Detection of multiple hypervirulent Klebsiella pneumoniae strains in a New York City hospital through screening of virulence genes.

OBJECTIVES: The 'hypervirulent' variant of Klebsiella pneumoniae (hvKp) is a predominant cause of community-acquired pyogenic liver abscess in Asia, and is an emerging pathogen in Western countries. hvKp infections have demonstrated 'metastatic' dissemination in immunocompetent hosts, an unusual mode of infection associated with severe complications. Two cases alerted us to the possible presence of hvKp at our hospital, both involving elderly Hispanic males who presented with recurrent fever, bacteraemia, epigastric pain and liver abscesses/phlegmon, thus prompting an assessment of hvKp prevalence. METHODS: A surveillance of K. pneumoniae blood, body fluid and wound isolates was conducted using real-time PCR to detect virulence-associated genes (uni-rmpA, iucA and peg344). Positive isolates were further characterized by wzi gene sequencing to determine capsular types (K-type) and by multilocus sequence typing and pulsed-field gel electrophoresis to determine strain relatedness. RESULTS: Four-hundred and sixty-three K. pneumoniae isolates, derived from 412 blood, 21 body fluids and 30 abdominal wound specimens, were screened over a 3-year period. Isolates included 98 multidrug-resistant strains. Eighteen isolates from 17 patients, including two from the index patient, screened positive for all three virulence genes. Sixteen of 18 positive isolates had K-types associated with hvKp, and isolates from different patients were unrelated strains, indicating likely community acquisition. Of 13 patients with significant morbidity, five died; eight patients had co-existing hepatobiliary disease, and six had diabetes mellitus. CONCLUSIONS: Multiple strains of hvKp are emerging in New York City and are associated with high mortality relative to multidrug-resistant and classical Klebsiella infections. Co-existing hepatobiliary disease appears to be a potential risk factor for these infections.

A novel toolkit for the prediction of clinical outcomes following mechanical thrombectomy.

AIM: To develop a robust toolkit to aid decision-making for mechanical thrombectomy (MT) based on readily available patient variables that could accurately predict functional outcome following MT. MATERIALS AND METHODS: Data from patients with anterior circulation stroke who underwent MT between October 2009 and January 2018 (n=239) were identified from our MT database. Patient explanatory variables were age, sex, National Institutes of Health Stroke Scale (NIHSS), Alberta Stroke Program Early CT Score (ASPECTS), collateral score, and Glasgow Coma Scale. Five models were developed from the data to predict five outcomes of interest: model 1: prediction of survival: modified Rankin Scale (mRS) of 0-5 (alive) or 6 (dead); model 2: prediction of good/poor outcome: mRS of 0-3 (good), or 4-6 (poor); model 3: prediction of good/poor outcome: mRS of 0-2 (good), or 3-6 (poor); model 4: prediction of mRS category: mRS of 0-2 (no disability), 3 (minor disability), 4-5 (severe disability) or 6 (dead); model 5: prediction of the exact mRs score (mRs as a continuous variable). The accuracy and discriminative power of each predictive model were tested. RESULTS: Prediction of survival was 87% accurate (area under the curve [AUC] 0.89). Prediction of good/poor outcome was 91% accurate (AUC 0.94) for Model 2 and 95% accurate (AUC 0.98) for Model 3. Prediction of mRS category was 76% accurate, and increased to 98% using the "one-score-out rule". Prediction of the exact mRS value was accurate to an error of 0.89. CONCLUSIONS: This novel toolkit provided accurate estimations of outcome for MT.

Mechanical thrombectomy in acute ischaemic stroke: a review of the different techniques.

Endovascular mechanical thrombectomy (MT) is reserved for acute ischaemic stroke secondary to large vessel occlusion. The various MT techniques employed in the treatment of hyperacute strokes are constantly evolving with new devices and improvisation of existing technology (Wahlgren, et al 2016). In this review, we describe a variety of MT techniques gained from our experience of performing over 350 procedures in 7 years of providing a 24/7 service within the national framework of a hyperacute stroke centre. We outline a number of endovascular techniques, procedure limitations, and potential complications.

Increased cortisol levels in hair of recent Ecstasy/MDMA users.

Previous research has revealed an acute 8-fold increase in salivary cortisol following self-administrated Ecstasy/MDMA in dance clubbers. It is currently not known to what extent repeated usage impacts upon activity of the hypothalamic-pituitary-adrenal axis over a more prolonged period of time. This study investigated the integrated cortisol levels in 3-month hair samples from recent Ecstasy/MDMA users and non-user controls. One hundred and one unpaid participants (53 males, 48 females; mean age 21.75 years) completed the University of East London recreational drug use questionnaire, modified to cover the past 3-months of usage. They comprised 32 light recent Ecstasy/MDMA users (1-4 times in last 3 months), 23 recent heavy MDMA users (+5 times in last 3 months), and 54 non-user controls. Volunteers provided 3 cm hair samples for cortisol analysis. Hair cortisol levels were observed to be significantly higher in recent heavy MDMA users (mean = 55.0 ± 80.1 pg/mg), compared to recent light MDMA users (19.4 ± 16.0 pg/mg; p=0.015), and to non-users (13.8 ± 6.1 pg/mg; p<0.001). Hence the regular use of Ecstasy/MDMA was associated with almost 4-fold raised hair cortisol levels, in comparison with non-user controls. The present results are consistent with the bio-energetic stress model for Ecstasy/MDMA, which predicts that repeated stimulant drug use may increase cortisol production acutely, and result in greater deposits of the hormone in hair. These data may also help explain the neurocognitive, psychiatric, and other psychobiological problems of some abstinent users. Future study design and directions for research concerning the psychoneuroendocrinological impact of MDMA are also discussed.

MDMA and temperature: a review of the thermal effects of 'Ecstasy' in humans.

AIMS: To review the thermal effects of MDMA in humans, and discuss the practical implications. METHODS: The literature on Ecstasy/MDMA, body temperature, and subjective thermal self-ratings was reviewed, and explanatory models for the changes in thermal homeostasis were examined and debated. RESULTS: In human placebo-controlled laboratory studies, the effects of MDMA were dose related. Low doses had little effect, moderate doses increased body temperature by around +0.4°C, and higher doses caused a mean increase of +0.7°C. With Ecstasy/MDMA using dance clubbers, the findings showed greater variation, due possibly to uncontrolled factors such as physical activity, ambient temperature, and overcrowding. Some real world studies found average body temperature increases of over +1.0°C. Thermal homeostasis involves a balance between heat production and heat dissipation, and MDMA affects both aspects of this homeostatic equation. Cellular metabolic heat output is increased, and heat dissipation mechanisms are stressed, with the onset of sweating delayed. Subjective responses of 'feeling hot' or 'hot-cold flushes' are frequent, but can show individual variation. Some recreational users report that heat increases or reinstates the positive mood effects of Ecstasy/MDMA. The dangers of acute hyperthermia can include rare fatalities. It is unclear why moderate hyperthermia can occasionally progress to severe hyperpyrexia, although it may reflect a combination or cascade of events. In chronic terms, the bioenergetic stress model notes that the adverse psychobiological effects of MDMA are heightened by various co-stimulatory factors, including heat stress. CONCLUSIONS: MDMA increases core body temperature and thermal stress in humans.

Hair MDMA samples are consistent with reported ecstasy use: findings from a study investigating effects of ecstasy on mood and memory.

AIMS: Our group has conducted several Internet investigations into the biobehavioural effects of self-reported recreational use of MDMA (3,4-methylenedioxymethamphetamine or Ecstasy) and other psychosocial drugs. Here we report a new study examining the relationship between self-reported Ecstasy use and traces of MDMA found in hair samples. METHODS: In a laboratory setting, 49 undergraduate volunteers performed an Internet-based assessment which included mood scales and the University of East London Drug Use Questionnaire, which asks for history and current drug use. They also provided a hair sample for determination of exposure to MDMA over the previous month. RESULTS: Self-report of Ecstasy use and presence in hair samples were consistent (p < 0.00001). Both subjective and objective measures predicted lower self-reported ratings of happiness and higher self-reported stress. Self-reported Ecstasy use, but not presence in hair, was also associated with decreased tension. CONCLUSION: Different psychoactive drugs can influence long-term mood and cognition in complex and dynamically interactive ways. Here we have shown a good correspondence between self-report and objective assessment of exposure to MDMA. These data suggest that the Internet has potentially high utility as a useful medium to complement traditional laboratory studies into the sequelae of recreational drug use.

Priority water research questions as determined by UK practitioners and policy makers.

Several recent studies have emphasised the need for a more integrated process in which researchers, policy makers and practitioners interact to identify research priorities. This paper discusses such a process with respect to the UK water sector, detailing how questions were developed through inter-disciplinary collaboration using online questionnaires and a stakeholder workshop. The paper details the 94 key questions arising, and provides commentary on their scale and scope. Prioritization voting divided the nine research themes into three categories: (1) extreme events (primarily flooding), valuing freshwater services, and water supply, treatment and distribution [each >150/1109 votes]; (2) freshwater pollution and integrated catchment management [100-150 votes] and; (3) freshwater biodiversity, water industry governance, understanding and managing demand and communicating water research [50-100 votes]. The biggest demand was for research to improve understanding of intervention impacts in the water environment, while a need for improved understanding of basic processes was also clearly expressed, particularly with respect to impacts of pollution and aquatic ecosystems. Questions that addressed aspects of appraisal, particularly incorporation of ecological service values into decision making, were also strongly represented. The findings revealed that sustainability has entered the lexicon of the UK water sector, but much remains to be done to embed the concept operationally, with key sustainability issues such as resilience and interaction with related key sectors, such as energy and agriculture, relatively poorly addressed. However, the exercise also revealed that a necessary condition for sustainable development, effective communication between scientists, practitioners and policy makers, already appears to be relatively well established in the UK water sector.

snaR genes: recent descendants of Alu involved in the evolution of chorionic gonadotropins.

We identified a novel family of human noncoding RNAs by in vivo cross-linking to the nuclear factor 90 (NF90) protein. These small NF90-associated RNAs (snaRs) are transcribed by RNA polymerase III and display restricted tissue distribution, with high expression in testis and discrete areas of the brain. The most abundant human transcript, snaR-A, interacts with the cell's transcription and translation systems. snaR genes have evolved in African Great Apes (human, chimpanzee, and gorilla) and some are unique to humans. We traced their ancestry to the Alu SINE (short interspersed nucleotide element) family, via two hitherto unreported sets of short genetic elements termed ASR (Alu/snaR-related) and CAS (Catarrhine ancestor of snaR). This derivation entails a series of internal deletions followed by expansions. The evolution of these genes coincides with major primate speciation events: ASR elements are found in all monkeys and apes, whereas CAS elements are limited to Old World monkeys and apes. In contrast to ASR and CAS elements, which are retrotransposons, human snaR genes are predominantly located in three clusters on chromosome 19 and have been duplicated as part of a larger genetic element. Insertion of the element containing snaR-G into a gene encoding a chorionic gonadotropin beta subunit generated new hormone genes in African Great Apes.

Cortisol and 3,4-methylenedioxymethamphetamine: neurohormonal aspects of bioenergetic stress in ecstasy users.

AIMS: 3,4-Methylenedioxymethamphetamine (MDMA) can affect both neurotransmitter and neurohormonal activity. This review will debate the role of the metabolic activation hormone cortisol for the psychobiological effects of ecstasy/MDMA. METHODS: The empirical literature on cortisol release following acute MDMA administration and cortisol functioning in drug-free recreational ecstasy/MDMA users will be reviewed. This will be followed by an overview of cortisol as a bioenergetic stress neurohormone, and a debate on how it could be modulating the acute and chronic psychobiological effects of MDMA. RESULTS: Cortisol release is increased by stimulatory factors, including physical activity, thermal stress and stimulant drugs. In laboratory studies MDMA leads to an acute cortisol increase of around 150% in sedentary humans. In MDMA-using dance clubbers, the cortisol levels are increased by around 800%, possibly due to the combined factors of stimulant drug, physical exertion and psychosocial stimulation. Regular ecstasy/MDMA users also demonstrate changes in baseline cortisol levels and cortisol reactivity, with compromised hypothalamic-pituitary-adrenal activity. Nonpharmacological research has shown how cortisol is important for psychological aspects such as memory, cognition, sleep, impulsivity, depression and neuronal damage. These same functions are often impaired in recreational ecstasy/MDMA users, and cortisol may be an important modulatory co-factor. CONCLUSIONS: The energizing hormone cortisol is involved in the psychobiology of MDMA, probably via its effects on energy metabolism. Acute cortisol release may potentiate the stimulating effects of MDMA in dance clubbers. Chronically, cortisol may contribute to the variance in functional and structural consequences of repeated ecstasy usage.

Attributions for psychobiological changes in ecstasy/MDMA and other polydrug users.

Ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] use has been associated with a number of psychopathological problems. However, research suggests that reported symptoms might be associated more with heavy polydrug use in general rather than ecstasy per se. The current study aimed to determine the role of other drug use in reports of long-term effects by some ecstasy-polydrug users. Problematic ecstasy users (n = 53), reporting problems which they attributed to ecstasy use, were compared with non-problematic ecstasy users (n = 62), polydrug (n = 62) and alcohol/nicotine using controls (n = 111). Drug use was recorded, and positive and negative life changes were assessed along with which previous drug use, if any, they attributed these changes too. Both ecstasy groups reported higher drug use compared with polydrug controls. Polydrug and ecstasy users more often reported life changes compared with non-drug users, and ecstasy users appeared to experience more life changes than polydrug users, with problematic ecstasy users experiencing most alterations. Ecstasy users reported changes more to a combination of drugs than to one specific drug, suggesting that polydrug use in these groups has an impact on their life experiences. These findings emphasise that research into the psychological effects of ecstasy should not underestimate the role of other polydrug use.

Cannabis and Ecstasy/ MDMA: empirical measures of creativity in recreational users.

This study investigated the associations between chronic cannabis and Ecstasy/MDMA use and one objective and two subjective measure of creativity. Fifteen abstinent Ecstasy users, 15 abstinent cannabis users, and 15 nondrug-user controls, completed three measures of creativity: the Consequences behavioral test of creativity, self-assessed performance on the Consequences test, and Gough's Trait Self-Report Creative Adjective Checklist. The Consequences test involved five scenarios where possible consequences had to be devised; scoring was conducted by the standard blind rating (by two independent judges) for "remoteness" and "rarity," and by a frequency and rarity of responses method. Cannabis users had significantly more "rare-creative" responses than controls (Tukey, p < 0.05); this effect remained significant with gender as a covariate. There were no significant differences between the groups on the number of standard scoring "remote-creative" ideas or for fluency of responses. On self-rated creativity, there was a significant ANOVA group difference (p < 0.05), with Ecstasy users tending to rate their answers as more creative than controls (Tukey comparison; p = 0.058, two-tailed). Ecstasy users did not differ from controls on the behavioral measures of creativity, although there was a borderline trend for self-assessment of greater creativity. Cannabis users produced significantly more "rare-creative" responses, but did not rate themselves as more creative.

Dance clubbing on MDMA and during abstinence from Ecstasy/MDMA: prospective neuroendocrine and psychobiological changes.

BACKGROUND/AIMS: The present study is the first to prospectively compare a group of recreational Ecstasy users when dance clubbing on 3,4-methylenedioxymethamphetamine (MDMA) and when clubbing during abstinence from Ecstasy/MDMA. METHODS: Twelve normal healthy volunteers (mean age = 23.2 years) were assessed at a Saturday night dance club under self-administered MDMA. On the other weekend they went to the same dance club without taking MDMA (order counterbalanced). Both conditions involved 5 test sessions conducted at similar times: pre-drug baseline, 1 h post-drug clubbing, 2.5 h post-drug clubbing, and 2 and 4 days later. The assessments included body and ambient temperature, physical activity (pedometer), as well as self-ratings for mood state, physical activity, thermal comfort and thirst. Saliva samples were analyzed for MDMA, cortisol and testosterone. RESULTS: The cortisol levels increased significantly by 800% when dance clubbing on MDMA, while testosterone increased significantly by 75%; neither neuroendocrine measure was altered during abstinence. Saliva analyses confirmed the presence of MDMA when dancing on Ecstasy and its absence when dancing off Ecstasy. The pedometer values and self-rated levels of dancing were similar at both weekends. Hot and cold flushes and feeling hot increased significantly under MDMA. The mean body temperature did not change significantly, although there was a borderline trend for increased values after MDMA. Feelings of happiness and excitement increased under MDMA, although they were not significantly greater than when clubbing during abstinence. CONCLUSIONS: Neurohormonal release may be an important part of the acute MDMA experience. The large cortisol increase provides further data on the bioenergetic stress model of recreational Ecstasy/MDMA.

Cannabis and Ecstasy/MDMA (3,4-methylenedioxymethamphetamine): an analysis of their neuropsychobiological interactions in recreational users.

The majority of recreational Ecstasy/MDMA users (90-98%) also take cannabis. This co-drug usage is often viewed as a methodological confound, which needs to be removed statistically. Here we take a rather different approach, and debate the potential complexities of their psychobiological interactions. The ring-substituted amphetamine derivate MDMA (3,4-methylendioxymethamphetmaine, or 'Ecstasy') is a powerful CNS stimulant, whereas cannabis is a relaxant. Their co-usage may reflect opposing effects in three psychobiological areas: arousal, body temperature, and oxidative stress. Firstly MDMA is alerting whereas cannabis is sedating. Secondly MDMA is hyperthermic whereas cannabis is hypothermic. Thirdly MDMA increases oxidative stress whereas cannabinoids are antioxidant. Hence cannabis may modulate the acute and sub-acute reactions to MDMA, reduce the acute hyperthermia induced by MDMA, and ameliorate the oxidative stress caused by MDMA. The limited empirical evidence on each topic will be critically examined. In terms of chronic effects each drug is functionally damaging, so that polydrug users generally display cumulative neurobiological impairments. However in certain aspects their neuropsychobiological effects may interactive rather than additive. In particular, the combined use of cannabis and MDMA may have rather different neuropsychobiological implications, than their separate usage. In order to investigate these potential complexities, future research will need better empirical data on the exact patterns of co-drug usage.

The psychotherapeutic potential of MDMA (3,4-methylenedioxymethamphetamine): an evidence-based review.

UNLABELLED: AIMS AND RATIONALE: The purpose of this study was to review whether methylenedioxymethamphetamine (MDMA) has the appropriate pharmacodynamic profile to be a therapeutic agent. MATERIALS AND METHODS: Empirical descriptions of MDMA's subjective effects in humans will be reviewed to evaluate the proposal that MDMA has psychotherapeutic properties. The focus will be published evidence on its functional effects in therapeutic, medical, and other situations. RESULTS: MDMA is a powerful central nervous system (CNS) stimulant which affects several neurotransmitter systems and intensifies a range of psychobiological functions. Its acute mood effects can be very positive and life enhancing, and the affirmative cognitions engendered during MDMA therapy may well endure afterwards. However, MDMA also has a number of potential anti-therapeutic characteristics. Acutely, it can also intensify negative cognitions, and these may similarly endure over time. Psychotherapists have found that setting, intention, and expectancy are crucial for a positive outcome, but these factors cannot be guaranteed. Post-MDMA, there is a period of neurotransmitter recovery when low moods predominate, and these may exacerbate psychiatric distress. The explanations proposed for MDMA-assisted therapy are all psychodynamic, and a neurochemical model needs to be outlined. It has been suggested that enduring therapeutic gains can follow a single session, but again, this lacks a clear psychopharmacological rationale. Finally, diathesis-stress models suggest that psychiatric individuals are more prone to acute and chronic abreactions to CNS stimulants such as MDMA. CONCLUSIONS: There are a number of issues which need to be addressed before it can be argued that MDMA might be clinically useful for psychotherapy.