A model for malaria treatment evaluation in the presence of multiple species.

Plasmodium falciparum and P. vivax are the two most common causes of malaria. While the majority of deaths and severe morbidity are due to P. falciparum, P. vivax poses a greater challenge to eliminating malaria outside of Africa due to its ability to form latent liver stage parasites (hypnozoites), which can cause relapsing episodes within an individual patient. In areas where P. falciparum and P. vivax are co-endemic, individuals can carry parasites of both species simultaneously. These mixed infections complicate dynamics in several ways: treatment of mixed infections will simultaneously affect both species, P. falciparum can mask the detection of P. vivax, and it has been hypothesised that clearing P. falciparum may trigger a relapse of dormant P. vivax. When mixed infections are treated for only blood-stage parasites, patients are at risk of relapse infections due to P. vivax hypnozoites. We present a stochastic mathematical model that captures interactions between P. falciparum and P. vivax, and incorporates both standard schizonticidal treatment (which targets blood-stage parasites) and radical cure treatment (which additionally targets liver-stage parasites). We apply this model via a hypothetical simulation study to assess the implications of different treatment coverages of radical cure for mixed and P. vivax infections and a "unified radical cure" treatment strategy where P. falciparum, P. vivax, and mixed infections all receive radical cure after screening glucose-6-phosphate dehydrogenase (G6PD) normal. In addition, we investigated the impact of mass drug administration (MDA) of blood-stage treatment. We find that a unified radical cure strategy leads to a substantially lower incidence of malaria cases and deaths overall. MDA with schizonticidal treatment was found to decrease P. falciparum with little effect on P. vivax. We perform a univariate sensitivity analysis to highlight important model parameters.

Clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation (CASSETTE)-an open-labelled pilot randomized controlled trial.

BACKGROUND: Combination antibiotic therapy with an antitoxin agent, such as clindamycin, is included in some guidelines for severe, toxin-mediated Staphylococcus aureus infections. The evidence to support this practice is currently limited to in vitro, animal and observational human case-series data, with no previous randomized controlled trials (RCTs). OBJECTIVES: This pilot RCT aimed to determine the feasibility of conducting a clinical trial to examine if adjunctive clindamycin with standard therapy has greater efficacy than standard therapy alone for S. aureus infections. METHODS: We performed an investigator-initiated, open-label, multicentre, pilot RCT (ACTRN12617001416381p) in adults and children with severe S. aureus infections, randomized to standard antibiotic therapy with or without clindamycin for 7 days. RESULTS: Over 28 months, across nine sites, 127 individuals were screened and 34 randomized, including 11 children (32%). The primary outcome-number of days alive and free of systemic inflammatory response syndrome ≤14 days-was similar between groups: clindamycin (3 days [IQR 1-6]) versus standard therapy (4 days [IQR 0-8]). The 90 day mortality was 0% (0/17) in the clindamycin group versus 24% (4/17) in the standard therapy group. Secondary outcomes-microbiological relapse, treatment failure or diarrhoea-were similar between groups. CONCLUSIONS: As the first clinical trial assessing adjunctive clindamycin for S. aureus infections, this study indicates feasibility and that adults and children can be incorporated into one trial using harmonized endpoints, and there were no safety concerns. The CASSETTE trial will inform the definitive S. aureus Network Adaptive Platform (SNAP) trial, which includes an adjunctive clindamycin domain and participants with non-severe disease.

Histopathological frequency of feline hepatobiliary disease in the UK.

OBJECTIVES: To determine the histopathological frequency of feline hepatobiliary diseases in the UK and to identify breed, age and gender predispositions to developing individual diseases. METHODS: Histopathology results from 1452 feline liver biopsies were assessed. A control population of microchipped cats was used for breed comparison. Data were retrospectively categorised into hepatobiliary diseases according to World Small Animal Veterinary Association standards. Odds ratios and 95% confidence intervals were calculated to determine breed predispositions to the 10 most frequent diseases. Gender and age distributions were also evaluated. RESULTS: The most frequent diseases based on histopathology were neutrophilic cholangitis (20·5%), reactive hepatitis (20·4%), reversible hepatocellular injury (8·4%), lymphocytic cholangitis (6·8%), biliary cysts (5·7%), acute hepatitis (5·6%), haematopoietic neoplasia (5·6%), hepatocellular neoplasia (4·9%), congenital portosystemic shunt (3·8%) and cholangiocellular neoplasia (3·1%). Some previously unreported breed and age predispositions were identified. CLINICAL SIGNIFICANCE: This is the first study to document the histopathological frequency of hepatobiliary diseases in a large cohort of cats in the UK, as well as novel breed and age predispositions. These data may help increase the index of suspicion of a particular disease in the absence of a biopsy-confirmed diagnosis.

Inferring within-host bottleneck size: A Bayesian approach.

Recent technical developments in microbiology have led to new discoveries on the within-host dynamics of bacterial infections in laboratory animals. In particular, they have highlighted the importance of stochastic bottlenecks at the onset of invasive disease. A number of approaches exist for bottleneck-size estimation with respect to within-host bacterial infections; however, some are more appropriate than others under certain circumstances. A Bayesian comparison of several approaches is made in terms of the availability of isogenic multitype bacteria (e.g., WITS), knowledge of post-bottleneck dynamics, and the suitability of dilution with monotype bacteria. A sampling approach to bottleneck-size estimation is also introduced. The results are summarised by a guiding flowchart, which we hope will promote the use of quantitative models in microbiology to refine the analysis of animal experiment data.

Domain-wall spin dynamics in kagome antiferromagnets.

We report magnetization and neutron scattering measurements down to 60 mK on a new family of Fe based kagome antiferromagnets, in which a strong local spin anisotropy combined with a low exchange path network connectivity lead to domain walls intersecting the kagome planes through strings of free spins. These produce unfamiliar slow spin dynamics in the ordered phase, evolving from exchange-released spin flips towards a cooperative behavior on decreasing the temperature, probably due to the onset of long-range dipolar interaction. A domain structure of independent magnetic grains is obtained that could be generic to other frustrated magnets.

Patient-initiated mandatory boluses for ambulatory continuous interscalene analgesia: an effective strategy for optimizing analgesia and minimizing side-effects.

BACKGROUND: This prospective, randomized study tested the hypothesis that a reduced dose continuous interscalene regimen incorporating a low background infusion with mandatory boluses would provide similar shoulder surgery analgesia compared with a dose regimen incorporating a conventional higher background infusion. METHODS: After rotator cuff surgery, patients received via an interscalene catheter, one of two elastomeric pumps, each having a 5 ml per 60 min bolus function and a 2 ml h⁻¹ (n=38) or 5 ml h⁻¹ (n=43) ropivacaine 2 mg ml⁻¹ infusion. Boluses commenced from the onset of pain and continued for >48 h as required (pro re nata, PRN) up to every hour for a numerical rating pain score (NRPS, 0-10) >2. Group 2 ml h⁻¹ received mandatory 6 hourly boluses irrespective of the NRPS. Rescue tramadol was available. Patients were questioned on postoperative days 1 and 2 for treatment effectiveness and side-effects. RESULTS: Postoperative pain was similar between the groups [Group 2 ml h⁻¹ day 2 median (IQR) (95% confidence interval of the mean) worst movement pain=4 (1-5) (2.8-4.7) vs 4 (2-5) (3.1-4.6), P=0.99], as were night awakenings and tramadol consumption. Numerically rated numbness and weakness were similar between the groups; however, nine patients (21%) in the 5 ml h⁻¹ group vs one (3%) in the 2 ml h⁻¹ group required a temporary infusion cessation due to side-effects (predominantly hand numbness) (P=0.02). CONCLUSIONS: Continuous interscalene ropivacaine 0.2% 2 ml h⁻¹ with mandatory 6 hourly (and PRN) boluses provides similar analgesia after rotator cuff repair but with reduced side-effects compared with 5 ml h⁻¹ with PRN only boluses.

Analgesic effectiveness of ropivacaine 0.2% vs 0.4% via an ultrasound-guided C5-6 root/superior trunk perineural ambulatory catheter.

BACKGROUND: In this prospective, randomized, triple-blinded study, we tested the hypothesis that a 48 h continuous C5-6 root/superior trunk patient-controlled infusion of ropivacaine 0.4% would provide superior analgesia after shoulder surgery compared with the same infusion of ropivacaine 0.2%. METHODS: Patients presenting for painful shoulder surgery were recruited. A perineural catheter was placed under ultrasound guidance immediately adjacent to the C5-6 roots/superior trunk. Ropivacaine 5 mg ml(-1) (30 ml) was administered via this catheter before surgery under general anaesthesia. At the end of surgery, patients were randomized to receive ropivacaine 2 mg ml(-1) (0.2%) (n=32) or 4 mg ml(-1) (0.4%) (n=33) via an elastomeric pump delivering 2 ml h(-1) with on-demand patient-controlled boluses of 5 ml as required. Acetaminophen and diclofenac were administered if any postoperative pain occurred, ropivacaine boluses for a numerical rating pain score (NRPS, 0-10) of >2, and rescue tramadol for an NRPS >3. All patients were phoned on postoperative days 1 and 2 and questioned for indices of treatment effectiveness and adverse effects. RESULTS: NRPS, patient ropivacaine demands, and supplemental tramadol consumption were similar in each group [median 'average daily pain' days 1/2 (0.2%=1/3, 0.4%=2/3)]. Episodes of an insensate/densely blocked arm occurred only with ropivacaine 0.4% (5 vs 0 episodes, P=0.05). Satisfaction (numerical rating scale, 0-10) was higher for ropivacaine 0.2% [mean difference (95% confidence interval)=1.3 (0.3-2.4), P=0.01)]. CONCLUSIONS: After major shoulder surgery, ropivacaine 0.2% at 2 ml h(-1) with on-demand 5 ml boluses administered via an ultrasound-guided C5-6 root/superior trunk perineural catheter produces similar analgesia, but higher patient satisfaction compared with ropivacaine 0.4%. TRIAL REGISTRATION: ANZCTR: ACTRN12608000591358. URL: www.anzctr.org.au/registry/trial_review.aspx?ID=83028.

The shoulder block: a new alternative to interscalene brachial plexus blockade for the control of postoperative shoulder pain.

This report describes the development of the shoulder block, an alternative to interscalene brachial plexus blockade for the control of postoperative pain following shoulder surgery. Included is a review of the relevant anatomy of the shoulder joint and its associated structures. Two nerves provide the bulk of the innervation to this area: the suprascapular nerve and the axillary (circumflex) nerve. The shoulder block technique involves selective blockade of both of these nerves instead of general blockade of the entire brachial plexus via the interscalene route. The technique of Meier is used to block the suprascapular nerve in the supraspinous fossa. No descriptions of axillary nerve block were available in the literature, so a technique for blocking this nerve as it travels across the posterior surface of the humerus was developed and is described, along with a discussion of the author's initial clinical experience.

Producing ultrastrong magnetic fields in neutron star mergers.

We report an extremely rapid mechanism for magnetic field amplification during the merger of a binary neutron star system. This has implications for the production of the short class of gamma-ray bursts, which recent observations suggest may originate in such mergers. In detailed magnetohydrodynamic simulations of the merger process, the fields are amplified by Kelvin-Helmholtz instabilities beyond magnetar field strength and may therefore represent the strongest magnetic fields in the universe. The amplification occurs in the shear layer that forms between the neutron stars and on a time scale of only 1 millisecond, that is, long before the remnant can collapse into a black hole.

One year results of the Middlesbrough early revascularisation to limit infarction (MERLIN) trial.

OBJECTIVE: To report one year results of the MERLIN (Middlesbrough early revascularisation to limit infarction) trial, a prospective randomised trial comparing the strategy of coronary angiography and urgent revascularisation with conservative treatment in patients with failed fibrinolysis complicating ST segment elevation myocardial infarction (STEMI). The 30 day results have recently been published. At the planning stage of the trial, it was determined that follow up of trial patients would continue annually to three years to determine whether late benefit occurred. SUBJECTS: 307 patients who received a fibrinolytic for STEMI but failed to reperfuse early according to previously described ECG criteria and did not develop cardiogenic shock. METHODS: Patients were randomly assigned to receive either emergency coronary angiography with a view to proceeding to urgent revascularisation (rescue percutaneous coronary intervention (rPCI) arm) or continued medical treatment (conservative arm). The primary end point was all cause mortality at 30 days. The secondary end points included the composite end point of death, reinfarction, stroke, unplanned revascularisation, or heart failure at 30 days. The same end points were evaluated at one year and these results are presented. RESULTS: All cause mortality at one year was similar in the conservative arm and the rPCI arm (13.0% v 14.4%, p = 0.7, risk difference (RD) -1.4%, 95% confidence interval (CI) -9.3 to 6.4). The incidence of the composite secondary end point of death, reinfarction, stroke, unplanned revascularisation, or heart failure was significantly higher in the conservative arm (57.8% v 43.1%, p = 0.01, RD 14.7%, 95% CI 3.5% to 25.5%). This was driven almost exclusively by a significantly higher incidence of subsequent unplanned revascularisation in the conservative arm (29.9% v 12.4%, p < 0.001, RD 17.5%, 95% CI 8.5% to 26.4%). Reinfarction and clinical heart failure were numerically, but not statistically, more common in the conservative arm (14.3% v 10.5%, p = 0.3, RD 3.8%, 95% CI -3.7 to 11.4, and 31.2% v 26.1%, p = 0.3, RD 5.0%, 95% CI -5.1 to 15.1). There was a strong trend towards fewer strokes in the conservative arm (1.3% v 5.2%, p = 0.06, RD -3.9%, 95% CI -8.9 to 0.06). CONCLUSION: At one year of follow up, there was no survival advantage in the rPCI arm compared with the conservative arm. The incidence of the composite secondary end point was significantly lower in the rPCI arm, but this was driven almost entirely by a highly significant reduction in the incidence of further revascularisation.

The management of patients with ischaemic heart disease undergoing non-cardiac elective surgery: a survey of Australian and New Zealand clinical practice.

Improvements in patient risk stratification and peri-operative beta-blockade have been suggested as methods which can reduce cardiovascular risk in patients with known cardiac risk factors. A postal questionnaire was sent to all Australian and New Zealand teaching hospitals to identify patterns of pre-operative cardiac risk evaluation and methods of peri-operative beta-blocker use. In all, 67 replies were evaluated (64% response rate). Specialist anaesthetists are present in the majority of pre-admission clinics (78%), with a designated peri-operative physician in 9%. Further cardiological referral was possible in almost all institutions (96%), and specific peri-operative physician referral in 54%. Waiting times for specialist consultation were < 7 days in the majority of cases. Whilst 79% of institutions used peri-operative beta-blockade, specific protocols were available in only 10%. In 60% of institutions, beta-blockers were administered to high-risk patients, and in 25% they were given to intermediate risk group patients. There was a wide range in the duration of pre- and postoperative beta-blocker administration. Whilst peri-operative risk assessment appears to be consistent, the pattern of beta-blockade, a known beneficial intervention, is variable. Reasons need to be identified, protocols developed and consistent administration targeted for further improvements to be made.

Early and late reactions following the use of iopamidol 340, iomeprol 350 and iodixanol 320 in cardiac catheterization.

GOAL: To investigate the incidence of early (< 24 hours) and late (> 24 hours to 7 days) reactions to 3 contrast agents commonly used in cardiac catheterization. METHODS AND RESULTS: A total of 2,108 patients undergoing cardiac catheterization in a Regional Cardiothoracic Unit were randomly assigned to receive 1 of 3 commonly used contrast agents in a prospective, double-blind study. The contrast agents were iopamidol 340 (Niopam ), a nonionic monomer; iomeprol 350 (Iomeron ), a nonionic dimer; and iodixanol 320 (Visipaque ), a nonionic dimer. The main outcome measures were the incidence of early (< 24 hours) reactions following catheterization and the incidence of late (24 hours to 7 days) reactions. Early reactions, excluding patients with heat on left ventriculography as the sole symptom, were relatively common (7.4%), but there was no significant difference between the 3 agents (p = 0.35). Late skin reactions, excluding reactions solely at the site of the arterial puncture and continuations of early urticarial reactions, were also relatively common (5.4%), but the incidence differed between the 3 agents. Such reactions occurred in 2.7% of those receiving iopamidol 340 (Niopam ), 3.5% of those receiving iomeprol 350 (Iomeron ) and 10.4% of those receiving iodixanol 320 (Visipaque ) (p < 0.01). CONCLUSION: The incidence of early adverse reactions is similar with these 3 contrast agents. However, late skin reactions are significantly more common with iodixanol 320 (Visipaque ) than with the other 2 agents. Although such reactions were rarely troublesome, patients should be advised accordingly.

The transcription factor Pax6 is required for development of the diencephalic dorsal midline secretory radial glia that form the subcommissural organ.

During brain development, Pax6 is expressed in specific regions of the diencephalon including secretory cells of the subcommissural organ (SCO), a circumventricular organ at the forebrain-midbrain boundary that originates from the pretectal dorsal midline neuroepithelial cells beneath the posterior commissure (PC). Homozygous small eye (Sey/Sey) mice lack functional Pax6 protein and fail to develop the SCO, a normal PC and the pineal gland. Small eye heterozygotes (Sey/+) show defective development of the SCO's basal processes which normally penetrate the PC, indicating that normal development of the gland requires normal Pax6 gene-dosage. A correlation between the defects of SCO formation and altered R- and OB-cadherin expression patterns in the SCO is observed in mutants suggesting a role for cadherins in SCO development.

Improved convergence of binding affinities with free energy perturbation: application to nonpeptide ligands with pp60src SH2 domain.

Free Energy Perturbations (FEP) in the context of Monte Carlo (MC) simulations were conducted to predict the relative free energies of binding for a series of human Src SH2 domain ligands. Two procedures for disappearing atoms during a single-topology FEP are investigated and dramatic differences in free energy convergence behavior are seen. Comparison of these two protocols suggests that the coupling of the removal of angular constraints with the disappearance of an atom may significantly slow free energy convergence. The series of ligands under investigation here cover a range of modifications at the 3-position of 4-([[4-(cyclohexyl methoxy)benzyl]amino]carbonyl) phenyl phosphate. Unlike any other compound in this study, the 3-amide analog can form two hydrogen bonds within the region of the perturbation, one to a backbone amide hydrogen and one to a highly coordinated water molecule. Agreement with experimental trends in binding affinity is seen, although the computed relative free energy of binding of the amido compound is underestimated. These results are reconciled by examination of the hydration energies of model systems, which predict primary amides as too hydrophilic.

The fates of cells generated at the end of neurogenesis in developing mouse cortex.

Most cerebral cortical neurons are generated between embryonic days 11 and 17 (E11-17) in the mouse. Radial glial cells also proliferate during this time; they can give rise to neurons and many later transform into astrocytes. It is thought that most glial cells comprising the mature cortex, including additional astrocytes, are generated after neurogenesis is complete. Little is known about the cellular events that occur during the transition from the phase dominated by neurogenesis to that of gliogenesis. We labeled cells generated on E18 and E19 and the day of birth (P0) with bromodeoxyuridine and followed their fates over the following 20 days. Our results showed that, on E18-P0, cells divide throughout the ventricular zone, subventricular zone, intermediate zone, and to a lesser extent, the developing cortical plate, whereas neuronal precursors generated prior to E18 divide in the ventricular zone. Our results indicated that 30-40% of cells dividing on E18 give rise to neurons that migrate to the most superficial part of the cortex. The rest of the cells dividing on E18 and 76-94% of cells generated on E19 and P0 express the QKI RNA-binding protein, indicating that they either remain as multipotential progenitors or develop into glial cells. Nine to fifteen percent of cells generated on E18-P0 become glial fibrillary acidic protein-positive astrocytes. Many E19 and P0 labeled cells disappear between 2 and 20 days postlabeling, probably because they continue to divide. We conclude that the population of cells produced at the end of cortical neurogenesis is heterogeneous and comprises postmitotic neurons, glia (including astrocytes), and possibly multipotential progenitors.

Radial migration in the cerebral cortex is enhanced by signals from thalamus.

The six layered cerebral cortex derives from cells that divide in the ventricular zone and migrate to their final destination in the cortical plate (future cortex). In the mouse, cortical layer III and IV neurons undergo their final mitotic division at around E16, at which time thalamic axons are beginning to enter the cortex. We used bromodeoxyuridine-birth dating of cells in cortical slice cultures to show that the thalamus enhances the migration out of the ventricular zone of future layer III/IV cells. When cortical slices were cultured alone, less than 35% of cells born in vitro on E16 were present in the pial half of the slice after 48 h in culture. In contrast, when cortical slices were cocultured with thalamus, 69% of these cells were found in the pial half of the slice. Explants of other developing tissues did not mimic the effect of the thalamus. The thalamus had no obvious effect on cortical radial glial cells, cortical cell viability or maintenance of cortical slice structure. We found that most precursors born at a similar age but in vivo, shortly before cortical slices were isolated, migrated to the pial half of the cultured slices in the absence of a cocultured thalamic explant. Thus, E16 cortical slices cultured without thalamus permit migration of cells born in vivo and therefore already exposed to the thalamus. Our results indicate that the thalamus provides factors to E16-born cortical precursors that enhance their directed migration out of the ventricular zone to the cortical plate.

Target-derived neurotrophic factors regulate the death of developing forebrain neurons after a change in their trophic requirements.

Many neurons die as the normal brain develops. How this is regulated and whether the mechanism involves neurotrophic molecules from target cells are unknown. We found that cultured neurons from a key forebrain structure, the dorsal thalamus, develop a need for survival factors including brain-derived neurotrophic factor (BDNF) from their major target, the cerebral cortex, at the age at which they innervate it. Experiments in vivo have shown that rates of dorsal thalamic cell death are reduced by increasing cortical levels of BDNF and are increased in mutant mice lacking functional BDNF receptors or thalamocortical projections; these experiments have also shown that an increase in the rates of dorsal thalamic cell death can be achieved by blocking BDNF in the cortex. We suggest that the onset of a requirement for cortex-derived neurotrophic factors initiates a competitive mechanism regulating programmed cell death among dorsal thalamic neurons.