Psychotropic and other medicine use at time of death by suicide: a population-level analysis of linked dispensing and forensic toxicology data.

OBJECTIVES: To determine the numbers and types of medicines dispensed around the time of death to people who die by suicide; to compare the medicines recently dispensed and those recorded in post mortem toxicology reports. DESIGN, SETTING, PARTICIPANTS: Analysis of linked National Coronial Information System (NCIS) and Pharmaceutical Benefits Scheme (PBS) data from the Australian Suicide Prevention using Health Linked Data (ASHLi) study, a population-based case series study of closed coronial cases for deaths of people in Australia aged ten years or more during 1 July 2013 - 10 October 2019 deemed by coroners to be the result of intentional self-harm. MAIN OUTCOME MEASURES: Proportions of people to whom medicines were dispensed around the time of death, by medicine group, class, and specific medicine; comparison of medicines recently dispensed and those detected by post mortem toxicology. RESULTS: Toxicology reports were available for 13 541 of 14 206 people who died by suicide (95.3%; 10 246 men, 75.7%); poisoning with medicines contributed to 1163 deaths (8.6%). At least one PBS-subsidised medicine had been dispensed around the time of death to 7998 people (59.1%). For three medicine classes, the proportions of people in whom the medicines were detected post mortem and their death was deemed medicine-related were larger for those without records of recent dispensing than for people for whom they had been dispensed around the time of death: antidepressants (17.7% v 12.0%), anxiolytics (16.3% v 14.8%), and sedatives/hypnotics (24.3% v 16.5%). At least one recently dispensed medicine not detected post mortem was identified for 6208 people (45.8%). CONCLUSIONS: A considerable proportion of people who died by suicide were not taking psychotropic medicines recently dispensed to them, suggesting non-adherence to pharmacotherapy, and a smaller than expected proportion were using antidepressants. Conversely, medicines that had not recently been dispensed were detected post mortem in many people for whom poisoning with medicines was a contributing factor, suggesting medicine stockpiling.

Disparate properties of Burkholderia multivorans and Pseudomonas aeruginosa regarding outer membrane chemical permeabilization to the hydrophobic substances novobiocin and triclosan.

Burkholderia multivorans causes opportunistic pulmonary infections and is intrinsically resistant to many antibacterial compounds including the hydrophobic biocide triclosan. Chemical permeabilization of the Pseudomonas aeruginosa outer membrane affects sensitization to hydrophobic substances. The purpose of the present study was to determine if B. multivorans is similarly susceptive suggesting that outer membrane impermeability properties underlie triclosan resistance. Antibiograms and conventional macrobroth dilution bioassays were employed to establish baseline susceptibility levels to hydrophobic antibacterial compounds. Outer membrane permeabilizers compound 48/80, polymyxin B, polymyxin B-nonapeptide, and ethylenediaminetetraacetic acid were used in attempts to sensitize disparate B. multivorans isolates to the hydrophobic agents novobiocin and triclosan, and to potentiate partitioning of the hydrophobic fluorescent probe 1-N-phenylnapthylamine (NPN). The lipophilic agent resistance profiles for all B. multivorans strains were essentially the same as that of P. aeruginosa except that they were resistant to polymyxin B. Moreover, they resisted sensitization to hydrophobic compounds and remained inaccessible to NPN when treated with outer membrane permeabilizers. These data support the notion that while both phylogenetically-related organisms exhibit general intrinsic resistance properties to hydrophobic substances, the outer membrane of B. multivorans either resists permeabilization by chemical modification or sensitization is mitigated by a supplemental mechanism not present in P. aeruginosa.

Outcomes of traumatic brain injury patients in an adult intensive care unit of a South African regional hospital, without on-site neurosurgical service: A retrospective quantitative study on the neurological improvement at discharge.

Background: Traumatic brain injury (TBI) is a major cause of mortality and disability. The South African (SA) province of Kwazulu-Natal faces challenges in providing appropriate care for TBI patients owing to limited resources and delayed access to healthcare services. We aimed to assess the outcomes of patients with TBI who were treated at a hospital without a neurosurgical unit (NSU). Objectives: The primary objective was to compare the Glasgow Coma Scale (GCS) scores at admission and discharge from the intensive care unit (ICU) for patients with TBI receiving neuroprotection. Secondary objectives included analysing demographics and identifying predictive factors associated with GCS score improvement. Methods: This retrospective study analysed data from the already established ICU Integrated Critical Care Electronic Database. Data on patient demographics, mechanisms of injury and GCS scores were collected and analysed. Results: The analysis included 95 TBI patients, most of whom were young males. Interpersonal violence and transport-related trauma were the main causes of injury among patients. Approximately 63% of patients had a GCS score improvement >1 upon discharge from the ICU. Patients who received >12 hours of neuroprotection in the emergency department had significantly lower rates of improvement. Conclusion: Sixty-three percent of TBI patients had improved GCS scores by >1 on discharge from the ICU, but outcomes varied. Delayed ICU admission from the emergency department of >12 hours might contribute to worse outcomes. Timely neuroprotection, improved access to neurosurgical care and better understanding of the factors affecting outcomes are needed. Contribution of the study: This study explores the outcomes of patients with TBI admitted to a non-neurosurgical ICU. Factors contributing to a worse outcome are identified, highlighting the need for adequate numbers of ICU beds and prompt admission from the emergency department.

Examining the population level and individual level longitudinal stability of psychosocial measures in the US Army's Global Assessment Tool (GAT).

As a component of the US Army's Comprehensive Soldier and Family Fitness program (CSF2), the Global Assessment Tool (GAT) represents a multidimensional constellation of measures designed to assess characteristics related to resilience. Using a foundation of validated measures from prior research, the GAT has been the vehicle for self-assessment to provide Soldiers, their families, and Army Civilians snapshots of their psychosocial wellness. Despite the long history of the measurement instrument (first implemented in 2009) and widespread use (mandatory for all active-duty Soldiers annually), the longitudinal capabilities of the GAT has received little attention. Here, we examine the longitudinal stability of the GAT across an approximate five-year time frame and multiple statistical approaches that demonstrate measurement stability at both the aggregate population level (people on average) and the individual level. We find evidence that the majority of the measures within the GAT are relatively stable over time both at the population level and individual level. This evidence contributes to knowledge of how best to improve the GAT for future use with the pay-off for the Army being a self-assessment tool that is more effective and efficient.

The clinical utility of a memory specialization index in epilepsy surgery patients with unilateral hippocampal sclerosis.

OBJECTIVE: Although group studies provide some support for the material-specific model of memory function, there are considerable individual variations in memory function in people with temporal lobe epilepsy, even in those with the same underlying pathology. In this proof-of-concept study, we examined the sensitivity and specificity of a single measure of an individual's relative strength for the encoding of verbal or visual learning. METHODS: Six hundred ninety-two patients with left hemisphere language dominance and unilateral hippocampal sclerosis completed verbal and visual encoding tasks with similar test structures as part of their presurgical evaluation. Three hundred one patients had right hippocampal sclerosis (RHS), and 391 patients had left hippocampal sclerosis (LHS). A memory specialization index (MSI) was calculated by subtracting the Visual Learning z-score from the Verbal Learning z-score. A positive value on the MSI indicates a relative strength in verbal learning. A negative score indicates a relative strength in visual learning. RESULTS: Employing cut-offs of ±1, the MSI had a positive predictive value of 71% (confidence interval [CI] 95% 0.64-0.77) for LHS and 64% (CI 95% 0.55-0.74) for RHS and was superior to the standalone z-scores from the verbal and visual tests in each respect. In the LHS group, the MSI was significantly correlated with age and duration of epilepsy. Older patients who had a longer duration of epilepsy were more likely to demonstrate a similar level of impairment in both verbal and visual learning, with a decreasing discrepancy between the scores on the two tasks over time. SIGNIFICANCE: Our MSI provides a measure with high specificity for RHS. The pattern of strengths and weaknesses in visual and verbal encoding may evolve with age and duration of epilepsy, and clinicians should be aware of these factors when interpreting the lateralizing significance of test scores, particularly in a presurgical setting.

Psychological Inflexibility Predicts Suicidality Over Time in College Students.

OBJECTIVE: It is essential to identify modifiable risk factors that can be targeted to reduce suicidal ideation (SI) and behavior in college students. Psychological inflexibility, a pattern of responding to internal experiences in a literal and rigid way, and attempting to control those experiences even when it interferes with valued living, could theoretically lead to SI or increase its intensity. METHOD: Psychological inflexibility and its component processes were tested as a predictor of SI in a longitudinal survey of college students (n = 603, age M = 20.62, 68.9% female, and 94.0% White) in a series of cross-sectional and longitudinal hierarchical regression models, controlling for relevant predictors such as distress and baseline SI. Interactions were also tested between psychological inflexibility and distress, cognitive defusion, values obstruction, and values progress in predicting SI. RESULTS: Psychological inflexibility predicted SI cross-sectionally and longitudinally, controlling for distress and baseline SI. Psychological inflexibility interacted with distress, cognitive fusion, and values progress such that distress, cognitive fusion, and values progress had the strongest association with suicidal ideation among those who were high in psychological inflexibility. CONCLUSIONS: Psychological inflexibility may be a useful mechanism to target for suicide prevention in college students.

Relational factors critical in the link between childhood emotional abuse and suicidal ideation.

Understanding the pathways leading to suicidal behavior is critical for the development and implementation of effective assessment efforts and suicide prevention programs in public health care systems. Childhood trauma, such as emotional abuse, is one robust risk factor, but only recently have efforts been made to determine mediators of the link between childhood emotional abuse and suicidal ideation. Given that adult survivors of childhood emotional abuse often have attachment difficulties and problems securing positive social support, these interpersonal factors may serve such a mediating role. Using bootstrapping techniques, this investigation tested attachment security and social-support-seeking behaviors as serial mediators of the association between childhood emotional abuse and suicidal ideation in a sample of 150 low-income African American female childhood emotional abuse survivors receiving services in a public health system. Support seeking from family members and friends were tested separately. Results revealed the presence of serial mediation, as predicted. Specifically, increased childhood emotional abuse was associated with decreased attachment security, which, in turn, was related to decreased social support seeking from family members and from friends. These 3 factors combined in sequence subsequently were associated with increased suicidal ideation. Results illuminate the importance of attending to attachment security and social-support-seeking behaviors when designing and implementing assessment and suicide prevention programs for African American women who are survivors of childhood emotional abuse seeking services in public health care systems. Suggestions for universal, selective, and targeted prevention efforts for this population are discussed. (PsycINFO Database Record

Benzodiazepine Use in Older Adults in the United States, Ontario, and Australia from 2010 to 2016.

OBJECTIVES: To detail annual trends in benzodiazepine incidence and prevalence in older adults between 2010 and 2016 in three countries. DESIGN: Observational multicountry cohort study with harmonized study protocol. SETTING: The United States (veteran population); Ontario, Canada; and Australia. PARTICIPANTS: All people aged 65 and older (8,270,000 people). MEASUREMENTS: Annual incidence and prevalence of benzodiazepine use stratified according to age group (65-74, 75-84, ≥85) and sex. We performed multiple regression analyses to assess whether rates of incident and prevalent use changed significantly over time. RESULTS: Over the study period, we observed a significant decrease in incident benzodiazepine use in the United States (2.6% to 1.7%) and Ontario (6.0% to 4.4%) but not Australia (7.0% to 6.7%). We found significant declines in prevalent use in all countries (United States: 9.2% to 7.3%; Ontario: 18.2% to 13.4%; Australia: 20.2% to 16.8%). Although incidence and prevalence increased with age in Ontario and Australia, they decreased with age in the United States. Incidence and prevalence were higher in women in all countries. CONCLUSION: Consistent with other international studies, there have been small but significant reductions in the incidence and prevalence of benzodiazepine use in older adults in all three countries, with the exception of incidence in Australia, although use remains inappropriately high-particularly in those aged 85 and older-which warrants further attention from clinicians and policy-makers.

Cell surface physiology and outer cell envelope impermeability for hydrophobic substances in Burkholderia multivorans.

PURPOSE: The purpose of the present study was to obtain a better understanding of the relationship between cell surface physiology and outer cellular envelope permeability for hydrophobic substances in mucoid and non-mucoid B. multivorans strains, as well as in two capsule-deficient derivatives of a mucoid parental strain. METHODOLOGY: Cell surface hydrophobicity properties were determined using the hydrocarbon adherence method, while outer cell envelope accessibility and permeability for non-polar compounds were measured using hydrophobic antimicrobial agent susceptibility and fluorescent probe assays. Extracellular polysaccharide (EPS) production was assessed by cultivating strains of disparate origin on yeast extract agar (YEA) containing different sugars, while the resultant colonial and cellular morphological parameters were assessed macro- and microscopically, respectively.Results/Key findings. The cell surfaces of all the strains were hydrophilic, impermeable to mechanistically disparate hydrophobic antibacterial agents and inaccessible to the hydrophobic probe N-phenyl-1-napthylamine, regardless of EPS phenotype. Supplementation of basal YEA with eight different sugars enhanced macroscopic EPS expression for all but one non-mucoid strain, with mannose potentiating the greatest effect. Despite acquisition of the mucoid phenotype, non-mucoid strains remained non-capsulated and capsulation of a hyper-mucoid strain and its two non-mucoid derivative strains was unaffected, as judged by microscopic observation. CONCLUSION: These data support the conclusion that EPS expression and the consistent mucoid phenotype are not necessarily associated with the ability of the outer cell surface to associate with non-polar substances or cellular capsulation.

Adapting the nominal group technique for priority setting of evidence-practice gaps in implementation science.

BACKGROUND: There are a variety of methods for priority setting in health research but few studies have addressed how to prioritise the gaps that exist between research evidence and clinical practice. This study aimed to build a suite of robust, evidence based techniques and tools for use in implementation science projects. We applied the priority setting methodology in lung cancer care as an example. METHODS: We reviewed existing techniques and tools for priority setting in health research and the criteria used to prioritise items. An expert interdisciplinary consensus group comprised of health service, cancer and nursing researchers iteratively reviewed and adapted the techniques and tools. We tested these on evidence-practice gaps identified for lung cancer. The tools were pilot tested and finalised. A brief process evaluation was conducted. RESULTS: We based our priority setting on the Nominal Group Technique (NGT). The adapted tools included a matrix for individuals to privately rate priority gaps; the same matrix was used for group discussion and reaching consensus. An investment exercise was used to validate allocation of priorities across the gaps. We describe the NGT process, criteria and tool adaptations and process evaluation results. CONCLUSIONS: The modified NGT process, criteria and tools contribute to building a suite of methods that can be applied in prioritising evidence-practice gaps. These methods could be adapted for other health settings within the broader context of implementation science projects.

Cell envelope phospholipid composition of Burkholderia multivorans.

Burkholderia multivorans causes opportunistic pulmonary infections in cystic fibrosis and immunocompromised patients. The purpose of the present study was to determine the nature of the phospholipids and their fatty acid constituents comprising the cell envelope membranes of strains isolated from three disparate sources. A conventional method for obtaining the readily extractable lipids fraction from bacteria was employed to obtain membrane lipids for thin-layer chromatographic and gas chromatography-mass spectrophotometric analyses. Major fatty acid components of the B. multivorans readily extractable lipid fractions included C(16:0) (palmitic acid), C(16:1) (palmitoleic acid), and C(18:1) (oleic acid), while C(14:0) (myristic acid), ΔC(17:0) (methylene hexadecanoic acid), C(18:0) (stearic acid), and ΔC(19:0) (methylene octadecanoic acid) were present in lesser amounts. Fatty acid composition differed quantitatively among strains with regard to C(16:0), C(16:1), ΔC(17:0), C(18:1), and ΔC(19:0) with the unsaturated:saturated fatty acid ratios being significantly less in a cystic fibrosis type strain than either environmental or chronic granulomatous disease strains. Phospholipids identified in all B. multivorans strains included lyso-phosphatidylethanolamine, phosphatidylglycerol, phosphatidylethanolamine, and diphosphatidylglycerol in similar ratios. These data support the conclusion that the cell envelope phospholipid profiles of disparate B. multivorans strains are similar, while their respective fatty acyl substituent profiles differ quantitatively under identical cultivation conditions.

Predicting and preventing psychopathology following temporal lobe epilepsy surgery.

Less than 3% of temporal lobe epilepsy (TLE) surgical outcome studies have investigated the psychiatric sequelae and morbidity associated with surgery. This is disproportionate to the extent of the problem. Variable prevalence rates have been reported for post-surgical depression, anxiety, and interictal psychosis. Until recently, very few studies distinguished de novo postoperative presentations from pre-existing conditions, making it difficult to accurately assess the impact of TLE surgery on psychiatric morbidity. Predictors of de novo postoperative presentations have proved elusive. This current review summarizes the findings from a systematic literature review of the psychiatric morbidity associated with TLE surgery including newly published follow-up data from our own series of 280 surgical patients. A framework for future research, possible pathophysiological mechanisms, and translational models are also discussed.

rac-cis,cis-Dicarbonyl-dichlorido{1-[2-(diphenyl-phosphan-yl)benz-yl]-3-mesityl-imidazol-2-yl-idene}ruthenium(II) dichloro-methane monosolvate.

The Ru(II) atom in the title compound, [RuCl(2)(C(31)H(29)N(2)P)(CO)(2)]·CH(2)Cl(2), exhibits a distorted octahedral coordination environment. The bond angles of the cis substituents at the Ru(II) atom range from 82.72 (9) to 97.20 (3)°. This mol-ecule is of inter-est in the field of catalytic transfer hydrogenation.

Changes in anticonvulsant prescribing for Australian children: implications for Quality Use of Medicines.

AIMS: The evidence-base guiding choices between newer versus established anticonvulsants in children is limited. Inappropriate use exposes children to potentially ineffective and/or harmful medicines. Our objective is to describe recent anticonvulsant prescribing patterns in the Australian paediatric population, evaluating overall trends and extent of off-label prescribing of newer agents. METHODS: Aggregated national data on 15 anticonvulsants with Pharmaceutical Benefits Scheme subsidy dispensed by community pharmacies for children aged <16 years were obtained from the Drug Utilisation Subcommittee, which is part of the Australian Government Department of Health and Ageing. We analysed trends for the five most prescribed anticonvulsants dispensed between 2002 and 2009 and off-label prescribing for agents where approved Australian product information stipulates a minimum age. RESULTS: Valproate was the most frequently prescribed anticonvulsant with no marked change in prescription numbers per 1000 children aged 0-16 years (11.3-11.8 prescriptions/year). Lamotrigine was the most frequently prescribed newer anticonvulsant (7.9-9.3 prescriptions/year). Carbamazepine prescriptions decreased by 38% and topiramate prescriptions increased by 19% over the 7-year study period; 3.6% of topiramate prescriptions were off-label (by age) for children aged <2 years. Since Pharmaceutical Benefits Scheme listing in 2003, levetiracetam prescriptions increased steeply to 2.5 prescriptions/year per 1000 children in 2009; 4.2% were off-label for children aged <4 years. CONCLUSIONS: The substantial reduction in carbamazepine use and corresponding increase in newer anticonvulsant prescribing, including off-label uses, raises questions about potentially suboptimal Quality Use of Medicines. Such major changes in prescribing may have important clinical and economic consequences. Further study to better understand paediatric prescribing choices and outcomes is needed.

Testicular lumicrine factors regulate ERK, STAT, and NFKB pathways in the initial segment of the rat epididymis to prevent apoptosis.

The initial segment of the epididymis is vital for male fertility; therefore, it is important to understand the mechanisms that regulate this important region. Deprival of testicular luminal fluid factors/lumicrine factors from the epididymis results in a wave of apoptosis in the initial segment. In this study, a combination of protein array and microarray analyses was used to examine the early changes in downstream signal transduction pathways following loss of lumicrine factors. We discovered the following cascade of events leading to the loss of protection and eventual apoptosis: in the first 6 h after loss of lumicrine factors, down-regulation of the ERK pathway components was observed at the mRNA expression and protein activity levels. Microarray analysis revealed that mRNA levels of several key components of the ERK pathway, Dusp6, Dusp5, and Etv5, decreased sharply, while the analysis from the protein array revealed a decline in the activities of MAP2K1/2 and MAPK1. Immunostaining of phospho-MAPK3/1 indicated that down-regulation of the ERK pathway was specific to the epithelial cells of the initial segment. Subsequently, after 12 h of loss of lumicrine factors, levels of mRNA expression of STAT and NFKB pathway components increased, mRNA levels of several genes encoding cell cycle inhibitors increased, and levels of protein expression of several proapoptotic phosphatases increased. Finally, after 18 h of loss of protection from lumicrine factors, apoptosis was observed. In conclusion, testicular lumicrine factors protect the cells of the initial segment by activating the ERK pathway, repressing STAT and NFKB pathways, and thereby preventing apoptosis.

S100B protein is released from rat neonatal neurons, astrocytes, and microglia by in vitro trauma and anti-S100 increases trauma-induced delayed neuronal injury and negates the protective effect of exogenous S100B on neurons.

S100B protein is found in brain, has been used as a marker for brain injury and is neurotrophic. Using a well-characterized in vitro model of brain cell trauma, we have previously shown that strain injury causes S100B release from neonatal rat neuronal plus glial cultures and that exogenous S100B reduces delayed post-traumatic neuronal damage even when given at 6 or 24 h post-trauma. The purpose of the current studies was to measure post-traumatic S100B release by specific brain cell types and to examine the effect of an antibody to S100 on post-traumatic delayed (48 h) neuronal injury and the protective effect of exogenous S100B. Neonatal rat cortical cells grown on a deformable elastic membrane were subjected to a strain (stretch) injury produced by a 50 ms displacement of the membrane. S100B was measured with an ELISA kit. Trauma released S100B from pure cultures of astrocytes, microglia, and neurons. Anti-S100 reduced released S100B to below detectable levels, increased delayed neuronal injury in traumatized cells and negated the protective effect of exogenous S100B on injured cells. Heat denatured anti-S100 did not exacerbate injury. These studies provide further evidence for a protective role for S100B following neuronal trauma.

Putative regulation of expression of members of the Ets variant 4 transcription factor family and their downstream targets in the rat epididymis.

Several genes expressed in the initial segment of the epididymis depend on factors from the testis that reach the epididymis via the luminal system. These include gamma-glutamyl transpeptidase mRNA IV (Ggt_pr4), steroid 5 alpha reductase (Srd5a1), glutathione peroxidase 5 (Gpx5), and cystatin-related epididymal spermatogenic (Cst8) genes. Promoter analyses indicated that these genes contain several ETS DNA-binding sites. Members of the polyomavirus enhancer activator 3 (ETV4) family bind to ETS sites on the promoter of target genes to regulate transcription. In this study, the role of ETV4 family members (ETV4, ETV5, ETV1) in the transcription of initial segment specific genes was evaluated. All three ETV4 family mRNAs are expressed in the principal cells of the initial segment and depend upon the presence of testicular luminal fluid factors. ETV4 protein was localized to principal cell nuclei and displayed the highest expression in the most proximal region of the initial segment. In addition, ETV4 protein levels were diminished after loss of testicular luminal fluid factors. A dominant-negative construct of ETV5 was in vivo electroporated into the initial segment to determine if ETV4 family members can regulate the transcription of testicular luminal fluid factor-regulated genes. Quantitative PCR indicated that 1 day postelectroporation, all three ETV4 family member mRNAs were significantly decreased. In addition, Ggt_pr4, Srd5a1, and Gpx5 mRNA levels were also significantly decreased. The data suggest that ETV4 family members regulate their own expression, and that they regulate transcription of a subset of genes that are dependent upon testicular luminal fluid factors.

Identifying putative contraceptive targets by dissecting signal transduction networks in the epididymis using an in vivo electroporation (electrotransfer) approach.

Our studies have focused on understanding how the initial segment is regulated, in particular, by testicular luminal fluid factor(s). Our working hypothesis is that testicular luminal fluid growth factors, e.g. FGFs, regulate initial segment function via activation of signal transduction pathways and PEA3 family transcription factors. These, in turn, regulate downstream genes that are important for providing an appropriate fluid milieu for the protection and survival of sperm and the initial segment. To test this hypothesis and to look for potential contraceptive targets, we used an in vivo electroporation technique to introduce dominant-negative plasmids of FGF Receptor 1 and ERM into the initial segment of the rat epididymis. The levels of several putative downstream genes were estimated using quantitative-PCR (q-PCR). Data suggests that initial segment genes are regulated by 5alpha-reductase-dependent and -independent pathways and that multiple growth factor pathways are activated to coordinate the expression of these genes.