Apramycin efficacy against carbapenem- and aminoglycoside-resistant Escherichia coli and Klebsiella pneumoniae in murine bloodstream infection models.

BACKGROUND: The aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, the potential of apramycin in the treatment of drug-resistant bloodstream infections (BSIs) has not yet been assessed. METHODS: The resistance gene annotations of 40 888 blood-culture isolates were analysed. In vitro profiling of apramycin comprised cell-free translation assays, broth microdilution, and frequency of resistance determination. The efficacy of apramycin was studied in a mouse peritonitis model for a total of nine Escherichia coli and Klebsiella pneumoniae isolates. RESULTS: Genotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistant Enterobacterales blood-culture isolates, colistin resistance was shown in 46.4% and apramycin in 2.1%. Apramycin activity against methylated ribosomes was > 100-fold higher than that for other aminoglycosides. Frequencies of resistance were < 10-9 at 8 × minimum inhibitory concentration (MIC). Tentative epidemiological cut-offs (TECOFFs) were determined as 8 µg/mL for E. coli and 4 µg/mL for K. pneumoniae. A single dose of 5 to 13 mg/kg resulted in a 1-log colony-forming unit (CFU) reduction in the blood and peritoneum. Two doses of 80 mg/kg resulted in an exposure that resembles the AUC observed for a single 30 mg/kg dose in humans and led to complete eradication of carbapenem- and aminoglycoside-resistant bacteraemia. CONCLUSION: Encouraging coverage and potent in vivo efficacy against a selection of highly drug-resistant Enterobacterales isolates in the mouse peritonitis model warrants the conduct of clinical studies to validate apramycin as a drug candidate for the prophylaxis and treatment of BSI.

Differential sensitivity of intraindividual variability dispersion and global cognition in the prediction of functional outcomes and mortality in precariously housed and homeless adults.

OBJECTIVE: To examine cognitive intraindividual variability (IIV) dispersion as a predictor of everyday functioning and mortality in persons who are homeless or precariously housed. METHOD: Participants were 407 community-dwelling adults, followed for up to 13 years. Neurocognition was assessed at baseline and IIV dispersion was derived using a battery of standardized tests. Functional outcomes (social, physical) were obtained at baseline and last follow-up. Mortality was confirmed with Coroner's reports and hospital records (N = 103 deaths). Linear regressions were used to predict current social and physical functioning from IIV dispersion. Repeated measures Analysis of Covariance were used to predict long-term change in functioning. Cox regression models examined the relation between IIV dispersion and mortality. Covariates included global cognition (i.e. mean-level performance), age, education, and physical comorbidities. RESULTS: Higher IIV dispersion predicted poorer current physical functioning (B = -0.46 p = .010), while higher global cognition predicted better current (B = 0.21, p = .015) and change in social functioning over a period of up to 13 years (F = 4.23, p = .040). Global cognition, but not IIV dispersion, predicted mortality in individuals under 55 years old (HR = 0.50, p = .013). CONCLUSIONS: Our findings suggest that indices of neurocognitive functioning (i.e. IIV dispersion and global cognition) may be differentially related to discrete dimensions of functional outcomes in an at-risk population. IIV dispersion may be a complimentary marker of emergent physical health dysfunction in precariously housed adults and may be best used in conjunction with traditional neuropsychological indices.

Relationship between drug-induced movement disorders and psychosis in adults living in precarious housing or homelessness.

BACKGROUND: Studies have reported positive associations between drug-induced movement disorders (DIMDs) and symptoms of psychosis in patients with schizophrenia. However, it is not clear which subtypes of symptoms are related to each other, and whether one symptom precedes another. The current report assessed both concurrent and temporal associations between DIMDs and symptoms of psychosis in a community-based sample of homeless individuals. METHODS: Participants were recruited in Vancouver, Canada. Severity of DIMDs and psychosis was rated annually, allowing for the analysis of concurrent associations between DIMDs and Positive and Negative Syndrome Scale (PANSS) five factors. A brief version of the PANSS was rated monthly using five psychotic symptoms, allowing for the analysis of their temporal associations with DIMDs. Mixed-effects linear and logistic regression models were used to assess the associations. RESULTS: 401 participants were included, mean age of 40.7 years (SD = 11.2) and 77.4% male. DIMDs and symptoms of psychosis were differentially associated with each other, in which the presence of parkinsonism was associated with greater negative symptoms, dyskinesia with disorganized symptoms, and akathisia with excited symptoms. The presence of DIMDs of any type was not associated with depressive symptoms. Regarding temporal associations, preceding delusions and unusual thought content were associated with parkinsonism, whereas dyskinesia was associated with subsequent conceptual disorganization. CONCLUSIONS: The current study found significant associations between DIMDs and symptoms of psychosis in individuals living in precarious housing or homelessness. Moreover, there were temporal associations between parkinsonism and psychotic symptoms (delusions or unusual thought content), and the presence of dyskinesia was temporally associated with higher odds of clinically relevant conceptual disorganization.

Using serial position effects to investigate memory dysfunction in homeless and precariously housed persons.

Background: Homeless and precariously housed persons exhibit significant memory impairment, but the component processes underlying memory dysfunction have not been explored. We examined the serial position profile (i.e., primacy and recency effects) of verbal memory and its neuroanatomical correlates to identify the nature of memory difficulties in a large cohort of homeless and precariously housed adults. Method: The sample included 227 community-dwelling homeless and precariously housed adults. Serial position scores (primacy, middle, recency) were computed using the Hopkins Verbal Learning Test-Revised. Paired sample t-tests were used to compare percent recall from each word list region. Age-adjusted correlations assessed associations between serial position scores and other cognitive domains (attention, processing speed, executive functioning). Regression analyses were conducted to examine regional brain volumes of interest (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex [DLPFC]) and their differential associations with serial position scores. Results: The serial position profile was characterized by a diminished recency effect in relation to the primacy effect. Serial position scores positively correlated with sustained attention and cognitive control. Larger hippocampal volume was associated with better primacy item recall. DLPFC volume was not associated with serial position recall after adjustment for false discovery rate. There were no associations between regional brain volumes and recency item recall. Conclusion: Our results suggest that commonly reported memory difficulties in homeless and precariously housed adults are likely secondary to a core deficit in executive control due to compromised frontal lobe functioning. These findings have implications for cognitive rehabilitation in this complex and vulnerable group.

Model-Informed Drug Development for Antimicrobials: Translational PK and PK/PD Modeling to Predict an Efficacious Human Dose for Apramycin.

Apramycin represents a subclass of aminoglycoside antibiotics that has been shown to evade almost all mechanisms of clinically relevant aminoglycoside resistance. Model-informed drug development may facilitate its transition from preclinical to clinical phase. This study explored the potential of pharmacokinetic/pharmacodynamic (PK/PD) modeling to maximize the use of in vitro time-kill and in vivo preclinical data for prediction of a human efficacious dose (HED) for apramycin. PK model parameters of apramycin from four different species (mouse, rat, guinea pig, and dog) were allometrically scaled to humans. A semimechanistic PK/PD model was developed from the rich in vitro data on four Escherichia coli strains and subsequently the sparse in vivo efficacy data on the same strains were integrated. An efficacious human dose was predicted from the PK/PD model and compared with the classical PK/PD index methodology and the aminoglycoside dose similarity. One-compartment models described the PK data and human values for clearance and volume of distribution were predicted to 7.07 L/hour and 26.8 L, respectively. The required fAUC/MIC (area under the unbound drug concentration-time curve over MIC ratio) targets for stasis and 1-log kill in the thigh model were 34.5 and 76.2, respectively. The developed PK/PD model predicted the efficacy data well with strain-specific differences in susceptibility, maximum bacterial load, and resistance development. All three dose prediction approaches supported an apramycin daily dose of 30 mg/kg for a typical adult patient. The results indicate that the mechanistic PK/PD modeling approach can be suitable for HED prediction and serves to efficiently integrate all available efficacy data with potential to improve predictive capacity.

Cognitive decline and mortality in a community-based sample of homeless and precariously housed adults: 9-year prospective study.

BACKGROUND: Homeless and precariously housed individuals experience a high burden of comorbid illnesses, and excess mortality. Cross-sectional studies report a high rate of cognitive impairment. Long-term trajectories have not been well investigated in this group. AIMS: To longitudinally assess risks for premature and/or accelerated cognitive ageing, and the relationship with early mortality in homeless and precariously housed people. METHOD: This is a 9-year community-based study of 375 homeless and precariously housed individuals from Vancouver, Canada. Annual cognitive testing assessed verbal learning and memory, and inhibitory control. Linear mixed-effects models examined associations between clinical risk factors (traumatic brain injury, psychotic disorders, viral exposure, alcohol dependence) and cognitive change over 9 years. Cox regression models examined the association between cognition and mortality. RESULTS: Traumatic brain injury and alcohol dependence were associated with decline in verbal memory. Inhibitory control declined, independent of risk factors and to a greater extent in those who died during the study. Better inhibitory control was associated with a 6.6% lower risk of mortality at study entry, with a 0.3% greater effect for each year of life. For each one-point increase in the Charlson Comorbidity Index score at study entry, the risk of mortality was 9.9% higher, and was consistent across age. Adjusting for comorbidities, inhibitory control remained a significant predictor of mortality. CONCLUSIONS: Findings raise the possibility of a premature onset, and accelerated trajectory, of cognitive ageing in this group of homeless and precariously housed people. Traumatic brain injury, alcohol dependence and cognition could be treatment priorities.

Patch Testing with a New Composition of Mercapto Mix: A Multi-centre Study by the Swedish Contact Dermatitis Research Group.

This study investigated whether more patients with contact allergies were detected by patch testing with mercapto mix with a higher concentration of 2-mercaptobenzothiazolinone (MBT) than the commonly used mercapto mix. A total of 3,143 dermatitis patients in 5 Swedish dermatology departments were patch- tested with 3 mercapto test preparations: MBT 2.0% petrolatum (pet.); mercapto mix 2.0% pet.; and mercapto mix 3.5% pet. Positive reactions to these mercapto mixes varied between 0-0.50%, 0-0.93%, and 0-1.4%, respectively, in the 5 centres. Numerically, mercapto mix 3.5% pet. detected all positive patients and more patch-test positive patients than did the 2 other substances, but the difference was not statistically significant. The authors recommend replacing mercapto mix 2.0% pet. in the Swedish baseline series with mercapto mix 3.5% pet., since the latter also detected those patients who would have been missed because MBT 2.0% is not included in the Swedish baseline series.

Examining the Role of Attention and Sensory Stimulation in the Attentional Repulsion Effect.

It has been suggested that visual attention warps space, such that stimuli appearing near its locus are perceived as farther away than they actually are. This is known as the attentional repulsion effect (ARE). Recent data challenge the role of attention as the sole factor responsible for the ARE, suggesting instead that the ARE is, at least in part, a product of low level sensory interactions between a peripheral orienting cue and the Vernier target stimulus used to measure the effect. Here, we directly test whether attentional orienting, without a cue in peripheral vision to guide attention, is sufficient for generating an ARE. In Experiment 1, attention was guided to the visual periphery by a central symbolic cue that reliably indicated the locations of to-be-identified targets in peripheral vision. On a subset of trials, we probed for an ARE with Vernier targets. Reaction time (RT) data revealed that the cue guided attention but there was no trace of an ARE. In Experiment 2, we ensured that the Vernier targets were sensitive to the ARE by using the standard spatially uninformative peripheral cue to guide attention instead of the central symbolic cue. RT data again revealed that the cue guided attention, while the Vernier targets revealed an ARE. Collectively, these data suggest that attentional orienting without peripheral sensory stimulation is not sufficient for generating an ARE.

In vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii.

OBJECTIVES: Widespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chemical structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clinical isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants. METHODS: A thorough antibacterial assessment of apramycin with 1232 clinical isolates from Europe, Asia, Africa and South America was performed by standard CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity. RESULTS: MIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic analysis revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clinical isolates resistant to standard-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin. CONCLUSIONS: Its superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-negative infections that are resistant to treatment with other aminoglycoside antibiotics.

Substance abusers' motives for using anabolic androgenic steroids.

BACKGROUND: The use of anabolic androgenic steroids (AAS) has been associated with the use of illegal drugs. Earlier observations suggested that users of illegal drugs may use AAS for reasons other than increasing muscle strength or size. The aim of the present study was to investigate the motives for AAS use among outpatients at a substance abuse center in Stockholm, Sweden. METHODS: All male patients under the age of 50 were asked whether they had used AAS during a 2-month period. An AAS survey was administered to those who reported AAS experiences in the admittance interview. RESULTS: Twenty of the 175 respondents (11%) reported using AAS. The most frequently reported motives were related to anabolic effects (i.e., for a good-looking body, to become stronger, or to perform better in sports). However, some users reported other motives; for example, to conceal concomitant drug use, to alleviate insecurity or low self-esteem, to become brave, or in preparation of committing a crime. Furthermore, many respondents reported side effects that were associated with AAS; most notably, irritability and depression/suicidal ideation. CONCLUSION: Some users of illicit drugs also use AAS for reasons other than the anabolic properties of these compounds. Therefore, considering that AAS may cause or contribute to diverse morbidity, it is important to ask users of illicit drugs about AAS use, even when obvious external signs of AAS use are lacking.

The significance of anabolic androgenic steroids in a Swedish prison population.

Use of anabolic androgenic steroids (AAS) has been associated with adverse psychiatric effect, violent behavior, and criminality. The aim of this study was to further investigate the motives for and consequences of AAS use, with focus on violent and antisocial behavior. Fifty-nine prisoners were interviewed on their use of AAS, and their history was mapped with Addiction Severity Index interviews. Of these prisoners, 56% admitted previous use of AAS, of whom 24% declared to have committed violent crimes in connection with use of AAS. However, the only significant difference between users and nonusers with regard to criminal history when measured with the Addiction Severity Index was that the AAS users more often stated that they had been prosecuted for crimes labeled as "other crimes," which did not include violent crimes. The reported side effects of AAS corresponded well to those previously reported. These results indicate that use of AAS is common among Swedish prisoners and that the motives and consequences of such use are similar to what has been observed in other AAS-using populations. Furthermore, this study supports earlier notions that misuse of AAS might cause violent behavior, but only in certain individuals and mainly in combination with other substances.

Violent crime and substance abuse: a medico-legal comparison between deceased users of anabolic androgenic steroids and abusers of illicit drugs.

Several case reports and survey studies have indicated that abuse of anabolic androgenic steroids (AAS) often leads to increased aggressiveness and feelings of hostility that may occasionally trigger violent behaviour. Other observations indicate that many users of AAS also abuse alcohol and/or various illegal substances. Since substance abuse is a well-known risk factor for violent behaviour, it could be that violence committed by AAS users might, at least in many cases, actually be caused by abuse of other drugs. In order to examine this possibility further here, the criminal histories (in terms of incidences of convictions) of deceased users of AAS with (AASpos-subst.pos) and without (AASpos-subst.neg) signs of abuse of other illegal substances were compared to the corresponding histories of deceased users of illicit substances testing negatively for AAS (subst.pos-AASneg) at the time of autopsy. The risk of being convicted for a crime against property was significantly higher in the subst.pos-AASneg group than in either the AASpos-subst.neg or AASpos-subst.pos groups (RR=0.048 versus 0.408). At the same time, the risk of being convicted for a crime of violence was at least as high for the two AAS-positive groups as for the AAS-negative group. Furthermore, when compared with the first 3 years after the first criminal conviction, a pronounced increase in the proportion of incidence of violent crimes and a marked reduction in the proportion of incidence of crime against property was observed during the 3-year period immediately preceding death only among the AASpos-subst.neg subjects. In conclusion, the incidence of violent crime among users of AAS without signs of other drug abuse was comparable to the corresponding incidences for drug addicts without AAS use. This observation suggests that the violent criminality observed among AAS users is not confounded in any systematic fashion by abuse of other drugs. The findings also indicate that use of AAS in certain predisposed individuals might cause a high rate of violent crimes, especially if the use of AAS is combined with the use of other illegal substances.

A water activity control system for enzymatic reactions in organic media.

A water activity control system for enzymatic synthesis in organic media, for litre-scale reactors has been constructed. Water activity, a(w), is a key factor when using enzymes in non-conventional media and the optimum value varies for different enzymes. The control system consists of a water activity sensor in the headspace of a jacketed glass reactor (equipped with narrow steel tubes to introduce air), gas-washing bottles containing blue silica gel (a(w)=0) and water (a(w)=1), a PC to monitor water activity and a programmable logic controller (PLC) to control the water activity. The system was evaluated by adjusting water activity in the medium, with a deviation from the set point of less than +/-0.05. Synthesis of cetyl palmitate, under controlled water activity and catalysed by two different lipase preparations, namely, Novozym 435 (immobilised Candida antarctica lipase B) and immobilised Candida rugosa lipase, were also performed. Novozym 435 catalyses reactions very well at extremely low water activity while C. rugosa lipase shows low activity for a(w)<0.5.

Toxicological findings and manner of death in autopsied users of anabolic androgenic steroids.

With the aim to characterize patterns in toxicological profile and manner of death in deceased users of anabolic androgenic steroids (AAS), a retrospective autopsy protocol study of 52 deceased users of AAS was undertaken. The AAS users were compared to 68 deceased users of amphetamine and/or heroin who were consecutively tested and found to be negative for AAS. Use of AAS was in the majority of cases (79%) associated with concomitant use of psychotropic substances. AAS-related deaths differed in several respects from deaths among users of heroin or amphetamine, most strikingly with regard to: (a) the median age at death, which was significantly lower for AAS users (24.5 years) than for users of heroin and/or amphetamine (34 and 40 years, respectively); (b) the manner of death, with AAS users dying significantly more often from homicide or suicide than users of other drugs; and (c) the body mass index (BMI), with AAS users exhibiting significantly higher BMI than users of other drugs. These results support the earlier reported association between use of AAS and use of other psychoactive substances. In addition, the data suggest that AAS users are more likely to become involved in incidents leading to violent death and have a higher risk of dying at a younger age than users of other drugs.

Morbidity and mortality in patients testing positively for the presence of anabolic androgenic steroids in connection with receiving medical care. A controlled retrospective cohort study.

Observations by health-care professionals suggest that the use of anabolic androgenic steroids (AAS) may be associated with lethal complications, but this has not yet been confirmed by controlled epidemiological studies. Here, we investigated the diagnoses (in the Swedish patient care records) and mortality rate among patients who tested positively for the presence of AAS (n = 248) in connection with receiving medical care. Patients who had tested negatively (n = 1215) were used for comparison. The proportions of patients who had received institutionalized care for substance abuse, psychiatric disorder or central thoracic pain were significantly higher in the AAS-positive subjects (RR = 2.2, 95% CI = 1.2-4.2; RR = 2.1, 95% CI = 1.4-3.2 and RR = 3.5, 95% CI = 1.1-10.9, respectively). Furthermore, unspecified convulsions were highly over-represented in the AAS-positive group (RR = 53.9, 95% CI = 7.0-415.7) and one of these patients died during a seizure. The standardized mortality ratios (SMR) in the AAS-positive patients and -negative patients were 20.43 (95% CI = 10.56-35.70) and 6.02 (95% CI = 3.77-9.12), respectively. The relatively higher SMR in the AAS-positive patients was observed irrespective of what type clinic had referred the patients for AAS testing. In conclusion, use of AAS appears to be an indicator of increased risk for premature death in several categories of patients. However, the nature of the association between AAS and premature death remains unclear and additional research on this question is urgently required.

Pharmacoepidemiology of anabolic androgenic steroids: a review.

Non-prescribed use of anabolic androgenic steroids (AAS) has been associated with a number of physical and psychiatric/behavioural complications, some of which are potentially lethal. Here, we review both observational and experimental studies on human subjects concerned with such side-effects. The only physical complication of AAS use that receives definitive support from such investigations is unfavourable changes in blood lipid profiles. Support for various psychiatric complications has also been provided by a number of cross-sectional studies, most involving comparisons between weight-training individuals who use or do not use AAS. Certain of these complications, in particular hypomania and increased aggressiveness, have been confirmed in some, but not all, randomized controlled studies. Epidemiological attempts to determine whether AAS use triggers violent behaviour have failed, primarily because of high rates of non-participation. Studies regarding the prevalence of AAS use in different populations typically report life-time prevalences of 1-5% among adolescents. However, the life-time prevalence (i.e. use on at least one occasion) is of doubtful relevance in attempting to estimate the number of individuals at risk for side-effects, as most of these complications appear to develop during prolonged use of AAS. Furthermore, it is reasonable to assume that the symptoms and signs of AAS use are often overlooked by healthcare professionals, so that the number of cases of possible AAS-related complications is virtually unknown. These limitations, together with an apparently low prevalence of prolonged AAS use among the general population, indicate that future epidemiological research in this area should focus on retrospective case-control studies and, perhaps, also on prospective cohort studies of populations selected for a high prevalence of AAS use, rather than attempting to perform large-scale population-based studies.

Nutritional status of deceased illicit drug addicts in Stockholm, Sweden--a longitudinal medicolegal study.

Autopsy investigations, toxicological analyses, and calculation of body mass index were performed in 1180 deceased illicit drug addicts (IDAs) in Stockholm. Sweden during 1988-2000, i.e., during a period of time when the general population in numerous countries showed a dramatic increase in the prevalence of overweight. Nutritional deficit in IDAs has been pointed out as a threat to their health as well as to their quality of life. The prevalence of overweight in deceased IDAs increased from 27.4% in 1988 to 45.5% in 2000. The prevalence of overweight among all heroin users, heroin injectors, methadone, cocaine, and amphetamine users was 36.0, 38.4, 43.1, 45.0 and 50.9%, respectively, the lowest prevalence being among users of cannabis alone and HIV-positive IDAs (22.0 and 16.1%, respectively). In conclusion, Stockholm's IDAs are affected by the past decade's dramatically increased prevalence of overweight, at least to the same degree as the general population. The increased body weight seems not to influence the danger of dying upon heroin administration.