Prediction of delirium using data mining: A systematic review.

Delirium remains a significant cause of morbidity, mortality and economic burden to society. "Big data" refers to data of significantly large volume, obtained from a variety of resources, which is created and processed at high velocity. We conducted a systematic review and meta-analysis exploring whether big data could predict the incidence of delirium of patients in the inpatient setting. Medline, Embase, the Cochrane Library, Web of Science, CINAHL, clinicaltrials.gov, who.int and IEEE Xplore were searched using MeSH terms "big data", "data mining", "delirium" and "confusion" up to 30th September 2019. We included both randomised and observational studies. The primary outcome of interest was development of delirium and the secondary outcomes of interest were type of statistical methods used, variables included in the mining algorithms and clinically important outcomes such as mortality and length of hospital stay. The quality of studies was graded using the CHARMs checklist. Six retrospective single centre observational studies were included (n = 178,091), of which 17, 574 participants developed delirium. Studies were of generally of low to moderate quality. The most commonly studied method was random forest, followed by support vector machine and artificial neural networks. The model with best performance for delirium prediction was random forest, with area under receiver operating curve (AUROC) ranging from 0.78 to 0.91. Sensitivity ranged from 0.59 to 0.81 and specificity ranged from 0.73 to 0.92. Our systematic review suggests that machine-learning techniques can be utilised to predict delirium.

Assessment of the adequacy of counselling regarding reproductive-related issues in women of childbearing age on anti-epileptic drugs.

BACKGROUND: The use of anti-epileptic drugs (AEDs) in women of childbearing age (WCBA) necessitates careful counselling regarding reproductive-related issues. AIM: (i) To compare documentation of appropriate counselling regarding reproductive-related issues in WCBA prescribed AEDs for non-epilepsy vs. epilepsy indications, and (ii) to examine whether the frequency of counselling improved after introduction of 'standardized typed advice'. DESIGN: Retrospective audit and quality assessment and improvement programme. METHODS: We analysed medical records of all WCBA prescribed gabapentin, pregabalin, topiramate, valproate or carbamazepine by a general neurology clinical service before (Study period A) and after (Study period B) introduction of standardized typed passages regarding potential teratogenicity ± interactions with hormonal contraception at a university teaching hospital. The χ2 test or the Fisher's exact test was employed, as appropriate. RESULTS: In WCBA prescribed AEDs for non-epilepsy indications, documentation of appropriate counselling regarding potential teratogenicity improved from 49% (17/35 patients) in Period A to 79% (27/34 patients) in Period B (P = 0.008). The frequency of counselling regarding teratogenicity was higher in patients prescribed AEDs for epilepsy compared with non-epilepsy indications in Study period A (100% vs. 49%, P = 0.002), but was no longer significantly different in Study period B (86% vs. 79%, P = 0.64). Documentation of counselling regarding potential interaction of enzyme-inducing AEDs with hormonal contraception did not significantly change between study periods. CONCLUSION: Significant improvements in documentation regarding potential teratogenicity of AEDs prescribed for non-epilepsy indications can be achieved by introducing standardized, typed passages copied to patients. Such a practice change is practical and widely applicable to neurological and non-neurological practice worldwide.

Mining for natural product antileishmanials in a fungal extract library.

Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the World's poorest, however vaccines are absent and drug therapy limited. Recently, public-private partnerships have developed to identify new modes of controlling leishmaniasis. Most of these collaborative efforts have relied upon the small molecule synthetic compound libraries held by industry, but the number of New Chemical Entities (NCE) identified and entering development as antileishmanials has been very low. In light of this, here we describe a public-private effort to identify natural products with activity against Leishmania mexicana, a causative agent of cutaneous leishmanaisis (CL). Utilising Hypha Discovery's fungal extract library which is rich in small molecule (<500 molecular weight) secondary metabolites, we undertook an iterative phenotypic screening and fractionation approach to identify potent and selective antileishmanial hits. This led to the identification of a novel oxidised bisabolane sesquiterpene which demonstrated activity in an infected cell model and was shown to disrupt multiple processes using a metabolomic approach. In addition, and importantly, this study also sets a precedent for new approaches for CL drug discovery.

Electron paramagnetic resonance studies of type 1 copper in type 2 depleted fungal laccase A.

The electron paramagnetic resonance (EPR) spectra of type 1 copper(II) in 63Cu-enriched Coriolus versicolor laccase A (benzenediol:oxygen oxidoreductase, EC 1.10.3.2) have been studied. The X-band EPR spectrum in type 2 copper-depleted [63Cu]laccase A exhibited well-resolved ligand superhyperfine structure in the g perpendicular region. This structure was assigned to an interaction with two nitrogens and two protons, an assignment which is consistent with a model in which the two nitrogens belong to two histidine ligands and the two protons are the methylene protons of a coordinating cysteine. It also requires the delocalization of a substantial amount of the type 1 copper(II) unpaired electron density onto the cysteine sulphur.

Arterial bifurcations in the cardiovascular system of a rat.

Arterial bifurcations in the cardiovascular system of a rat were studied, using a resin cast of the entire arterial tree. At each bifurcation, measurements were made of the diameters of the three vessels involved, the two branching angles, and the angle delta, which the parent artery makes with the plane containing the two branches. The results were found to be consistent with those reported previously in man and monkey. In addition, measurements of delta in the present study indicate that arterial bifurcations are mostly two dimensional.

Antitumor benzothiazoles. 3. Synthesis of 2-(4-aminophenyl)benzothiazoles and evaluation of their activities against breast cancer cell lines in vitro and in vivo.

A new series of 2-(4-aminophenyl)benzothiazoles substituted in the phenyl ring and benzothiazole moiety has been synthesized by simple, high-yielding routes. The parent molecule 5a shows potent inhibitory activity in vitro in the nanomolar range against a panel of human breast cancer cell lines, but is inactive (IC50 > 30 microM) against other cell types: activity against the sensitive breast lines MCF-7 and MDA 468 is characterized by a biphasic dose-response relationship. Structure-activity relationships derived using these cell types has revealed that activity follows the heterocyclic sequence benzothiazole > benzoxazole >> benzimidazole and that 2-(4-aminophenyl)benzothiazoles bearing a 3'-methyl- 9a, 3'-bromo- 9c, 3'-iodo- 9f, and 3'-chloro-substituent 9i are especially potent and their activity extends to ovarian, lung, and renal cell lines. Four compounds have been evaluated in vivo against human mammary carcinoma models in nude mice. Compound 9a showed the most potent growth inhibition against the ER+ (MCF-7 and BO) and ER- (MT-1 and MT-3) tumors. Our efforts to identify a pharmacological mechanism of action for these intriguing compounds have not, as yet, been successful.

Antitumor benzothiazoles. 7. Synthesis of 2-(4-acylaminophenyl)benzothiazoles and investigations into the role of acetylation in the antitumor activities of the parent amines.

2-(4-Aminophenyl)benzothiazoles display potent and selective antitumor activity against inter alia breast, ovarian, colon, and renal cell lines, but their mechanism of action, though yet to be defined, may be novel. Metabolism is suspected to play a central role in the mode of action of these benzothiazoles since drug uptake and biotransformation were observed in sensitive cell lines (e.g., breast MCF-7 and MDA 468 cells) in vitro, whereas insensitive cell lines (e.g., prostate PC 3 cells) showed negligible uptake and biotransformation. N-Acyl derivatives of the arylamines have been synthesized, and in vitro studies confirm N-acetylation and oxidation as the main metabolic transformations of 2-(4-aminophenyl)benzothiazoles, with the predominant process being dictated by the nature of the 3'-substituent. The prototype amine 3 underwent mainly N-acetylation in vitro, while 3'-substituted analogues 4 and 5 were primarily oxidized. N-Acetylation of 4 to 11 exerts a drastic dyschemotherapeutic effect in vitro, but acetylation of the halogeno congeners 5-7 gave acetylamines 12-14 which substantially retain selective antitumor activity. In vivo pharmacokinetic studies in rats confirmed rapid and exclusive N-acetylation of the 3'-methyl analogue 4, but less acetylation with the 3'-chloro analogue 5. Distinct expression patterns of N-acetyltransferase NAT1 and NAT2 have been demonstrated in our panel of cell lines.

Differential regulation of CD3- and CD28-induced IL-2 and IFN-gamma production by a novel tyrosine kinase inhibitor XR774 from Cladosporium cf. cladosporioides.

Inhibition of CD28 signalling after an immune response impedes T cell activation and can lead to immunosuppression. To identify inhibitors of anti-CD28 induced IL-2 production, a library of fungal metabolites was screened in a cell-based, high throughput assay. A reduced novel benzofluoranthene, tentatively named as (6bS, 7R, 8S)-7-methoxy-4, 8, 9-trihydroxy-1, 6b, 7, 8-tetrahydro-2H-benzo[j] fluoranthen-3-one (XR774), from Cladosporium cf. cladosporioides, was isolated. XR774 inhibited IL-2 mRNA and protein expression induced by anti-CD28 and anti-CD3 but had no effect on IL-2 induction by PMA and ionomycin. Moreover, XR774 inhibited the activity of the tyrosine kinases, Fyn, Lck, Abl and epidermal growth factor receptor (EGFR) with nanomolar activity, whereas micromolar concentrations of XR774 were ineffective on the serine-threonine kinase, PKA. Kinetic analysis of Fyn kinase inhibition was consistent with XR774 as a competitive inhibitor with respect to ATP. In peripheral blood, mononuclear cells (PBMC), XR774 inhibited anti-CD3 and anti-CD28 induced IL-2 and IL-2R alpha chain (CD25) expression but was consistently less active for inhibition of IFN-gamma production. On stimulation with PMA and anti-CD28, XR774 inhibited IL-2 production but had no effect on CD25 expression and enhanced IFN-gamma production. In contrast, the ansamycin, geldanamycin, inhibited both IL-2 and IFN-gamma production induced by anti-CD3 and anti-CD28 or PMA and anti-CD28. No significant associated cytotoxicity or inhibition of protein synthesis was observed at concentrations up to 14 microM. Thus, XR774 represents a novel class of pharmacological agent with selective biological activities that distinguish it from other natural product inhibitors, such as the ansamycins.

High-performance liquid chromatography comparison of supercritical-fluid extraction and solvent extraction of microbial fermentation products.

The use of supercritical fluids for the extraction of biologically active compounds from the biomass of microbial fermentations has been compared with extraction using the organic solvents methanol and dichloromethane. Compounds representing a range of structural types were selected for investigation. All the extracts obtained were examined using reversed-phase high-performance liquid chromatography. The extractability of metabolites using unmodified and methanol-modified supercritical-fluid carbon dioxide was examined in particular detail for six microbial metabolites: chaetoglobosin A, mycolutein, luteoreticulin, 7,8-dihydro-7,8-epoxy-1-hydroxy-3-hydroxymethyl-xanthone-8-carboxyl ic acid methyl ester, sydowinin B and elaiophylin. The extraction strength of supercritical-fluid carbon dioxide alone appeared to be lower than that of dichloromethane. All the components of interest that were extractable with dichloromethane and methanol were also extractable with methanol-modified carbon dioxide.

Novel reduced benzo[j]fluranthen-3-ones from Cladosporium cf. cladosporioides with cytokine production and tyrosine kinase inhibitory properties.

A series of reduced benzo[j]fluoranthen-3-ones (1-4) was isolated from fermentations of a fungal strain CBUK20700 (CBS 100220), classified as Cladosporium cf. cladosporioides, during a microbial extract screening programme to identify inhibitors of anti-CD28-induced interleukin-2 (IL-2) production by Jurkat E6-1 cells as potential immunosuppressive agents. These compounds were also found to be tyrosine kinase inhibitors. The structures of compounds 1-4 were elucidated by spectroscopic methods including the HMQC, HMBC and NOESY NMR experiments. The most potent compound in the series, (6bS,7R,8S)-7-methoxy-4,8,9-trihydroxy-1,6b,7,8-tetrahydro-2H-benzo[j]fluoranthen-3-one (1) inhibited anti-CD28-induced IL-2 production and Abl tyrosine kinase with IC50 values of 400 and 60 nM respectively. The 6b-stereoisomeric 2 was a moderate inhibitor of both IL-2 production and Abl tyrosine kinase while the 8-oxo derivative 3 was inactive in both assays. The 8-O-methyl ether 4 was a moderate inhibitor of IL-2 production but exhibited potent inhibition of Abl tyrosine kinase with an IC50 of 45 nM.

Novel drimane sesquiterpene esters from Aspergillus ustus var. pseudodeflectus with endothelin receptor binding activity.

A series of novel drimane sesquiterpene esters (1-6) was isolated from fermentations of Aspergillus ustus var. pseudodeflectus and their structures elucidated by spectroscopic methods including the HMQC, HMBC and INADEQUATE NMR experiments. The major component of the fermentation, 1, was (2'E,4'E,6'E)-6-(1'-carboxy-2',4',6'-trien)-9-hydroxydrim-7-ene-11 ,12-olide. Compounds 1, 2, 3 and 5 exhibited endothelin receptor binding inhibitory activity against rabbit endothelin-A and rat endothelin-B receptors with IC50 values in the range 20-150 microM. These compounds had similar levels of activity in assays for binding to human endothelin A and endothelin B receptors. The isolation of 9,11-dihydroxy-6-oxodrim-7-ene, 7, a probable biosynthetic precursor to the drimane esters is also reported.

Azaphilones with endothelin receptor binding activity produced by Penicillium sclerotiorum: taxonomy, fermentation, isolation, structure elucidation and biological activity.

A series of azaphilones produced by Penicillium sclerotiorum (Xenova culture collection number X11853) active in assays for the detection of antagonists of the endothelin-A (ETA) and endothelin-B (ETB) receptors has been identified. The series includes two novel sclerotiorin analogues, (8S,8 alpha-R)-7-deacetyl-1,O8,8,8a-tetrahydro-7-epi-sclerotiorin, 1, and its 5-dechloro analogue, 2. It also includes 5-chloroisorotiorin, 6, previously unreported as a natural product, in addition to the major product of these fermentations, (+)-sclerotiorin, 5. Data for the inhibition of endothelin-1 (ET-1) and endothelin-3 (ET-3) binding in the ETA and ETB receptor assays respectively are reported for this series. Compounds 1 and 2 were more selective for the rabbit ETA receptor than for the rat ETB receptor. The IC50 values for 1 and 2 were 9 and 28 microM respectively in an assay based on binding of ET-1 to rabbit ETA receptors. In an assay based on the binding of ET-3 to the rat ETB receptor compounds 1 and 2 exhibited IC50's of 77 and 172 microM. Members of this series of compounds demonstrated antagonist behavior in a secondary assay based on blockade of ET-1 stimulated arachidonic acid release from rabbit renal artery smooth muscle cells, when present at concentrations of > or = 30 microM.

A novel (6S)-4,6-dimethyldodeca-2E,4E-dienoyl ester of phomalactone and related alpha-pyrone esters from a Phomopsis sp. with cytokine production inhibitory activity.

A series of novel 6-substituted 5,6-dihydro-5-hydroxy-alpha-pyrone esters, 1 approximately 3, isolated from fermentations of a Phomopsis sp. (Xenova culture collection no. X22502) have been identified as inhibitors of lipopolysaccharide (LPS)-induced cytokine production. These include the (6S)-4,6-dimethyldodecadien-2E,4E-dienoyl ester of phomalactone, 1, and two analogues bearing a prop-2E-enoic acid moiety at the 6-position of the alpha-pyrone ring. (6S)-4,6-Dimethyl-2E,4E-dienoic acid, 4, and a hydroxylated analogue, 5, were also isolated and characterised. The most potent cytokine production inhibitor was 1, which inhibited LPS-induced tumour necrosis factor alpha (TNFalpha) production by U937 cells and LPS-induced interleukin 1beta (IL-1beta) production by peripheral blood mononuclear cells (PBMC) with IC50 values of 80 nM and 190 nM respectively. The effect of 1 in PBMC was selective for IL-1beta relative to TNFalpha. The inhibition of IL-1beta production by 1 involved a post-translational mechanism of action at the level of IL-1beta secretion as demonstrated by the lack of an effect on cell-associated IL-1beta production. 1 showed no effect on the activity of caspase 1 in cytosolic extracts from the THP1 monocytic cell line.

Novel streptopyrroles from Streptomyces rimosus with bacterial protein histidine kinase inhibitory and antimicrobial activities.

A series of halogenated pyrrolo [2,1-b] [1,3] benzoxazines (1 approximately 9) was isolated from fermentations of an actinomycete strain X10/78/978 (NCIMB40808), identified as Streptomyces rimosus, during a microbial extract screening programme to identify inhibitors of bacterial histidine kinase. The structures of these compounds were elucidated by spectroscopic methods including the HMQC, HMBC and INADEQUATE NMR experiments. The structure of 1 was confirmed by X-ray crystallographic studies. Compounds 5 and 6 were produced in fermentations in the presence of NaBr and NaI respectively. The most abundant member of the series, streptopyrrole, 1, inhibited the nitrogen regulator II (NRII) histidine kinase from Escherichia coli with an IC50 of 20 microM and exhibited antimicrobial activity against a range of bacteria and fungi.

Scale-up of filamentous organisms from tubes and shake-flasks into stirred vessels.

The choice of small-scale fermentation systems contributes significantly to a successful scale-up. Creasing of flasks and the chosen shaker parameters influence the production of secondary metabolites in a strain- and even compound-specific manner. Using actinomycetes and fungi as model organisms the influence of the small-scale fermentation system on the production of various secondary metabolites is described and the effects on screening success and scale-up are considered.

Resistance to atracurium in a patient with an increase in plasma alpha 1 globulins.

We observed that a female patient with a poorly differentiated adenocarcinoma of the stomach undergoing gastrectomy was markedly resistant to the action of the neuromuscular blocking drug atracurium. There was no evidence of tumour metastasis and her liver function tests were normal. Electrophoresis of plasma proteins revealed a marked increase in alpha 1 globulin. Alpha 1 acid glycoprotein is an acute phase reactant that is increased in patients with cancer and is present in the alpha 1 globulin electrophoresis pattern. It is likely that the mechanism for the resistance to neuromuscular block in the patient was an increase in drug binding to alpha 1 acid glycoprotein.