Duloxetine for the Treatment of Patients with Suspected Sphincter of Oddi Dysfunction: A Pilot Study.

OBJECTIVE: To examine the tolerability and efficacy of duloxetine in patients with suspected sphincter of Oddi dysfunction (SOD). METHODS: An open-label, single-center, 12-week trial of duloxetine 60 mg once daily was conducted in 20 patients with suspected SOD. All patients were evaluated by expert pancreato-biliary specialists. The primary outcome measure was a Patient Global Impression of Change (PGIC) scale. Secondary measures included the pain burden, assessed by the Recurrent Abdominal Pain Intensity and Disability scale, the Short-Form Health Survey, and the Hospital Anxiety and Depression Scale. A positive clinical response was defined as a PGIC score of much or very much improved at 3 months and was estimated using a two-sided 90 % confidence interval. The primary outcome was analyzed using a one-sample binomial test at a significance level of 0.10. RESULTS: Of the 20 screened patients, 18 were enrolled; 14 completed at least one post-baseline evaluation; and 10 patients completed the third month endpoint visit. Patients missing the third month visit were considered non-responders for the primary outcome. Response rates were 90 % for study completers (n = 10; 90 % CI 74-100; p = 0.02) and 64 % for patients who completed at least one post-baseline evaluation (n = 14; 90 % CI 43-85; p = 0.42). Seven patients did not complete the study due to adverse events (mostly fatigue and nausea). CONCLUSIONS: Duloxetine showed an indication of efficacy in the treatment of pain in patients with suspected SOD, but adverse events limited its use. These preliminary, open-label results justify definitive placebo-controlled trials.

Antiretroviral treatment use, co-morbidities and clinical outcomes among Aboriginal participants in the Australian HIV Observational Database (AHOD).

BACKGROUND: There are few data regarding clinical care and outcomes of Indigenous Australians living with HIV and it is unknown if these differ from non-Indigenous HIV-positive Australians. METHODS: AHOD commenced enrolment in 1999 and is a prospective cohort of HIV-positive participants attending HIV outpatient services throughout Australia, of which 20 (74 %) sites report Indigenous status. Data were collected up until March 2013 and compared between Indigenous and non-Indigenous participants. Person-year methods were used to compare death rates, rates of loss to follow-up and rates of laboratory testing during follow-up between Indigenous and non-Indigenous participants. Factors associated with time to first combination antiretroviral therapy (cART) regimen change were assessed using Kaplan Meier and Cox Proportional hazards methods. RESULTS: Forty-two of 2197 (1.9 %) participants were Indigenous. Follow-up amongst Indigenous and non-Indigenous participants was 332 & 16270 person-years, respectively. HIV virological suppression was achieved in similar proportions of Indigenous and non-Indigenous participants 2 years after initiation of cART (81.0 % vs 76.5 %, p = 0.635). Indigenous status was not independently associated with shorter time to change from first- to second-line cART (aHR 0.95, 95 % CI 0.51-1.76, p = 0.957). Compared with non-Indigenous participants, Indigenous participants had significantly less frequent laboratory monitoring of CD4 count (rate:2.76 tests/year vs 2.97 tests/year, p = 0.025) and HIV viral load (rate:2.53 tests/year vs 2.93 tests/year, p < 0.001), while testing rates for lipids and blood glucose were almost half that of non-indigenous participants (rate:0.43/year vs 0.71 tests/year, p < 0.001). Loss to follow-up (23.8 % vs 29.8 %, p = 0.496) and death (2.4 % vs 7.1 %, p = 0.361) occurred in similar proportions of indigenous and non-Indigenous participants, respectively, although causes of death in both groups were mostly non-HIV-related. CONCLUSIONS: As far as we are aware, these are the first data comparing clinical outcomes between Indigenous and non-Indigenous HIV-positive Australians. The forty-two Indigenous participants represent over 10 % of all Indigenous Australians ever diagnosed with HIV. Although outcomes were not significantly different, Indigenous patients had lower rates of laboratory testing for HIV and lipid/glucose parameters. Given the elevated risk of cardiovascular disease in the general Indigenous community, the additional risk factor of HIV infection warrants further focus on modifiable risk factors to maximise life expectancy in this population.

Facilitators and barriers to implementation of a pragmatic clinical trial in Aboriginal health services.

OBJECTIVE: To identify facilitators and barriers to clinical trial implementation in Aboriginal health services. DESIGN: Indepth interview study with thematic analysis. SETTING: Six Aboriginal community-controlled health services and one government-run service involved in the Kanyini Guidelines Adherence with the Polypill (KGAP) study, a pragmatic randomised controlled trial that aimed to improve adherence to indicated drug treatments for people at high risk of cardiovascular disease. PARTICIPANTS: 32 health care providers and 21 Aboriginal and Torres Strait Islander patients. RESULTS: A fundamental enabler was that participants considered the research to be governed and endorsed by the local health service. That the research was perceived to address a health priority for communities was also highly motivating for both providers and patients. Enlisting the support of Aboriginal and Torres Strait Islander staff champions who were visible to the community as the main source of information about the trial was particularly important. The major implementation barrier for staff was balancing their service delivery roles with adherence to often highly demanding trial-related procedures. This was partially alleviated by the research team's provision of onsite support and attempts to make trial processes more streamlined. Although more intensive support was highly desired, there were usually insufficient resources to provide this. CONCLUSION: Despite strong community and health service support, major investments in time and resources are needed to ensure successful implementation and minimal disruption to already overstretched, routine services. Trial budgets will necessarily be inflated as a result. Funding agencies need to consider these additional resource demands when supporting trials of a similar nature.

Human Hematopoietic Signal peptide-containing Secreted 1 (hHSS1) modulates genes and pathways in glioma: implications for the regulation of tumorigenicity and angiogenesis.

BACKGROUND: Human Hematopoietic Signal peptide-containing Secreted 1 (hHSS1) is a truly novel protein, defining a new class of secreted factors. We have previously reported that ectopic overexpression of hHSS1 has a negative modulatory effect on cell proliferation and tumorigenesis in glioblastoma model systems. Here we have used microarray analysis, screened glioblastoma samples in The Cancer Genome Atlas (TCGA), and studied the effects of hHSS1 on glioma-derived cells and endothelial cells to elucidate the molecular mechanisms underlying the anti-tumorigenic effects of hHSS1. METHODS: Gene expression profiling of human glioma U87 and A172 cells overexpressing hHSS1 was performed. Ingenuity® iReport™ and Ingenuity Pathway Analysis (IPA) were used to analyze the gene expression in the glioma cells. DNA content and cell cycle analysis were performed by FACS, while cell migration, cell invasion, and effects of hHSS1 on HUVEC tube formation were determined by transwell and matrigel assays. Correlation was made between hHSS1 expression and specific genes in glioblastoma samples in the TCGA database. RESULTS: We have clarified the signaling and metabolic pathways (i.e. role of BRCA1 in DNA damage response), networks (i.e. cell cycle) and biological processes (i.e. cell division process of chromosomes) that result from hHSS1effects upon glioblastoma growth. U87-overexpressing hHSS1 significantly decreased the number of cells in the G0/G1 cell cycle phase, and significantly increased cells in the S and G2/M phases (P < 0.05). U87-overexpressing hHSS1 significantly lost their ability to migrate (P < 0.001) and to invade (P < 0.01) through matrigel matrix. hHSS1-overexpression significantly decreased migration of A172 cells (P < 0.001), inhibited A172 tumor-induced migration and invasion of HUVECs (P < 0.001), and significantly inhibited U87 tumor-induced invasion of HUVECs (P < 0.001). Purified hHSS1 protein inhibited HUVEC tube formation. TCGA database revealed significant correlation between hHSS1 and BRCA2 (r = -0.224, P < 0.0005), ADAMTS1 (r = -0.132, P <0.01) and endostatin (r = 0.141, P < 0.005). CONCLUSIONS: hHSS1-overexpression modulates signaling pathways involved in tumorigenesis. hHSS1 inhibits glioma-induced cell cycle progression, cell migration, invasion and angiogenesis. Our data suggest that hHSS1 is a potential therapeutic for malignant glioblastoma possessing significant antitumor and anti-angiogenic activity.

Prototype Design for Grading Structures in Powder Bed Fusion Processes.

While targeted alignment in certain additive manufacturing (AM) methods such as material extrusion (MEX) and stereolithography (SLA) has been well documented in the research community, a method for targeted alignment of added fillers or fibrous materials in powder bed fusion (PBF) AM devices has yet to be successfully achieved. Similarly, incorporation of multimaterials does not work easily with any of the AM technologies. This study creates a prototype design that could be integrated into a PBF system to allow for multimaterial layer deposition and alignment of powders and powder blends. The rheological properties of polyamide powder and a range of polyamide composite blends (incorporating milled carbon fibre, graphite flakes, polytetrafluoroethylene, and glass microspheres) in different concentrations were studied, and together with the particle size distribution and particle morphology analysis were applied for the design of a prototype hopper for incorporation in the PBF system to create targeted multimaterial deposition. Different concept designs, multichambered and multi-hopper with hopper angles calculated specifically for the composite blend powders selected, were proposed. Initial deposition trials outside a PBF process were tested, and the deposited layers were measured.

The impact of Fc engineering on an anti-CD19 antibody: increased Fcgamma receptor affinity enhances B-cell clearing in nonhuman primates.

CD19, a B cell-restricted receptor critical for B-cell development, is expressed in most B-cell malignancies. The Fc-engineered anti-CD19 antibody, XmAb5574, has enhanced Fcgamma receptor (FcgammaR) binding affinity, leading to improved FcgammaR-dependent effector cell functions and antitumor activity in murine xenografts compared with the non-Fc-engineered anti-CD19 IgG1 analog. Here, we use XmAb5574 and anti-CD19 IgG1 to further dissect effector cell functions in an immune system closely homologous to that of humans, the cynomolgus monkey. XmAb5574 infusion caused an immediate and dose-related B-cell depletion in the blood (to <10% of baseline levels) concomitant with a sustained reduction of natural killer (NK) cells. NK cells had fully recovered by day 15, whereas B-cell recovery was underway by day 57. B cells in secondary lymphoid tissues were depleted (to 34%-61% of vehicle), with involuted germinal centers apparent in the spleen. Anti-CD19 IgG1 had comparable serum exposure to XmAb5574 but demonstrated no B-cell depletion and no sustained NK-cell reduction. Thus, increasing FcgammaR binding affinity dramatically increased B-cell clearing. We propose that effector cell functions, possibly those involving NK cells, mediate XmAb5574 potency in cynomolgus monkeys, and that enhancing these mechanisms should advance the treatment of B-cell malignancies in humans.

Snorkelling and breath-hold diving fatalities in New Zealand, 2007 to 2016.

INTRODUCTION: New Zealand's (NZ) long coastline offers a diverse underwater environment with abundant opportunities for harvesting seafood and for recreation. Fatalities from snorkelling/breath-hold diving have been reported from the 1960s through to 2006. Those from 2007 to 2016 are reported here. METHODS: The National Coronial Information System, the Australasian Diving Safety Foundation diving fatality database, and the Water Safety NZ "Drownbase" were searched and additional coronial data provided by the NZ Ministry of Justice. An anonymised database was created and analysed for multiple factors. A chain of events analysis was performed for each case. RESULTS: There were 38 snorkelling or breath-hold-related deaths in NZ, 33 men and five women. Twenty-nine were breath-hold divers involved in gathering seafood, and six 'surface snorkellers', predominantly sightseeing. Two-thirds were diving alone and/or were not being observed by anyone out of the water. Twenty-eight victims were classified as overweight or obese and 19/38 were Maori. Pre-existing health factors that may have or definitely contributed to the fatality were present in 30 cases. The most common of these were cardiac (18/38). Two divers had insulin-dependent diabetes mellitus, one each epilepsy and asthma whilst cannabis and/or alcohol were possible factors in seven deaths. Five (possibly six) deaths resulted from apnoeic hypoxia. CONCLUSIONS: Overall, death from snorkelling/breath-hold diving was an uncommon event (38 in 10 years). Poor judgement was a common feature. Middle-aged Maori men with pre-existing disease feature strongly. This suggests an on-going need for appropriate water safety education within and beyond the Maori community.

Using an electronic health record alert to prompt blood-borne virus testing in primary care.

BACKGROUND: Late diagnosis of HIV, hepatitis B (HBV) and hepatitis C (HCV) remains relatively common in the UK and many people who present late have missed opportunities for testing in primary care. The objective was to assess the effectiveness and acceptance of a prototype application (BBV_TP1), embedded in a primary care electronic health record (EHR), to increase real-time blood-borne virus (BBV) testing. METHODS: This prospective cohort study assessed BBV_TP1 in 14 general practices in North East England, in comparison with 54 similar practices in 2019. Rates of HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) testing in practices were measured before and after the application was activated. Patient and clinician acceptance of the technology was assessed by surveys. RESULTS: In the 6 months following the intervention, HIV testing rates increased 555% and combined HBV/HCV testing rates increased 362%. No significant differences were observed for any BBV testing rates in the nonintervention practices over the same period. Monthly testing rates declined towards baseline after initial increases. Clinician's perceptions of the prompt system were positive, with average additional time required for BBV test discussion in consultations estimated at 2 min. The patient survey also showed high acceptance of the technology. CONCLUSION: This pilot study demonstrated that BBV_TP1 increased BBV testing rates in primary care via targeted screening, although testing rates subsequently fell whilst the application remained active. Such systems can potentially reduce late diagnoses, while having high acceptance by clinicians and patients. Larger studies with longer follow-up are needed to demonstrate efficacy and cost-effectiveness.

A Reasonable Officer: Examining the Relationships Among Stress, Training, and Performance in a Highly Realistic Lethal Force Scenario.

Under conditions of physiological stress, officers are sometimes required to make split-second life-or-death decisions, where deficits in performance can have tragic outcomes, including serious injury or death and strained police-community relations. The current study assessed the performance of 122 active-duty police officers during a realistic lethal force scenario to examine whether performance was affected by the officer's level of operational skills training, years of police service, and stress reactivity. Results demonstrated that the scenario produced elevated heart rates (i.e., 150 beats per minute), as well as perceptual and cognitive distortions, such as tunnel vision, commensurate with those observed in naturalistic use of force encounters. The average performance rating from the scenario was 59%, with 27% of participants making at least one lethal force error. Elevated stress reactivity was a predictor of poorer performance and increased lethal force errors. Level of training and years of police service had differential and complex effects on both performance and lethal force errors. Our results illustrate the need to critically reflect on police training practices and continue to make evidence-based improvements to training. The findings also highlight that while training may significantly improve outcomes, flawless performance is likely not probable, given the limits of human performance under stress. Implications for the objective reasonableness standard, which is used to assess the appropriateness of force in courts of law, are discussed.

Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists.

This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.

Discovery of a potent and selective aurora kinase inhibitor.

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.

Provisional report on diving-related fatalities in Australian waters in 2012.

INTRODUCTION: An individual case review of known diving-related deaths that occurred in Australia in 2012 was conducted. METHOD: The case studies were compiled using statements from witnesses and reports of the police and coroners. In each case, the particular circumstances of the accident and details from the post-mortem examination, where available, are provided. RESULTS: There were 26 reported fatalities (four less than the previous year). Only two of the victims were female (one snorkeller and one scuba diver). Fourteen deaths occurred while snorkelling and/or breath-hold diving, 11 while scuba diving and one diver died while using surface supplied breathing apparatus in a commercial pearl diving setting. Two breath-hold divers likely drowned as a result of apnoeic hypoxia. Cardiac-related issues were thought to have contributed to the deaths of at least three and possibly seven snorkellers and four scuba divers. CONCLUSIONS: Pre-existing medical conditions; poor organisation, planning and supervision; equipment-related problems; snorkelling or diving alone or with loose buddy oversight and apnoeic hypoxia were features in several deaths in this series.

Excited delirium syndrome (ExDS): Situational factors and risks to officer safety in non-fatal use of force encounters.

STUDY OBJECTIVE: Police use of force (UoF) encounters include individuals with Excited Delirium Syndrome (ExDS) with some frequency. Situational factors and risks to officer safety associated with these encounters have not been well studied. We examined the likelihood that subjects displaying various concomitant features of ExDS were under the influence of drugs and/or alcohol. We also examined the extent of subject violence, and the impact of this behaviour on the encounter (e.g., the odds of a struggle). Greater understanding of the prevalence of ExDS and the specific risk it represents to law enforcement officers and the subjects they encounter will guide appropriate policy and response strategies. METHODS: A prospective evaluation of a consecutive cohort of subjects involved in UoF encounters with police was conducted. Data were collected from January 2012 to December 2015. Consistent with previous research, the presence of six or more features was used to identify probable cases of ExDS. The odds that subjects in a state of probable ExDS were under the influence of drugs and/or alcohol was calculated and compared against subjects who exhibited less than three features of ExDS. In addition, the violent nature of subjects (e.g., the odds of a subject being in possession of a weapon) displaying various concomitant features of the syndrome was examined. The number of sudden and unexpected arrest-related death (ARDs) was documented. RESULTS: UoF occurred in 9006 of 10.9 million police-public interactions (0.08%). Of the UoF encounters, 156 (1.7%) subjects displayed six or more features of ExDS. With four recorded sudden and unexpected ARDs of violent and agitated subjects in our cohort, up to 6.3% of these subjects experiencing probable ExDS could be expected to be at risk of sudden death. Logistic regression analyses indicated that there were significantly higher odds that subjects exhibiting more features of ExDS (e.g., six or more) were under the influence of drugs. On the other hand, there were significantly lower odds that individuals exhibiting ExDS were under the influence of alcohol alone. In addition, those displaying a greater number of features demonstrated higher odds of engaging in assaultive behaviour, presenting a threat of grievous bodily harm or death, and being involved in a struggle that went to the ground with an officer. A slight increase in the presence of weapons was observed in encounters with probable ExDS. CONCLUSION: Our study provides important information to guide the development of policy and procedure in law enforcement. Police encounter a subject with ExDS 1 in every 58 UoF incidents (1.7%). Those individuals are at higher odds of being intoxicated with drugs according to officers' assessments and at risk of being further exerted during a struggle on the ground, both of which appear to play a major role in deaths associated to ExDS. There is a demonstrable increase in risk to officers and public safety from the violent behaviour displayed by subjects presenting a greater number of features of ExDS. Our data suggests that up to 6.3% of subjects in a state of ExDS could succumb to ARDs; however, we cannot comment on the prevalence of death for persons with ExDS who do not encounter police. Further research is needed to determine which force options optimize outcome for police and subjects. Additionally, research surrounding pathophysiology leading to death should focus on subjects with six or more features of ExDS. Ultimately, a better understanding in this area will contribute to improving the outcomes of these encounters for those suffering from ExDS and those tasked with assisting them.

Gender differences in the slow delayed (IKs) but not in inward (IK1) rectifier K+ currents of canine Purkinje fibre cardiac action potential: key roles for IKs, beta-adrenoceptor stimulation, pacing rate and gender.

As the beagle dog is a commonly used preclinical species to test the effects of new drugs on cardiac repolarisation and Purkinje fibres have become an established in vitro preparation to assess the effects of these new drugs on action potential duration (APD), the main aim of this study was therefore to evaluate the relative contribution of the inward (I(K1)) and slow delayed (I(Ks)) rectifier cardiac K(+) currents to action potential repolarisation in beagle Purkinje fibres under three different experimental conditions: (i) selective block of I(K1) with BaCl(2), (ii) selective block of I(Ks) with (-) chromanol 293B under basal conditions and (iii) selective block of I(Ks) during beta-adrenoceptor stimulation. Furthermore, the dependence of this contribution on gender and pacing rate was investigated. Microelectrode techniques were employed to measure APD in Purkinje fibres from adult female and male dogs. At stimulation rates of 3.33, 1.0 and 0.2 Hz, the degree of prolongation of APD evoked by BaCl(2) (10 microM) was comparable in fibres from female and male dogs. At the same stimulation rates, 10 microM (-) chromanol 293B did not change the APD in fibres from female and male dogs. During beta-adrenoceptor stimulation with 0.1 microM isoproterenol, an APD prolonging effect of (-) chromanol 293B was detected. In the presence of isoproterenol, action potentials in fibres from male dogs get shorter when changing the stimulation rate from 1.0 to 0.2 Hz, while the opposite is seen in fibres from female dogs. This alteration was completely reversed by (-) chromanol 293B. In conclusion, our findings confirm that beta-adrenoceptor stimulation is one condition where there may be an increased role of I(Ks) in action potential repolarisation. Gender differences in the autonomic modulation of I(Ks) could be a contributing factor to the reported increased susceptibility of female hearts to arrhythmias.

Resuscitating the autopsy in Australian hospitals.

Previous studies have consistently shown that autopsy examination after surgery can identify a significant rate of discrepant and/or erroneous diagnoses. Findings gleaned from autopsies can be invaluable for the medical community and science as a whole, ultimately leading to improvements in quality surgical care. Despite the proven benefits of this underused tool, the number of autopsies carried out in Australian hospitals is declining dramatically, with autopsy rates plummeting from 21% in 1992-1993 to 12% in 2002-2003. This notable decline ought to be a genuine source of concern and deserves further examination. This review seeks to address the reasons for decline, while reasserting the value and relevance of autopsies within modern surgical practice Down Under.

Distinguishing features of Excited Delirium Syndrome in non-fatal use of force encounters.

STUDY OBJECTIVE: The frequency with which the police encounter non-fatal cases of Excited Delirium Syndrome (ExDS) has not been well studied. To date only a single prospective, epidemiologic study has been completed to determine the prevalence of the features of ExDS in police use of force (UoF) encounters. We examined a cluster of previously published features associated with ExDS to establish if these features were consistently recognizable across policing populations, thus demonstrating reproducibility. We further sought to determine whether any feature or number of concomitant features were likely to have physiologic significance. These are important first steps in determining a case definition of ExDS in a law enforcement and medical setting. METHODS: A prospective evaluation of a consecutive cohort of subjects involved in UoF encounters with police was conducted. Data were collected through the UoF reporting database of a large Canadian law enforcement agency from January, 2012 to December, 2013. The ten core characteristics of ExDS that have been observed in past research were documented by officers and, consistent with previous research, the presence of six or more features was used to identify probable cases of ExDS and a state of medical emergency. RESULTS: UoF occurred in 4799 of 5.4 million police-public interactions (0.09%). Of the UoF encounters, 73 (1.5%) subjects displayed six or more features of ExDS. Upwards of 9.2% of these subjects could be expected to be at risk of sudden and unexpected arrest-related death (ARD). Features with the highest odds of being presented with a large number of concomitant features included "Does not Fatigue", "Superhuman Strength" and "Tactile Hyperthermia" (287, 137 and 93 times higher, respectively). Moreover, "Tactile Hyperthermia" demonstrated the highest odds of being presented in individuals with a large number of features as opposed to those with fewer (33 times higher). CONCLUSION: We demonstrate that there is the ability for law enforcement officers to consistently recognize and report features of ExDS that have been associated with ARD. The varying presence of features across the examined categories indicates that some features are more distinguishing than others, which may enable narrowing the scope of features that represent ExDS and understanding its pathophysiology. The current debate surrounding whether or not ExDS exists limits first responders and emergency physicians in their ability to increase awareness, improve training and interventions, and design appropriate policy and response protocols to reduce ARDs.

A computational model of invasive aspergillosis in the lung and the role of iron.

BACKGROUND: Invasive aspergillosis is a severe infection of immunocompromised hosts, caused by the inhalation of the spores of the ubiquitous environmental molds of the Aspergillus genus. The innate immune response in this infection entails a series of complex and inter-related interactions between multiple recruited and resident cell populations with each other and with the fungal cell; in particular, iron is critical for fungal growth. RESULTS: A computational model of invasive aspergillosis is presented here; the model can be used as a rational hypothesis-generating tool to investigate host responses to this infection. Using a combination of laboratory data and published literature, an in silico model of a section of lung tissue was generated that includes an alveolar duct, adjacent capillaries, and surrounding lung parenchyma. The three-dimensional agent-based model integrates temporal events in fungal cells, epithelial cells, monocytes, and neutrophils after inhalation of spores with cellular dynamics at the tissue level, comprising part of the innate immune response. Iron levels in the blood and tissue play a key role in the fungus' ability to grow, and the model includes iron recruitment and consumption by the different types of cells included. Parameter sensitivity analysis suggests the model is robust with respect to unvalidated parameters, and thus is a viable tool for an in silico investigation of invasive aspergillosis. CONCLUSIONS: Using laboratory data from a mouse model of invasive aspergillosis in the context of transient neutropenia as validation, the model predicted qualitatively similar time course changes in fungal burden, monocyte and neutrophil populations, and tissue iron levels. This model lays the groundwork for a multi-scale dynamic mathematical model of the immune response to Aspergillus species.

Nonclinical proarrhythmia models: predicting Torsades de Pointes.

Prolongation of the QT interval and the cardiac action potential have been linked to a potentially fatal but rare tachyarrhythmia known as Torsades de Pointes (TdP). Nonclinical assays, such as those investigating the effect on I(Kr) (the hERG channel current), prolongation of the action potential duration (APD) and the QT interval, in vivo, have been developed to predict the risk of QT interval prolongation and TdP in man. However, there seems to be a dissociation between the risk of QT interval prolongation and the torsadogenic risk. There is an increasing mass of evidence showing that an increase in the QT interval does not necessarily lead to TdP. Thus, it appears that while standard assays are very good, although perhaps not infallible, at predicting the risk of QT interval prolongation in man they do not predict the proarrhythmic risk. Recently there has been a plethora of publications suggesting that there are electrophysiological markers associated with drug-induced TdP other than hERG channel activity, APD and the QT interval, and these markers may be better predictors of TdP. In this review, three in vitro and, briefly, three in vivo models or methods are discussed. These proarrhythmia models use electrophysiological markers such as transmural dispersion of repolarization, action potential triangulation, instability, reverse use-dependence, and the incidence of early after-depolarizations to predict the risk of TdP. Most of the models presented have been published widely. The particular variable or set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome. While each variable/model has been shown to discriminate between antiarrhythmic and nonarrhythmic drugs, these reports should be interpreted cautiously since none has been independently (externally) assessed. Each model is discussed along with its particular merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others. Proarrhythmia models, in particular in vitro models, challenge current perceptions of appropriate surrogates for TdP in man and question existing nonclinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key proarrhythmia mechanisms. Regardless of regulatory acceptance, with further validation these models may still enhance pharmaceutical company decision-making to provide a rational basis for drug progression, particularly in areas of unmet medical need.

Sexual behaviour, drug use and health service use by young Noongar people in Western Australia: a snapshot.

UNLABELLED: Background This study aimed to describe sexual health behaviour, alcohol and other drug use, and health service use among young Noongar people in the south-west of Western Australia. METHOD: A cross-sectional survey was undertaken among a sample of 244 Noongar people aged 16-30 years. RESULTS: The sample was more disadvantaged than the wider Noongar population. Sexual activity was initiated at a young age, 18% had two or more casual sex partners in the previous 12 months, with men more likely to have done so than women (23% vs 14%). Condoms were always or often carried by 57% of men and 37% of women, and 36% of men and 23% of women reported condom use at last sex with a casual partner. Lifetime sexually transmissible infection diagnosis was 14%. Forty percent currently smoked tobacco and 25% reported risky alcohol consumption on a weekly and 7% on an almost daily basis. Cannabis was used by 37%, 12% used drugs in addition to cannabis and 11% reported recently injecting drugs. In the previous 12 months, 66% had a health check and 31% were tested for HIV or sexually transmissible infections. Additionally, 25% sought advice or assistance for mental health or alcohol and other drug issues. DISCUSSION: Although some respondents engaged in risky sexual behaviour, alcohol and other drug use or both, most did not. Particularly encouraging was the engagement of respondents with the health care system, especially among those engaging in risky behaviours. The results confound negative stereotypes of Aboriginal people and demonstrate a level of resilience among respondents.

Evidence for gender differences in electrophysiological properties of canine Purkinje fibres.

Women are more prone to develop torsades de pointes, a rare life-threatening polymorphic ventricular tachycardia, than are men during administration of medicines that have the potential to block I(Kr) (rapid delayed rectifier cardiac K(+) current) and to prolong the QT interval. Blockade of I(Kr), hypokalaemia and extreme bradycardia were used to evaluate whether there are gender differences in cardiac repolarisation in canine Purkinje fibres (PFs). Microelectrode techniques were employed to measure action potential (AP) parameters in PFs from adult female and male dogs. Under control conditions, fibres from female animals in normal or low K(+) conditions exhibited significantly longer AP durations at 50% (APD(50)) and 90% (APD(90)) of repolarisation as compared with APDs of fibres from male animals. Gender-related difference to rate adaptation was also present in APD(90) of fibres from female animals compared to males. At a stimulation rate of 0.2 Hz, but not at 1.0 Hz, dofetilide elicited a significantly higher increase in APD(90), incidence of early afterdepolarisations, triggered and sustained-triggered activities (TAs) in fibres from female animals compared to males in either normal or low K(+) conditions. The sustained TAs were reversed by raising the concentration of [K(+)](0) in Purkinje preparations from both male (one out of one) and female (12 out of 12) dogs. In conclusion, our data provide experimental evidence pointing to gender differences in canine AP repolarisation. PFs from female dogs can be used in safety pharmacology studies as a sensitive model for evaluating the potential proarrhythmic events in vitro of a new medicinal product.