Utilization of Poly(ADP-Ribose) Polymerase Inhibitors in Ovarian Cancer: A Retrospective Cohort Study of US Healthcare Claims Data.

INTRODUCTION: We aimed to characterize real-world utilization of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) in women with ovarian cancer (OC). METHODS: This retrospective observational study of claims data from US MarketScan® Commercial/Medicare Supplemental databases included women with OC initiating olaparib, niraparib, or rucaparib from January 1, 2017, to May 31, 2019. Patients were observed from first outpatient prescription until at least 30 days' follow-up. Clinical events of interest (CEIs), based on adverse reactions in PARPi prescribing information, were identified from claims using ICD-9/10 codes. Other outcomes included dose modification, persistence, adherence, healthcare resource utilization (HCRU), and cost. RESULTS: Overall, 303, 348, and 162 women with OC received olaparib, niraparib, and rucaparib, respectively. During follow-up, risk of any CEI was higher with niraparib versus olaparib (odds ratio 3.36 [95% confidence interval 2.00-5.65]) and niraparib versus rucaparib (2.09 [1.10-3.95]), with no significant difference between rucaparib and olaparib (1.61 [0.93-2.79]). PARPi dose decreases were observed in 21.1%, 35.1%, and 30.2% of olaparib-, niraparib-, and rucaparib-treated patients, respectively. Persistence (no treatment gaps of more than 90 days) was significantly higher (P < 0.05) with olaparib (62.2%) versus niraparib (35.9%) and rucaparib (48.7%); adherence (medication possession ratio, MPR ≥ 80%) was 80.2% versus 38.6% and 63.2%, respectively (P < 0.001). Inpatient admissions and outpatient service use were higher with niraparib and rucaparib versus olaparib, reflected in mean (± standard deviation) total medical costs (excluding pharmacy) of $5393 ± 8828 for olaparib, $7732 ± 14,054 for niraparib, and $6868 ± 7929 for rucaparib. CONCLUSION: Differences between the licensed PARPi were observed in the risk of experiencing a CEI, likelihood of dose modifications, ability to receive continuous PARPi therapy, HCRU, and costs.

Real-world outcomes in patients with advanced endometrial cancer: A retrospective cohort study of US electronic health records.

OBJECTIVES: To characterize clinical outcomes of women with advanced/recurrent endometrial cancer (AEC) in routine practice using electronic health records from a real-world database. METHODS: Adult women diagnosed with AEC (stage III/IV, or early stage with locoregional/distant recurrence) between January 1, 2013 and September 30, 2020, inclusive, were eligible provided they received platinum-based chemotherapy at any time following diagnosis and had ≥2 clinical visits. Follow-up was from initiation of systemic treatment after advanced diagnosis (index) until March 30, 2021, last available follow-up, or death, whichever occurred first. Outcomes, by histological subtype, included Kaplan-Meier estimates of overall survival (OS) and time to first subsequent therapy or death (TFST). RESULTS: Of the 2202 women with AEC, most were treated in a community setting (82.7%) and presented with stage III/IV disease at initial diagnosis (74.0%). The proportion with endometrioid carcinoma, uterine serous carcinoma (USC), and other AEC subtypes was 59.8%, 25.0%, and 15.2%, respectively. The most common first systemic treatment following advanced/recurrent diagnosis was platinum-based combination chemotherapy (82.0%). Median OS (95% CI) from initiation of first systemic treatment was shorter with USC (31.3 [27.7-34.3] months) and other AECs (29.4 [21.4-43.9] months) versus endometrioid carcinoma (70.8 [60.5-83.2] months). Similar results were observed for TFST. Black/African American women had worse OS and TFST than white women. CONCLUSIONS: Women with AEC had poor survival outcomes, demonstrating the requirement for more effective therapies. To our knowledge, this is the most comprehensive evaluation of contemporary treatment of AEC delivered in a community setting to date.

Adverse events in women switching from olaparib capsules to tablets: retrospective observational study of US claims data.

Aim: Describe rates of prespecified adverse events in patients who switched from olaparib capsules to tablets. Patients & methods: Retrospective, observational cohort analysis using self-controlled, pre-post design. Data on patients with ovarian cancer who switched from olaparib capsules to tablets between January 2015 and February 2019 were obtained from a US claims database. Results: Among all patients (n = 48), proportion with any prespecified adverse event was 45.8% (95% confidence interval: 31.4-60.8) during initial 90 days' capsule use and 35.4% (22.2-50.5) during initial 90 days' tablets use; difference -10.4% (-28.8-9.0). Conclusion: Switching from olaparib capsules to tablets was manageable with no evidence of increased toxicity. This real-world study supports the manageable tolerability of olaparib in women with ovarian cancer.

Rate of Adverse Events and Associated Health Care Costs for the Management of Inflammatory Bowel Disease in Germany.

PURPOSE: Therapeutic management of inflammatory bowel disease (IBD) is challenging, and available therapies are associated with adverse events (AEs) that may lead to treatment discontinuation. This study evaluated the rate of drug-related AEs of special interest (AESIs) associated with IBD therapies and compare health care costs among patients with IBD who did and did not experience AESIs. METHODS: A retrospective cohort analysis was conducted using claims data from a German Sickness Fund (Allgemeine Ortskrankenkasse PLUS). Patients were diagnosed with ulcerative colitis (UC) or Crohn's disease (CD) and newly initiating treatment with immunosuppressant, anti-tumor necrosis factor α, or anti-integrin therapies from January 1, 2011, to December 31, 2015. Patients were required to have continuous insurance coverage and no evidence of use of these IBD therapies for 12 months before the date of newly initiating therapy (index date). Rates of AESIs were based on 28 different events or chronic conditions associated with IBD treatment. Direct health care costs were reported separately for patients who did or did not experience AESIs. Only treatment periods lasting ≥60 days were considered. AESI rates related to all possible treatment patterns were calculated and reported as the number of events per 10,000 patient-years. Health care costs were calculated based on IBD-related health care resource use. FINDINGS: A total of 1126 (CD, n = 676; UC, n = 450) patients met the inclusion criteria. Mean age was 36.5 years for patients with CD and 42.5 years for patients with UC; 60.5% and 47.6% were female, respectively. Median observed time since the index date was 1460 and 1552 days, for patients with CD and UC. The overall rate for any AESI was 1392.4 and 1917.9 events per 10,000 patient-years in patients with CD and those with UC. Severe infections and diabetes mellitus were the most common AESIs. Significant differences in mean total direct health care costs were found for CD patients with AESIs versus those without (€8920.08 and €6004.86; P < 0.001). A similar trend was observed with mean drug costs and mean medical costs. In UC, total direct health care costs, although generally higher in patients with AESIs, were not significantly different; however, medical costs were (€1946.93 vs €971.28; P < 0.001). IMPLICATIONS: AEs are common in patients with IBD treated with current therapies and associated with substantial health care costs. An urgent need exists for development of IBD treatments that are associated with lower rates of AEs.

Analysis of Safety, Medical Resource Utilization, and Treatment Costs by Drug Class for Management of Inflammatory Bowel Disease in the United States Based on Insurance Claims Data.

INTRODUCTION: Conventional pharmaceutical interventions for inflammatory bowel disease (IBD) provide limited disease/symptom control and are associated with an increased risk of adverse events (AEs). These limitations increase patient morbidity, medical resource utilization (MRU), and costs. METHODS: The IQVIA™ Real-World Data Adjudicated Claims-US database was leveraged to identify adult patients (> 18 years) with Crohn's disease (Crohn's) or ulcerative colitis (UC), who were new and chronic users (≥ 60 days) of oral corticosteroids (OCS), immunosuppressants (IS), anti-tumor necrosis factor agents (anti-TNF) or combinations thereof. Using aminosalicylate-treated patients as a reference, we compared AE incidence, MRU, and medical costs across drug classes. RESULTS: The analysis included 30,676 patients (Crohn's: n = 14,528; UC: n  = 16,148). OCS monotherapy was the strongest predictor of any AE occurring [Crohn's: hazard ratio 1.62 (1.51-1.73); UC: hazard ratio 1.57 (1.49-1.66)]. A similar pattern was observed for severe infection and bone-related conditions. Patients with UC or Crohn's receiving OCS or IS plus OCS were more likely to have emergency department visits, IBD-related hospitalizations/visits/procedures, and gastrointestinal surgery than were patients receiving other therapies. Annualized total medical costs (pharmacy plus hospital service costs) were greatest for anti-TNF plus IS or anti-TNF therapy in both Crohn's and UC. Annualized medical service costs (excluding IBD drug costs) were highest for patients initiating OCS-containing therapies [Crohn's: OCS, $27,041 (24,882-29,200) and OCS plus IS, $23,332 (19,889-26,775); UC: OCS, $19,659 (17,977-21,340)]. CONCLUSION: Although biologic therapies have higher pharmacy costs, treatment decisions should consider the increased AE risks and long-term MRU costs associated with chronic use of OCS-containing therapies. FUNDING: This study was funded by F. Hoffmann-La Roche Ltd. The journal's Rapid Service Fee and Open Access publication were paid for by ApotheCom on behalf of Genentech, a member of the Roche group who funded the study.

Changes in behaviors after diagnosis of type 2 diabetes and 10-year incidence of cardiovascular disease and mortality.

BACKGROUND: Large changes in health behaviors achieved through intensive lifestyle intervention programs improve cardiovascular disease (CVD) risk factors among adults with type 2 diabetes. However, such interventions are not widely available, and there is limited evidence as to whether changes in behaviors affect risk of CVD events. METHODS: Among 852 adults with screen-detected type 2 diabetes in the ADDITION-Cambridge study, we assessed changes in diet, physical activity, and alcohol use in the year following diabetes diagnosis. Participants were recruited from 49 general practices in Eastern England from 2002 to 2006, and were followed through 2014 for incidence of CVD events (n = 116) and all-cause mortality (n = 127). We used Cox proportional hazards regression to estimate hazard ratios (HR) for the associations of changes in behaviors with CVD and all-cause mortality. We estimated associations with CVD risk factors using linear regression. We considered changes in individual behaviors and overall number of healthy changes. Models adjusted for demographic factors, bodyweight, smoking, baseline value of the health behavior, and cardio-protective medication use. RESULTS: Decreasing alcohol intake by ≥ 2 units/week was associated with lower hazard of CVD vs maintenance [HR: 0.56, 95% CI 0.36, 0.87]. Decreasing daily calorie intake by ≥ 300 kcal was associated with lower hazard of all-cause mortality vs maintenance [HR: 0.56, 95% CI 0.34, 0.92]. Achieving ≥ 2 healthy behavior changes was associated with lower hazard of CVD vs no healthy changes [HR: 0.39, 95% CI 0.18, 0.82]. CONCLUSIONS: In the year following diabetes diagnosis, small reductions in alcohol use were associated with lower hazard of CVD and small reductions in calorie intake were associated with lower hazard of all-cause mortality in a population-based sample. Where insufficient resources exist for specialist-led interventions, achievement of moderate behavior change targets is possible outside of treatment programs and may reduce long-term risk of CVD complications. Trial registration This trial is registered as ISRCTN86769081. Retrospectively registered 15 December 2006.

Moderate weight change following diabetes diagnosis and 10 year incidence of cardiovascular disease and mortality.

AIMS/HYPOTHESIS: Adults with type 2 diabetes are at high risk of developing cardiovascular disease (CVD). Evidence of the impact of weight loss on incidence of CVD events among adults with diabetes is sparse and conflicting. We assessed weight change in the year following diabetes diagnosis and estimated associations with 10 year incidence of CVD events and all-cause mortality. METHODS: In a cohort analysis among 725 adults with screen-detected diabetes enrolled in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION)-Cambridge trial, we estimated HRs for weight change in the year following diabetes diagnosis and 10 year incidence of CVD (n = 99) and all-cause mortality (n = 95) using Cox proportional hazards regression. We used linear regression to estimate associations between weight loss and CVD risk factors. Models were adjusted for age, sex, baseline BMI, smoking, occupational socioeconomic status, cardio-protective medication use and treatment group. RESULTS: Loss of ≥5% body weight in the year following diabetes diagnosis was associated with improvements in HbA1c and blood lipids and a lower hazard of CVD at 10 years compared with maintaining weight (HR 0.52 [95% CI 0.32, 0.86]). The associations between weight gain vs weight maintenance and CVD (HR 0.41 [95% CI 0.15, 1.11]) and mortality (HR 1.63 [95% CI 0.83, 3.19]) were less clear. CONCLUSIONS/INTERPRETATION: Among adults with screen-detected diabetes, loss of ≥5% body weight during the year after diagnosis was associated with a lower hazard of CVD events compared with maintaining weight. These results support the hypothesis that moderate weight loss may yield substantial long-term CVD reduction, and may be an achievable target outside of specialist-led behavioural treatment programmes.

Change in lifestyle behaviors and diabetes risk: evidence from a population-based cohort study with 10 year follow-up.

BACKGROUND: Promoting positive changes in lifestyle behavior in the whole population may be a feasible and effective approach to reducing type 2 diabetes burden, but the impact of population shifts of modifiable risk factors remains unclear. Currently most of the evidence on modifiable lifestyle behavior and type 2 diabetes risk on a population level comes from studies of between-individual differences. The objective of the study was to investigate the association and potential impact on disease burden for within-individual change in lifestyle behavior and diabetes risk. METHODS: Population-based prospective cohort study of 35,680 participants aged 30-50 at baseline in 1990-2003 in Västerbotten County, Sweden (follow-up until 2013). Five self-reported modifiable lifestyle behaviors (tobacco use, physical activity, alcohol intake, dietary fiber intake and dietary fat intake) were measured at baseline and 10 year follow-up. Lifestyle behaviors were studied separately, and combined in a score. Incident diabetes was detected by oral glucose tolerance tests. Multivariate logistic regression models and population attributable fractions (PAF) were used to analyze the association between change in lifestyle behavior between baseline and 10 year follow-up, and risk of incident diabetes. RESULTS: Incident diabetes was detected in 1,184 (3.3%) participants at 10 year follow-up. There was a reduced diabetes risk associated with increase in dietary fiber intake, odds ratio (OR) 0.79 (95% confidence interval (CI) 0.66, 0.96) for increase of at least one unit standard deviation (3.0 g/1,000 kcal) of the baseline distribution, PAF 16.0% (95% CI 4.2, 26.4%). Increase in the lifestyle behavior score was associated with reduced diabetes risk, OR 0.92 (95% CI 0.85, 0.99) per unit increase of the score. CONCLUSIONS: These results support a causal link between lifestyle behavior and type 2 diabetes incidence. A small shift in lifestyle behaviors, in particular intake of dietary fiber, has the potential to reduce diabetes burden in the population and might be a suitable target for public health intervention.

Impact of weight maintenance and loss on diabetes risk and burden: a population-based study in 33,184 participants.

BACKGROUND: Weight loss in individuals at high risk of diabetes is an effective prevention method and a major component of the currently prevailing diabetes prevention strategies. The aim of the present study was to investigate the public health potential for diabetes prevention of weight maintenance or moderate weight loss on a population level in an observational cohort with repeated measurements of weight and diabetes status. METHODS: Height, weight and diabetes status were objectively measured at baseline and 10 year follow-up in a population-based cohort of 33,184 participants aged 30-60 years between 1990 and 2013 in Västerbotten County, Sweden. The association between risk of incident diabetes and change in BMI or relative weight was modelled using multivariate logistic regression. Population attributable fractions (PAF) were used to assess population impact of shift in weight. RESULTS: Mean (SD) BMI at baseline was 25.0 (3.6) kg/m2. Increase in relative weight between baseline and follow-up was linearly associated with incident diabetes risk, odds ratio (OR) 1.05 (95% confidence interval (CI) 1.04-1.06) per 1% change in weight. Compared to weight maintenance (±1.0 kg/m2), weight gain of > +1.0 kg/m2 was associated with an increased risk of incident diabetes, OR 1.52 (95% CI 1.32, 1.74), representing a PAF of 21.9% (95% CI 15.8, 27.6%). For moderate weight loss (-1.0 to -2.0 kg/m2) the OR was 0.72 (95% CI 0.52, 0.99). CONCLUSIONS: Weight maintenance in adulthood is strongly associated with reduced incident diabetes risk and there is considerable potential for diabetes prevention in promoting this as a whole population strategy.

Prospective associations between sedentary time, physical activity, fitness and cardiometabolic risk factors in people with type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to examine the prospective associations between objectively measured physical activity energy expenditure (PAEE), sedentary time, moderate-to-vigorous-intensity physical activity (MVPA), cardiorespiratory fitness (CRF) and cardiometabolic risk factors over 4 years in individuals with recently diagnosed diabetes. METHODS: Among 308 adults (mean age 61.0 [SD 7.2] years; 34% female) with type 2 diabetes from the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care (ADDITION)-Plus study, we measured physical activity using individually calibrated combined heart rate and movement sensing. Multivariable linear regression models were constructed to examine the associations between baseline PAEE, sedentary time, MVPA, CRF and cardiometabolic risk factors and clustered cardiometabolic risk (CCMR) at follow-up, and change in these exposures and change in CCMR and its components over 4 years of follow-up. RESULTS: Individuals who increased their PAEE between baseline and follow-up had a greater reduction in waist circumference (-2.84 cm, 95% CI -4.84, -0.85) and CCMR (-0.17, 95% CI -0.29, -0.04) compared with those who decreased their PAEE. Compared with individuals who decreased their sedentary time, those who increased their sedentary time had a greater increase in waist circumference (3.20 cm, 95% CI 0.84, 5.56). Increases in MVPA were associated with reductions in systolic blood pressure (-6.30 mmHg, 95% CI -11.58, -1.03), while increases in CRF were associated with reductions in CCMR (-0.23, 95% CI -0.40,-0.05) and waist circumference (-3.79 cm, 95% CI -6.62, -0.96). Baseline measures were generally not predictive of cardiometabolic risk at follow-up. CONCLUSIONS/INTERPRETATION: Encouraging people with recently diagnosed diabetes to increase their physical activity and decrease their sedentary time may have beneficial effects on their waist circumference, blood pressure and CCMR.

Medication burden in the first 5†years following diagnosis of type 2 diabetes: findings from the ADDITION-UK trial cohort.

INTRODUCTION: Individuals with screen-detected diabetes are likely to receive intensified pharmacotherapy to improve glycaemic control and general cardiometabolic health. Individuals are often asymptomatic, and little is known about the degree to which polypharmacy is present both before, and after diagnosis. We aimed to describe and characterize the pharmacotherapy burden of individuals with screen-detected diabetes at diagnosis, 1 and 5 years post-diagnosis. METHODS: The prescription histories of 1026 individuals with screen-detected diabetes enrolled in the ADDITION-UK trial of the promotion of intensive treatment were coded into general medication types at diagnosis, 1 and 5 years post-diagnosis. The association between change in the count of several medication types and age, baseline 10-year UK Prospective Diabetes Study (UKPDS) cardiovascular disease (CVD risk), sex, intensive treatment group and number of medications was explored. RESULTS: Just under half of individuals were on drugs unrelated to cardioprotection before diagnosis (42%), and this increased along with a rise in the number of prescribed diabetes-related and cardioprotective drugs. The medication profile over the first 5 years suggests multimorbidity and polypharmacy is present in individuals with screen-detected diabetes. Higher modeled CVD risk at baseline was associated with a greater increase in cardioprotective and diabetes-related medication, but not an increase in other medications. CONCLUSION: As recommended in national guidelines, our results suggest that treatment of diabetes was influenced by the underlying risk of CVD. While many individuals did not start glucose lowering and cardioprotective therapies in the first 5 years after diagnosis, more information is required to understand whether this represents unmet need, or patient-centered care. TRIAL REGISTRATION NUMBER: CNT00237549.

Healthy behavior change and cardiovascular outcomes in newly diagnosed type 2 diabetic patients: a cohort analysis of the ADDITION-Cambridge study.

OBJECTIVE: To examine whether improvements in health behaviors are associated with reduced risk of cardiovascular disease (CVD) in individuals with newly diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: Population-based prospective cohort study of 867 newly diagnosed diabetic patients aged between 40 and 69 years from the treatment phase of the ADDITION-Cambridge study. Because the results for all analyses were similar by trial arm, data were pooled, and results were presented for the whole cohort. Participants were identified via population-based stepwise screening between 2002 and 2006, and underwent assessment of physical activity (European Prospective Investigation into Cancer-Norfolk Physical Activity Questionnaire), diet (plasma vitamin C and self-report), and alcohol consumption (self-report) at baseline and 1 year. A composite primary CVD outcome was examined, comprised of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and revascularization. RESULTS: After a median (interquartile range) follow-up period of 5.0 years (1.3 years), 6% of the cohort experienced a CVD event (12.2 per 1,000 person-years; 95% CI 9.3-15.9). CVD risk was inversely related to the number of positive health behaviors changed in the year after diabetes diagnosis. The relative risk for primary CVD event in individuals who did not change any health behavior compared with those who adopted three/four healthy behaviors was 4.17 (95% CI 1.02-17.09), adjusting for age, sex, study group, social class, occupation, and prescription of cardioprotective medication (P for trend = 0.005). CONCLUSIONS: CVD risk was inversely associated with the number of healthy behavior changes adopted in the year after the diagnosis of diabetes. Interventions that promote early achievement of these goals in patients with newly diagnosed diabetes could help reduce the burden of diabetes-related morbidity and mortality.

Temporal shifts in cardiovascular risk factor distribution.

BACKGROUND: Complementary strategies to shift risk factor population distributions and target high-risk individuals are required to reduce the burden of type 2 diabetes and cardiovascular disease (CVD). PURPOSE: To examine secular changes in glucose and CVD risk factors over 20 years during an individual and population-based CVD prevention program in Västerbotten County, Sweden. METHODS: Population-based health promotion intervention was conducted and annual invitation for individuals turning 40, 50, and 60 years to attend a health assessment, including an oral glucose tolerance test, biochemical measures, and a questionnaire. Data were collected between 1991 and 2010, analyzed in 2012 and available for 120,929 individuals. Linear regression modeling examined age-adjusted differences in CVD risk factor means over time. Data were direct-age-standardized to compare disease prevalence. RESULTS: Between 1991-1995 and 2006-2010, mean age-adjusted cholesterol (men=-0.53, 95% CI=-0.55, -0.50 mmol/L; women=-0.48, 95% CI=-0.50, -0.45 mmol/L) and systolic blood pressure declined (men=-3.06, 95% CI=-3.43, -2.70 mm Hg; women=-5.27, 95% CI=-5.64, -4.90 mm Hg), with corresponding decreases in the age-standardized prevalence of hypertension and hyperlipidemia. Mean age-adjusted 2-hour plasma glucose (men=0.19, 95% CI=0.15, 0.23 mmol/L; women=0.08, 95% CI=0.04, 0.11 mmol/L) and BMI increased (men=1.12, 95% CI=1.04, 1.21; women=0.65, 95% CI=0.55, 0.75), with increases in the age-standardized prevalence of diabetes and obesity. CONCLUSIONS: These data demonstrate the potential of combined individual- and population-based approaches to CVD risk factor control and highlight the need for additional strategies addressing hyperglycemia and obesity.

Generalism and the evolution of parasite virulence.

The evolution of parasite-imposed host harm (virulence) will be affected by numerous factors, not least the range of hosts that parasites can infect. Here, we consider four ways that parasite host range (generalism) might directly affect observed levels of parasite virulence: costs of generalism, multiplicity of infection, maladaptive virulence, and host availability. Integrating parasite infectivity range with life-history evolution will generate novel general hypotheses for the evolutionary ecology of virulence, as well as explicit predictions about the virulence of emerging diseases resulting from host shifts.

Socio-demographic and behavioural correlates of physical activity perception in individuals with recently diagnosed diabetes: results from a cross-sectional study.

BACKGROUND: Physical activity (PA) levels in type 2 diabetes mellitus (T2DM) patients are generally low. Poor PA perception may impede healthy behaviour change in this high risk group. We describe (i) objective PA levels, (ii) the difference between objective and self-reported PA ('PA disparity') and the correlates of (iii) PA disparity and (iv) overestimation in recently diagnosed T2DM patients. METHODS: Cross-sectional analysis of 425 recently diagnosed T2DM patients aged 42 to 71, participating in the ADDITION-Plus study in Eastern England, UK. We define 'PA disparity' as the non-negative value of the difference (in mathematical terms the absolute difference) between objective and self-reported physical activity energy expenditure (PAEE in kJ · kg-1 · day-1). 'Overestimators' comprised those whose self-reported- exceeded objective-PAEE by 4.91 kJ · kg-1 · day-1(the equivalent of 30 minutes moderate activity per day). Multivariable linear regression examined the association between PA disparity (continuous) and socio-demographic, clinical, health behaviour, quality of life and psychological characteristics. Logistic regression examined the association between PA overestimation and individual characteristics. RESULTS: Mean objective and self-reported PAEE levels ± SD were 34.4 ± 17.0 and 22.6 ± 19.4 kJ · kg-1·day-1, respectively (difference in means =11.8; 95% CI=9.7 to 13.9 kJ · kg-1 · day-1). Higher PA disparity was associated with male sex, younger age, lower socio-economic status and lower BMI. PA overestimators comprised 19% (n=80), with those in routine/manual occupations more likely to be overestimators than those in managerial/professional occupations. CONCLUSIONS: T2DM patients with poor physical activity perception are more likely to be male, younger, from a lower socio-economic class and to have a lower BMI. PA overestimators were more likely to be in lower socio-economic categories. Self-monitoring and targeted feedback, particularly to those in lower socio-economic categories, may improve PA perceptions and optimise interventions in T2DM patients. Our findings suggest that strategies for enabling realistic assessment of physical activity levels, through self-monitoring or feedback, warrant further investigation and may help refine and improve physical activity interventions.

How can immunopathology shape the evolution of parasite virulence?

Immunopathology (immune-mediated pathology) is a ubiquitous cause of disease during infection, but how will parasite exploitation strategies evolve in its presence? Immunopathology can act to increase parasite fitness if it increases transmission rate, but can equally act to decrease parasite fitness if it increases host mortality. The focus here is on understanding how immunopathology, mediated through different immune mechanisms, can influence parasite fitness and how experimental manipulations of the immune system can be carried out to examine this. A better understanding of how parasite fitness scales with, or responds to, immunopathology is crucial to understanding the nature of selection acting on parasite virulence traits and will allow more informed predictions to be made regarding the trajectory of parasite virulence evolution.

Consequences of immunopathology for pathogen virulence evolution and public health: malaria as a case study.

Evolutionary theories explaining virulence-the fitness damage incurred by infected hosts-often focus on parasite strategies for within-host exploitation. However, much virulence can be caused by the host's own immune response: for example, pro-inflammatory cytokines, although essential for killing malaria parasites, also damage host tissue. Here we argue that immune-mediated virulence, or 'immunopathology,' may affect malaria virulence evolution and should be considered in the design of medical interventions. Our argument is based on the ability of immunopathology to disrupt positive virulence-transmission relationships assumed under the trade-off theory of virulence evolution. During rodent malaria infections, experimental reduction of inflammation using reagents approved for field use decreases virulence but increases parasite transmission potential. Importantly, rodent malaria parasites exhibit genetic diversity in the propensity to induce inflammation and invest in transmission-stage parasites in the presence of pro-inflammatory cytokines. If immunopathology positively correlates with malaria parasite density, theory suggests it could select for relatively low malaria virulence. Medical interventions which decrease immunopathology may therefore inadvertently select for increased malaria virulence. The fitness consequences to parasites of variations in immunopathology must be better understood in order to predict trajectories of parasite virulence evolution in heterogeneous host populations and in response to medical interventions.

Identifying the age cohort responsible for transmission in a natural outbreak of Bordetella bronchiseptica.

Identifying the major routes of disease transmission and reservoirs of infection are needed to increase our understanding of disease dynamics and improve disease control. Despite this, transmission events are rarely observed directly. Here we had the unique opportunity to study natural transmission of Bordetella bronchiseptica--a directly transmitted respiratory pathogen with a wide mammalian host range, including sporadic infection of humans--within a commercial rabbitry to evaluate the relative effects of sex and age on the transmission dynamics therein. We did this by developing an a priori set of hypotheses outlining how natural B. bronchiseptica infections may be transmitted between rabbits. We discriminated between these hypotheses by using force-of-infection estimates coupled with random effects binomial regression analysis of B. bronchiseptica age-prevalence data from within our rabbit population. Force-of-infection analysis allowed us to quantify the apparent prevalence of B. bronchiseptica while correcting for age structure. To determine whether transmission is largely within social groups (in this case litter), or from an external group, we used random-effect binomial regression to evaluate the importance of social mixing in disease spread. Between these two approaches our results support young weanlings--as opposed to, for example, breeder or maternal cohorts--as the age cohort primarily responsible for B. bronchiseptica transmission. Thus age-prevalence data, which is relatively easy to gather in clinical or agricultural settings, can be used to evaluate contact patterns and infer the likely age-cohort responsible for transmission of directly transmitted infections. These insights shed light on the dynamics of disease spread and allow an assessment to be made of the best methods for effective long-term disease control.

Dynamic models of immune responses: what is the ideal level of detail?

BACKGROUND: One of the goals of computational immunology is to facilitate the study of infectious diseases. Dynamic modeling is a powerful tool to integrate empirical data from independent sources, make novel predictions, and to foresee the gaps in the current knowledge. Dynamic models constructed to study the interactions between pathogens and hosts' immune responses have revealed key regulatory processes in the infection. OPTIMUM COMPLEXITY AND DYNAMIC MODELING: We discuss the usability of various deterministic dynamic modeling approaches to study the progression of infectious diseases. The complexity of these models is dependent on the number of components and the temporal resolution in the model. We comment on the specific use of simple and complex models in the study of the progression of infectious diseases. CONCLUSIONS: Models of sub-systems or simplified immune response can be used to hypothesize phenomena of host-pathogen interactions and to estimate rates and parameters. Nevertheless, to study the pathogenesis of an infection we need to develop models describing the dynamics of the immune components involved in the progression of the disease. Incorporation of the large number and variety of immune processes involved in pathogenesis requires tradeoffs in modeling.

Acellular pertussis vaccination facilitates Bordetella parapertussis infection in a rodent model of bordetellosis.

Despite over 50 years of population-wide vaccination, whooping cough incidence is on the rise. Although Bordetella pertussis is considered the main causative agent of whooping cough in humans, Bordetella parapertussis infections are not uncommon. The widely used acellular whooping cough vaccines (aP) are comprised solely of B. pertussis antigens that hold little or no efficacy against B. parapertussis. Here, we ask how aP vaccination affects competitive interactions between Bordetella species within co-infected rodent hosts and thus the aP-driven strength and direction of in-host selection. We show that aP vaccination helped clear B. pertussis but resulted in an approximately 40-fold increase in B. parapertussis lung colony-forming units (CFUs). Such vaccine-mediated facilitation of B. parapertussis did not arise as a result of competitive release; B. parapertussis CFUs were higher in aP-relative to sham-vaccinated hosts regardless of whether infections were single or mixed. Further, we show that aP vaccination impedes host immunity against B. parapertussis-measured as reduced lung inflammatory and neutrophil responses. Thus, we conclude that aP vaccination interferes with the optimal clearance of B. parapertussis and enhances the performance of this pathogen. Our data raise the possibility that widespread aP vaccination can create hosts more susceptible to B. parapertussis infection.