Publications by authors named "Christopher Yates"

85 Publications

Chronic atmospheric reactive N deposition has breached the N sink capacity of a northern ombrotrophic peatbog increasing the gaseous and fluvial N losses.

Sci Total Environ 2021 Sep 15;787:147552. Epub 2021 May 15.

Department of Geography, Earth and Environmental Science, University of Birmingham, UK.

Peatlands play an important role in modulating the climate, mainly through sequestration of carbon dioxide into peat carbon, which depends on the availability of reactive nitrogen (Nr) to mosses. Atmospheric Nr deposition in the UK has been above the critical load for functional and structural changes to peatland mosses, thus threatening to accelerate their succession by vascular plants and increasing the possibility of Nr export to downstream ecosystems. The N balance of peatlands has received comparatively little attention, mainly due to the difficulty in measuring gaseous N losses as well as the Nr inputs due to biological nitrogen fixation (BNF). In this study we have estimated the mean annual N balance of an ombrotrophic bog (Migneint, North Wales) by measuring in situ N + NO gaseous fluxes and also BNF in peat and mosses. Fluvial N export was monitored through a continuous record of DON flux, while atmospheric N deposition was modelled on a 5 × 5 km grid. The mean annual N mass balance was slightly positive (0.7 ± 4.1 kg N ha y) and varied interannually indicating the fragile status of this bog ecosystem that has reached N saturation and is prone to becoming a net N source. Gaseous N losses were a major N output term accounting for 70% of the N inputs, mainly in the form of the inert N gas, thus providing partial mitigation to the adverse effects of chronic Nr enrichment. BNF was suppressed by 69%, compared to rates in pristine bogs, but was still active, contributing ~2% of the N inputs. The long-term peat N storage rate (8.4 ± 0.8 kg N ha y) cannot be met by the measured N mass balance, showing that the bog catchment is losing more N than it can store due its saturated status.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147552DOI Listing
September 2021

Muddying the waters of hyperparathyroidism management in chronic kidney disease: a brown tumour in a predialysis patient.

Intern Med J 2021 Mar;51(3):450-451

Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/imj.15235DOI Listing
March 2021

Variation of drugs involved in acute drug toxicity presentations based on age and sex: an epidemiological approach based on European emergency departments.

Clin Toxicol (Phila) 2021 Mar 16:1-13. Epub 2021 Mar 16.

Emergency Department, Hospital Clínic, IDIBAPS, Barcelona, Spain.

Objective: To analyse the relative percentage of acute recreational drug toxicity emergency department (ED) presentations involving the main drug groups according to age and sex and investigate different patterns based on sex and age strata.

Methods: We analysed all patients with acute recreational drug toxicity included by the Euro-DEN Plus dataset (22 EDs in 14 European countries) between October 2013 and December 2016 (39 months). Drugs were grouped as: opioids, cocaine, cannabis, amphetamines, gamma-hydroxybutyrate (GHB), hallucinogens, new psychoactive substances (NPS), benzodiazepines and ketamine. Descriptive data by age and sex are presented and compared among age/sex categories and among drug families.

Results: Of 17,371 patients were included during the 39-month period, 17,198 (99.0%) had taken at least one of the investigated drugs (median age: 31 years; 23.9% female; ethanol co-ingestion recorded in 41.5%, unknown in 31.2%; multiple drug use in 37.9%). Opioids (in 31.4% of patients) and amphetamines (23.3%) were the most frequently involved and hallucinogens (1.9%) and ketamine (1.7%) the least. Overall, female patients were younger than males, both in the whole cohort (median age 29 vs. 32 years;  < 0.001) and in all drug groups except benzodiazepines (median age 36 vs. 36 years;  = 0.83). The relative proportion of each drug group was different at every age strata and some patterns could be clearly described: cannabis, NPS and hallucinogens were the most common in patients <20 years; amphetamines, ketamine and cocaine in the 20- to 39-year group; GHB/GBL in the 30- to 39-year group; and opioids and benzodiazepines in patients ≥40 years. Ethanol and other drug co-ingestion was more frequent at middle-ages, and multidrug co-ingestion was more common in females than males.

Conclusion: Differences in the drugs involved in acute drug toxicity presentations according to age and sex may be relevant for developing drug-prevention and education programs for some particular subgroups of the population based on the increased risk of adverse events in specific sex and/or age strata.
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http://dx.doi.org/10.1080/15563650.2021.1884693DOI Listing
March 2021

Rhabdomyolysis related to acute recreational drug toxicity-A Euro-DEN study.

PLoS One 2021 11;16(3):e0246297. Epub 2021 Mar 11.

Department of Clinical Toxicology, Medical University of Gdansk, Gdansk, Poland.

Background: This study was conducted to retrospectively assess the relationships between: rhabdomyolysis (quantified by creatine kinase (CK) activity) and kidney injury (quantified by serum creatinine concentration), sex, age, body temperature on admission, presence of seizures, and agitation or aggression in patients presenting to the Emergency Department with acute recreational drug toxicity. We also investigated the association with the substances ingested.

Methods: All presentations to the 16 sentinel Euro-DEN centres in 10 European countries with acute recreational drug toxicity during the first year of the Euro-DEN study (October 2013 to September 2014) were considered. Cases that had abnormal CK activity recorded as part of routine clinical care were divided into 3 cohorts depending on peak CK activity. Cases with normal CK activity were included as a control group (4th cohort).

Results: Only 1,015 (18.4%) of the 5,529 Euro-DEN presentations had CK activity concentration recorded. Of this group 353 (34.8%) had also creatinine concentration measured. There were 375 (36.9%) with minor rhabdomyolysis, 69 (6.8%) with moderate rhabdomyolysis, and 24 (2.4%) with severe rhabdomyolysis; 547 (53.9%) were included in the control group. There was a positive correlation between CK activity and creatinine concentration (correlation coefficient r = 0.71, p<0.0001). There was no correlation between CK activity and body temperature at the time of presentation to the ED (correlation coefficient r = 0.07, p = 0.03). There was a positive correlation between CK activity and length of stay in the hospital (r = 0.31, p<0.001). There was no association between CK activity and the presence of seizures (p = 0.33) or agitation/aggression (p = 0.45), patients age (p = 0.4) or sex (p = 0.25). The 5 most common agents amongst patients presenting with rhabdomyolysis were: cocaine (n = 107; 22.9% presentations), amphetamine (76; 16.2%), cannabis (74; 15.8%), GHB/GBL (72; 15.4%) and heroin (67; 14.3%). The distribution of rhabdomyolysis in 5 most common drugs was (drug; patients with rhabdomyolysis, patients without rhabdomyolysis): cocaine (107, 122), cannabis (74, 117), GHB/GBL (72, 81), amphetamine (76, 66), heroin (67, 70).

Conclusions: Abnormal values of CK activity occurred in almost half (46.1%) of presentations to the Emergency Department with acute recreational drug toxicity in whom CK activity was measured; however, severe rhabdomyolysis is seen in only a small minority (2.4%). Those with rhabdomyolysis are at significantly higher risk of kidney injury and have a longer length of hospital stay.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246297PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951866PMC
March 2021

MDMA-related presentations to the emergency departments of the European Drug Emergencies Network plus (Euro-DEN Plus) over the four-year period 2014-2017.

Clin Toxicol (Phila) 2021 02 17;59(2):131-137. Epub 2020 Jul 17.

Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland.

Context: 3,4-Methylenedioxymethamphetamine (MDMA) remains one of the most commonly used recreational drugs in Europe. Monitoring of Emergency Department (ED) presentations with acute toxicity associated with MDMA is important to determine trends in MDMA use and harms.

Methods: Data were extracted from the European Drug Emergencies Network (Euro-DEN) Plus database for all ED presentations with acute toxicity involving MDMA use, alone or in combination with other substances, between 1 January 2014 and 31 December 2017. Geographical distribution, time trends, patient demographics, clinical features, management and outcome were analysed.

Results: Out of 23,947 presentations, 2013 (8.4%) involved MDMA, used alone (88, 4.4%) or with other substances (1925, 95.6%). The proportion of MDMA presentations varied by country, from over 15% in France to less than 5% in Norway. For the 15 sentinel centres where data were available for all four years, MDMA-related presentations peaked in 2016 (10.4% 8.1% in 2015,  < 0.0001), thereafter decreasing in 2017 (8.2%,  = 0.0002). 1436 (71.3%) presentations involved males. Females were significantly younger than males (median 23 years, interquartile range, IQR, 20-27 years, median 25 years, IQR 21-30 years,  < 0.0001). Compared to presentations of acute toxicity with lone-use cocaine, presentations with lone-use MDMA occurred more frequently during the weekend (58.0% 43.9%,  = 0.02), were more frequently medically discharged directly from the ED (74.7% 62.4%,  = 0.03), and less frequently received sedation (43.5% 66.5%,  = 0.003).

Conclusions: This large multicentre series of MDMA presentations to EDs showed geographical variation and changes in time trends and in patient demographics. Triangulation with data from complementary sources including seizures, prevalence of use and wastewater analysis, will enable a greater understanding of the public health implications of MDMA use in Europe.
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http://dx.doi.org/10.1080/15563650.2020.1784914DOI Listing
February 2021

Acute toxicity related to misuse (nonmedical use) of tramadol: Experience of the European Drug Emergencies Network Plus.

Br J Clin Pharmacol 2021 Apr 15;87(4):1668-1675. Epub 2020 Jul 15.

Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK.

Following the development of the tramadol crisis currently affecting countries in the Middle East, and Africa, there has been increasing international interest in the regulation of tramadol. This study investigates the misuse of tramadol in patients presenting to emergency departments across Europe. Data from 32 emergency departments in 21 countries were extracted from the Euro-DEN Plus database for the 4-year period from 1 January 2014 to 31 December 2017. Of the reported 24,957 emergency department presentations, tramadol misuse was reported in 105 (0.4% presentations). Tramadol misuse was most common in Bratislava (Slovakia; n = 11, 7.5% of all presentations to this centre), Riga (Latvia; n = 4, 4.9%) and Munich (Germany; n = 17, 2.9%). On arrival, 14 (13.3%) of presentations were in coma/Glasgow coma score ≤ 8 and 9 of these had a respiratory rate <12 breaths/min. These presentations potentially pose a significant burden on emergency departments with a large proportion requiring admission to hospital for ongoing care.
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http://dx.doi.org/10.1111/bcp.14408DOI Listing
April 2021

Insights into pituitary tumorigenesis: from Sanger sequencing to next-generation sequencing and beyond.

Expert Rev Endocrinol Metab 2019 11 2;14(6):399-418. Epub 2019 Dec 2.

Department of Medicine, The University of Melbourne, Parkville, Australia.

: This review explores insights provided by next-generation sequencing (NGS) of pituitary tumors and the clinical implications.: Although syndromic forms account for just 5% of pituitary tumours, past Sanger sequencing studies pragmatically focused on them. These studies identified mutations in and causing Multiple Endocrine Neoplasia-1 (MEN1), MEN4, Carney Complex-1, McCune Albright Syndrome and 3P association syndromes, respectively. Furthermore, linkage analysis of single-nucleotide polymorphisms identified mutations in 20% with familial isolated pituitary adenomas (FIPA). NGS has enabled further investigation of sporadic tumours. Thus, mutations of and were identified in corticotrophinomas, in papillary craniopharyngiomas and in adamantinomatous craniopharyngiomas. NGS also revealed that pituitary tumours occur in the DICER1 syndrome, due to mutations, and mutations occur in FIPA. These discoveries revealed novel therapeutic targets and studies are underway of inhibitors for papillary craniopharyngiomas, and EGFR and USP8 inhibitors for corticotrophinomas.: It has become apparent that single-nucleotide variants and small insertion/deletion DNA mutations cannot explain all pituitary tumorigenesis. Integrated and improved analyses including whole-genome sequencing, copy number, and structural variation analyses, RNA sequencing and epigenomic analyses, with improved genomic technologies, are likely to further define the genomic landscape.
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http://dx.doi.org/10.1080/17446651.2019.1689120DOI Listing
November 2019

Quantifying Use of a Health Virtual Community of Practice for General Practitioners' Continuing Professional Development: A Novel Methodology and Pilot Evaluation.

J Med Internet Res 2019 11 27;21(11):e14545. Epub 2019 Nov 27.

Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia.

Background: Health care practitioners (HPs), in particular general practitioners (GPs), are increasingly adopting Web-based social media platforms for continuing professional development (CPD). As GPs are restricted by time, distance, and demanding workloads, a health virtual community of practice (HVCoP) is an ideal solution to replace face-to-face CPD with Web-based CPD. However, barriers such as time and work schedules may limit participation in an HVCoP. Furthermore, it is difficult to gauge whether GPs engage actively or passively in HVCoP knowledge-acquisition for Web-based CPD, as GPs' competencies are usually measured with pre- and posttests.

Objective: This study investigated a method for measuring the engagement features needed for an HVCoP (the Community Fracture Capture [CFC] Learning Hub) for learning and knowledge sharing among GPs for their CPD activity.

Methods: A prototype CFC Learning Hub was developed using an Igloo Web-based social media software platform and involved a convenience sample of GPs interested in bone health topics. This Hub, a secure Web-based community site, included 2 key components: an online discussion forum and a knowledge repository (the Knowledge Hub). The discussion forum contained anonymized case studies (contributed by GP participants) and topical discussions (topics that were not case studies). Using 2 complementary tools (Google Analytics and Igloo Statistical Tool), we characterized individual participating GPs' engagement with the Hub. We measured the GP participants' behavior by quantifying the number of online sessions of the participants, activities undertaken within these online sessions, written posts made per learning topic, and their time spent per topic. We calculated time spent in both active and passive engagement for each topic.

Results: Seven GPs participated in the CFC Learning Hub HVCoP from September to November 2017. The complementary tools successfully captured the GP participants' engagement in the Hub. GPs were more active in topics in the discussion forum that had direct clinical application as opposed to didactic, evidence-based discussion topics (ie, topical discussions). From our knowledge hub, About Osteoporosis and Prevention were the most engaging topics, whereas shared decision making was the least active topic.

Conclusions: We showcased a novel complementary analysis method that allowed us to quantify the CFC Learning Hub's usage data into (1) sessions, (2) activities, (3) active or passive time spent, and (4) posts made to evaluate the potential engagement features needed for an HVCoP focused on GP participants' CPD process. Our design and evaluation methods for ongoing use and engagement in this Hub may be useful to evaluate future learning and knowledge-sharing projects for GPs and may allow for extension to other HPs' environments. However, owing to the limited number of GP participants in this study, we suggest that further research with a larger cohort should be performed to validate and extend these findings.
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http://dx.doi.org/10.2196/14545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906624PMC
November 2019

The Genomic Landscape of Sporadic Prolactinomas.

Endocr Pathol 2019 Dec;30(4):318-328

Department of Genetics and Molecular Pathology, Centre for Cancer Biology, an SA Pathology and University of South Australia Alliance, Adelaide, Australia.

Somatic GNAS and USP8 mutations have been implicated in sporadic somatotrophinomas and corticotrophinomas, respectively. However, no genes are known to be recurrently mutated in sporadic prolactinomas. The prevalence of copy number variants (CNV), which is emerging as a mechanism of tumorigenesis in sporadic pituitary adenomas in general, is also unclear in prolactinomas. To characterize the genetic events underpinning sporadic prolactinomas, we performed whole exome sequencing of paired tumor and germline DNA from 12 prolactinoma patients. We observed recurrent large-scale CNV, most commonly in the form of copy number gains. We also identified sequence variants of interest in 15 genes. This included the DRD2, PRL, TMEM67, and MLH3 genes with plausible links to prolactinoma formation. Of the 15 genes of interest, CNV was seen at the gene locus in the corresponding tumor in 10 cases, and pituitary expression of eight genes was in the top 10% of tissues. However, none of our shortlisted somatic variants appeared to be classical driver mutations as no variant was found in more than one tumor. Future directions of research include mechanistic studies to investigate how CNV may contribute to prolactinoma formation, larger studies of relevant prolactinoma subsets according to clinical characteristics, and additional genetic investigations for aberrations not captured by whole exome sequencing.
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http://dx.doi.org/10.1007/s12022-019-09587-0DOI Listing
December 2019

Predicting experimentally-derived failure load at the distal radius using finite element modelling based on peripheral quantitative computed tomography cross-sections (pQCT-FE): A validation study.

Bone 2019 12 28;129:115051. Epub 2019 Aug 28.

Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia; Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, Australia; Bone and Mineral Medicine, Royal Melbourne Hospital, Melbourne, Australia. Electronic address:

Dual energy X-ray absorptiometry, the current clinical criterion method for osteoporosis diagnosis, has limitations in identifying individuals with increased fracture risk, especially at the distal radius. Peripheral quantitative computed tomography (pQCT) can provide volumetric bone density data, as well as information on bone geometry, which makes it possible to establish finite element (FE) models of the distal radius from which bone strength and stiffness can be calculated. In this study, we compared experimental mechanical failure load data of the forearm with pQCT- based FE (pQCT-FE) modelling properties. Sixteen cadaveric forearm specimens were experimentally loaded until failure. Estimated stiffness and strength variables of compression, shear, bending and torsion were calculated from pQCT-FE modelling of single cross-sections of 0.2 × 0.2 × 2.4 mm of the radius pQCT image. A moderate-to-strong coefficient of determination (r) was observed between experimental failure load and pQCT-FE variables. The highest r was observed for bending stiffness (r = 0.83). This study validates the use of pQCT-FE in the assessment of distal radius bone strength for future studies.
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http://dx.doi.org/10.1016/j.bone.2019.115051DOI Listing
December 2019

Ambiguous medical abbreviation study: challenges and opportunities.

Intern Med J 2020 09;50(9):1073-1078

Department of General Medicine, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Background: Healthcare workers often abbreviate for convenience, but ambiguous abbreviations may cause miscommunication, which jeopardises patient care. Robust large-scale research to quantify abbreviation frequency and ambiguity in medical documents is lacking.

Aims: To calculate the frequency of abbreviations used in discharge summaries, the proportion of these abbreviations that are ambiguous and the potential utility of auto-expansion software.

Methods: We designed a software programme to extract all instances of abbreviations from every General Medical Unit discharge summary from the Royal Melbourne Hospital in 2015. We manually expanded abbreviations using published inventories and clinical experience, logging multiple expansions for any abbreviation if identified. Abbreviations were classified based on well defined criteria as standardised and likely to be well understood, or ambiguous. Outcome measures included the range and frequency of standardised and ambiguous abbreviations, and the feasibility of electronic auto-expansion software based on these measures.

Results: Of the 1 551 537 words analysed from 2336 documents, 137 997 (8.9%) were abbreviations with 1741 distinct abbreviations identified. Most abbreviations (88.7%) had a single expansion. The most common abbreviation was PO (per os/orally), followed by BD (bis in die/twice daily) and 68.1% of abbreviations were standardised, largely pertaining to pathology/chemicals. This meant, however, that a large proportion (31.9%) of abbreviations (2.8% of all words) were ambiguous. The most common ambiguous abbreviation was Pt (patient/physiotherapy), followed by LFT (liver function test/lung function test).

Conclusions: Close to one-third of abbreviations used in general medical discharge summaries were ambiguous. Electronic auto-expansion of ambiguous abbreviations is likely to reduce miscommunication and improve patient safety.
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http://dx.doi.org/10.1111/imj.14442DOI Listing
September 2020

Impact of the Major Candida glabrata Triazole Resistance Determinants on the Activity of the Novel Investigational Tetrazoles VT-1598 and VT-1161.

Antimicrob Agents Chemother 2019 10 23;63(10). Epub 2019 Sep 23.

University of Tennessee Health Science Center, Memphis, Tennessee, USA

VT-1161 and VT-1598 are promising investigational tetrazole antifungals that have shown and activity against and other fungi. is a problematic opportunistic pathogen that is associated with high mortality in invasive infection, as well as both intrinsic and rapidly acquired antifungal resistance. The MICs of VT-1161 and VT-1598 were determined by CLSI methodology to evaluate their activities against clinical isolates and strains containing individual deletions of the zinc cluster transcription factor genes and as well as the efflux transporter genes , , and Overall, both tetrazoles demonstrated relative activities comparable to those of the tested triazole antifungals against clinical isolates (MIC range, 0.25 to 2 mg/liter and 0.5 to 2 μg/ml for VT-1161 and VT-1598, respectively). Deletion of the gene in fluconazole-resistant matched clinical isolate SM3 abolished the decreased susceptibility phenotype completely for both VT-1161 and VT-1598, similarly to the triazoles. deletion also increased susceptibility to both triazoles and tetrazoles but to a lesser extent than deletion. Of the three major transporter genes regulated by Pdr1, deletion resulted in the largest MIC reductions for all agents tested, while and deletion individually impacted MICs very little. Overall, both VT-1161 and VT-1598 have comparable activities to those of the available triazoles, and decreased susceptibility to these tetrazoles in is driven by many of the same known resistance mechanisms.
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http://dx.doi.org/10.1128/AAC.01304-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761532PMC
October 2019

Microbial uptake kinetics of dissolved organic carbon (DOC) compound groups from river water and sediments.

Sci Rep 2019 08 2;9(1):11229. Epub 2019 Aug 2.

Bangor University, Environment Centre Wales, Bangor, LL57 2UW, UK.

Dissolved organic matter (DOM) represents a key component of carbon (C) cycling in freshwater ecosystems. While the behaviour of bulk dissolved organic carbon (DOC) in aquatic ecosystems is well studied, comparatively little is known about the turnover of specific DOC compounds. The aim of this study was to investigate the persistence of C-labelled low molecular weight (LMW) DOC at a wide range of concentrations (0.1 µM to 10 mM), in sediments and waters from oligotrophic and mesotrophic rivers within the same catchment. Overall, rates of DOC loss varied between compound groups (amino acids > sugars = organic acids > phenolics). Sediment-based microbial communities contributed to higher DOC loss from river waters, which was attributed, in part, to its greater microbial biomass. At higher DOC compound concentrations, DOC loss was greater in mesotrophic rivers in comparison to oligotrophic headwaters. A lag-phase in substrate use within sediments provided evidence of microbial growth and adaptation, ascribed here to the lack of inorganic nutrient limitation on microbial C processing in mesotrophic communities. We conclude that the higher microbial biomass and available inorganic nutrients in sediments enables the rapid processing of LMW DOC, particularly during high C enrichment events and in N and P-rich mesotrophic environments.
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http://dx.doi.org/10.1038/s41598-019-47749-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677892PMC
August 2019

A Case of Surreptitious Glargine Overdose Confirmed by Insulin Pharmacokinetic Time Curves.

J Anal Toxicol 2019 Jul;43(6):e4-e6

Department of Diabetes and Endocrinology, The Royal Melbourne Hospital, Melbourne, Australia.

Case: A 49-year-old man presented with recurrent altered conscious state suggestive of encephalitis. This was followed by an episode of severe hypoglycemia requiring protracted intravenous glucose administration. Comparing the pharmacokinetic time curves of serum insulin levels on two insulin immunoassays with different insulin analog cross-reactivity allowed the likely diagnosis of surreptitious glargine overdose to be made rapidly.

Discussion: The differing insulin analog cross-reactivity of serum insulin immunoassays, in this case the Abbott ARCHITECT and Roche Elecsys, allows the presence of insulin analog to be detected. Through comparison of time curves the characteristic signature of the specific causative insulin analog can be identified. This information confirms surreptitious insulin overdose in a timely manner, therefore avoiding the expensive and time-consuming investigations required to exclude alternate causes of severe hypoglycemia.
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http://dx.doi.org/10.1093/jat/bkz025DOI Listing
July 2019

Development of Highly Selective Pyrimidine-Based Aldosterone Synthase (CYP11B2) Inhibitors.

ACS Med Chem Lett 2019 Jul 7;10(7):1056-1060. Epub 2019 Jun 7.

Selenity Therapeutics, 4505 Emperor Boulevard, Durham, North Carolina 27703, United States.

Excess aldosterone production and signaling are primary contributors to numerous cardiovascular disorders including primary aldosteronism and resistant hypertension. Recently, inhibition of aldosterone synthesis via the enzyme aldosterone synthase (CYP11B2) has been pursued to ameliorate the negative effects of elevated aldosterone. Herein, we report the development of aldosterone synthase inhibitors using a pyrimidine-based metal binding group leading to the highly selective CYP11B2 inhibitor . Superior selectivity combined with robust pharmacokinetics afforded highly selective aldosterone suppression in a monkey model of adrenal steroidogenesis, demonstrating the potential for selective aldosterone lowering in humans with pyrimidine .
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http://dx.doi.org/10.1021/acsmedchemlett.9b00152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628572PMC
July 2019

Clinical relevance of ethanol coingestion in patients with GHB/GBL intoxication.

Toxicol Lett 2019 Oct 10;314:37-42. Epub 2019 Jul 10.

Emergency Department, Hospital Clínic, Barcelona, IDIBAPS, Barcelona, Spain; Medical School, University of Barcelona, Spain.

Objective: Ethanol intake can increase the sedative effects of gamma-hydroxybutyrate/gamma-butyrolactone (GHB/GBL), although the real clinical impact is unknown. We studied the clinical impact of the co-ingestion of ethanol in patients presenting to the Emergency Department (ED) with acute toxicity related to GHB/GBL use.

Method: We performed a secondary analysis of the Euro-DEN Plus Registry (14 countries, 22 EDs) which includes 17,371 consecutive patients presenting to the ED with acute recreational drug toxicity over 39 consecutive months (October 2013 - December 2016). We compared the epidemiological and clinical characteristics and ED management of patients identified as presenting with acute toxicity related to lone GHB/GBL (Group A) or GHB/GBL combined with ethanol (Group B) without other concomitant drugs.

Results: A total of 609 patients were included (age 32 (8) years; 116 women (19%); Group A: 183 patients and Group B: 426). The most common features were reduction in consciousness (defined as Glasgow Coma Score <13 points: 56.1%) and agitation/aggressiveness (33.6%). Those with ethanol co-ingestion were younger patients (Group A/B: 31.5/33.1 years, p = 0.029) and ethanol co-ingestion was associated with a lower frequency of bradycardia (23.5%/15.7%, p = 0.027) and more frequent arrival at the ED by ambulance (68.3/86.6%; p < 0.001), reduction in consciousness (58.9%/49.1%; p = 0.031), need for treatment in the ED (49.2%/60.4%; p = 0.011), use of sedatives (20.1%/12.8%; p = 0.034), admission to critical care units (22.4%/55.3%; p < 0.001), and longer hospital stay (stay longer than 6 h: 16.9%/28.4%; p = 0.003).

Conclusions: Co-ingestion of ethanol increases the adverse effects of patients intoxicated by GHB/GBL, leading to greater depression of consciousness, need for treatment, admission to the ICU and longer hospital stay.
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http://dx.doi.org/10.1016/j.toxlet.2019.07.001DOI Listing
October 2019

Author’s reply.

Emergencias 2019 06;31(3):220

Área de Urgencias, Hospital Clínic, Barcelona, España.

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June 2019

Acute myeloid leukaemia presenting with diabetes insipidus.

Intern Med J 2019 06;49(6):785-788

Department of Diabetes and Endocrinology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.

A 41-year-old man was diagnosed with hypogonadotropic hypogonadism managed with gonadotropins after routine fertility review. Eight months later he presented with new polydipsia and polyuria, lethargy and easy bruising. A full blood count showed 28% circulating blasts. A bone marrow biopsy confirmed a diagnosis of acute myeloid leukaemia with inv(3)(q21.3q26.2) with additional monosomy 7. Central diabetes insipidus (DI) was diagnosed following a water deprivation test. Pituitary magnetic resonance imaging showed a slightly thickened pituitary stalk, stable Rathke's cyst, and new absence of the pituitary bright spot. The patient was commenced on desmopressin and induction chemotherapy, subsequently requiring a bone marrow transplant. Bone marrow examination at 100 days post-transplant revealed cytogenetic remission. All symptoms of DI resolved and magnetic resonance imaging showed return of the posterior bright spot and a pituitary stalk of normal thickness. Biochemical hypogonadotropic hypogonadism persisted but was uninterpretable in the context of systemic illness and recent chemotherapy. DI is a rare complication of haematological malignancies, and the prevalence and pathophysiology of DI in this context are poorly understood. Pathogenic mechanisms proposed include leukaemic infiltration of the pituitary, interference with antidiuretic hormone synthesis, and abnormal thrombopoiesis influencing hormone levels. Particular cytogenetic abnormalities such as inv(3)(q21.3q26.2) and monosomy 7 appear to be more commonly associated with DI and also appear to confer worse outcomes. Aetiologies in the literature remain elusive but as DI is a recognised association of haematological malignancies it should be considered in a patient presenting with polydipsia and polyuria.
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http://dx.doi.org/10.1111/imj.14312DOI Listing
June 2019

Guidelines for reporting case studies and series on drug-induced QT interval prolongation and its complications following acute overdose.

Clin Toxicol (Phila) 2020 01 24;58(1):20-28. Epub 2019 Apr 24.

Department of Emergency Medicine, Hôpital Charles-Lemoyne, Greenfield Park, Canada.

The assessment and management of patients with QT interval prolongation in poisoning requires an appropriate method of measuring and adjusting the QT interval for the heart rate (HR) in order to decide if the patient is at risk of life-threatening dysrhythmias, notably torsade de pointes (TdP). As the Clinical Toxicology Collaborative (CTC) workgroup reviewed the published literature on drug-induced QT interval prolongation in poisoning, it became obvious that many publications were missing essential data that were necessary to thoroughly assess and compare the evidence. The aim of this guidance document is to identify essential and ideal criteria required when reporting a case of drug-induced QT interval prolongation and/or TdP in poisoning. We employed a mixed methods approach as follows. Initially, we reviewed 188 cases of available published case reports and series in the literature regarding drug-induced QT interval prolongation and/or TdP in poisoning as the first step to another project. Common features and deficiencies were identified. Given the large gaps in reporting quality, we conducted an iterative consultative process involving all 23 members of the CTC to identify essential and ideal criteria to analyse publications of QT interval prolongation in poisoning. standards were developed for acceptance or rejection of individual criteria. Survey response was 100%. A minimum set of essential criteria for reporting cases of QT interval prolongation and drug-induced TdP in overdose setting are provided and a 35-item checklist is presented. We report a QT reporting checklist to ensure published case reports and series describing drug-induced QT interval prolongation in poisoning can contribute to the fund of knowledge of QT interval prolongation, TdP and other malignant dysrhythmias.
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http://dx.doi.org/10.1080/15563650.2019.1605077DOI Listing
January 2020

The Role of 68Ga-DOTA-Octreotate PET/CT in Follow-Up of SDH-Associated Pheochromocytoma and Paraganglioma.

J Clin Endocrinol Metab 2019 11;104(11):5091-5099

Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Victoria, Australia.

Purpose: Germline succinate dehydrogenase (SDHx) mutation carriers, especially SDHB, are at increased risk for malignancy and require life-long surveillance. Current guidelines recommend periodic whole-body MRI imaging. We assessed the incremental value of 68Ga-DOTA-octreotate (GaTate) positron emission tomography (PET)/CT compared with conventional imaging in such patients.

Methods: SDHx mutation carriers who had GaTate PET/CT were retrospectively reviewed. Detection of lesions were compared with MRI or CT on a per-patient and per-lesion basis. Proof of lesions were based on histopathology or clinical/imaging follow-up.

Results: Twenty consecutive patients (median age, 46 years; 10 males) were reviewed. Fourteen patients had SDHB, four, SDHD, one SDHC, and one SDHA mutation. Fifteen had prior surgery and/or radiotherapy. Indications for PET/CT were as follows: 7 patients for surveillance for previously treated disease, 9 residual disease, 2 asymptomatic mutation carriers, and 2 for elevated catecholamines. Median time between modalities was 1.5 months.GaTate PET/CT had higher sensitivity and specificity than conventional imaging. On a per-patient basis: PET/CT sensitivity 100%, specificity 100%; MRI/CT 85% and 50%. Per-lesion basis: PET/CT sensitivity 100%, specificity 75%; MRI/CT 80% and 25%. PET/CT correctly identified additional small nodal and osseous lesions. MRI/CT had more false-positive findings. Change of management resulted in 40% (8/20 patients): 3 received localized treatment instead of observation, 1 changed to observation given extra disease detected, 4 with metastases had radionuclide therapy.

Conclusions: GaTate PET/CT provided incremental diagnostic information with consequent management impact in SDHx-pheochromocytoma and paraganglioma. Incorporating this modality as part of a surveillance program seems prudent. Further research is needed to define the optimal surveillance strategy including use of MRI.
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http://dx.doi.org/10.1210/jc.2019-00018DOI Listing
November 2019

Seizures as a complication of recreational drug use: Analysis of the Euro-DEN Plus data-set.

Neurotoxicology 2019 07 8;73:183-187. Epub 2019 Apr 8.

Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust and King's Health Partners, London, UK; Clinical Toxicology, Faculty of Life Sciences and Medicine, King's College London, London, UK.

Seizures are a recognized and potentially serious complication of recreational drug use. This study examined a large international data set of presentations to Emergency Departments with acute recreational drug toxicity, the European Drug Emergencies Plus (Euro-DEN Plus) Network, to compare presentations with and without seizures and estimate incidence and associated drugs. Amongst 23,947 presentations between January 2014 and December 2017, there were 1013 (4.2%) with reported seizures. Clinical and demographic features were similar between individuals who had a seizure and those who did not, although rates of coma, cardiac arrest, intubation, intensive care admission, and death were significantly higher in those with seizures. There was a significant association between specific drugs and a higher seizure incidence, including fentanyl (odds ratio 2.63, 95% confidence interval 1.20-5.80), and synthetic cannabinoids (OR 2.90, 95% CI 2.19-3.84). Other drugs were associated with a lower seizure incidence, including heroin (OR 0.46, 95% CI 0.35-0.61), clonazepam (OR 0.22, 95% CI 0.06-0.91), and cannabis (OR 0.65, 95% CI 0.50-0.86). This substantiates observations that the synthetic cannabinoids as a group of novel psychoactive substances are clinically different in consequence of intoxication than cannabis, and that individuals who suffer a seizure in the context of recreational drug intoxication are likely to have worse outcomes overall. Utilising this information of what substances have a greater risk of seizures, could provide tailored harm reduction and education strategies to users to reduce the risk of seizures and their associated complications.
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http://dx.doi.org/10.1016/j.neuro.2019.04.003DOI Listing
July 2019

Activities of the Novel Investigational Tetrazoles VT-1161 and VT-1598 Compared to the Triazole Antifungals against Azole-Resistant Strains and Clinical Isolates of .

Antimicrob Agents Chemother 2019 06 24;63(6). Epub 2019 May 24.

University of Tennessee Health Science Center, Memphis, Tennessee, USA

The fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new therapies to combat fungal infections, including spp. To evaluate their activities compared to other azoles, MICs were determined by Clinical and Laboratory Standards Institute (CLSI) method for VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and posaconazole against 68  clinical isolates well characterized for azole resistance mechanisms and mutant strains representing individual azole resistance mechanisms. VT-1161 and VT-1598 demonstrated potent activity (geometric mean MICs ≤0.15 μg/ml) against predominantly fluconazole-resistant (≥8 μg/ml) isolates. However, five of 68 isolates exhibited MICs greater than six dilutions (>2 μg/ml) to both tetrazoles compared to fluconazole-susceptible isolates. Four of these isolates likewise exhibited high MICs beyond the upper limit of the assay for all triazoles tested. A premature stop codon in likely explained the high-level resistance in one isolate. VT-1598 was effective against strains with hyperactive Tac1, Mrr1, and Upc2 transcription factors and against most mutant strains. VT-1161 MICs were elevated compared to the control strain SC5314 for hyperactive Tac1 strains and two strains with Erg11 substitutions (Y132F and Y132F&K143R) but showed activity against hyperactive Mrr1 and Upc2 strains. While mutations affecting Erg3 activity appear to greatly reduce susceptibility to VT-1161 and VT-1598, the elevated MICs of both tetrazoles for four isolates could not be explained by known azole resistance mechanisms, suggesting the presence of undescribed resistance mechanisms to triazole- and tetrazole-based sterol demethylase inhibitors.
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http://dx.doi.org/10.1128/AAC.00341-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535515PMC
June 2019

Characterisation of treated effluent from four commonly employed wastewater treatment facilities: A UK case study.

J Environ Manage 2019 Feb 10;232:919-927. Epub 2018 Dec 10.

Department of Earth, Ocean and Atmospheric Science, Florida State University, Tallahassee, FL, 32306, USA.

Sewage treatment systems are a common feature across the landscape of the United Kingdom, serving an estimated 96% of the population and discharging approximately eleven billion litres of treated wastewater daily. While large treatment facilities are ubiquitous across the landscape, they are not the only method employed in domestic wastewater treatment. This study investigates whether differences in nutrient export (carbon, nitrogen and phosphorus) and organic matter composition (determined by optical indices, SUVA, S and E:E) from treated effluent could be detected between four of the most common facilities employed in the treatment of wastewater across the UK. Set in the context of the River Wylye, a small headwater catchment, treatment facilities studied included; a septic tank system, small packet treatment works, and two large sewage treatment works, one of which employed phosphorus stripping for phosphorus removal. Inorganic N and P concentrations ranged between 7.51 and 42.4 mg N l and 0.22 and 8.9 mg P l respectively, with DOC concentrations ranging between 1.63 and 11.8 mg C l. Optical indices were comparable to those observed in catchments where organic matter is dominated by autochthonous production, suggesting the dominance of low molecular weight material when compared to values observed across temperate aquatic systems. Combining data from both the Environment Agency and Ordinance Survey we estimate that only 15% of domestic properties not connected to mains sewerage in the study catchment have an Environment Agency consent/exemption permit. This calculation suggests that the quantity of small point sources are significantly underestimated, undermining efforts under current legislation to improve stream ecosystem health.
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http://dx.doi.org/10.1016/j.jenvman.2018.12.006DOI Listing
February 2019

Epidemiology, clinical features and management of patients presenting to European emergency departments with acute cocaine toxicity: comparison between powder cocaine and crack cocaine cases.

Clin Toxicol (Phila) 2019 Aug 30;57(8):718-726. Epub 2019 Jan 30.

Emergency Department , Hospital Clínic, Barcelona; IDIBAPS , Barcelona , Spain.

: To analyse the epidemiology, clinical picture and emergency department (ED) management of a large series of patients who presented to European EDs after cocaine consumption, comparing data from powder (C group) and crack (C group) consumers. : Between October 2013 and December 2016, the Euro-DEN Plus Registry recorded 17,371 consecutive acute recreational drug toxicity presentations to 22 EDs in 14 European countries. Epidemiological and demographic data, co-ingestion of alcohol and other drugs, clinical features, ED management and outcome (death) were analysed for cocaine cases, and comparison of clinical picture in C and C patients were performed adjusting for alcohol and other drug co-ingestion. : We included 3002 cases (C: 2600; C: 376; mixed consumption: 26): mean age 32(9) years, 23% female. The proportion of presentations involving cocaine varied significantly between countries (>30% in Malta, Spain, France, Denmark) and only centres in France, United Kingdom, Poland, Ireland and Malta recorded crack-related cases. Cocaine was frequently used with ethanol (74.3%, C>C) and other drugs (56.8%, C>C), the most frequent amphetamine (19.4%, C>C) and opioids (18.9%, C>C). C patients were more likely to have clinically significant episodes of hypotension (adjusted OR = 2.35; 95%CI = 1.42-3.89), and bradypnea (1.81; 1.03-3.16) and systolic blood pressure >180 mmHg on ED arrival (2.59; 1.28-5.25); while less likely anxiety (0.51; 0.38-0.70), chest pain (0.47; 0.31-0.70), palpitations (0.57; 0.38-0.84), vomiting (0.54; 0.32-0.90), and tachycardia on ED arrival (0.52; 0.39-0.67). Sedative drugs were given in 29.3%. The median length of hospital stay was 4:02 h, 22.1% patients were hospitalized, and 0.4% ( = 12) died. : Cocaine is commonly involved in European ED presentations with acute recreational drug toxicity, but there is variation across Europe not just in the involvement of cocaine but in the proportion related to powder versus crack. Some differences in clinical picture and ED management exist between powder cocaine and crack consumers.
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http://dx.doi.org/10.1080/15563650.2018.1549735DOI Listing
August 2019

Emergencies related to recreational drug abuse in Spain compared to emergencies attended in 3 European areas.

Emergencias 2018 Dic;30(6):385-394

Área de Urgencias, Hospital Clínic, Barcelona; Grupo de Investigación "Urgencias: Procesos y Patologías", IDIBAPS, Barcelona, España.

Objectives: To analyze epidemiologic, clinical, and care characteristics in cases in which patients came to 2 Spanish emergency departments (EDs) with symptoms caused by recreational drug abuse. To compare the characteristics with those reported for other areas of Europe.

Material And Methods: Secondary analysis of the registry of the European Drug Emergencies Network (Euro-DEN Plus), which collects cases in 14 European countries and 20 EDs. The registry included all patients attending EDs with symptoms of recreational drug abuse (excepting cases involving alcohol alone) over a period of 39 consecutive months (October 2013 to December 2016). We compared the cases from the 2 Spanish EDs (in Barcelona and Palma de Mallorca) to those from the 5 EDs in Ireland and the UK, 6 in northern Europe, and 7 in central Europe.

Results: A total of 17 104 patients' cases were included: Spain, 1186; UK and Ireland, 6653; northern Europe, 6097; and central Europe, 3168. Spain saw more emergencies related to cocaine (48.4%) and fewer related to opioids (12.4%) than the other areas. The Spanish patients were younger (32.2 years) on average than those in northern Europe and older than those in the UK and Ireland and central Europe. Fewer patients were women in Spain (21.9%) than in northern or central Europe. Fewer arrived in ambulances in Spain (70.0%) than in the UK and Ireland or northern Europe. The Spanish EDs recorded the temperature and respiratory frequency of fewer patients (29.8% and 30.3%, respectively). Clinical signs differed between geographical areas attributable to differences in drug-use patterns. In Spain, naloxone was used by fewer patients (9.6%) than in the UK and Ireland and northern Europe, and flumazenil was used by more patients (5.6%) than in other areas. Spain saw lower percentages of admissions (4.6%) and patients who left without an ED discharge (6.2%) in comparison with other areas. Mortality rates in the Spanish EDs (0.4%) and after discharge from them (0.7%) were higher than in northern Europe.

Conclusion: The characteristics of emergencies related to recreational drug abuse registered by the Spanish EDs were differed from those registered in other parts of Europe due to different patterns of drug use. We also detected differences between the Spanish and other European EDs with respect to examinations or tests performed, treatment given, and discharge disposition.
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July 2019

The Fungal Cyp51-Specific Inhibitor VT-1598 Demonstrates and Activity against Candida auris.

Antimicrob Agents Chemother 2019 03 26;63(3). Epub 2019 Feb 26.

University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

is an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluated and against Susceptibility testing was performed against 100 clinical isolates of by broth microdilution. Neutropenic mice were infected intravenously with , and treatment began 24 h postinoculation with a vehicle control, oral VT-1598 (5, 15, and 50 mg/kg of body weight once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstrated activity against , with a mode MIC of 0.25 μg/ml and MICs ranging from 0.03 to 8 μg/ml. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival, 15 and >21 days for VT-1598 at 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (reductions of 1.88 to 3.61 log CFU/g) compared to the control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to those with the control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused by .
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http://dx.doi.org/10.1128/AAC.02233-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395925PMC
March 2019

MiR-15a/miR-16-1 expression inversely correlates with cyclin D1 levels in Men1 pituitary NETs.

J Endocrinol 2018 Sep 1. Epub 2018 Sep 1.

R Thakker, University of Oxford, Radcliffe Department of Medicine, Oxford Centre for Diabetes Endocrinology and Metabolism, Oxford, United Kingdom of Great Britain and Northern Ireland.

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic islet tumours, and is due to mutations of the MEN1 gene, which encodes the tumour suppressor protein menin. Menin has multiple roles in genome stability, transcription, cell division and proliferation, but its mechanistic roles in tumourigenesis remain to be fully elucidated. MicroRNAs (miRNA) are non-coding single stranded RNAs that post-transcriptionally regulate gene expression and have been associated with tumour development, although the contribution of miRNAs to MEN1-associated tumourigenesis and their relationship with menin expression are not fully understood. Alterations in miRNA expression, including downregulation of three putative 'tumour suppressor' miRNAs, miR-15a, miR-16-1 and let-7a, have been reported in several tumour types including non-MEN1 pituitary adenomas. We have therefore investigated the expression of miR-15a, miR-16-1 and let-7a in pituitary tumours that developed after 12 months of age in female mice with heterozygous knock out of the Men1 gene (Men1+/- mice). The miRNAs miR-15a, miR-16-1 and let-7a were significantly downregulated in pituitary tumours (by 2.3-fold, p<0.05; 2.1-fold p<0.01 and 1.6-fold p<0.05, respectively) of Men1+/- mice, compared to normal wild type pituitaries. MiR-15a and miR-16-1 expression inversely correlated with expression of cyclin D1, a known pro-tumourigenic target of these miRNAs, and knock down of menin in a human cancer cell line (HeLa), and AtT20 mouse pituitary cell line resulted in significantly decreased expression of miR-15a (p<0.05), indicating that the decrease in miR-15a may be a direct result of lost menin expression.
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http://dx.doi.org/10.1530/JOE-18-0278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347280PMC
September 2018

The application of finite element modelling based on clinical pQCT for classification of fracture status.

Biomech Model Mechanobiol 2019 Feb 6;18(1):245-260. Epub 2018 Oct 6.

Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

Fracture risk assessment using dual-energy X-ray absorptiometry (DXA) frequently fails to diagnose osteoporosis amongst individuals who later experience fragility fractures. Hence, more reliable techniques that improve the prediction of fracture risk are needed. In this study, we evaluated a finite element (FE) modelling framework based on clinical peripheral quantitative computed tomography (pQCT) imaging of the tibial epiphysis and diaphysis to predict the stiffness at these locations in compression, shear, torsion and bending. The ability of these properties to identify a group of women who had recently sustained a low-trauma fracture from an age- and weight-matched control group was determined and compared to clinical pQCT and DXA properties and structural properties based on composite beam theory. The predicted stiffnesses derived from the FE models and composite beam theory were significantly different (p < 0.05) between the control and fracture groups, whereas no meaningful differences were observed using DXA and for the stress-strain indices (SSIs) derived using pQCT. The diagnostic performance of each property was assessed by the odds ratio (OR) and the area under the receiver operating curve (AUC), and both were greatest for the FE-predicted shear stiffness (OR 16.09, 95% CI 2.52-102.56, p = 0.003) (AUC: 0.80, 95% CI 0.67-0.93). The clinical pQCT variable total density (ρ) and a number of structural and FE-predicted variables had a similar probability of correct classification between the control and fracture groups (i.e. ORs and AUCs with mean values greater than 5.00 and 0.80, respectively). In general, the diagnostic characteristics were lower for variables derived using DXA and for the SSIs (i.e. ORs and AUCs with mean values of 1.65-2.98 and 0.64-0.71, respectively). For all properties considered, the trabecular-dominant tibial epiphysis exhibited enhanced classification characteristics, as compared to the cortical-dominant tibial diaphysis. The results of this study demonstrate that bone properties may be derived using FE modelling that have the potential to enhance fracture risk assessment using conventional pQCT or DXA instruments in clinical settings.
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http://dx.doi.org/10.1007/s10237-018-1079-7DOI Listing
February 2019

VT-1598 inhibits the in vitro growth of mucosal Candida strains and protects against fluconazole-susceptible and -resistant oral candidiasis in IL-17 signalling-deficient mice.

J Antimicrob Chemother 2018 08;73(8):2089-2094

Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, NIAID, National Institutes of Health, Bethesda, MD, USA.

Background: Chronic mucocutaneous candidiasis (CMC) treatment often induces drug resistance, posing long-term challenges. A novel broad-spectrum fungal CYP51 inhibitor, VT-1598, specifically targets fungal CYP51, but not human CYP enzymes.

Objectives: To determine the efficacy of VT-1598 in the treatment of oral Candida infection caused by fluconazole-susceptible and -resistant clinical isolates.

Methods: The MICs of VT-1598 and fluconazole for 28 Candida isolates recovered from patients with inherited CMC were determined using CLSI M27-A3 and M27-S4 guidelines. Plasma and tongue VT-1598 or fluconazole concentrations were measured in mice following oral administration to determine tissue distribution. Tongue fungal load was determined in IL-17 signalling-deficient Act1-/- mice following sublingual Candida albicans infection and oral treatment with fluconazole or VT-1598.

Results: Among the 28 Candida isolates, 10 (36%) had fluconazole MICs of ≥4 mg/L, whereas VT-1598 demonstrated potent in vitro activity against all isolates (MIC90, 0.125 mg/L). After oral administration, VT-1598 levels in mouse plasma and tongue were significantly greater than those of fluconazole. In vivo, VT-1598 exhibited significant efficacy against fluconazole-susceptible and -resistant C. albicans, even at low drug doses. Furthermore, after a 10 day washout period, tongue fungal burdens in fluconazole-treated mice returned to vehicle control levels, whereas, in contrast, they were undetectable in mice treated with VT-1598.

Conclusions: VT-1598 effectively controls in vitro growth of mucosally derived Candida clinical isolates, including fluconazole-resistant strains. In vivo, VT-1598 eliminates C. albicans, even after a long washout period or at low doses. Therefore, VT-1598 is a promising drug candidate that may significantly improve treatment options for CMC patients.
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http://dx.doi.org/10.1093/jac/dky170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054247PMC
August 2018

Difficulties in cerebrospinal fluid βhCG interpretation in a patient with an infundibular lesion.

Endocrinol Diabetes Metab Case Rep 2018 23;2018. Epub 2018 Feb 23.

Department of Endocrinology and DiabetesWestern Health, St Albans, Victoria, Australia.

A variety of neoplastic, inflammatory and congenital conditions can cause pituitary stalk thickening. Differentiating between these causes is important as targeted treatment may be offered. Diagnostic work-up consists of a thorough history, examination, biochemical analysis and imaging. We present the case of a 33-year-old male who presented with diabetes insipidus and had pituitary stalk thickening on magnetic resonance imaging. Further investigations revealed an elevated CSF βhCG, which raised the possibility of an intracranial germ cell tumor. However, when repeated on four different assays, the βhCG levels were discordant. On serial imaging, the pituitary stalk thickening reduced slightly, which would be unexpected for a germ cell tumor. This case raises the difficulties interpreting CSF βhCG, as not all immunoassays for βhCG have been validated for use in CSF. The Roche Diagnostics Elecsys and Siemens Centaur assays have been validated for CSF βhCG, and so we advocate using one of these methods. If unavailable or serum/CSF results are ambiguous, serial MRI is appropriate, with pituitary stalk biopsy considered if the stalk measures >6.5 mm or other imaging abnormalities are present.

Learning Points: Most adult patients with central diabetes insipidus have imaging abnormalities on a pituitary MRI. The most common abnormalities are loss of the posterior pituitary bright spot and pituitary stalk thickening, both of which are non-specific.Causes of pituitary stalk thickening include neoplastic, inflammatory, infective and congenital lesions.Investigation of pituitary stalk thickening should encompass the many possible causes and include biochemical analyses as well as imaging of the chest, abdomen and pelvis. Further investigations should be guided by the clinical context, but may include testicular ultrasound, CSF analysis and pituitary stalk biopsy.Germ cell tumors involving the pituitary stalk may be suspected on clinical grounds, but in the absence of a tissue diagnosis (biopsy) confirmation may be difficult and relies on biochemical assessment of blood and possibly CSF as well as serial MRI imaging.CSF βhCG levels should be analyzed on an instrument validated for use in CSF or on multiple instruments, and the pitfalls of testing this marker (false negative in some germ cell tumors, false positives in other conditions, lack of internationally agreed reference ranges for diagnosing germ cell tumors) should be considered when interpreting the results.
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http://dx.doi.org/10.1530/EDM-17-0168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825882PMC
February 2018