The mediating role of socioeconomic status on the relationship between pregnancy history and later-life cognition.

OBJECTIVE: The association of pregnancy with later-life cognition is not well understood. We examined whether full-term and incomplete pregnancies were associated with cognition in a sample of postmenopausal women, and whether socioeconomic status (SES) factors mediated these relationships. METHODS: A total of 1016 cognitively normal women from the National Health and Nutrition Examination Survey (NHANES) were examined. Cognitive measures included the Digit Symbol Substitution Test (DSST), Animal Fluency (AF) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning (CERAD-WL) and Delayed Recall (CERAD-DR) tasks. Analyses examined the relationship between the number of term and incomplete pregnancies with cognitive performance, as well as the mediating effects of education and the federal income-to-poverty ratio (PIR). RESULTS: A greater number of term pregnancies was associated with worse performance on the DSST (ß = -0.09, 95% confidence interval [CI]: -0.12, -0.06), AF (ß = -0.03, 95% CI: -0.07, 0.00) and CERAD-DR (ß = -0.04, 95% CI: -0.08, -0.01). More incomplete pregnancies were associated with better CERAD-DR performance (ß = 0.07, 95% CI: 0.01, 0.13), and 28% (95% CI: 0.17, 0.42) of the association of term pregnancies with the DSST was mediated by the PIR. CONCLUSIONS: A higher number of term pregnancies was associated with worse cognitive performance, whereas a higher number of incomplete pregnancies was associated with better cognitive performance. Results indicate the necessity to consider SES factors when studying the relationship between pregnancy and cognition.

Validation and reproducibility of an Australian caffeine food frequency questionnaire.

The aim of this study was to measure validity and reproducibility of a caffeine food frequency questionnaire (C-FFQ) developed for the Australian population. The C-FFQ was designed to assess average daily caffeine consumption using four categories of food and beverages including; energy drinks; soft drinks/soda; coffee and tea and chocolate (food and drink). Participants completed a seven-day food diary immediately followed by the C-FFQ on two consecutive days. The questionnaire was first piloted in 20 adults, and then, a validity/reproducibility study was conducted (n = 90 adults). The C-FFQ showed moderate correlations (r = .60), fair agreement (mean difference 63 mg) and reasonable quintile rankings indicating fair to moderate agreement with the seven-day food diary. To test reproducibility, the C-FFQ was compared to itself and showed strong correlations (r = .90), good quintile rankings and strong kappa values (κ = 0.65), indicating strong reproducibility. The C-FFQ shows adequate validity and reproducibility and will aid researchers in Australia to quantify caffeine consumption.

Tick abundances in South London parks and the potential risk for Lyme borreliosis to the general public.

Tick abundances and prevalences of infection with Borrelia burgdorferi sensu lato, the causative agent of Lyme disease, were investigated in four South London parks. A total of 360 transects were sampled using three methods of collection (blanket, leggings and flags) simultaneously. No ticks were found on Wimbledon Common or at Hampton Court, but 1118 Ixodes ricinus (Ixodida: Ixodidae) ticks were collected at Richmond and Bushy Parks. At Richmond Park, lower canopy humidity [odds ratio (OR) 0.94; P = 0.005], increased mat depth (OR 1.15; P < 0.001) and increased soil moisture (OR 1.40; P = 0.001) predicted the presence of I. ricinus, and increased sward height [incidence rate ratio (IRR) 1.01; P = 0.006] and decreased ground temperature (IRR 0.90; P = 0.009) predicted increased abundance. At Bushy Park, thicker mat depth predicted tick presence (OR 1.17; P = 0.006) and increasing temperature correlated with tick absence (OR 0.57; P = 0.023). A total of 279 ticks were screened for the presence of B. burgdorferi using quantitative polymerase chain reaction. Point prevalences of 0% for larvae (n = 78), 2.14% for nymphs (n = 174) and 0% for adult ticks (n = 7) related to an acarological risk of 0.22 infected ticks per 40 m transect in Richmond Park. The abundance of ticks and the acarological risk, particularly at Richmond Park, highlight the need for appropriate communication of the associated risk to the general public frequenting these recreational areas.

Pilot phase I/II personalized therapy trial for metastatic colorectal cancer: evaluating the feasibility of protein pathway activation mapping for stratifying patients to therapy with imatinib and panitumumab.

This nonrandomized phase I/II trial assessed the efficacy/tolerability of imatinib plus panitumumab in patients affected by metastatic colorectal cancer (mCRC) after stratification to treatment by selection of activated imatinib drug targets using reverse-phase protein array (RPPA). mCRC patients presenting with a biopsiable liver metastasis were enrolled. Allocation to the experimental and control arms was established using functional pathway activation mapping of c-Kit, PDGFR, and c-Abl phosphorylation by RPPA. The experimental arm received run-in escalation therapy with imatinib followed by panitumumab. The control arm received panitumumab alone. Seven patients were enrolled in the study. For three of the seven patients, sequential pre- and post-treatment biopsies were used to evaluate the effect of the therapeutic compounds on the drug targets and substrates. A decrease in the activation level of the drug targets and downstream substrates was observed in two of three patients. Combination therapy increased the activation of the AKT-mTOR pathway and several receptor tyrosine kinases. This study proposes a novel methodology for stratifying patients to personalized treatment based on the activation level of the drug targets. This workflow provides the ability to monitor changes in the signaling pathways after the administration of targeted therapies and to identify compensatory mechanisms.

Insecticide-treated clothes for the control of vector-borne diseases: a review on effectiveness and safety.

Insecticide-treated clothing has been used for many years by the military and in recreational activities as personal protection against bites from a variety of arthropods including ticks, chigger mites, sandflies and mosquitoes. Permethrin is the most commonly used active ingredient, but others, including bifenthrin, deltamethrin, cyfluthrin, DEET (N,N-diethyl-3-methylbenz-amide) and KBR3023, have also been trialled. Treatment is usually carried out by home or factory dipping. However, new microencapsulation technologies which may prolong the activity of insecticides on clothing are now available and may help to overcome the inevitable reduction in efficacy over time that occurs as a result of washing, ultraviolet light exposure, and the normal wear and tear of the fabric. The aim of this article is to review the evidence base for the use of insecticide-treated clothing for protection against bites from arthropods and its effect on arthropod-borne pathogen transmission. Although some studies do demonstrate protection against pathogen transmission, there are surprisingly few, and the level of protection provided varies according to the disease and the type of study conducted. For example, insecticide-treated clothing has been reported to give between 0% and 75% protection against malaria and between 0% and 79% protection against leishmaniasis. Studies vary in the type of treatment used, the age group of participants, the geographical location of the study, and the pathogen transmission potential. This makes it difficult to compare and assess intervention trials. Overall, there is substantial evidence that insecticide-treated clothing can provide protection against arthropod bites. Bite protection evidence suggests that insecticide-treated clothing may be useful in the prevention of pathogen transmission, but further investigations are required to accurately demonstrate transmission reduction.

A tool to aid talking about dementia and dying--development and evaluation.

BACKGROUND: Health professionals often avoid talking about death and dying with patients and relatives, and this avoidance is compounded in cases of dementia by lack of knowledge of trajectory and prognosis. Unfortunately, this impacts on care, with many terminally ill dementia clients receiving inadequate palliation and excessive intervention at end-of-life. This study developed and evaluated a tool to facilitate conversations about death and dying in aged care facilities. METHODS: This study utilised available best-practice evidence, feedback from aged care facility nursing and care staff and specialist input to develop the 'discussion tool', which was subsequently trialled and qualitatively evaluated, via thematic analysis of data from family interviews and staff diaries. The study was part of a larger mixed method study, not yet reported. The tool provided knowledge and also skills-based 'how to' information and specific examples of 'what to say'. RESULTS: The tool facilitated a more open dialogue between dementia palliation resource nurses (a role specifically developed during this project) and family members. Both resource nurses and family members gained confidence in discussing the death of their relative with dementia, and in relevant cases discussed specific decisions around future care. Family members and nurses reported satisfaction with these discussions. CONCLUSION: Providing specific skills-based support, such as the 'discussion tool' can help staff to gain confidence and change practice in situations where unfamiliar and uncomfortable practices might normally be avoided. As our populations age, health professionals will increasingly need to be able to openly discuss care options towards end-of-life.

Landscape genetics of an early successional specialist in a disturbance-prone environment.

Species that specialize in disturbed habitats may have considerably different dispersal strategies than those adapted to more stable environments. However, little is known of the dispersal patterns and population structure of such species. This information is important for conservation because many postfire specialists are at risk from anthropogenic changes to natural disturbance regimes. We used microsatellite markers to assess the effect of landscape variation and recent disturbance history on dispersal by a small mammal species that occupies the early seral stage of vegetation regeneration in burnt environments. We predicted that a postfire specialist would be able to disperse over multiple habitat types (generalist) and not exhibit sex-biased dispersal, as such strategies should enable effective colonization of spatially and temporally variable habitat. We found significant differentiation between sites that fitted an isolation-by-distance pattern and spatial autocorrelation of multilocus genotypes to a distance of 2-3 km. There was no consistent genetic evidence for sex-biased dispersal. We tested the influence of different habitat- and fire-specific landscape resistance scenarios on genetic distance between individuals and found a significant effect of fire. Our genetic data supported recently burned vegetation having greater conductance for gene flow than unburnt habitat, but variation in habitat quality between vegetation types and occupied patches had no effect on gene flow. Postfire specialists must evolve an effective dispersal ability to move over distances that would ensure access to early successional stage vegetation. Natural disturbance and natural heterogeneity may therefore not influence population genetic structure as negatively as expected.

Sex differences in the medial temporal lobe during encoding and recognition of pseudowords and abstract designs.

Sex differences in various cognitive abilities have been demonstrated in terms of performance differentials and, more recently, in differences in activation patterns during fMRI. Hemispheric lateralization is sometimes accentuated in sex differences; e.g., women demonstrating greater activation of the left hemisphere than men during verbal tasks. We were interested in whether this phenomenon applies to memory for words and designs (i.e., material specific memory). Using analogous verbal (pseudowords) and nonverbal (abstract designs) encoding and recognition tasks completed back-to-back in a 3T scanner, we found that women tend to show exaggerated left hippocampal activation during certain stages of encoding and recognition of verbal information, compared with men. Likewise (although to a lesser extent), men showed more right hippocampal activation than women did during the abstract design learning task. These results have important implications for the generalization of fMRI memory study results, for example to clinical populations such as patients undergoing epilepsy surgery.

Initial experience of TAS-102 chemotherapy in Australian patients with Chemo-refractory metastatic colorectal cancer.

For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. This study aims to investigate the efficacy and safety of TAS-102 in a real-world population from Victoria, Australia. A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to those enrolled in the registration study (RECOURSE). Across 13 sites, 107 patients were treated with TAS-102. The median age was 60 years (range: 31-83), compared to 63 for RECOURSE. Comparing registry TAS-102-treated and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 36% vs 49% were RAS wild-type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median progression-free survival (PFS) was 3.3 months compared to 2 months in RECOURSE, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths, where TAS-102 dose at treatment initiation was at clinician discretion.TRACC registry patients treated with TAS-102 were younger than those from the RECOURSE trial, with similar overall survival observed. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS.

An efficient route to thermal rate constants in reduced dimensional quantum scattering simulations: applications to the abstraction of hydrogen from alkanes.

We present an efficient approach to the determination of two-dimensional potential energy surfaces for use in quantum reactive scattering simulations. Our method involves first determining the minimum energy path (MEP) for the reaction by means of an ab initio intrinsic reaction coordinate calculation. This one-dimensional potential is then corrected to take into account the zero point energies of the spectator modes. These are determined from Hessians in curvilinear coordinates after projecting out the modes to be explicitly treated in quantum scattering calculations. The final (1+1)-dimensional potential is constructed by harmonic expansion about each point along the MEP before transforming the whole surface to hyperspherical coordinates for use in the two-dimensional scattering simulations. This new method is applied to H-atom abstraction from methane, ethane and propane. For the latter, both reactive channels (producing i-C(3)H(7) or n-C(3)H(7)) are investigated. For all reactions, electronic structure calculations are performed using an efficient, explicitly correlated, coupled cluster methodology (CCSD(T)-F12). Calculated thermal rate constants are compared to experimental and previous theoretical results.

Monotonous driving induces shifts in spatial attention as a function of handedness.

Current evidence suggests that the ability to detect and react to information under lowered alertness conditions might be more impaired on the left than the right side of space. This evidence derives mainly from right-handers being assessed in computer and paper-and-pencil spatial attention tasks. However, there are suggestions that left-handers might show impairments on the opposite (right) side compared to right-handers with lowered alertness, and it is unclear whether the impairments observed in the computer tasks have any real-world implications for activities such as driving. The current study investigated the alertness and spatial attention relationship under simulated monotonous driving in left- and right-handers. Twenty left-handed and 22 right-handed participants (15 males, mean age = 23.6 years, SD = 5.0 years) were assessed on a simulated driving task (lasting approximately 60 min) to induce a time-on-task effect. The driving task involved responding to stimuli appearing at six different horizontal locations on the screen, whilst driving in a 50 km/h zone. Decreases in alertness and driving performance were evident with time-on-task in both handedness groups. We found handedness impacts reacting to lateral stimuli differently with time-on-task: right-handers reacted slower to the leftmost stimuli, while left-handers showed the opposite pattern (although not statistically significant) in the second compared to first half of the drive. Our findings support suggestions that handedness modulates the spatial attention and alertness interactions. The interactions were observed in a simulated driving task which calls for further research to understand the safety implications of these interactions for activities such as driving.

Caffeine may disrupt the impact of real-time drowsiness on cognitive performance: a double-blind, placebo-controlled small-sample study.

Caffeine is widely used to promote alertness and cognitive performance under challenging conditions, such as sleep loss. Non-digestive modes of delivery typically reduce variability of its effect. In a placebo-controlled, 50-h total sleep deprivation (TSD) protocol we administered four 200 mg doses of caffeine-infused chewing-gum during night-time circadian trough and monitored participants' drowsiness during task performance with infra-red oculography. In addition to the expected reduction of sleepiness, caffeine was found to disrupt its degrading impact on performance errors in tasks ranging from standard cognitive tests to simulated driving. Real-time drowsiness data showed that caffeine produced only a modest reduction in sleepiness (compared to our placebo group) but substantial performance gains in vigilance and procedural decisions, that were largely independent of the actual alertness dynamics achieved. The magnitude of this disrupting effect was greater for more complex cognitive tasks.

N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin.

Inhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N omega-amino-L-arginine (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N omega-amino-L-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVRI and PVRI, p less than or equal to 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p = 0.046) compared with controls (n = 6). Moreover, N omega-amino-L-arginine increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of L-arginine did not improve survival or alter the cardiopulmonary effects of N omega-amino-L-arginine, which suggests that inhibition of NOS may not have been competitive. In normal animals, N omega-amino-L-arginine alone (n = 3) increased SVRI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N omega-amino-L-arginine, or both.

Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock.

Survivors of both human and animal bacterial shock develop a characteristic pattern of progressive changes in cardiovascular function over a period of 7-10 d. In this present study, we examined whether endotoxin (a product of Gram-negative bacteria) or TNF (a cytokine released from macrophages) could reproduce the same complex cardiovascular changes observed in septic shock over a period of 7-10 d. To test this hypothesis, we implanted a thrombin-fibrin clot containing purified endotoxin from E. coli into the peritoneal cavity of eight dogs, and infused TNF into eight different dogs. Over the next 10 d, serial simultaneous heart scans and thermodilution cardiac outputs were performed in these awake nonsedated animals. By day 2 after challenge with either endotoxin or TNF, animals developed a decrease (p less than 0.05) in both mean arterial pressure and left ventricular ejection fraction. With fluid resuscitation, animals manifested left ventricular dilatation (increased [p less than 0.05] end diastolic volume index), increased or normal cardiac index, and decreased or normal systemic vascular resistance index. In surviving animals, these changes returned to normal with 7-10 d. The time course of these changes was concordant (p less than 0.05) with that previously described in a canine model of septic shock using viable bacteria. During the 10-d study, control animals receiving sterile clots or heat-inactivated TNF had not significant changes in hemodynamics. The results from this canine model demonstrate that either endotoxin or TNF alone can produce many of the same hemodynamic abnormalities seen in human septic shock and in a canine septic shock model induced by live bacteria. These findings support the hypothesis that the action of endogenous mediators (TNF) responding to bacterial products (endotoxin) is the common pathway that produces the serial cardiovascular changes found in septic shock.

Quantifying dog meniscal volume at 1.5T and 3.0T MRI.

The dog has been used extensively as an experimental model to study meniscal treatments such as meniscectomy, meniscal repair and regeneration. Accurate quantification of meniscal size and morphology are a crucial step for developing models of the meniscus. 3.0T magnetic resonance imaging (MRI) has been found to be highly accurate in analyzing the meniscus in both clinical and research fields. However, 3.0T MRI systems are still uncommonly used in veterinary medicine. The goal of the study was to compare meniscal volume measurements from 1.5T MRI system with 3.0T MRI system using proton density sequence, a clinically relevant protocol. The MR images were segmented to reconstruct 3D surface representations of both medial and lateral menisci to compare the meniscal volumes measurements. Average volume differences were 8.8% (P=0.42) and 8.9% (P=0.535) for medial and lateral meniscus, respectively. No significant volume differences were found between 1.5T and 3.0T magnetic resonance (MR) measurements, with high Pearson's correlation coefficient of r > 0.8 and the intraclass correlation coefficient (ICC) of 0.899. For inter- and intra-observer reproducibility, high correlation (ICC = 0.942 and 0.814) was observed, but with high variability for intra-observer reproducibility (lower bound 0.478, upper bound 0.949). We have shown that common clinical MR scanners and pulse sequences can be used to quantify dogs' meniscal volumes with good reproducibility. We believe that repeatable measurements of meniscal volumes using MR may provide a useful capability for assessment of postoperative results following meniscal treatments such as meniscectomy and meniscal regeneration.

The relationship between alertness and spatial attention under simulated shiftwork.

Higher and lower levels of alertness typically lead to a leftward and rightward bias in attention, respectively. This relationship between alertness and spatial attention potentially has major implications for health and safety. The current study examined alertness and spatial attention under simulated shiftworking conditions. Nineteen healthy right-handed participants (M = 24.6 ± 5.3 years, 11 males) completed a seven-day laboratory based simulated shiftwork study. Measures of alertness (Stanford Sleepiness Scale and Psychomotor Vigilance Task) and spatial attention (Landmark Task and Detection Task) were assessed across the protocol. Detection Task performance revealed slower reaction times and higher omissions of peripheral (compared to central) stimuli, with lowered alertness; suggesting narrowed visuospatial attention and a slight left-sided neglect. There were no associations between alertness and spatial bias on the Landmark Task. Our findings provide tentative evidence for a slight neglect of the left side and a narrowing of attention with lowered alertness. The possibility that one's ability to sufficiently react to information in the periphery and the left-side may be compromised under conditions of lowered alertness highlights the need for future research to better understand the relationship between spatial attention and alertness under shiftworking conditions.

Synthesis of RNA-polyadenylic acid by isolated brain nuclei.

Nuclei, isolated from mouse brain tissue at various stages of postnatal development and incubated under cell-free conditions, synthesized RNA molecules that were associated with polyadenylic acid [poly(A)]. The RNA synthesized by these nuclei was similar to the poly(A)-associated products described for intact eukaryotic cells. The brain nuclei synthesized a similar proportion of RNA-poly(A) in the presence either of Mg(2+) or of Mn(2+) with (NH(4))(2)So(4). The RNA from neonatal brain nuclei appeared to have a greater proportion of poly(A)-containing RNA than nuclear products obtained from more mature neural tissue.

Tibiofemoral kinematic analysis of knee flexion for a medial pivot knee.

The performance of total knee arthroplasty in deeply flexed postures is of increasing concern as the procedure is performed on younger, more physically active and more culturally diverse populations. Several implant design factors, including tibiofemoral conformity, tibial slope and posterior condylar geometry have been shown directly to affect deep flexion performance. The goal of this study was to evaluate the kinematics of a fixed-bearing, asymmetric, medial rotation arthroplasty design in moderate and deep flexion. Thirteen study participants (15 knees) with a medial rotation knee arthroplasty were observed performing a weight-bearing lunge activity to maximum comfortable flexion and kneeling on a padded bench from 90 degrees to maximum comfortable flexion using lateral fluoroscopy. Subjects averaged 74 years of age and nine were female. At maximum weight-bearing flexion, the knees exhibited 115 degrees of implant flexion (102 degrees-125 degrees) and 7 degrees (-3 degrees to 12 degrees) of tibial internal rotation. The medial and lateral condylar translated posteriorly by 2 and 5 mm, respectively. At maximum kneeling flexion, the knees exhibited 119 degrees of implant flexion (101 degrees-139 degrees ) and 5 degrees (-2 degrees to 14 degrees) of tibial internal rotation. The lateral condyle translated posteriorly by 11 mm. The medial rotation knee exhibited motion patterns similar to those observed in the normal knee, but less tibial rotation. The medially conforming articulation beneficially controls femoral AP position in deep flexion, in patients who require such motion as part of their lifestyle.

Three-dimensional tibiofemoral kinematics during deep flexion kneeling in a mobile-bearing total knee arthroplasty.

Achieving very deep flexion after total knee arthroplasty is an important goal of most patients in Japan, Asia, and the Middle East because of floor-sitting lifestyles. Numerous knee arthroplasty designs have been introduced to permit high flexion. We performed an in vivo radiographic analysis of tibiofemoral motions during weight-bearing kneeling in one high-flexion knee arthroplasty design. Twenty knees implanted with a posterior-stabilized rotating-platform knee arthroplasty flexed an average of 126 degrees. The femoral condyles translated posteriorly from extension to maximum flexion. Total posterior condylar translations averaged 11.6 and 4.7 mm for the lateral and medial condyles, respectively. Tibial internal rotation in 19 knees averaged 9 degrees from extension to maximum flexion. Knees implanted with a posterior-stabilized, rotating-platform knee arthroplasty show deep flexion knee kinematics consistent with the implant design intent.