A large proportion of asymptomatic Plasmodium infections with low and sub-microscopic parasite densities in the low transmission setting of Temotu Province, Solomon Islands : challenges for malaria diagnostics in an elimination setting

Background Many countries are scaling up malaria interventions towards elimination. This transition changes demands on malaria diagnostics from diagnosing ill patients to detecting parasites in all carriers including asymptomatic infections and infections with low parasite densities. Detection methods suitable to local malaria epidemiology must be selected prior to transitioning a malaria control programme to elimination. A baseline malaria survey conducted in Temotu Province, Solomon Islands in late 2008, as the first step in a provincial malaria elimination programme, provided malaria epidemiology data and an opportunity to assess how well different diagnostic methods performed in this setting. Methods During the survey, 9,491 blood samples were collected and examined by microscopy for Plasmodium species and density, with a subset also examined by polymerase chain reaction (PCR) and rapid diagnostic tests (RDTs). The performances of these diagnostic methods were compared. Results A total of 256 samples were positive by microscopy, giving a point prevalence of 2.7%. The species distribution was 17.5% Plasmodium falciparum and 82.4% Plasmodium vivax. In this low transmission setting, only 17.8% of the P. falciparum and 2.9% of P. vivax infected subjects were febrile (≥38°C) at the time of the survey. A significant proportion of infections detected by microscopy, 40% and 65.6% for P. falciparum and P. vivax respectively, had parasite density below 100/μL. There was an age correlation for the proportion of parasite density below 100/μL for P. vivax infections, but not for P. falciparum infections. PCR detected substantially more infections than microscopy (point prevalence of 8.71%), indicating a large number of subjects had sub-microscopic parasitemia. The concordance between PCR and microscopy in detecting single species was greater for P. vivax (135/162) compared to P. falciparum (36/118). The malaria RDT detected the 12 microscopy and PCR positive P. falciparum, but failed to detect 12/13 microscopy and PCR positive P. vivax infections. Conclusion Asymptomatic malaria infections and infections with low and sub-microscopic parasite densities are highly prevalent in Temotu province where malaria transmission is low. This presents a challenge for elimination since the large proportion of the parasite reservoir will not be detected by standard active and passive case detection. Therefore effective mass screening and treatment campaigns will most likely need more sensitive assays such as a field deployable molecular based assay.

Efficient simulation of stochastic chemical kinetics with the Stochastic Bulirsch-Stoer extrapolation method

Background Biochemical systems with relatively low numbers of components must be simulated stochastically in order to capture their inherent noise. Although there has recently been considerable work on discrete stochastic solvers, there is still a need for numerical methods that are both fast and accurate. The Bulirsch-Stoer method is an established method for solving ordinary differential equations that possesses both of these qualities. Results In this paper, we present the Stochastic Bulirsch-Stoer method, a new numerical method for simulating discrete chemical reaction systems, inspired by its deterministic counterpart. It is able to achieve an excellent efficiency due to the fact that it is based on an approach with high deterministic order, allowing for larger stepsizes and leading to fast simulations. We compare it to the Euler τ-leap, as well as two more recent τ-leap methods, on a number of example problems, and find that as well as being very accurate, our method is the most robust, in terms of efficiency, of all the methods considered in this paper. The problems it is most suited for are those with increased populations that would be too slow to simulate using Gillespie’s stochastic simulation algorithm. For such problems, it is likely to achieve higher weak order in the moments. Conclusions The Stochastic Bulirsch-Stoer method is a novel stochastic solver that can be used for fast and accurate simulations. Crucially, compared to other similar methods, it better retains its high accuracy when the timesteps are increased. Thus the Stochastic Bulirsch-Stoer method is both computationally efficient and robust. These are key properties for any stochastic numerical method, as they must typically run many thousands of simulations.

Elucidating the host-pathogen interactions between in vitro human cells and enterovirus 71 in Hand, Foot and Mouth Disease (HFMD)

This study has provided further understanding of the pathogenesis of EV71, one of the major etiological agents associated with significant mortality in Hand, Foot and Mouth disease. Elucidating the host-pathogen interaction and the mechanism that the virus uses to bypass host defence systems to establish infection will aid in the development of potential antiviral therapeutics against EV71.

Vibrational spectroscopy of phthalocyanine and naphthalocyanine in sandwich-type (na)phthalocyaninato and porphyrinato rare earth complexes: Part 14. The infrared and Raman characteristics of phthalocyanine in “pinwheel-like” homoleptic bis[1,8,15,22-tetrakis(3-pentyloxy)phthalocyaninato] rare earth(III) double-decker complexes

The infrared (IR) spectroscopic data and Raman spectroscopic properties for a series of 13 “pinwheel-like” homoleptic bis(phthalocyaninato) rare earth complexes M[Pc(α-OC5H11)4]2 [M = Y and Pr–Lu except Pm; H2Pc(α-OC5H11)4 = 1,8,15,22-tetrakis(3-pentyloxy)phthalocyanine] have been collected and comparatively studied. Both the IR and Raman spectra for M[Pc(α-OC5H11)4]2 are more complicated than those of homoleptic bis(phthalocyaninato) rare earth analogues, namely M(Pc)2 and M[Pc(OC8H17)8]2, but resemble (for IR) or are a bit more complicated (for Raman) than those of heteroleptic counterparts M(Pc)[Pc(α-OC5H11)4], revealing the decreased molecular symmetry of these double-decker compounds, namely S8. Except for the obvious splitting of the isoindole breathing band at 1110–1123 cm−1, the IR spectra of M[Pc(α-OC5H11)4]2 are quite similar to those of corresponding M(Pc)[Pc(α-OC5H11)4] and therefore are similarly assigned. With laser excitation at 633 nm, Raman bands derived from isoindole ring and aza stretchings in the range of 1300–1600 cm−1 are selectively intensified. The IR spectra reveal that the frequencies of pyrrole stretching and pyrrole stretching coupled with the symmetrical CH bending of –CH3 groups are sensitive to the rare earth ionic size, while the Raman technique shows that the bands due to the isoindole stretchings and the coupled pyrrole and aza stretchings are similarly affected. Nevertheless, the phthalocyanine monoanion radical Pc′− IR marker band of bis(phthalocyaninato) complexes involving the same rare earth ion is found to shift to lower energy in the order M(Pc)2 > M(Pc)[Pc(α-OC5H11)4] > M[Pc(α-OC5H11)4]2, revealing the weakened π–π interaction between the two phthalocyanine rings in the same order.

Quantitative electroencephalographic comodulation : an investigation of patterns in chronic fatigue syndrome

Introduction. This is a pilot study of quantitative electro-encephalographic (QEEG) comodulation analysis, which is used to assist in identifying regional brain differences in those people suffering from chronic fatigue syndrome (CFS) compared to a normative database. The QEEG comodulation analysis examines spatial-temporal cross-correlation of spectral estimates in the resting dominant frequency band. A pattern shown by Sterman and Kaiser (2001) and referred to as the anterior posterior dissociation (APD) discloses a significant reduction in shared functional modulation between frontal and centro-parietal areas of the cortex. This research attempts to examine whether this pattern is evident in CFS. Method. Eleven adult participants, diagnosed by a physician as having CFS, were involved in QEEG data collection. Nineteen-channel cap recordings were made in five conditions: eyes-closed baseline, eyes-open, reading task one, math computations task two, and a second eyes-closed baseline. Results. Four of the 11 participants showed an anterior posterior dissociation pattern for the eyes-closed resting dominant frequency. However, seven of the 11 participants did not show this pattern. Examination of the mean 8-12 Hz amplitudes across three cortical regions (frontal, central and parietal) indicated a trend of higher overall alpha levels in the parietal region in CFS patients who showed the APD pattern compared to those who did not have this pattern. All patients showing the pattern were free of medication, while 71% of those absent of the pattern were using antidepressant medications. Conclusions. Although the sample is small, it is suggested that this method of evaluating the disorder holds promise. The fact that this pattern was not consistently represented in the CFS sample could be explained by the possibility of subtypes of CFS, or perhaps co-morbid conditions. Further, the use of antidepressant medications may mask the pattern by altering the temporal characteristics of the EEG. The results of this pilot study indicate that further research is warranted to verify that the pattern holds across the wider population of CFS sufferers.

8-Ammonionaphthalene-2-sulfonate monohydrate : the zwitterionic hydrate of 1,7-Cleve's acid

The structure of 8-amino-2-naphthalenesulfonic acid monohydrate (1,7-Cleve's acid hydrate), C10H9NO3S.H2O, shows the presence of a sulfonate-aminium group zwitterion, both groups and the water molecule of solvation giving cyclic R3/3(8) intermolecular hydrogen-bonding interactions forming chains which extend down a axis of the unit cell. Additional peripheral associations, including weak aromatic ring pi-pi interactions [centroid-centroid distance 3.6299(15)A], result in a two-dimensional sheet structure.

Raman spectroscopic study of the uranyl sulphate mineral jáchymovite (UO2)8(SO4)(OH)14•13H2O

Raman spectra of jáchymovite, (UO2)8(SO4)(OH)14•13H2O, were studied, complemented with infrared spectra, and compared with published Raman and infrared spectra of uranopilite, [(UO2)6(SO4)O2(OH)6(H2O)6] •6H2O. Bands related to the stretching and bending vibrations of (UO2)2+, (SO4)2-, (OH)- and water molecules were assigned. U-O bond lengths in uranyl and O-H…O hydrogen bond lengths were calculated from the Raman and infrared spectra.

An examination of the utility of the AUDIT in people with schizophrenia

Objective: To examine the reliability and validity of the Alcohol Use Disorders Identification Test (AUDIT) compared to a structured diagnostic interview, the Composite international Diagnostic Interview (CIDI; 12-month version) in psychiatric patients with a diagnosis of schizophrenia. Method: Patients (N = 71, 53 men) were interviewed using the CIDI (Alcohol Misuse Section; 12-month version) and then completed the AUDIT. Results: The CIDI identified 32.4% of the sample as having an alcohol use disorder. Of these, 5 (7.0%) met diagnostic criteria for harmful use of alcohol, 1 (1.4%) met diagnostic criteria for alcohol abuse and 17 (23.9%) met diagnostic criteria for alcohol dependence. The AUDIT was found to have good internal reliability (coefficient = 0.85). An AUDIT cutoff of greater than or equal to 8 had a sensitivity of 87% and specificity of 90% in detecting CIDI-diagnosed alcohol disorders. All items except Item 9 contributed significantly to discriminant validity. Conclusions: The findings replicate and extend previous findings of high rates of alcohol use disorders in people with severe mental illness. The AUDIT was found to be reliable and valid in this sample and can be used with confidence as a screening instrument for alcohol use disorders in people with schizophrenia.

(-)-CGP12177 increases contractile force through beta1l-adrenoceptors but not through beta3-adrenoceptors in human right atrial myocardium

(-)-CGP12177 is a non-conventional partial agonist that causes modest and transient increases of contractile force in human atrial trabeculae (Kaumann and Molenaar, 2008). These effects are markedly increased and maintained by inhibition of phosphodiesterase PDE3. As verified with recombinant receptors, the cardiostimulant effect of (-)-CGP12177 is mediated through a site at the beta1-adrenoceptor with lower affinity (beta1LAR) compared to the site through which (-)-CGP12177 antagonizes the effects of catecholamines (beta1HAR). However, in a recent report it was proposed that the positive inotropic effects of CGP12177 are mediated through beta3-adrenoceptors (Skeberdis et al 2008). We therefore investigated whether the effects of (-)-CGP12177 on human atrial trabeculae are antagonized by the beta3-adrenoceptor-selective antagonist L-748,337 (1 microM). (-)-CGP12177 (200 nM) caused a stable increase in force which was significantly reduced by the addition of (-)-bupranolol (1 microM), P = 0.002, (basal 4.45 ± 0.78 mN, IBMX (PDE inhibitor) 5.47 ± 1.01 mN, (-)-CGP12177 9.34 ± 1.33 mN, (-)-bupranolol 5.79 ± 1.08 mN, n = 6) but not affected by the addition of L-748,337 (1 microM), P = 0.12, (basal 4.48 ± 1.32 mN, IBMX 7.15 ± 2.28 mN, (-)-CGP12177 12.51 ± 3.71 mN, L-748,337 10.90 ± 3.49 mN, n = 6). Cumulative concentration-effect curves for (-)-CGP12177 were not shifted to the right by L-748,337 (1 microM). The –logEC50M values of (-)-CGP12177 in the absence and presence of L-748,337 were 7.21±0.09 and 7.41±0.13, respectively (data from 25 trabeculae from 8 patients, P=0.2) The positive inotropic effects of (-)-CGP12177 (IBMX present) were not antagonized by L-748,337 but were blunted by (-)-bupranolol (1 microM). The results rule out an involvement of beta3-adrenoceptors in the positive inotropic effects (-)-CGP12177 in human right atrial myocardium and are consistent with mediation through beta1LAR. Kaumann A and Molenaar P (2008) Pharmacol Ther 118, 303-336 Skeberdis VA et al (2008) J Clin Invest, 118, 3219-3227

Year 8, 9 and 10 students’ understanding and access of percent knowledge

This paper reports on Years 8, 9 and 10 students’ knowledge of percent problem types, use of diagrams, and type of solution strategy. Non- and semi-proficient students displayed the expected inflexible formula approach to solution but proficient students used a flexible mixture of estimation, number sense and trial and error instead of expected schema based methods.

A comparison of executive function in very preterm and term infants at 8 months corrected age

Executive function (EF) emerges in infancy and continues to develop throughout childhood. Executive dysfunction is believed to contribute to learning and attention problems in children at school age. Children born very preterm are more prone to these problems than their full-term peers.

Quality issues for the National Bowel Cancer Screening Program (NBCSP)

Purpose: This two-part research project was undertaken as part of the planning process by Queensland Health (QH), Cancer Screening Services Unit (CSSU), Queensland Bowel Cancer Screening Program (QBCSP), in partnership with the National Bowel Cancer Screening Program (NBCSP), to prepare for the implementation of the NBCSP in public sector colonoscopy services in QLD in late 2006. There was no prior information available on the quality of colonoscopy services in Queensland (QLD) and no prior studies that assessed the quality of colonoscopy training in Australia. Furthermore, the NBCSP was introduced without extra funding for colonoscopy service improvement or provision for increases in colonoscopic capacity resulting from the introduction of the NBCSP. The main purpose of the research was to record baseline data on colonoscopy referral and practice in QLD and current training in colonoscopy Australia-wide. It was undertaken from a quality improvement perspective. Implementation of the NBCSP requires that all aspects of the screening pathway, in particular colonoscopy services for the assessment of positive Faecal Occult Blood Tests (FOBTs), will be effective, efficient, equitable and evidence-based. This study examined two important aspects of the continuous quality improvement framework for the NBCSP as they relate to colonoscopy services: (1) evidence-based practice, and (2) quality of colonoscopy training. The Principal Investigator was employed as Senior Project Officer (Training) in the QBCSP during the conduct of this research project. Recommendations from this research have been used to inform the development and implementation of quality improvement initiatives for provision of colonoscopy in the NBCSP, its QLD counterpart the QBCSP and colonoscopy services in QLD, in general. Methods – Part 1 Chart audit of evidence-based practice: The research was undertaken in two parts from 2005-2007. The first part of this research comprised a retrospective chart audit of 1484 colonoscopy records (some 13% of all colonoscopies conducted in public sector facilities in the year 2005) in three QLD colonoscopy services. Whilst some 70% of colonoscopies are currently conducted in the private sector, only public sector colonoscopy facilities provided colonoscopies under the NBCSP. The aim of this study was to compare colonoscopy referral and practice with explicit criteria derived from the National Health & Medical Research Council (NHMRC) (1999) Clinical Practice Guidelines for the Prevention, Early Detection and Management of Colorectal Cancer, and describe the nature of variance with the guidelines. Symptomatic presentations were the most common indication for colonoscopy (60.9%). These comprised per rectal bleeding (31.0%), change of bowel habit (22.1%), abdominal pain (19.6%), iron deficiency anaemia (16.2%), inflammatory bowel disease (8.9%) and other symptoms (11.4%). Surveillance and follow-up colonoscopies accounted for approximately one-third of the remaining colonoscopy workload across sites. Gastroenterologists (GEs) performed relatively more colonoscopies per annum (59.9%) compared to general surgeons (GS) (24.1%), colorectal surgeons (CRS) (9.4%) and general physicians (GPs) (6.5%). Guideline compliance varied with the designation of the colonoscopist. Compliance was lower for CRS (62.9%) compared to GPs (76.0%), GEs (75.0%), GSs (70.9%, p<0.05). Compliance with guideline recommendations for colonoscopic surveillance for family history of colorectal cancer (23.9%), polyps (37.0%) and a past history of bowel cancer (42.7%), was by comparison significantly lower than for symptomatic presentations (94.4%), (p<0.001). Variation with guideline recommendations occurred more frequently for polyp surveillance (earlier than guidelines recommend, 47.9%) and follow-up for past history of bowel cancer (later than recommended, 61.7%, p<0.001). Bowel cancer cases detected at colonoscopy comprised 3.6% of all audited colonoscopies. Incomplete colonoscopies occurred in 4.3% of audited colonoscopies and were more common among women (76.6%). For all colonoscopies audited, the rate of incomplete colonoscopies for GEs was 1.6% (CI 0.9-2.6), GPs 2.0% (CI 0.6-7.2), GS 7.0% (CI 4.8-10.1) and CRS 16.4% (CI 11.2-23.5). 18.6% (n=55) of patients with a documented family history of bowel cancer had colonoscopy performed against guidelines recommendations (for general (category 1) population risk, for reasons of patient request or family history of polyps, rather than for high risk status for colorectal cancer). In general, family history was inadequately documented and subsequently applied to colonoscopy referral and practice. Methods - Part 2 Surveys of quality of colonoscopy training: The second part of the research consisted of Australia-wide anonymous, self-completed surveys of colonoscopy trainers and their trainees to ascertain their opinions on the current apprenticeship model of colonoscopy in Australia and to identify any training needs. Overall, 127 surveys were received from colonoscopy trainers (estimated response rate 30.2%). Approximately 50% of trainers agreed and 27% disagreed that current numbers of training places were adequate to maintain a skilled colonoscopy workforce in preparation for the NBCSP. Approximately 70% of trainers also supported UK-style colonoscopy training within dedicated accredited training centres using a variety of training approaches including simulation. A collaborative approach with the private sector was seen as beneficial by 65% of trainers. Non-gastroenterologists (non-GEs) were more likely than GEs to be of the opinion that simulators are beneficial for colonoscopy training (χ2-test = 5.55, P = 0.026). Approximately 60% of trainers considered that the current requirements for recognition of training in colonoscopy could be insufficient for trainees to gain competence and 80% of those indicated that ≥ 200 colonoscopies were needed. GEs (73.4%) were more likely than non-GEs (36.2%) to be of the opinion that the Conjoint Committee standard is insufficient to gain competence in colonoscopy (χ2-test = 16.97, P = 0.0001). The majority of trainers did not support training either nurses (73%) or GPs in colonoscopy (71%). Only 81 (estimated response rate 17.9%) surveys were received from GS trainees (72.1%), GE trainees (26.3%) and GP trainees (1.2%). The majority were males (75.9%), with a median age 32 years and who had trained in New South Wales (41.0%) or Victoria (30%). Overall, two-thirds (60.8%) of trainees indicated that they deemed the Conjoint Committee standard sufficient to gain competency in colonoscopy. Between specialties, 75.4% of GS trainees indicated that the Conjoint Committee standard for recognition of colonoscopy was sufficient to gain competence in colonoscopy compared to only 38.5% of GE trainees. Measures of competency assessed and recorded by trainees in logbooks centred mainly on caecal intubation (94.7-100%), complications (78.9-100%) and withdrawal time (51-76.2%). Trainees described limited access to colonoscopy training lists due to the time inefficiency of the apprenticeship model and perceived monopolisation of these by GEs and their trainees. Improvements to the current training model suggested by trainees included: more use of simulation, training tools, a United Kingdom (UK)-style training course, concentration on quality indicators, increased access to training lists, accreditation of trainers and interdisciplinary colonoscopy training. Implications for the NBCSP/QBCSP: The introduction of the NBCSP/QBCSP necessitates higher quality colonoscopy services if it is to achieve its ultimate goal of decreasing the incidence of morbidity and mortality associated with bowel cancer in Australia. This will be achieved under a new paradigm for colonoscopy training and implementation of evidence-based practice across the screening pathway and specifically targeting areas highlighted in this thesis. Recommendations for improvement of NBCSP/QBCSP effectiveness and efficiency include the following: 1. Implementation of NBCSP and QBCSP health promotion activities that target men, in particular, to increase FOBT screening uptake. 2. Improved colonoscopy training for trainees and refresher courses or retraining for existing proceduralists to improve completion rates (especially for female NBCSP/QBCSP participants), and polyp and adenoma detection and removal, including newer techniques to detect flat and depressed lesions. 3. Introduction of colonoscopy training initiatives for trainees that are aligned with NBCSP/QBCSP colonoscopy quality indicators, including measurement of training outcomes using objective quality indicators such as caecal intubation, withdrawal time, and adenoma detection rate. 4. Introduction of standardised, interdisciplinary colonoscopy training to reduce apparent differences between specialties with regard to compliance with guideline recommendations, completion rates, and quality of polypectomy. 5. Improved quality of colonoscopy training by adoption of a UK-style training program with centres of excellence, incorporating newer, more objective assessment methods, use of a variety of training tools such as simulation and rotations of trainees between metropolitan, rural, and public and private sector training facilities. 6. Incorporation of NHMRC guidelines into colonoscopy information systems to improve documentation, provide guideline recommendations at the point of care, use of gastroenterology nurse coordinators to facilitate compliance with guidelines and provision of guideline-based colonoscopy referral letters for GPs. 7. Provision of information and education about the NBCSP/QBCSP, bowel cancer risk factors, including family history and polyp surveillance guidelines, for participants, GPs and proceduralists. 8. Improved referral of NBCSP/QBCSP participants found to have a high-risk family history of bowel cancer to appropriate genetics services.