MONitoring Knockbacks in EmergencY (MONKEY) - An Audit of Disposition Outcomes in Emergency Patients with Rejected Admission Requests.

Background: Emergency Department (ED) clinicians commonly experience difficulties in referring patients to inpatient teams for hospital admission. There is limited literature reporting on patient outcomes following these complicated referrals, where ED requests for inpatient admission are rejected - which study investigators termed a "knockback". Purpose: To identify disposition outcomes and referral accuracy in ED patients whose admission referral was initially rejected. Secondary objectives were to identify additional patient, clinician and systemic factors associated with knockbacks. Selection and Methodology: Emergency clinicians prospectively nominated a convenience sample of patients identified as having knockbacks over two time periods (Jan-Feb 2020 and Aug 2020 to Jan 2021) at a tertiary Australian ED. Data were analyzed with a mixed-methods approach and subsequent descriptive and thematic analyses were performed. Results: A total of 109 patients were identified as knockbacks. The referrals were warranted, with 89.0% of cases (n = 97) ultimately requiring a hospital admission. In 60.6% (n = 66) of the admissions, patients were admitted under the inpatient team initially referred to by the ED, suggesting referrals were generally accurate. The number of in-hospital units involved in the admission process and ED length of stay were positively correlated (0.409, p < 0.001). Patient factors associated with knockbacks include pre-existing chronic medical conditions and presenting acutely unwell. Analysis of clinicians' perspectives yielded recurring themes of disagreements over admission destination and diagnostic uncertainty. Conclusion: In this patient sample, emergency referrals for admission were mostly warranted and accurate. Knockbacks increase ED length of stay and may adversely affect patient care. Further focused discussion and clearer referral guidelines between ED clinicians and their inpatient colleagues are required.

Structure and Orientation of Water and Choline Chloride Molecules around a Methane Hydrophobe: A Computer Simulation Study.

Recent studies have reported manifold industrial applications of aqueous choline chloride (ChCl) solution as an alternative to deep eutectic solvent. ChCl also serves as a protecting co-solvent for proteins by restricting urea to approach the protein surface and thereby maintaining the water structure around the protein. However, a detailed molecular-level picture of the ChCl and water, even in the absence of urea around a representative hydrophobe is largely lacking. This motivates us to probe the effect of varying wt % of ChCl on the occupancy and orientations of the constituents around a representative solute like methane using computer simulations. Accumulation of water molecules and preferential exclusion of ChCl from the surface of methane perturb the tetrahedral geometry of water around it. We find a tangential alignment of the polar part of the ChCl molecules that interact with water, whereas its hydrophobic part is preferentially facing the methane. With an increase in ChCl wt %, a disruption in the tetrahedrality is evident for water molecules accompanied by a reduction in hydrogen bonds between water pairs in the solution. In short, ChCl induces crowding and modifies the microscopic arrangement and hydrogen bonding structure of the water around the methane and beyond.

Cannabinoid hyperemesis syndrome: A 6-year audit of adult presentations to an urban district hospital.

OBJECTIVE: To describe the local experience of adult patients presenting with cannabinoid hyperemesis syndrome (CHS) to an urban ED in the outer northern suburbs of Melbourne. METHODS: Retrospective chart review of adult patients presenting to the ED with a documented history of CHS or equivalent terminology from January 2015 to January 2021. Age, sex, cannabis use, clinical features, pathology results, imaging and symptomatic management were examined as well as outcomes regarding disposition, representation, morbidity and mortality. RESULTS: One hundred and forty-two adult presentations were included. Sixty-seven were unique presentations and 29 were patients who represented during the study period. Most represented within 3 months (37.8%) and most represented at least twice. Males were overrepresented (68.7%). Patients were young (median age 31 years, interquartile range 23-35 years) and all had a history of regular cannabis use (usually daily). Cyclical nausea and/or vomiting was the most common clinical feature compared to others in previously reported diagnostic criteria. Patients typically had elevated white cell counts with associated neutrophilia (75.8%) and mild hypokalaemia (57.9%). Lipase was not elevated, and C-reactive protein was typically less than 50 mmol/L (98.2%). Imaging was not commonly performed but largely normal. Treatment was supportive with anti-emetic use, intravenous fluids and analgesia. There were no deaths or admissions to intensive care. CONCLUSIONS: Cyclical nausea and vomiting was the most common feature observed in this cohort compared to other clinical features reported in prior studies. Serum lipase was normal and C-reactive protein only mildly elevated. Prospective studies are required to further assess these findings.

In Silico Elucidation of Molecular Picture of Water-Choline Chloride Mixture.

Choline chloride (ChCl) is a component of several deep eutectic solvents (DESs) having numerous applications. Recent studies have reported manifold promising use of aqueous choline chloride solution as an alternative to DES, where water plays the role of the hydrogen-bond donor. The characteristic physical properties of the DESs and aqueous DES originate from the "inter-" and intraspecies hydrogen-bond network formed by the constituents. However, a detailed molecular-level picture of choline chloride and water mixture is largely lacking in the literature. This motivates us to carry out extensive all-atom molecular dynamics simulations of the ChCl-water mixture of varying compositions. Our analyses clearly show an overall increase in the interspecies association with an increase in ChCl concentration. At higher concentrations, the trimethylammonium groups of choline are stabilized by a nonpolar interaction, whereas the hydroxyl groups preferentially interact with water. Chloride ions are found to be involved in two types of interactions: one where chloride ions intercalate two or more choline cations, and the other one where they are surrounded by five to six water molecules forming solvated chloride ions. However, the relative fractions of these two types of associations depend on the concentration of ChCl in the mixture. Another important structural aspect is the disruption of the hydrogen-bonded water network due to the presence of both choline cations and chloride ions. However, chloride ions participate to partially restore the tetrahedral arrangement of partners around water molecules.

Microscopic structural features of water in aqueous-reline mixtures of varying compositions.

Reline, a mixture of urea and choline chloride in a 2 : 1 molar ratio, is one of the most frequently used deep eutectic solvents. Pure reline and its aqueous solution have large scale industrial use. Owing to the presence of active hydrogen bond formation sites, urea and choline cations can disrupt the hydrogen-bonded network in water. However, a quantitative understanding of the microscopic structural features of water in the presence of reline is still lacking. We carry out extensive all-atom molecular dynamics simulations to elucidate the effect of the gradual addition of co-solvents on the microscopic arrangements of water molecules. We consider four aqueous solutions of reline, between 26.3 and 91.4 wt%. A disruption of the local hydrogen-bonded structure in water is observed upon inclusion of urea and choline chloride. The extent of deviation of the water structure from tetrahedrality is quantified using the tetrahedral order parameter (qtet). Our analyses show a monotonic increase in the structural disorder as the co-solvents are added. Increase in the qtet values are observed when highly electro-negative hetero-atoms like nitrogen, oxygen of urea and choline cations are counted as partners of the central water molecules. Further insights are drawn from the characterization of the hydrogen-bonded network in water and we observe the gradual rupturing of water-water hydrogen bonds and their subsequent replacement by the water-urea hydrogen bonds. A negligible contribution from the hydrogen bonds between water and bulky choline cations has also been found. Considering all the constituents as the hydrogen bond partners we calculate the possibility of a successful hydrogen bond formation with a central water molecule. This gives a clear picture of the underlying mechanism of water replacement by urea.

Choline Chloride as a Nano-Crowder Protects HP-36 from Urea-Induced Denaturation: Insights from Solvent Dynamics and Protein-Solvent Interactions.

Urea at sufficiently high concentration unfolds the secondary structure of proteins leading to denaturation. In contrast, choline chloride (ChCl) and urea, in 1 : 2 molar ratio, form a deep eutectic mixture, a liquid at room temperature, protecting proteins from denaturation. In order to get a microscopic picture of this phenomenon, we perform extensive all-atom molecular dynamics simulations on a model protein, HP-36. Based on our calculation of Kirkwood-Buff integrals, we analyze the relative accumulation of urea and ChCl around the protein. Additional insights are drawn from the translational and rotational dynamics of solvent molecules and hydrogen bond auto-correlation functions. In the presence of urea, water shows slow subdiffusive dynamics around the protein owing to a strong interaction of water with the backbone atoms. Urea also shows subdiffusive motion. The addition of ChCl further slows down the dynamics of urea, restricting its accumulation around the protein backbone. Adding to this, choline cations in the first solvation shell of the protein show the strongest subdiffusive behavior. In other words, ChCl acts as a nano-crowder by excluding urea from the protein backbone and thereby slowing down the dynamics of water around the protein. This prevents the protein from denaturation and makes it structurally rigid, which is supported by the smaller radius of gyration and root mean square deviation values of HP-36.

On Perfect Clustering of High Dimension, Low Sample Size Data.

Popular clustering algorithms based on usual distance functions (e.g., the Euclidean distance) often suffer in high dimension, low sample size (HDLSS) situations, where concentration of pairwise distances and violation of neighborhood structure have adverse effects on their performance. In this article, we use a new data-driven dissimilarity measure, called MADD, which takes care of these problems. MADD uses the distance concentration phenomenon to its advantage, and as a result, clustering algorithms based on MADD usually perform well for high dimensional data. We establish it using theoretical as well as numerical studies. We also address the problem of estimating the number of clusters. This is a challenging problem in cluster analysis, and several algorithms are available for it. We show that many of these existing algorithms have superior performance in high dimensions when they are constructed using MADD. We also construct a new estimator based on a penalized version of the Dunn index and prove its consistency in the HDLSS asymptotic regime. Several simulated and real data sets are analyzed to demonstrate the usefulness of MADD for cluster analysis of high dimensional data.

Azadirachtin inhibits amyloid formation, disaggregates pre-formed fibrils and protects pancreatic ß-cells from human islet amyloid polypeptide/amylin-induced cytotoxicity.

The human islet amyloid polypeptide (hIAPP) or amylin is the major constituent of amyloidogenic aggregates found in pancreatic islets of type 2 diabetic patients that have been associated with ß-cell dysfunction and/or death associated with type 2 diabetes mellitus (T2DM). Therefore, developing and/or identifying inhibitors of hIAPP aggregation pathway and/or compound that can mediate disaggregation of preformed aggregates holds promise as a medical intervention for T2DM management. In the current study, the anti-amyloidogenic potential of Azadirachtin (AZD)-a secondary metabolite isolated from traditional medicinal plant Neem (Azadirachta indica)-was investigated by using a combination of biophysical and cellular assays. Our results indicate that AZD supplementation not only inhibits hIAPP aggregation but also disaggregates pre-existing hIAPP fibrils by forming amorphous aggregates that are non-toxic to pancreatic ß-cells. Furthermore, AZD supplementation in pancreatic ß-cells (INS-1E) resulted in inhibition of oxidative stress; along with restoration of the DNA damage, lipid peroxidation and the associated membrane damage, endoplasmic reticulum stress and mitochondrial membrane potential. AZD treatment also restored glucose-stimulated insulin secretion from pancreatic islets exposed to hIAPP. All-atom molecular dynamics simulation studies on full-length hIAPP pentamer with AZD suggested that AZD interacted with four possible binding sites in the amyloidogenic region of hIAPP. In summary, our results suggest AZD to be a promising candidate for combating T2DM and related amyloidogenic disorders.

Salt Induced Structural Collapse, Swelling, and Signature of Aggregation of Two ssDNA Strands: Insights from Molecular Dynamics Simulation.

Molecular dynamics simulations elucidate the structural collapse shown by two ssDNAs of the same base sequence in the presence of either Na+ or Mg2+, starting from in vivo ionic concentration to higher concentrations. Initially, an increase in ion concentration facilitates the structural distortion of individual ssDNA and helps to bring them close, and for this, Mg2+ is better than Na+. However, further addition of ions leads to structural reswelling of the DNA strands and inhibits their proximity. The structural changes are found to be guided by the strong interaction of the cations with the phosphinyl oxygen (pn_O). Additionally, a significant difference has been noticed in the interaction of the cations with phosphoester oxygen (pe_O) depending on the nature of the ion. The sequential and nonsequential base-pair stacking is one of the major factors in the structural collapse of individual ssDNA. Overall, the present investigation highlights some of the important aspects of aggregation of two ssDNA with the same base sequence at varying cationic concentration.

Friedelane, isolated from Pouzolzia indica Gaud. exhibits toxic effect against melanoma.

Melanoma is a predominant cause of skin cancer-related deaths. It was reported that, the methanolic extract of Pouzolzia Indica (P. indica) on chromatography gave five compounds (1-hentriacontanyl palmitate, myricyl alcohol, 6,7-dimethoxycoumarin, trichadonic acid and friedelane), which inhibited the acute promyelocytic leukemia cell lines, NB4, and HT93A. Friedelane was extracted as active compound from methanolic extract of P. indica. In this study, friedelane was tested on murine metastatic B16F10 and B16BL6 melanoma cell lines. To achieve the target, the cell viability using trypan blue exclusion, acridine orange/EtBr staining and cell cytotoxicity were tested using MTT assay. Caspase-3, caspase-9, Cyt-c, BAD and Bax protein were assayed to evidence the apoptosis induction. The compound friedelane shows potent cytotoxic effect against metastatic melanoma mouse cell lines in 10 µg/ml concentration.

Multilevel image thresholding based on 2D histogram and maximum Tsallis entropy--a differential evolution approach.

Multilevel thresholding amounts to segmenting a gray-level image into several distinct regions. This paper presents a 2D histogram based multilevel thresholding approach to improve the separation between objects. Recent studies indicate that the results obtained with 2D histogram oriented approaches are superior to those obtained with 1D histogram based techniques in the context of bi-level thresholding. Here, a method to incorporate 2D histogram related information for generalized multilevel thresholding is proposed using the maximum Tsallis entropy. Differential evolution (DE), a simple yet efficient evolutionary algorithm of current interest, is employed to improve the computational efficiency of the proposed method. The performance of DE is investigated extensively through comparison with other well-known nature inspired global optimization techniques such as genetic algorithm, particle swarm optimization, artificial bee colony, and simulated annealing. In addition, the outcome of the proposed method is evaluated using a well known benchmark--the Berkley segmentation data set (BSDS300) with 300 distinct images.