double-blind, randomised clinical trial

© 2021 The Authors Background: The safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated. Methods: A pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18–75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam (n = 56), olanzapine (n = 54), or haloperidol (n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118). Findings: Of 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine (p = 0·03) and haloperidol (p = 0·002). Adverse event rates were similar across the three arms. Dystonia (n = 1) and cardiac arrest (n = 1) were reported in the haloperidol group. Interpretation: Midazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects. Funding: Research Grants Council, Hong Kong

Serial Section Scanning Electron Microscopy (S(3)EM) on Silicon Wafers for Ultra-Structural Volume Imaging of Cells and Tissues.

High resolution, three-dimensional (3D) representations of cellular ultrastructure are essential for structure function studies in all areas of cell biology. While limited subcellular volumes have been routinely examined using serial section transmission electron microscopy (ssTEM), complete ultrastructural reconstructions of large volumes, entire cells or even tissue are difficult to achieve using ssTEM. Here, we introduce a novel approach combining serial sectioning of tissue with scanning electron microscopy (SEM) using a conductive silicon wafer as a support. Ribbons containing hundreds of 35 nm thick sections can be generated and imaged on the wafer at a lateral pixel resolution of 3.7 nm by recording the backscattered electrons with the in-lens detector of the SEM. The resulting electron micrographs are qualitatively comparable to those obtained by conventional TEM. S 3 EM images of the same region of interest in consecutive sections can be used for 3D reconstructions of large structures. We demonstrate the potential of this approach by reconstructing a 31.7 mm 3 volume of a calyx of Held presynaptic terminal. The approach introduced here, Serial Section SEM (S 3 EM), for the first time provides the possibility to obtain 3D ultrastructure of large volumes with high resolution and to selectively and repetitively home in on structures of interest. S 3 EM accelerates process duration, is amenable to full automation and can be implemented wit

Preferential Re-Replication of Drosophila Heterochromatin in the Absence of Geminin

To ensure genomic integrity, the genome must be duplicated exactly once per cell cycle. Disruption of replication licensing mechanisms may lead to re-replication and genomic instability. Cdt1, also known as Double-parked (Dup) in Drosophila, is a key regulator of the assembly of the pre-replicative complex (pre-RC) and its activity is strictly limited to G1 by multiple mechanisms including Cul4-Ddb1 mediated proteolysis and inhibition by geminin. We assayed the genomic consequences of disregulating the replication licensing mechanisms by RNAi depletion of geminin. We found that not all origins of replication were sensitive to geminin depletion and that heterochromatic sequences were preferentially re-replicated in the absence of licensing mechanisms. The preferential re-activation of heterochromatic origins of replication was unexpected because these are typically the last sequences to be duplicated in a normal cell cycle. We found that the re-replication of heterochromatin was regulated not at the level of pre-RC activation, but rather by the formation of the pre-RC. Unlike the global assembly of the pre-RC that occurs throughout the genome in G1, in the absence of geminin, limited pre-RC assembly was restricted to the heterochromatin by elevated cyclin A-CDK activity. These results suggest that there are chromatin and cell cycle specific controls that regulate the re-assembly of the pre-RC outside of G1