Web-Based Interventions to Help Australian Adults Address Depression, Anxiety, Suicidal Ideation, and General Mental Well-being: Scoping Review.

BACKGROUND: A large number of Australians experience mental health challenges at some point in their lives. However, in many parts of Australia, the wait times to see general practitioners and mental health professionals can be lengthy. With increasing internet use across Australia, web-based interventions may help increase access to timely mental health care. As a result, this is an area of increasing research interest, and the number of publicly available web-based interventions is growing. However, it can be confusing for clinicians and consumers to know the resources that are evidence-based and best meet their needs. OBJECTIVE: This study aims to scope out the range of web-based mental health interventions that address depression, anxiety, suicidal ideation, or general mental well-being and are freely available to Australian adults, along with their impact, acceptability, therapeutic approach, and key features. METHODS: The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for scoping reviews (PRISMA-ScR [PRISMA extension for Scoping Reviews]) guided the review process. Keywords for the search were depression, anxiety, suicide, and well-being. The search was conducted using Google as well as the key intervention databases Beacon, Head to Health, and e-Mental Health in Practice. Interventions were deemed eligible if they targeted depression, anxiety, suicidal ideation, or general mental well-being (eg, resilience) in adults; and were web-based, written in English, interactive, free, and publicly available. They also had to be guided by an evidence-based therapeutic approach. RESULTS: Overall, 52 eligible programs were identified, of which 9 (17%) addressed depression, 15 (29%) addressed anxiety, 13 (25%) addressed general mental well-being, and 13 (25%) addressed multiple issues. Only 4% (2/52) addressed distress in the form of suicidal ideation. The most common therapeutic approach was cognitive behavioral therapy. Half of the programs guided users through exercises in a set sequence, and most programs enabled users to log in and complete the activities on their own without professional support. Just over half of the programs had been evaluated for their effectiveness in reducing symptoms, and 11% (6/52) were being evaluated at the time of writing. Program evaluation scores ranged from 44% to 100%, with a total average score of 85%. CONCLUSIONS: There are numerous web-based programs for depression, anxiety, suicidal ideation, and general well-being, which are freely and publicly available in Australia. However, identified gaps include a lack of available web-based interventions for culturally and linguistically diverse populations and programs that use newer therapeutic approaches such as acceptance and commitment therapy and dialectical behavior therapy. Despite most programs included in this review being of good quality, clinicians and consumers should pay careful attention when selecting which program to recommend and use, as variations in the levels of acceptability and impact of publicly available programs do exist.

Chemical warfare agent and biological toxin-induced pulmonary toxicity: could stem cells provide potential therapies?

Chemical warfare agents (CWAs) as well as biological toxins present a significant inhalation injury risk to both deployed warfighters and civilian targets of terrorist attacks. Inhalation of many CWAs and biological toxins can induce severe pulmonary toxicity leading to the development of acute lung injury (ALI) as well as acute respiratory distress syndrome (ARDS). The therapeutic options currently used to treat these conditions are very limited and mortality rates remain high. Recent evidence suggests that human stem cells may provide significant therapeutic options for ALI and ARDS in the near future. The threat posed by CWAs and biological toxins for both civilian populations and military personnel is growing, thus understanding the mechanisms of toxicity and potential therapies is critical. This review will outline the pulmonary toxic effects of some of the most common CWAs and biological toxins as well as the potential role of stem cells in treating these types of toxic lung injuries.

Downstream procedures and outcomes after stress testing for chest pain without known coronary artery disease in the United States.

BACKGROUND: Millions of Americans with suspected coronary artery disease undergo noninvasive cardiac stress testing annually. Downstream procedures and subsequent outcomes among symptomatic patients without known coronary disease referred for stress testing are not well characterized in contemporary community practice. METHODS: We examined administrative insurance billing data from a national insurance provider from November 2004 through June 2007. After excluding patients with prior cardiac disease or chest pain evaluation, we identified 80,676 people age 40 to 64 years with outpatient cardiac stress testing within 30 days after an office visit for chest pain. We evaluated rates of invasive coronary angiography, coronary revascularization, and cardiovascular events after stress testing. RESULTS: Within 60 days, only 8.8% of stress test patients underwent cardiac catheterization and only 2.7% underwent revascularization; within 1 year, only 0.5% died and had myocardial infarction or stroke. There were marked geographic variations in 1-year rates of catheterization (3.8%-14.8%) and revascularization (1.2%-3.0%) across 20 hospital referral regions. CONCLUSIONS: In this large national cohort of middle-aged patients without previously coded cardiac diagnosis who were referred for stress testing after outpatient chest pain evaluation, few proceeded to invasive angiography or revascularization, and subsequent cardiovascular events were infrequent.

Neuroprotective effects of imidazenil against chemical warfare nerve agent soman toxicity in guinea pigs.

The chemical warfare nerve agent, soman irreversibly inhibits acetylcholinesterase (AChE) leading to hypercholinergy and seizures which trigger glutamate toxicity and status epilepticus ultimately resulting in neuropathology and neurobehavioral deficits. The standard emergency treatment comprising of anticholinergic, AChE reactivator and anticonvulsant does not completely protect against soman toxicity. We have evaluated imidazenil, a new anticonvulsant imidazo benzodiazepine with high affinity and intrinsic efficacy at α5-, α2-, and α3- but low intrinsic efficacy at α1-containing GABA(A) receptors and is devoid of cardiorespiratory depression, sedative/hypnoitc and amnestic actions and does not elicit tolerance and dependence liabilities unlike diazepam, for protection against soman toxicity. Guinea pigs implanted with bipotential radiotelemetry probes for recording EEG and ECG were administered with 26 µg/kg pyridostigmine bromide 30 min prior to 2× LD(50) soman exposure and 1 min later treated with a combination of 2mg/kg atropine sulfate and 25mg/kg 2-pralidoxime and various doses of imidazenil. Intramuscular administration of imidazenil, dose-dependently protected against 2× LD(50) of soman toxicity up to 1mg/kg. Further increase in the dose of imidazenil to 2.5mg/kg was less effective than 1mg/kg probably due to non-specific actions at sites other than GABA(A) receptors. Compared to vehicle group, 1mg/kg imidazenil treatment showed optimal increase in survival rate, reduction in behavioral manifestations and high power of EEG spectrum as well as neuronal necrosis. These data suggest that imidazenil is an effective anticonvulsant for medical countermeasure against soman-induced toxicity.

Association between physician billing and cardiac stress testing patterns following coronary revascularization.

CONTEXT: The degree to which financial factors may influence use of cardiac stress imaging procedures is unknown. OBJECTIVE: To examine the association of physician billing and nuclear stress and stress echocardiography testing following coronary revascularization. DESIGN, SETTING, AND PATIENTS: Using data from a national health insurance carrier, 17,847 patients were identified between November 1, 2004, and June 30, 2007, who had coronary revascularization and an index cardiac outpatient visit more than 90 days following the procedure. Based on overall billings, physicians were classified as billing for both technical (practice/equipment) and professional (supervision/interpretation) fees, professional fees only, or not billing for either. Logistic regression models were used to evaluate the association between physician billing and use of stress testing, after adjusting for patient and other physician factors. MAIN OUTCOME MEASURES: Incidence of nuclear and echocardiographic stress tests within 30 days of an index cardiac-related outpatient visit. RESULTS: The overall cumulative incidence of nuclear or echocardiography stress testing within 30 days of the index cardiac-related outpatient visit following revascularization was 12.2% (95% CI, 11.8%-12.7%). The cumulative incidence of nuclear stress testing was 12.6% (95% CI, 12.0%-13.2%), 8.8% (95% CI, 7.5%-10.2%), and 5.0% (95% CI, 4.4%-5.7%) among physicians who billed for technical and professional fees, professional fees only, or neither, respectively. For stress echocardiography, the cumulative incidence of testing was 2.8% (95% CI, 2.5%-3.2%), 1.4% (95% CI, 1.0%-1.9%), and 0.4% (95% CI, 0.3%-0.6%) among physicians who billed for the technical and professional fees, professional fees only, or neither, respectively. Adjusted odds ratios (ORs) of nuclear stress testing among patients treated by physicians who billed for technical and professional fees and professional fees only were 2.3 (95% CI, 1.8-2.9) and 1.6 (95% CI, 1.2-2.1), respectively, compared with those patients treated by physicians who did not bill for testing (P < .001). The adjusted OR of stress echocardiography testing among patients treated by physicians billing for both or professional fees only were 12.8 (95% CI, 7.6-21.6) and 7.1 (95% CI, 4.0-12.9), respectively, compared with patients treated by physicians who did not bill for testing (P < .001). CONCLUSION: Nuclear stress testing and stress echocardiography testing following revascularization were more frequent among patients treated by physicians who billed for technical fees, professional fees, or both compared with those treated by physicians who did not bill for these services.

[+]-Huperzine A protects against soman toxicity in guinea pigs.

The chemical warfare nerve agent (CWNA) soman irreversibly inhibits acetylcholinesterase (AChE) causing seizure, neuropathology and neurobehavioral deficits. Pyridostigmine bromide (PB), the currently approved pretreatment for soman, is a reversible AChE inhibitor that does not cross the blood-brain barrier (BBB) to protect against central nervous system damage. [-]-Huperzine A, a natural reversible AChE inhibitor, rapidly passes through the BBB and has numerous neuroprotective properties that are beneficial for protection against soman. However, [-]-Huperzine A is toxic at higher doses due to potent AChE inhibition which limits the utilization of its neuroprotective properties. [+]-Huperzine A, a synthetic stereoisomer of [-]-Huperzine A and a weak inhibitor of AChE, is non-toxic. In this study, we evaluated the efficacy of [+]-Huperzine A for protection against soman toxicity in guinea pigs. Pretreatments with [+]-Huperzine A, i.m., significantly increased the survival rate in a dose-dependent manner against 1.2× LD(50) soman exposures. Behavioral signs of soman toxicity were significantly reduced in 20 and 40 mg/kg [+]-Huperzine A treated animals at 4 and 24 h compared to vehicle and PB controls. Electroencephalogram (EEG) power spectral analysis showed that [+]-Huperzine A significantly reduces soman-induced seizure compared to PB. [+]-Huperzine A (40 mg/kg) preserved higher blood and brain AChE activity compared to PB in soman exposed animals. These data suggest that [+]-Huperzine A protects against soman toxicity stronger than PB and warrant further development as a potent medical countermeasure against CWNA poisoning.

Gene-delivered butyrylcholinesterase is prophylactic against the toxicity of chemical warfare nerve agents and organophosphorus compounds.

Gene delivery using an adenoviral system has been effective in introducing therapeutic proteins in vitro and in vivo. This study tested the feasibility of using adenovirus to deliver clinically relevant amounts of butyrylcholinesterase (BChE), a proven bioscavenger of nerve agents. The adenovirus construct expressed full-length mouse BChE. Mice were injected with a single dose of adenovirus (1.5 × 10(10) infectious units) in the tail vein; plasma was collected through day 11 and assayed for BChE activity. Maximum activity, representing a 300- to 3400-fold increase over baseline, was found on day 4. Expression levels returned to baseline by day 10. Nondenaturing gel electrophoresis showed the recombinant BChE was a dimer that could be converted to tetramers by addition of polyproline. The toxic compounds chosen for protection studies were positively charged organophosphorus agents, echothiophate, and O-ethyl-S-2-N,N-diisopropylaminoethyl methylphosphonothiolate (VX). Mice containing elevated blood levels of BChE (300- to 3,000-fold over the control mice) were challenged with incremental doses of echothiophate or VX. Mice showed no signs of toxicity and were protected from up to 30× LD(50) dose of echothiophate and 5× LD(50) dose of VX. A good correlation was observed between tolerated echothiophate dose and plasma BChE levels at time of challenge. The absolute increases in levels of circulating BChE and the sustained nature of the response resulted in a very high enzyme concentration, deemed critical in acute toxicity (5× LD(50) or more) scenarios. These results suggest that gene-delivered BChE is a prophylactic and affords protection equivalent to that of a multimilligram injection of the same.

Patterns of cardiac stress testing after revascularization in community practice.

OBJECTIVES: The purpose of this study was to determine the pattern of cardiac stress testing after coronary revascularization in community practice. BACKGROUND: The American College of Cardiology Foundation appropriate use criteria provide guidance for the use of cardiac stress imaging after coronary revascularization. However, little is known regarding the use of routine cardiac stress testing in coronary artery bypass grafting or percutaneous coronary intervention patients as well as their downstream use of invasive procedures after noninvasive testing in community practice. METHODS: Use and timing of stress testing more than 90 days after revascularization in patients 18 to 64 years of age were determined from a national health insurance claims database from July 1, 2004, through June 30, 2007. Subsequent rates of angiography and repeat revascularization after stress testing also were examined. RESULTS: Of 28,177 patients undergoing revascularization (21,046 percutaneous coronary intervention procedures and 7,131 coronary artery bypass grafting procedures), 59% had at least 1 cardiac stress test within 24 months. Sixty-one percent of patients with percutaneous coronary intervention and 51% of patients with coronary artery bypass grafting had undergone testing by 24 months. Nuclear imaging was the predominant testing method. The incidence of testing was found to increase at both 6 months and 12 months after revascularization, suggesting an association with elective follow-up office visits. Furthermore, testing varied according to geographic location. Of those tested, only 11% underwent subsequent cardiac catheterization and only 5% underwent repeat revascularization. CONCLUSIONS: Although there is limited consensus as to the appropriate role of elective stress testing after coronary revascularization, more than one half of all patients in community practice had at least 1 stress test within 24 months of revascularization. Yield on such testing was low: only 5% of patients tested ultimately required repeat revascularization. These findings support the need to define better the role of stress testing after recent revascularization.

A multicenter assessment of the use of single-photon emission computed tomography myocardial perfusion imaging with appropriateness criteria.

OBJECTIVES: The aim of this study was to assess the feasibility of evaluation for appropriate use of radionuclide myocardial perfusion imaging (MPI) in multiple clinical sites and to determine use patterns as well as identify areas of apparent inappropriate use. BACKGROUND: Although cardiac imaging is highly valued for decision-making, the growth and expense related to these procedures has raised questions regarding overuse. The publication of appropriate use criteria (AUC), including those for MPI, were designed to provide guidance in the rational use of testing. However, limited data regarding the implementation and evaluation of AUC are available. METHODS: Six diverse clinical sites enrolled consecutive patients undergoing MPI, collecting point-of-service data entered into an online form. An automated algorithm assigned a specific indication from the AUC that was classified as appropriate, uncertain, or inappropriate. Site-specific feedback was later provided to each practice on ordering patterns. RESULTS: Of the 6,351 patients enrolled, 93% were successfully assigned an appropriateness level. Inappropriate use of MPI was found in 14.4% of patients, with a range of 4% to 22% among practices. Women and younger patients were more likely to undergo inappropriate MPI. Asymptomatic, low-risk patients accounted for 44.5% of inappropriate testing. Elimination of the 5 most common inappropriate use indications would reduce overall imaging volume by 13.2%. Inappropriate use by physicians from within the practice performing imaging was not greater than physicians outside of the practice. Educational feedback might have resulted in reduced inappropriate test ordering in 1 site. CONCLUSIONS: The tracking of appropriate use is feasible in clinical practice, with an automated system that can readily identify practice patterns and targets for educational and quality improvement initiatives. This approach might provide an alternative to utilization management.

Manganese superoxide dismutase V16A single-nucleotide polymorphism in the mitochondrial targeting sequence is associated with reduced enzymatic activity in cryopreserved human hepatocytes.

Mitochondrial manganese superoxide dismutase (MnSOD), encoded by the SOD2 gene, represents a major cellular defense against environmental carcinogens that cause oxidative stress. Two single-nucleotide polymorphisms -9 T>C (V16A in the MnSOD mitochondrial targeting sequence) and -102 C>T (in the SOD2 promoter sequence) modify risk toward various types of malignancies and overall survival. Since little is known about the effects of these polymorphisms on overall enzyme function in normal human tissue, the goal of this study was to evaluate their functional effects in cryopreserved human hepatocytes. Cryopreserved human hepatocytes were genotyped for the MnSOD -9 T>C and -102 C>T polymorphisms by TaqMan allelic discrimination assays. MnSOD catalytic activities were determined in vitro in lysates derived from the hepatocytes. In random samplings of cryopreserved hepatocytes, 16% possessed the -9 T>C and 6% possessed polymorphism on at least one of the two alleles. -9 T>C (V16A) significantly (p < 0.02) reduced MnSOD catalytic activity whereas -102 C>T did not (p > 0.05). The -9 T>C (V16A) polymorphism in the MnSOD mitochondrial targeting sequence significantly reduced MnSOD catalytic activity in cryopreserved hepatocytes, consistent with its reported associations with cancer risk and treatment.

Structure-activity relationships for thiol reactivity and rat or human hepatocyte toxicity induced by substituted p-benzoquinone compounds.

Covalent binding of toxic chemicals to cellular targets is a molecular interaction that initiates a wide array of adverse biological effects. The creation of a covalent bond can be cited as a key initiating step along many toxicity pathways which must be predicted in order to predict the potential of a chemical to cause specific harmful effects. Currently, quantitative structure-activity relationship (QSAR) models are being improved by focusing on endpoints such as simple electrophile reactivity for covalent interactions rather than on commonly used complex toxicity endpoints. The cytotoxicity and electrophilic reactivity of 10 p-substituted benzoquinone derivatives, which are well known electrophilic alkylating agents, were investigated under the premise that QSAR toxicity models can be improved when the molecular triggering event is considered. Hepatocyte toxicity was determined by incubation of individual compounds with freshly isolated rat or cryopreserved human hepatocyte suspensions. The potential for chemical reactivity between a chemical and cellular target was measured by determining non-enzymic reactivity with glutathione, representing thiol nucleophiles. The decline in free thiol moieties was measured to characterize the electrophile reactivity. It was found that the degree of rat hepatotoxicity induced by benzoquinones correlated with the rate at which they non-enzymically react with glutathione and to various global and atomic electronic frontier orbital parameters which described electrophilicity. Human hepatocytes showed similar results but the statistical significance was much lower. The QSAR expressions suggest that covalent binding reactivity serves as a good correlate to hepatotoxicity and could improve QSAR modeling for potential toxicity risks.

Structure-activity relationships for halobenzene induced cytotoxicity in rat and human hepatocytes.

Halobenzenes are ubiquitous environmental contaminants, which are hepatotoxic in both rodents and humans. The molecular mechanism of halobenzene hepatotoxicity was investigated using Quantitative structure-activity relationships (QSAR) and accelerated cytotoxicity mechanism screening (ACMS) techniques in rat and human hepatocytes. The usefulness of isolated hepatocytes for prediciting in vivo xenobiotic toxicity was reassessed by correlating the LC(50) of 12 halobenzene congeners in phenobarbital (PB) induced rat hepatocytes in vitro determined by ACMS to the hepatotoxicities reported in vivo in PB-induced male Sprague-Dawely (SD) rats. A high correlation (r(2)=0.90) confirmed the application of hepatocytes as a "gold standard" for toxicity testing in vitro. QSARs were derived to determine the physico-chemcial variables that govern halobenzene toxicity in PB-induced rat, normal rat and human hepatocytes. We found that toxicity in normal rat and normal human hepatocytes both strongly correlate with hydrophobicity (logP), ease of oxidation (E(HOMO), energy of the highest molecular orbital) and on the asymmetric charge distribution according to arrangement of halogen substituents (dipole moment, mu). This suggests that halobenzene interaction with cytochrome P450 for oxidation is the metabolic activating path for toxicity and is similar in both species. In PB-induced rat hepatocytes the QSAR derivation is changed, where halobenzene toxicity strongly correlates to logP and dipole moment, but not E(HOMO). The changed QSAR suggests that oxidation is no longer the rate-limiting step in the cytotoxic mechanism when CYP2B/3A levels are increased, confirming CYP450 oxidation as the metabolic activating step under normal conditions.

New cytochrome P450 2D6*56 allele identified by genotype/phenotype analysis of cryopreserved human hepatocytes.

Genotype/phenotype analysis with human hepatocytes has identified a new inactive CYP2D6 allele, CYP2D6*56. Cryopreserved human hepatocytes from 51 livers were evaluated for CYP2D6 activity with dextromethorphan as the probe substrate. Hepatocyte lots that lacked CYP2D6 activity were further evaluated for CYP2D6 expression and known genetic variations, including CYP2D6*2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *14, *15, *17, *18, *19, *20, *25, *26, *29, *30, *35, *40, *41, *43, and various multiple copy CYP2D6 alleles (*1xn, *2xn, and *4xn) by the AmpliChip CYP450 prototype microarray (Roche Molecular Systems, Inc., Branchburg, NJ). Two discrepancies were uncovered between the CYP2D6 genotype and activity by this approach. In one sample, a previously unreported 3201C 224 T transition in exon 7 resulted in Arg344(CGA) being replaced by a stop codon (TGA), resulting in a CYP2D6 enzyme lacking the terminal 153 amino acids. This allele was given the designation of CYP2D6*56 and the GenBank accession number DQ282162. The lack of CYP2D6 activity in cryopreserved hepatocytes and microsomes found in the second sample, despite a normal level of CYP2D6 expression and a genotype (*10/*1) predictive of normal CYP2D6 activity, was attributed to enzyme inactivation by an unknown metabolite. The identification and characterization of the CYP2D6*56 allele indicates that commercial cryopreserved human hepatocytes may provide a valuable means to rapidly identify genetic variations with functional relevance. This integrated approach of identifying alleles and examining allele relationships to gene expression and function could be of tremendous value to understanding the mechanism responsible for functional differences in gene variation. The commercial availability of human cryopreserved hepatocytes also makes this potential readily available to any who are interested in it, not just those with access to private liver banks.