Relationships between in vivo dynamic knee joint loading, static alignment and tibial subchondral bone microarchitecture in end-stage knee osteoarthritis.

OBJECTIVE: To study, in end-stage knee osteoarthritis (OA) patients, relationships between indices of in vivo dynamic knee joint loads obtained pre-operatively using gait analysis, static knee alignment, and the subchondral trabecular bone (STB) microarchitecture of their excised tibial plateau quantified with 3D micro-CT. DESIGN: Twenty-five knee OA patients scheduled for total knee arthroplasty underwent pre-operative gait analysis. Mechanical axis deviation (MAD) was determined radiographically. Following surgery, excised tibial plateaus were micro-CT-scanned and STB microarchitecture analysed in four subregions (anteromedial, posteromedial, anterolateral, posterolateral). Regional differences in STB microarchitecture and relationships between joint loading and microarchitecture were examined. RESULTS: STB microarchitecture differed among subregions (P < 0.001), anteromedially exhibiting highest bone volume fraction (BV/TV) and lowest structure model index (SMI). Anteromedial BV/TV and SMI correlated strongest with the peak external rotation moment (ERM; r = -0.74, r = 0.67, P < 0.01), despite ERM being the lowest (by factor of 10) of the moments considered, with majority of ERM measures below accuracy thresholds; medial-to-lateral BV/TV ratios correlated with ERM, MAD, knee adduction moment (KAM) and internal rotation moment (|r|-range: 0.54-0.74). When controlling for walking speed, KAM and MAD, the ERM explained additional 11-30% of the variations in anteromedial BV/TV and medial-to-lateral BV/TV ratio (R2 = 0.59, R2 = 0.69, P < 0.01). CONCLUSIONS: This preliminary study suggests significant associations between tibial plateau STB microarchitecture and knee joint loading indices in end-stage knee OA patients. Particularly, anteromedial BV/TV correlates strongest with ERM, whereas medial-to-lateral BV/TV ratio correlates strongest with indicators of medial-to-lateral joint loading (MAD, KAM) and rotational moments. However, associations with ERM should be interpreted with caution.

Joint loading and proximal tibia subchondral trabecular bone microarchitecture differ with walking gait patterns in end-stage knee osteoarthritis.

OBJECTIVES: To (1) stratify patient subgroups according to their distinct walking gait patterns in end-stage knee osteoarthritis (OA); (2) compare measures of joint loading and proximal tibia subchondral trabecular bone (STB) microarchitecture among these gait subgroups. DESIGN: Twenty-five knee OA patients undergoing total knee arthroplasty (TKA) had pre-operative gait analysis. Following surgery, excised tibial plateaus were micro-CT-scanned and STB microarchitecture analysed in four tibial condylar regions of interest. Peak knee moments were input to k-means cluster analysis, to identify subgroups with homogeneous gait patterns. Joint loading and STB microarchitecture parameters were compared among gait subgroups (Kruskal-Wallis, Bonferroni-corrected Mann-Whitney U tests). RESULTS: Three gait subgroups were revealed: biphasics (n = 7), flexors (n = 9), counter-rotators (n = 9). Peak knee adduction moment (KAM) and KAM impulse were significantly higher (P < 0.05) in biphasics than in flexors and counter-rotators (KAM = -0.65, -0.40 and -0.21 Nm/kg, respectively), suggesting a higher medial-to-lateral tibiofemoral load ratio in biphasics. Interestingly, STB medial-to-lateral bone volume fraction (BV/TV) ratio was also significantly higher (more than double) in biphasics and flexors than in counter-rotators (2.24, 2.00 and 1.00, respectively), whereas in biphasics it was only 10% higher than in flexors and not significantly so. CONCLUSIONS: Within the confines of the limited sample size, data suggests that different mechanisms between the biphasic and flexor gait subroups may generate comparable loads upon the tibial plateau and corresponding bony responses, despite significantly lower KAM indices in flexors. Hence, in flexor gait OA patients, conservative treatments designed to reduce KAM, may not be appropriate. Understanding joint loading among walking gait patterns and relationships to bone microarchitecture may aid at identifying/improving management of persons at risk for developing knee OA.

Modelling the transmission dynamics of dengue in the presence of Wolbachia.

Use of the bacterium Wolbachia is an innovative new strategy designed to break the cycle of dengue transmission. There are two main mechanisms by which Wolbachia could achieve this: by reducing the level of dengue virus in the mosquito and/or by shortening the host mosquito's lifespan. However, although Wolbachia shortens the lifespan, it also gives a breeding advantage which results in complex population dynamics. This study focuses on the development of a mathematical model to quantify the effect on human dengue cases of introducing Wolbachia into the mosquito population. The model consists of a compartment-based system of first-order differential equations; seasonal forcing in the mosquito population is introduced through the adult mosquito death rate. The analysis focuses on a single dengue outbreak typical of a region with a strong seasonally-varying mosquito population. We found that a significant reduction in human dengue cases can be obtained provided that Wolbachia-carrying mosquitoes persist when competing with mosquitoes without Wolbachia. Furthermore, using the Wolbachia strain WMel reduces the mosquito lifespan by at most 10% and allows them to persist in competition with non-Wolbachia-carrying mosquitoes. Mosquitoes carrying the WMelPop strain, however, are not likely to persist as it reduces the mosquito lifespan by up to 50%. When all other effects of Wolbachia on the mosquito physiology are ignored, cytoplasmic incompatibility alone results in a reduction in the number of human dengue cases. A sensitivity analysis of the parameters in the model shows that the transmission probability, the biting rate and the average adult mosquito death rate are the most important parameters for the outcome of the cumulative proportion of human individuals infected with dengue.

Pandemic controllability: a concept to guide a proportionate and flexible operational response to future influenza pandemics.

The 2009 H1N1 influenza pandemic posed challenges for governments worldwide. Strategies designed to limit community transmission, such as antiviral deployment, were largely ineffective due to both feasibility constraints and the generally mild nature of disease, resulting in incomplete case ascertainment. Reviews of national pandemic plans have identified pandemic impact, primarily linked to measures of transmissibility and severity, as a key concept to incorporate into the next generation of plans. While an assessment of impact provides the rationale under which interventions may be warranted, it does not directly provide an assessment on whether particular interventions may be effective. Such considerations motivate our introduction of the concept of pandemic controllability. For case-targeted interventions, such as antiviral treatment and post-exposure prophylaxis, we identify the visibility and transmissibility of a pandemic as the key drivers of controllability. Taking a case-study approach, we suggest that high-impact pandemics, for which control is most desirable, are likely uncontrollable with case-targeted interventions. Strategies that do not rely on the identification of cases may prove relatively more effective. By introducing a pragmatic framework for relating the assessment of impact to the ability to mitigate an epidemic (controllability), we hope to address a present omission identified in pandemic response plans.

Effective reproduction numbers are commonly overestimated early in a disease outbreak.

Reproduction numbers estimated from disease incidence data can give public health authorities valuable information about the progression and likely size of a disease outbreak. Here, we show that methods for estimating effective reproduction numbers commonly give overestimates early in an outbreak. This is due to many factors including the nature of outbreaks that are used for estimation, incorrectly accounting for imported cases and outbreaks arising in subpopulations with higher transmission rates. Awareness of this bias is necessary to correctly interpret estimates from early disease outbreak data.

Estimating reproduction numbers for adults and children from case data.

We present a method for estimating reproduction numbers for adults and children from daily onset data, using pandemic influenza A(H1N1) data as a case study. We investigate the impact of different underlying transmission assumptions on our estimates, and identify that asymmetric reproduction matrices are often appropriate. Under-reporting of cases can bias estimates of the reproduction numbers if reporting rates are not equal across the two age groups. However, we demonstrate that the estimate of the higher reproduction number is robust to disproportionate data-thinning. Applying the method to 2009 pandemic influenza H1N1 data from Japan, we demonstrate that the reproduction number for children was considerably higher than that of adults, and that our estimates are insensitive to our choice of reproduction matrix.

Seasonal influenza vaccination and the risk of infection with pandemic influenza: a possible illustration of non-specific temporary immunity following infection.

Four Canadian studies have suggested that receipt of seasonal influenza vaccine increased the risk of laboratory-confirmed infection with 2009 pandemic influenza A(H1N1). During the influenza season of 2009 in Victoria, Australia, this virus comprised 97% of all circulating influenza viruses for which sub-typing was available. We found no evidence that seasonal influenza vaccine increased the risk of, or provided protection against, infection with the pandemic virus. Ferret experiments have suggested protection against pandemic influenza A(H1N1) 2009 from multiple prior seasonal influenza infections but not from prior seasonal vaccination. Modelling studies suggest that influenza infection leads to heterosubtypic temporary immunity which is initially almost complete. We suggest these observations together can explain the apparent discrepant findings in Canada and Victoria. In Victoria there was no recent prior circulation of seasonal influenza and thus no temporary immunity to pandemic influenza. There was no association of seasonal influenza vaccine with pandemic influenza infection. In Canada seasonal influenza preceded circulation of the pandemic virus. An unvaccinated proportion of the population developed temporary immunity to pandemic influenza from seasonal infection but a proportion of vaccinated members of the population did not get seasonal infection and hence did not develop temporary immunity to pandemic influenza. It may therefore have appeared as if seasonal vaccination increased the risk of infection with pandemic influenza A(H1N1) virus.

Transmissibility of 2009 pandemic influenza A(H1N1) in New Zealand: effective reproduction number and influence of age, ethnicity and importations.

The first wave of pandemic influenza A(H1N1) has subsided in New Zealand as in other southern hemisphere countries. This study aimed to estimate the effective reproduction number (R) of 2009 pandemic influenza A(H1N1) taking into account imported cases. It also aimed to show the temporal variation of R throughout the New Zealand epidemic, changes in age- and ethnicity-specific cumulative incidence, and the effect of school holidays. Using a new modelling method to account for imported cases, we have calculated the peak R during the containment phase of the pandemic as 1.55 (95% confidence interval: 1.16 to 1.86). This value is less than previously estimated in the country early in the pandemic but in line with more recent estimates in other parts of the world. Results also indicated an increase in the proportion of notifications among school-age children after the school holiday (3-19 July 2009). This finding provides support for the potential effectiveness of timely school closures, although such disruptive interventions need to be balanced against the severity of the pandemic.

Cost-effectiveness of continuous positive airway pressure therapy for moderate to severe obstructive sleep apnea/hypopnea.

BACKGROUND: Obstructive sleep apnea/hypopnea (OSAH) is a common disorder characterized by recurrent collapse of the upper airway during sleep, and is associated with an increased risk of motor vehicle crashes (MVCs). Common first-line therapy for OSAH is continuous positive airway pressure (CPAP). We assessed the cost-effectiveness of CPAP therapy vs none for the treatment of OSAH. METHODS: We used a 5-year Markov model that considers the costs and quality-of-life improvements of CPAP therapy, accounting for the gains from reduced MVC rates. Utility values were obtained from published studies. The MVC rates under the CPAP and no-CPAP scenarios were calculated from National Highway Traffic Safety Administration data and a systematic review of published studies. Costs of MVCs, equipment, and physicians were obtained from US Medicare and the National Highway Traffic Safety Administration. The target population included male and female patients aged 25 to 54 years and newly diagnosed as having moderate to severe OSAH. We examined the findings from the perspectives of a third-party payer and society. RESULTS: From a third-party payer or a societal perspective, CPAP therapy was more effective but more costly than no CPAP, with incremental cost-effectiveness ratios of $3354 or $314 per quality-adjusted life-year gained, respectively. The incremental cost-effectiveness ratio estimate was most dependent on viewpoint (varying more than 10-fold between societal and third-party payer perspectives) and choice of utility measurement method (varying more than 5-fold between the use of standard gamble and EuroQol 5D utility assessment values). CONCLUSION: When quality of life, costs of therapy, and MVC outcomes are considered, CPAP therapy for patients with OSAH is economically attractive.

Modeling thermal burns due to airbag deployment.

Automotive airbags are now a widely accepted safety measure designed to reduce morbidity associated with motor vehicle accidents. Their usage is increasing with multiple airbags (driver, passenger and side curtain) being fitted to many vehicles. However the deployment of airbags has been identified as causing injuries in some instances including minor burns. There are three mechanisms for thermal burns due to an airbag; contact with the hot expelled gases from the airbag, contact with the hot airbag itself and melting of clothing from either of these contacts. A mathematical model is used here to predict the likelihood and severity of the first two types of burns. It is shown that direct contact with high temperature exhaust gases venting from the airbag can indeed lead to burns and that burns from contacting the hot airbag material are possible but far less likely to occur.

Polyaromatic hydrocarbons administered in humans by dermal route increase total IgE.

Inhalation of polyaromatic hydrocarbons (PAHs) extracted from diesel exhaust particles (DEP) enhances local (nasal) production of IgE in humans. The aim of the present research is to investigate whether in humans dermal exposure to PAHs which are not extracted from DEPs increases serum IgE, and whether host factors modify the immunologic effect. In thirty-two patients with acute psoriatic lesions, a cream containing 3% of coal tar (which holds a variety of PAHs) was applied to the skin for 24 hours. Serum IgE were measured before (IgE0) and four (IgE4) and eight (IgE8) days after application. Replicated means were compared by analysis of variance for repeated measures and by the Newman-Keuls' test. IgE0, IgE4 and IgE8 were 151.19, 159.69 (a 6% excess) and 170.90 kU/L (a 13% excess) respectively; pairwise comparison showed IgE8 was significantly higher than IgE0 (p<0.05). At multiple linear regression analysis, the percentage increase in serum IgE across observation days was the dependent variable against age, sex, cigarettes/day, urinary 1-pyrenol, atopy, skin area treated, and grams of cream. Of the independent variables, only age had a significant (p<0.028) influence: the younger the age, the higher the IgE response to PAHs. We conclude that whatever the source and the route of entry (skin or respiratory tract), PAHs increase total serum IgE, mainly in younger age groups.

Acute tryptophan depletion in schizophrenia.

BACKGROUND: Brain 5-hydroxytryptamine (5-HT) function is implicated in the pathophysiology of schizophrenia and the action of new generation antipsychotic drugs. By the method of acute tryptophan depletion (ATD) 5-HT can be selectively manipulated. The aim of this study was to examine the effects of ATD on symptoms, mood and cognition in schizophrenic patients. METHODS: Twenty-eight schizophrenic patients participated in a within subject, double-blind, placebo-controlled counterbalanced cross-over study. Patients with a concurrent DSM-IV axis I diagnosis were excluded. Symptoms, mood and cognitive function were evaluated following ATD or ingestion of a control drink. RESULTS: The depleting drink significantly reduced plasma total and free tryptophan. Tryptophan/LNAA ratios did not alter with the administration of the control drink, but differed significantly with ATD; however there was no significant change in tyrosine/LNAA ratio. ATD led to impairment in executive function that was dependent upon the order of administration. Tests of sustained attention, speed of processing, and everyday memory were not affected. No effects were observed on subjective mood ratings, movement disorders or PANSS scores. CONCLUSIONS: Acute tryptophan depletion selectively alters cognition in schizophrenia, but has no effect on symptoms, mood ratings or movement disorders.

Nitrosothiol esters of diclofenac: synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs.

Despite its widespread use, diclofenac has gastrointestinal liabilities common to nonsteroidal antiinflammatory drugs (NSAIDs) that might be reduced by concomitant administration of a gastrointestinal cytoprotectant such as nitric oxide (NO). A series of novel diclofenac esters containing a nitrosothiol (-S-NO) moiety as a NO donor functionality has been synthesized and evaluated in vivo for bioavailability, pharmacological activity, and gastric irritation. All S-NO-diclofenac derivatives acted as orally bioavailable prodrugs, producing significant levels of diclofenac in plasma within 15 min after oral administration to mice. At equimolar oral doses, S-NO-diclofenac derivatives (20a-21b) displayed rat antiinflammatory and analgesic activities comparable to those of diclofenac in the carrageenan-induced paw edema test and the mouse phenylbenzoquinone-induced writhing test, respectively. All tested S-NO-diclofenac derivatives (20a-21b) were gastric-sparing in that they elicited markedly fewer stomach lesions as compared to the stomach lesions caused by a high equimolar dose of diclofenac in the rat. Nitrosothiol esters of diclofenac comprise a novel class of NO-donating compounds having therapeutic potential as nonsteroidal antiinflammatory agents with an enhanced gastric safety profile.

Developing a tool to measure holistic practice: a missing dimension in outcomes measurement within complementary therapies.

Despite the wide and continuing debate over the relevance of particular research methods to evaluate complementary therapies, less attention has been given to what outcome criteria and measures to use and/or whether these have a sufficient breadth in perspective. While complementary and alternative medicine researchers have paid heed to the importance of measuring the subjective experience of therapy users, they have left unmeasured the notion of holism, in particular, the measurement of the effect of the interaction between therapist and therapy user, and its underlying philosophy of health and healing. This paper reports on an exploratory, qualitative study aimed at developing a measure of holism and holistic practice. It draws out some key features requiring measurement and provides insight into the emerging measure. Further development work is needed before the measure can be used within research or routine practice.

Seasonality of eating pathology on the eating attitudes test in a nonclinical population.

OBJECTIVE: To determine whether there are seasonal fluctuations in eating pathology in a nonclinical population. METHOD: The Eating Attitudes Test (EAT) was completed by 322 subjects during winter and again during summer. Summer and winter responses were compared to investigate differences in EAT total and subscale scores and for individual EAT items. Numbers of subjects fluctuating across the seasons by more than 2 SDs of the cohort's scores were identified. RESULTS: The cohort showed no significant seasonal change on EAT-40 totals, EAT-26 totals, or within the EAT subscales. There were significant (p <.025) seasonal fluctuations on four of the EAT-40 questions. For individual respondents, there was no greater likelihood of scoring significantly higher in the winter than in the summer. DISCUSSION: Clinically significant seasonal fluctuations in eating pathology on the EAT did not occur in this nonclinical population. It is debatable whether items within the EAT which show significant seasonal fluctuations should be retained or discarded.

Rehospitalization of older psychiatric inpatients: an investigation of predictors.

The purpose of this study was to identify a combination of variables that could predict rehospitalization among a sample of 150 geropsychiatric inpatients. Logistic regression analyses testing a modified model identified risk factors for geropsychiatric rehospitalization and correctly classified approximately 80% of inpatients who were rehospitalized for subsequent treatment. Patients' psychiatric diagnosis (mood or schizophrenic disorder), poor general psychiatric functioning, depressive and agitated behavior at discharge, little or no supervision in living arrangements following discharge, limited social support, change in the social support system preceding hospitalization, and maladaptive family functioning could significantly predict geropsychiatric rehospitalization. The strongest independent predictor was maladaptive family functioning.

Comparing breastfeeding and breast pumps using a computer model.

There is a role for computer models in increasing the understanding of milk extraction from the human teat. A computer model can be used to investigate aspects of extracting milk from the human teat which are not feasible using clinical experiments. In this paper, the behavior of the human teat during an infant suckling and with the use of a breast pump is modeled. The model is used to (1) identify the role of suction and the peristaltic motion of the tongue during suckling and (2) compare the volume of milk extracted by an infant breastfeeding with that obtained using a breast pump. Infants use a peristaltic motion of the tongue, along with some suction, to extract milk. Breast pumps use a cyclic pattern of suction only. In the model, the human teat is represented as a cylindrical porous elastic material saturated with fluid. We mimic an infant suckling by imposing both suction and a peristaltic force in the computer model of the human teat. This is compared to the effect of suction only, which models the action of breast pumps. The results demonstrate that there is an optimal time to apply the peristaltic force during the suction cycle which will increase the milk volume. The model and results may be of use in the future design of effective breast pumps.

Dynamics of human milk extraction: a comparative study of breast feeding and breast pumping.

We describe a mathematical model of the flow and deformation in a human teat. Our aim is to compare the theoretical milk yield during infant breast feeding with that obtained through the use of a breast pump. Infants use a peristaltic motion of the tongue, along with some suction, to extract milk, whereas breast pumps use a cyclic pattern of suction only. Our model is based on quasi-linear poroelasticity whereby the teat is modelled as a cylindrical porous elastic material saturated with fluid. We impose a cyclic axial suction pressure difference across the teat and impose a radial compressive force moving along the teat which mimics infant suckling. This is compared to the case of cyclic and steady pumping only which models the action of breast pumps. The results illustrate that there is an optimal time to apply the compressive force during the suction cycle that will increase the flow rate in our theoretical teat. The model and results may be of use in the future design of effective breast pumps.

A study of enhanced management in patients with treatment-resistant schizophrenia.

The clinical efficacy of two intensive treatment packages (one including the new antipsychotic risperidone and the other not doing so) was compared with that of standard management in 43 patients with long-standing treatment-resistant schizophrenia. Significant differences between the groups in terms of total positive or total negative symptoms were not demonstrated, but the pattern of change between the treatment groups differed, so that benefit in positive symptomatology was seen in both intensive treatment groups and in negative symptomatology in the intensive treatment/risperidone group and the standard group. Changes in general psychopathology were most marked in the risperidone group and were compatible with a relatively non-sedative profile. Using the Disability Assessment Schedule, substantial significant advantages for the intensive treatment groups were found.

The use of videotaped assessment in relation to a study of enhanced management in treatment-resistant schizophrenia.

Videotaped assessments of standardized interviews were used to ensure blindness in relation to a clinical trial of multifaceted programmes of management in patients with treatment-resistant schizophrenia. The technique, although laborious, was feasible in all patients studied and offered advantages in relation not only to blindness but also to assessing the nature of psychopathological changes in patients with schizophrenic deficit syndrome of severe degree. The method is likely to be useful in further studies assessing the possible advantages of newer antipsychotic drugs.