Thalamic volume and thalamo-cortical white matter tracts correlate with motor and verbal memory performance.

Cognitive testing and diffusion tensor imaging data from 121 normal subjects were combined to investigate the relationship between thalamic connectivity and cognitive performance. Thalamic regions were segmented based on their cortical connectivity, and regions for both ipsilateral and contralateral thalamocortical connections were identified. White matter tracts corresponding to these regions were identified and the mean fractional anisotropy, and axial and radial diffusivities within each tract were measured. Motor task performance correlated with radial diffusivity in the dominant thalamo-precentral tract. Verbal memory corresponded with the thalamic volume connected to the left temporal lobe. These data support the use of diffusion tractography to identify functionally important regions within the thalamus. Our findings provide the first robust correlation between thalamic volumes and tract characteristics with cognitive performance data in normal subjects.

Tracking type specific prevalence of human papillomavirus in cervical pre-cancer: a novel sampling strategy.

BACKGROUND: Surveillance designed to detect changes in the type-specific distribution of HPV in cervical intraepithelial neoplasia grade 3 (CIN-3) is necessary to evaluate the effectiveness of the Australian vaccination programme on cancer causing HPV types. This paper develops a protocol that eliminates the need to calculate required sample size; sample size is difficult to calculate in advance because HPV's true type-specific prevalence is imperfectly known. METHOD: A truncated sequential sampling plan that collects a variable sample size was designed to detect changes in the type-specific distribution of HPV in CIN-3. Computer simulation to evaluate the accuracy of the plan at classifying the prevalence of an HPV type as low (< 5%), moderate (5-15%), or high (> 15%) and the average sample size collected was conducted and used to assess its appropriateness as a surveillance tool. RESULTS: The plan classified the proportion of CIN-3 lesions positive for an HPV type very accurately, with >90% of simulations correctly classifying a simulated data-set with known prevalence. Misclassifying an HPV type of high prevalence as being of low prevalence, arguably the most serious kind of potential error, occurred < 0.05 times per 100 simulations. A much lower sample size (21-22 versus 40-48) was required to classify samples of high rather than low or moderate prevalence. CONCLUSIONS: Truncated sequential sampling enables the proportion of CIN-3 due to an HPV type to be accurately classified using small sample sizes. Truncated sequential sampling should be used for type-specific HPV surveillance in the vaccination era.

Isotopomer subspaces as indicators of metabolic-pathway structure.

The relative abundances and rates of formation of particular isotopic isomers (isotopomers) of metabolic intermediates from (13)C-labelled substrates in living cells provide information on the routes taken by the initial (13)C-atoms. When a primary substrate such as [U,(13)C] d-glucose is added to human erythrocytes, the pattern of labels in terminal metabolites is determined by a set of carbon-group exchange reactions in both glycolysis and the pentose phosphate pathway (PPP). Of a given terminal metabolite, not all possible isotopomers will be produced from each possible primary substrate isotopomer. There are only 8 different (13)C-isotopomers of lactate but not all of these are produced when one of the 64 possible (13)C-isotopomers of glucose is used as the input substrate; thus a subset of all 63 glucose isotopomers x 8 lactate isotopomers+1 unlabelled glucose x 1 unlabelled lactate=505 pattern associations, would be produced if a complete experimental analysis were performed with all the glucose variants. The pattern of labelling in this isotopomer subspace reflects the nature of the re-ordering reactions that 'direct' the metabolism. Predicting the combinatorial rearrangements for particular sets of reactions and comparing these with real data should enable conclusions to be drawn about which enzymes are involved in the real metabolic system. An example of the glycolysis-PPP system is discussed in the context of a debate that occurred around the F- and L-type PPPs and which one actually operates in the human RBC. As part of this discussion we introduce the term 'combinatorial deficit' of all possible isotopomers and we show that this deficit is less for the F- than the L-type pathway.

Quantifying social distancing arising from pandemic influenza.

Local epidemic curves during the 1918-1919 influenza pandemic were often characterized by multiple epidemic waves. Identifying the underlying cause(s) of such waves may help manage future pandemics. We investigate the hypothesis that these waves were caused by people avoiding potentially infectious contacts-a behaviour termed 'social distancing'. We estimate the effective disease reproduction number and from it infer the maximum degree of social distancing that occurred during the course of the multiple-wave epidemic in Sydney, Australia. We estimate that, on average across the city, people reduced their infectious contact rate by as much as 38%, and that this was sufficient to explain the multiple waves of this epidemic. The basic reproduction number, R0, was estimated to be in the range of 1.6-2.0 with a preferred estimate of 1.8, in line with other recent estimates for the 1918-1919 influenza pandemic. The data are also consistent with a high proportion (more than 90%) of the population being initially susceptible to clinical infection, and the proportion of infections that were asymptomatic (if this occurs) being no higher than approximately 9%. The observed clinical attack rate of 36.6% was substantially lower than the 59% expected based on the estimated value of R0, implying that approximately 22% of the population were spared from clinical infection. This reduction in the clinical attack rate translates to an estimated 260 per 100000 lives having been saved, and suggests that social distancing interventions could play a major role in mitigating the public health impact of future influenza pandemics.

Apparatus for rapid adjustment of the degree of alignment of NMR samples in aqueous media: verification with residual quadrupolar splittings in (23)Na and (133)Cs spectra.

NMR spectra of (23)Na(+) and (133)Cs(+) in gelatine in a silicone rubber tube that was stretched to various extents showed remarkably reproducible resonance multiplicity. The relative intensities of the components of the split peaks had ratios, 3:4:3, and 7:12:15:16:15:12:7, respectively, that conformed with those predicted using a Mathematica program. The silicone-rubber tube was sealed at its lower end by a small rubber stopper and placed inside a thick-walled glass tube. Gelatine was injected in solution into the silicone tube and 'set' by cooling below 30 degrees C. A plastic thumb-screw held the silicone tube at various degrees of extension, up to approximately 2-fold. After constituting the gel in buffers containing NaCl and CsCl, both (23)Na and (133)Cs NMR spectroscopy revealed that after stretching the initial single Lorentzian line was split into a well-resolved triplet and a heptet, respectively. This was interpreted as being due to coupling between the electric quadrupoles of the nuclei and the average electric field gradient tensor of the collagen molecules of gelatine; these molecules became progressively more aligned in the direction of the main magnetic field, B(0), of the vertical bore magnet, as the gel was stretched. This apparatus provides a simple way of demonstrating fundamental physical characteristics of quadrupolar cations, some characteristics of gelatine under stretching, and a way to invoke static distortion of red blood cells. It should be useful with these and other cell types, for studies of metabolic and membrane transport characteristics that may change when the cells are distorted, and possibly for structural studies of macromolecules.

Fixed sized samples for type-specific surveillance of human papillomavirus in genital warts.

Surveillance data suggest that human papillomavirus (HPV) vaccination in Australia is reducing the incidence of genital warts. However, existing surveillance measures do not assess the proportion of the remaining cases of warts that are caused by HPV types other than 6 or 11, against which the vaccine has no demonstrated effectiveness. Using computer simulation rather than sample size formulae, we established that genotyping at least 60 warts can accurately test whether the proportion of warts due to HPV types not targeted by the vaccine has increased (Type I error probability ≤ 0.05, Type II error probability <0.07). Standard formulae for calculating sample size, in contrast, suggest that a sample size of more than 130 would be required for this task, but using these formulae entails making several strong assumptions. Our methods require fewer assumptions and demonstrate that a smaller sample size than anticipated could be used to address the question of what proportion of post-vaccination cases of warts are due to nonvaccine types. In conjunction with indications of incidence and prevalence provided by existing surveillance measures, this could indicate the number of cases of post-vaccination warts due to nonvaccine types and hence whether type replacement is occurring.

Treating and preventing influenza in aged care facilities: a cluster randomised controlled trial.

BACKGROUND: Influenza is an important cause of morbidity and mortality for frail older people. Whilst the antiviral drug oseltamivir (a neuraminidase inhibitor) is approved for treatment and prophylaxis of influenza during outbreaks, there have been no trials comparing treatment only (T) versus treatment and prophylaxis (T&P) in Aged Care Facilities (ACFs). Our objective was to compare a policy of T versus T&P for influenza outbreaks in ACFs. METHODS AND FINDINGS: We performed a cluster randomised controlled trial in 16 ACFs, that followed a policy of either "T"-oseltamivir treatment (75 mg twice a day for 5 days)-or "T&P"-treatment and prophylaxis (75 mg once a day for 10 days) for influenza outbreaks over three years, in addition to enhanced surveillance. The primary outcome measure was the attack rate of influenza. Secondary outcomes measures were deaths, hospitalisation, pneumonia and adverse events. Laboratory testing was performed to identify the viral cause of influenza-like illness (ILI) outbreaks. The study period 30 June 2006 to 23 December 2008 included three southern hemisphere winters. During that time, influenza was confirmed as the cause of nine of the 23 ILI outbreaks that occurred amongst the 16 ACFs. The policy of T&P resulted in a significant reduction in the influenza attack rate amongst residents: 93/255 (36%) in residents in T facilities versus 91/397 (23%) in T&P facilities (p=0.002). We observed a non-significant reduction in staff: 46/216 (21%) in T facilities versus 47/350 (13%) in T&P facilities (p=0.5). There was a significant reduction in mean duration of outbreaks (T=24 days, T&P=11 days, p=0.04). Deaths, hospitalisations and pneumonia were non-significantly reduced in the T&P allocated facilities. Drug adverse events were common but tolerated. CONCLUSION: Our trial lacked power but these results provide some support for a policy of "treatment and prophylaxis" with oseltamivir in controlling influenza outbreaks in ACFs. TRIAL REGISTRATION: [corrected] Australian Clinical Trials Registry ACTRN12606000278538.

The potential cost-effectiveness of infant pneumococcal vaccines in Australia.

Over the last decade infant pneumococcal vaccination has been adopted as part of routine immunisation schedules in many developed countries. Although highly successful in many settings such as Australia and the United States, rapid serotype replacement has occurred in some European countries. Recently two pneumococcal conjugate vaccines (PCVs) with extended serotype coverage have been licensed for use, a 10-valent (PHiD-CV) and a 13-valent (PCV-13) vaccine, and offer potential replacements for the existing vaccine (PCV-7) in Australia. To evaluate the cost-effectiveness of PCV programs we developed a static, deterministic state-transition model. The perspective for costs included those to the government and healthcare system. When compared to current practice (PCV-7) both vaccines offered potential benefits, with those estimated for PHiD-CV due primarily to prevention of otitis media and PCV-13 due to a further reduction in invasive disease in Australia. At equivalent total cost to vaccinate an infant, compared to no PCV the base-case cost per QALY saved were estimated at A$64,900 (current practice, PCV-7; 3+0), A$50,200 (PHiD-CV; 3+1) and A$55,300 (PCV-13; 3+0), respectively. However, assumptions regarding herd protection, serotype protection, otitis media efficacy, and vaccination cost changed the relative cost-effectiveness of alternative PCV programs. The high proportion of current invasive disease caused by serotype 19A (as included in PCV-13) may be a decisive factor in determining vaccine policy in Australia.

Unresolved questions concerning human papillomavirus infection and transmission: a modelling perspective.

Mathematical transmission models are widely used to forecast the potential impact of interventions such as vaccination and to inform the development of health policy. Effective vaccines are now available for the prevention of cervical cancer and other diseases attributable to human papillomavirus (HPV). Considerable uncertainties remain regarding the characterisation of HPV infection and its sequelae, infectivity, and both vaccine-conferred and naturally-acquired immunity. In this review, we discuss the key knowledge gaps that impact on our ability to develop accurate models of HPV transmission and vaccination.

z-Spectra of 23Na+ in stretched gels: quantitative multiple quantum analysis.

The (23)Na NMR spectrum of NaCl in various stretched hydrogels displays a well-resolved triplet with the theoretically predicted relative intensities of the components of 3:4:3. Families of such spectra were obtained using partially-saturating radio-frequency (RF) radiation over a range of off-set frequencies; the resulting steady-state irradiation envelopes, or 'z-spectra', have the notable feature that marked suppression of the three peaks occurs when the irradiation is applied on any of them or exactly in the middle between the central peak and either of the two satellites. We present a quantum mechanical analysis that describes this phenomenon and show that it depends on double and triple quantum transitions. The physical-mathematical analysis is an extension of our quadrupolar case for HDO with (2)H NMR. The experimental procedures and results have implications for enhancement of contrast in (23)Na magnetic resonance imaging of heterogeneous systems using quadrupolar interactions.

The waiting time for inter-country spread of pandemic influenza.

BACKGROUND: The time delay between the start of an influenza pandemic and its subsequent initiation in other countries is highly relevant to preparedness planning. We quantify the distribution of this random time in terms of the separate components of this delay, and assess how the delay may be extended by non-pharmaceutical interventions. METHODS AND FINDINGS: The model constructed for this time delay accounts for: (i) epidemic growth in the source region, (ii) the delay until an infected individual from the source region seeks to travel to an at-risk country, (iii) the chance that infected travelers are detected by screening at exit and entry borders, (iv) the possibility of in-flight transmission, (v) the chance that an infected arrival might not initiate an epidemic, and (vi) the delay until infection in the at-risk country gathers momentum. Efforts that reduce the disease reproduction number in the source region below two and severe travel restrictions are most effective for delaying a local epidemic, and under favourable circumstances, could add several months to the delay. On the other hand, the model predicts that border screening for symptomatic infection, wearing a protective mask during travel, promoting early presentation of cases arising among arriving passengers and moderate reduction in travel volumes increase the delay only by a matter of days or weeks. Elevated in-flight transmission reduces the delay only minimally. CONCLUSIONS: The delay until an epidemic of pandemic strain influenza is imported into an at-risk country is largely determined by the course of the epidemic in the source region and the number of travelers attempting to enter the at-risk country, and is little affected by non-pharmaceutical interventions targeting these travelers. Short of preventing international travel altogether, eradicating a nascent pandemic in the source region appears to be the only reliable method of preventing country-to-country spread of a pandemic strain of influenza.

Modelling the population-level impact of vaccination on the transmission of human papillomavirus type 16 in Australia.

BACKGROUND: Vaccines are now available to prevent the development of cervical cancer from genital human papillomavirus (HPV) infection. The decision to vaccinate depends on a vaccine's cost-effectiveness. A rigorous cost-effectiveness model for vaccinated individuals is presented in a companion paper; this paper investigates the additional benefits the community might receive from herd immunity. METHODS: A mathematical model was developed to estimate the impact of a prophylactic vaccine on transmission of HPV type 16 in Australia. The model was used to estimate the expected reduction in HPV incidence and prevalence as a result of vaccination, the time required to achieve these reductions, and the coverage required for elimination. The modelled population was stratified according to age, gender, level of sexual activity and HPV infection status using a differential equation formulation. Clinical trials show that the vaccine is highly effective at preventing persistent infection and pre-cancerous lesions. These trials do not, however, provide conclusive evidence that infection is prevented altogether. The possible modes of vaccine action were investigated to see how vaccination might change the conclusions. RESULTS: The model predicts that vaccination of 80% of 12-year-old girls will eventually reduce HPV 16 prevalence by 60-100% in vaccinated and 7-31% in unvaccinated females. If 80% of boys are also vaccinated, reductions will be 74-100% in vaccinated and 86-96% in unvaccinated females. A campaign covering only 12-year-old girls would require 5-7 years to achieve 50% of the eventual reduction. With a catch-up campaign covering 13-26-year-olds, this delay would be reduced to only 2 years. Unrealistically high coverage in both sexes would be required to eliminate HPV 16 from the population. Under pessimistic assumptions about the duration of vaccine-conferred immunity, HPV 16 incidence is predicted to rise in some older age groups. CONCLUSIONS: Mass vaccination with a highly effective vaccine against HPV 16 has the potential to substantially reduce the incidence and prevalence of infection. Catch-up vaccination offers the potential to substantially reduce the delay before the benefits of vaccination are observed. A booster vaccination might be required to prevent an increase in incidence of infection in women over 25 years of age.

Determination of Na+ binding parameters by relaxation analysis of selected 23Na NMR coherences: RNA, BSA and SDS.

Nuclear magnetic resonance provides several unique means of investigating the interactions between different inorganic ions and various macromolecules. (23)Na is a quadrupolar nucleus, meaning that relaxation analysis of the various coherences allows the measurement of its binding to biological macromolecules. In this study, we analyzed the quadrupolar relaxation of (23)Na(+) longitudinal magnetization and single- and triple-quantum coherences in aqueous systems containing RNA, bovine serum albumin and sodium dodecyl sulfate micelles. The effectiveness of the James-Noggle method for determining binding constants was evaluated in these systems, and also the applicability of various (23)Na coherences in providing information on the extent and affinity of binding to the three different classes of biomolecules.

Chemical shift and magnetic susceptibility contributions to the separation of intracellular and supernatant resonances in variable angle spinning NMR spectra of erythrocyte suspensions.

Factors contributing to the observation of two separate water resonance arising from erythrocyte suspensions under magic- and variable-angle spinning conditions were examined. By observing the 1H NMR spectra of different chemical species in erythrocytes at different spinning angles, two major effects of comparable magnitude were shown to contribute to the separation: 1) an isotropic chemical shift difference, and 2) a susceptibility difference between the intracellular and supernatant compartments. When the sample was spun at the magic angle, the susceptibility difference did not contribute to the separation. Use of different angles between the spinning axis and the main magnetic field provided a method for quantifiying the isotropic chemical shift and susceptibility differences between the compartments.