Using Shock Index as a Predictor of ICU Readmission: A Quality Iimprovement Project

Background: Adverse events will occur in one-third of patients discharged from the intensivecare unit (ICU) and evidence shows that ICU readmissions increase a patient’s length of stay,mortality, hospital costs, and nosocomial infections, as well as decrease long-term survival.Specific predictive factors that will accurately predict which patients are at risk of adverseevents requiring readmission are needed.Aim: The specific aim of this project was to identify if shock index (SI) values higher than 0.7at the time of transfer from the ICU are a useful predictor of ICU readmission.Methods: Using the Plan, Do, Study, Act (PDSA) framework, a retrospective chart review wasperformed using a matched cohort of 34 patients readmitted with 72 hours of discharge from theICU and 34 controls to obtain SI values at admission, transfer from and readmission to the ICU.A second PDSA cycle looked for SI trends within 24 hours prior to discharge from the ICU.Results: An odds ratio calculating the risk of readmission of patients with an elevated SI was2.96 (Confidence Interval (CI) 1.1 to 7.94, p-value=0.03). The odds ratio for an 80% SIelevation over 24 hours prior to discharge was 1.56 (CI 0.36 to 6.76, p-value=0.55).Conclusion and Implications for CNL Practice: Patients with elevated SIs at the time oftransfer are three times more likely to be readmitted to the ICU. Patients with elevations in atleast 80% of the 24 hour pre-discharge SIs showed no significant differences between thecontrol and readmitted cohorts. Implications of these results for the clinical nurse leader will bediscussed

A luciferase based viability assay for ATP detection in 384-well format for high throughput whole cell screening of Trypanosoma brucei brucei bloodstream form strain 427

<p>Abstract</p> <p>Background</p> <p>Human African Trypanosomiasis (HAT) is caused by two trypanosome species, <it>Trypanosoma brucei rhodesiense </it>and <it>Trypanosoma brucei gambiense</it>. Current drugs available for the treatment of HAT have significant issues related to toxicity, administration regimes with limited effectiveness across species and disease stages, thus there is a considerable need to find alternative drugs. A well recognised approach to identify new drug candidates is high throughput screening (HTS) of large compound library collections.</p> <p>Results</p> <p>We describe here the development of a luciferase based viability assay in 384-well plate format suitable for HTS of <it>T.b.brucei</it>. The parameters that were explored to determine the final HTS assay conditions are described in detail and include DMSO tolerability, Z', diluents and cell inoculum density. Reference compound activities were determined for diminazene, staurosporine and pentamidine and compared to previously published IC₅₀data obtained. The assay has a comparable sensitivity to reference drugs and is more cost effective than the 96-well format currently reported for <it>T.b.brucei</it>.</p> <p>Conclusion</p> <p>Due to the reproducibility and sensitivity of this assay it is recommended for potential HTS application. As it is commercially available this assay can also be utilised in many laboratories for both large and small scale screening.</p

The measurement of oestradiol, progesterone, LH, FSH and hCG for assisted reproduction: A comparison of the Siemens Centaur CP and Roche e411 automated analysers

Objective: To compare the results of two automated analysers by measuring reproductive hormones using the same quality control. Methods: Results obtained by the Roche Cobas e411 automated analyser in a specialised fertility clinic were compared to the Siemens Centaur CP for the reproductive hormones oestradiol, progesterone, LH, FSH and hCG. Results: Commercially-available quality control (QC) samples showed significant differences between the two assays for all five hormones at one or more levels. In clinical samples, the range of concentrations encountered was similar to the QC samples for LH and FSH but much higher for oestradiol, progesterone, and hCG showing the limitations of such QC samples in a specialised fertility setting when they are intended for general pathology use. There was a high degree of correlation for all hormones (all r\u3e0.985) and a gradient close to 1 for all, except for hCG when the Siemens analyser read ≥1 000 IU/L (r=1.209) and this is reflected in a large mean bias (-2 647.9 IU/L) and coefficient of repeatability (11 690.0 IU/L) when using a Bland-Altman plot. Conclusions: Despite an overall agreement between the two assay platforms for progesterone, LH and FSH, small differences between the two analysers in the concentrations of oestradiol and hCG as encountered in natural ovarian cycles or at the time of pregnancy testing may require a redefinition of clinical cut-offs

Tripanocidno i citotoksično djelovanje etanolskoga iscrpka lišća Psidium guajava određivano bojanjem alamarskim plavilom

Ethanolic extracts prepared from the leaves of Psidium guajava were evaluated for anti-trypanosoma and cytotoxicity activity in the bloodstream species of Trypanosoma brucei brucei (BS427) and HEK293 in 384-well Alamar Blue assays respectively. Cytotoxicity activity in HEK293 cells was subsequently used to estimate the selectivity index of the extracts. The activities of the plant extracts were determined to evaluate if further chemical and biological profi ling may be warranted for potential development in early drug discovery for African Sleeping Sickness. Two trypanocides, pentamidine and diminazene, were employed as reference drugs, while puromycin was also included as control for general cell growth inhibition. The results show that the extracts inhibited growth of T. b. brucei with an IC50 of 6.3 μg/mL and 48.9 μg/mL for 80% and 20% ethanolic preparations respectively, with corresponding activity of less than 50% against HEK293 at the highest screening dose of 238.10 μg/mL. The estimated selectivity index of the extracts compares favourably with pentamidine and diminazene. Meanwhile the reference compounds were found to have activities in agreement with published sensitivities at the doses screened. The lack of cytotoxicity at the doses screened and direct activity against T. b. brucei whole cells, make these extracts suitable candidates for further chemical elucidation and biological profiling.Istraženo je tripanocidno djelovanje etanolskog iscrpka lišća Psidium guajava na vrstu Trypanosoma brucei brucei (BS427) i njegova citotoksičnost na stanice HEK293 bojanjem alamarskim plavilom u 384 jažice. Citotoksični učinak na stanice HEK293 rabljen je za procjenu indeksa selektivnosti. Učinkovitost biljnih iscrpaka određivana je da bi se procijenila svrhovitost budućih kemijskih i bioloških istraživanja potencijalnoga lijeka za afričku bolest spavanja. U istraživanju su rabljena dva tripanocida, pentamidin i diminazen, te puromicin kao sredstvo koje usporava rast stanica. Rezultati su pokazali da 80% etanolskih pripravaka s IC50 od 6,3 μg/mL koči rast i razvoj tripanosoma, a samo 20% onih s IC50 od 48,9 μg/mL, s odgovarajućom aktivnosti manjom od 50% na stanice HEK293 u najvećoj dozi od 238,10 μg/mL. Indeks selektivnosti iscrpaka bio je sukladan s aktivnošću pentamidina i diminazena. Aktivnost istraživanih sastojaka bila je sukladna s razinom prije objavljene osjetljivosti. Izostanak citotoksičnosti na razini rabljenih koncentracija i izravna djelotvornost na stanice T. b. brucei daju osnovu za daljnja kemijska i biološka istraživanja predmetnih pripravaka

Consensus for the General Use of Equine Water Treadmills for Healthy Horses

Water treadmill exercise has become popular in recent years for the training and rehabilitation of equine athletes. In 2019, an equine hydrotherapy working group was formed to establish what was commonly considered to be best practice in the use of the modality. This article describes the process by which general guidelines for the application of water treadmill exercise in training and rehabilitation programmes were produced by the working group. The guidelines describe the consensus reached to date on (1) the potential benefits of water treadmill exercise, (2) general good practice in water treadmill exercise, (3) introduction of horses to the exercise, (4) factors influencing selection of belt speed, water depth and duration of exercise, and (5) monitoring movement on the water treadmill. The long-term goal is to reach a consensus on the optimal use of the modality within a training or rehabilitation programme. Collaboration between clinicians, researchers and experienced users is needed to develop research programmes and further guidelines regarding the most appropriate application of the modality for specific veterinary conditions

Re-evaluating pretomanid analogues for Chagas disease:Hit-to-lead studies reveal both in vitro and in vivo trypanocidal efficacy

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class

Design, synthesis and biological evaluation of 2-nitroimidazopyrazin-one/-es with antitubercular and antiparasitic activity

Tuberculosis and parasitic diseases, such as giardiasis, amebiasis, leishmaniasis and trypanosomiasis, all urgently require improved treatment options. Recently, it has been shown that anti-tubercular bicyclic nitroimidazoles such as pretomanid and delamanid have potential as repurposed therapeutics for the treatment of visceral leishmaniasis. Here we show that pretomanid also possesses potent activity against Giardia lamblia and Entamoeba histolytica, thus expanding the therapeutic potential of nitroimidazo-oxazines. Synthetic analogs with the novel nitroimidazopyrazin-one/-e bicyclic nitroimidazole chemotype were designed, synthesized and structure activity relationships generated. Selected derivatives had potent antiparasitic and antitubercular activity whilst maintaining drug-like properties such as low cytotoxicity against mammalian cell lines (CC50 >100 μM), good metabolic stability in human and mouse liver microsomes and high apparent permeability in a Caco-2 model of intestinal absorption. The kinetic solubility of the new bicyclic derivatives varied, and was found to be a key parameter for future optimization. Taken together, these results suggest promising subclasses of bicyclic nitroimidazoles containing different core architectures have potential for further development

Preclinical data do not support the use of amiodarone or dronedarone as antiparasitic drugs for Chagas disease at the approved human dosing regimen

The repurposing of approved drugs is an appealing method to fast-track the development of novel therapies for neglected diseases. Amiodarone and dronedarone, two approved antiarrhythmic agents, have been reported to have potential for the management of Chagas disease patients displaying symptomatic heart pathology. More recently, it has been suggested that both molecules not only have an antiarrhythmic effect, but also have trypanocidal activity against Trypanosoma cruzi, the causative agent of Chagas disease. In this work, we assessed the in vitro activity of these compounds against T. cruzi, the in vivo pharmacokinetics, and pharmacodynamics, to determine the potential for repurposing these drugs as therapies for Chagas disease. Based on these results, we were unable to reproduce the in vitro potencies of amiodarone and dronedarone described in the literature, and both drugs were found to be inactive or cytotoxic against a variety of different mammalian cell lines. The evaluation of in vivo efficacy in a bioluminescent murine model of T. cruzi did not show antiparasitic activity at the highest tolerated dose tested. While the potential of amiodarone and dronedarone as antiarrhythmic agents in Chagas cardiomyopathic patients cannot be completely excluded, a trypanocidal effect in patients treated with these two drugs appears unlikely