Can gait patterns be explained by joint structure in people with and without radiographic knee osteoarthritis? Data from the IMI-APPROACH cohort.

OBJECTIVE: To determine the association between joint structure and gait in patients with knee osteoarthritis (OA). METHODS: IMI-APPROACH recruited 297 clinical knee OA patients. Gait data was collected (GaitSmart®) and OA-related joint measures determined from knee radiographs (KIDA) and MRIs (qMRI/MOAKS). Patients were divided into those with/without radiographic OA (ROA). Principal component analyses (PCA) were performed on gait parameters; linear regression models were used to evaluate whether image-based structural and demographic parameters were associated with gait principal components. RESULTS: Two hundred seventy-one patients (age median 68.0, BMI 27.0, 77% female) could be analyzed; 149 (55%) had ROA. PCA identified two components: upper leg (primarily walking speed, stride duration, hip range of motion [ROM], thigh ROM) and lower leg (calf ROM, knee ROM in swing and stance phases). Increased age, BMI, and radiographic subchondral bone density (sclerosis), decreased radiographic varus angle deviation, and female sex were statistically significantly associated with worse lower leg gait (i.e. reduced ROM) in patients without ROA (R2 = 0.24); in ROA patients, increased BMI, radiographic osteophytes, MRI meniscal extrusion and female sex showed significantly worse lower leg gait (R2 = 0.18). Higher BMI was significantly associated with reduced upper leg function for non-ROA patients (R2 = 0.05); ROA patients with male sex, higher BMI and less MRI synovitis showed significantly worse upper leg gait (R2 = 0.12). CONCLUSION: Structural OA pathology was significantly associated with gait in patients with clinical knee OA, though BMI may be more important. While associations were not strong, these results provide a significant association between OA symptoms (gait) and joint structure.

Developmental adaptations of γδ T cells and B cells in blood and intestinal mucosa from birth until weaning in Holstein bull calves.

This study aimed to characterize the development of systemic and colon tissue resident B and γδ T cells in newborn calves from birth until weaning. At birth, calves have limited capacity to initiate immune responses, and the immune system gradually matures over time. Gamma delta (γδ) T cells are an important lymphocyte subset in neonatal calves that confer protection and promote immune tolerance. A total of 36 newborn calves were enrolled in a longitudinal study to characterize how systemic and colon tissue resident B and γδ T cells develop from birth until weaning. Blood and colon biopsy samples were collected on d 2, 28, and 42 to determine the proportions of various B and γδ T cell subsets by flow cytometry. We classified γδ T cells into different functional subsets according to the level of expression intensity of the coreceptors WC1.1 (effector function) and WC1.2 (regulatory function). Furthermore, naive B cells were classified based on the expression IgM receptor, and activation state was determined based on expression of CD21 and CD32, 2 receptors with opposing signals involved in B cell activation in early life. Additional colon biopsy samples were used for 16S sequencing, and microbial diversity data are reported. At birth, γδ T cells were the most abundant lymphocyte population in blood, accounting for 58.5% of the lymphocyte pool, after which the proportions of these cells declined to 38.2% after weaning. The proportion of γδ T cells expressing WC1.1 decreased by 50% from d 2 to d 28, whereas no change was observed in the expression of WC1.2. In the colon, there was a 50% increase of γδ T cells after weaning and the proportion of WC1.2+ γδ T cells doubled from d 28 to 42. The proportion of IgM+ B lymphocytes in blood increased from 23.6% at birth to 30% after weaning, were the proportion of B cells expressing CD21 increased by 25%, while the proportion of B cells expressing CD32 decreased by 30%. While no changes were observed for the overall proportion of IgM+ B lymphocytes in the colon, there was a 6-fold increase in the proportion of CD21+ B cells from pre- (d 28) to postweaning (d 42). Microbial diversity increased from d 2 of life to 28 and declined abruptly after weaning. The reduction in microbial diversity during weaning was negatively correlated with the increase in all γδ T cell subsets and CD21+ B cells. These data suggest that developmental adaptations after birth coordinate expansion of γδ T cells to provide early systemic protection, as well as to steer immune tolerance, while B cells mature over time. Additionally, the increase of colonic γδ T cells on d 42 suggests a protective role of these cells during weaning.

Reflections from the OARSI 2022 clinical trials symposium: The pain of OA-Deconstruction of pain and patient-reported outcome measures for the benefit of patients and clinical trial design.

OBJECTIVE: Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has had a significant impact on drug development programs and has led to hesitance among stakeholders. Since 2017, the Clinical Trials Symposium (CTS) has been hosted under the Osteoarthritis Research Society International (OARSI) leadership. OARSI and the CTS steering committee yearly invite and encourage discussions on selected special subject matter between regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists to progress drug development in the OA field. METHOD: The main topic for the 2022 OARSI CTS was to elucidate the many facets of pain in OA and to enable a discussion between regulators (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) and drug developers to clarify outcomes and study designs for OA drug development. RESULTS: Signs or symptoms indicative of nociceptive pain occur in 50-70% of OA patients, neuropathic-like pain in 15-30% of patients, and nociplastic pain in 15-50% of patients. Weight-bearing knee pain is associated with bone marrow lesions and effusions. There are currently no simple objective functional tests whose improvements correlate with patient perceptions. CONCLUSIONS: The CTS participants, in collaboration with the FDA and EMA, raised several suggestions that they consider key to future clinical trials in OA including the need for more precise differentiation of pain symptoms and mechanisms, and methods to reduce placebo responses in OA trials.

The association of immune response and colostral immunoglobulin G in Canadian and US Holstein-Friesian dairy cows.

In cattle, maternal immunoglobulins are transferred through colostrum to provide passive immunity to the neonatal calf once they are absorbed into circulation. Cows can be assessed for antibody- and cell-mediated immune responses (AMIR and CMIR, respectively), and through estimated breeding values (EBV) and genomic parent averages (GPA), cows can be classified as having high, average, or low immune response (IR). The objective of this study was to identify associations of colostral IgG concentrations with IR in dairy cows. High IR dairy cows identified by GPA or EBV were hypothesized to produce higher colostral IgG concentrations than cows with average or low IR. Colostrum was collected from Holstein dairy cows from 3 large commercial herds (n = 590) in the United States and 1 research herd at the Ontario Dairy Research Centre (n = 275) in Canada. For the US herds, IR GPA were available through genotyping. For the Canadian herd, IR EBV were available through phenotyping and pedigree information. Colostral IgG concentrations were measured by radial immunodiffusion and analyzed using general linear models in SAS. Based on a prediction equation, cows in US herds with a CMIR GPA of 1 would have colostral IgG concentrations 6.3 g/L higher on average than cows with a CMIR GPA of 0. High CMIR cows produced statistically greater colostral IgG concentrations (least squares mean ± standard error of the mean, 107.5 ± 7.7 g/L) than low CMIR cows (91.4 ± 7.1 g/L), with intermediate values for average CMIR cows (105.1 ± 5.6 g/L). No differences were found among AMIR categories in US cows. The Canadian herd showed a trend for cows with high CMIR EBV (continuous variable) to produce greater colostral IgG. No differences were observed among high, average, and low AMIR EBV classifications in Canadian cows. The findings suggest that selective breeding of Holstein cows to enhance CMIR could contribute to higher-quality colostrum in succeeding generations.

Effective behaviour change techniques for family and close friends: A systematic review and meta-analysis across the addictions.

This systematic review aimed to determine whether the use of specific behaviour change technique (BCT) groups are associated with greater effectiveness for psychosocial interventions delivered to family and close friends (FCFs) impacted by addiction. A systematic search of peer-reviewed and grey literature published until August 2021 identified 32 studies in 38 articles. An established BCT taxonomy (93 BCTs clustered into 16 groups) was adapted (inclusion of seven additional BCT groups) and applied to 57 interventions. The meta-analyses indicated that some, but not all, FCF outcomes were improved by the exclusion of BCTs within several groups (Reward and Threat, Scheduled Consequences, Confrontation of the Addicted Person to Engage in Treatment, and Goals and Planning) and inclusion of BCTs within the Restoring a Balanced Lifestyle group. Addicted person outcomes were improved by the inclusion of some BCTs within several groups (Repetition and Substitution, Reward and Threat, Scheduled Consequences, and Restoring a Balanced Lifestyle). Relationship functioning outcomes were improved by the inclusion of BCTs within the Confrontation of the Addicted Person to Engage in Treatment group. Future research involving the development and evaluation of numerous interventions or comprehensive multi-component interventions that can address the various needs of FCFs, without counteracting them, is required.

GaitSmart motion analysis compared to commonly used function outcome measures in the IMI-APPROACH knee osteoarthritis cohort.

BACKGROUND: There are multiple measures for assessment of physical function in knee osteoarthritis (OA), but each has its strengths and limitations. The GaitSmart® system, which uses inertial measurement units (IMUs), might be a user-friendly and objective method to assess function. This study evaluates the validity and responsiveness of GaitSmart® motion analysis as a function measurement in knee OA and compares this to Knee Injury and Osteoarthritis Outcome Score (KOOS), Short Form 36 Health Survey (SF-36), 30s chair stand test, and 40m self-paced walk test. METHODS: The 2-year Innovative Medicines Initiative-Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) knee OA cohort was conducted between January 2018 and April 2021. For this study, available baseline and 6 months follow-up data (n = 262) was used. Principal component analysis was used to investigate whether above mentioned function instruments could represent one or more function domains. Subsequently, linear regression was used to explore the association between GaitSmart® parameters and those function domains. In addition, standardized response means, effect sizes and t-tests were calculated to evaluate the ability of GaitSmart® to differentiate between good and poor general health (based on SF-36). Lastly, the responsiveness of GaitSmart® to detect changes in function was determined. RESULTS: KOOS, SF-36, 30s chair test and 40m self-paced walk test were first combined into one function domain (total function). Thereafter, two function domains were substracted related to either performance based (objective function) or self-reported (subjective function) function. Linear regression resulted in the highest R2 for the total function domain: 0.314 (R2 for objective and subjective function were 0.252 and 0.142, respectively.). Furthermore, GaitSmart® was able to distinguish a difference in general health status, and is responsive to changes in the different aspects of objective function (Standardized response mean (SRMs) up to 0.74). CONCLUSION: GaitSmart® analysis can reflect performance based and self-reported function and may be of value in the evaluation of function in knee OA. Future studies are warranted to validate whether GaitSmart® can be used as clinical outcome measure in OA research and clinical practice.

Effectiveness of problem gambling interventions in a service setting: a protocol for a pragmatic randomised controlled clinical trial.

INTRODUCTION: The primary purpose of this study is to evaluate the relative effectiveness of 2 of the best developed and most promising forms of therapy for problem gambling, namely face-to-face motivational interviewing (MI) combined with a self-instruction booklet (W) and follow-up telephone booster sessions (B; MI+W+B) and face-to-face cognitive-behavioural therapy (CBT). METHODS AND ANALYSIS: This project is a single-blind pragmatic randomised clinical trial of 2 interventions, with and without the addition of relapse-prevention text messages. Trial assessments take place pretreatment, at 3 and 12 months. A total of 300 participants will be recruited through a community treatment agency that provides services across New Zealand and randomised to up to 10 face-to-face sessions of CBT or 1 face-to-face session of MI+W+up to 5 B. Participants will also be randomised to 9 months of postcare text messaging. Eligibility criteria include a self-perception of having a current gambling problem and a willingness to participate in all components of the study (eg, read workbook). The statistical analysis will use an intent-to-treat approach. Primary outcome measures are days spent gambling and amount of money spent per day gambling in the prior month. Secondary outcome measures include problem gambling severity, gambling urges, gambling cognitions, mood, alcohol, drug use, tobacco, psychological distress, quality of life, health status and direct and indirect costs associated with treatment. ETHICS AND DISSEMINATION: The research methods to be used in this study have been approved by the Ministry of Health, Health and Disability Ethics Committees (HDEC) 15/CEN/99. The investigators will provide annual reports to the HDEC and report any adverse events to this committee. Amendments will also be submitted to this committee. The results of this trial will be submitted for publication in peer-reviewed journals and as a report to the funding body. Additionally, the results will be presented at national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12615000637549.

Short communication: Variation of total immunoglobulin G and ß-lactoglobulin concentrations in colostrum and milk from Canadian Holsteins classified as high, average, or low immune responders.

The objective of this study was to evaluate IgG and ß-lactoglobulin (ß-LG) concentrations in colostrum and milk of Canadian Holsteins (n=108) classified as high (H), average (A), or low (L) for antibody-mediated (AMIR) or cell-mediated immune responses (CMIR) based on estimated breeding values. It was hypothesized that H-AMIR and H-CMIR cows produce colostrum (first milking) and milk (d 5 postcalving) with higher concentrations of IgG and ß-LG. Data for IgG and ß-LG in colostrum and milk were analyzed independently using mixed linear models. Least squares means were compared using Tukey's test. Cows classified as H-AMIR had higher IgG and ß-LG concentrations in colostrum compared with A- and L-AMIR cows; 84% of H-AMIR, 69% of A-AMIR, and 68% of L-AMIR cows had over 5,000 mg/dL IgG in colostrum. No differences in IgG and ß-LG concentrations in colostrum were noted among cows ranked on CMIR or in milk of cows ranked on AMIR. ß-Lactoglobulin and IgG concentrations were positively correlated in colostrum. Breeding cows for H-AMIR status may reduce failure of passive transfer of IgG in their calves; ß-LG may play a role in bovine immune defenses. Colostrum from H-AMIR cows may serve as a more economical feedstock source for manufacturing natural health products.

Lactobacillus and Lactobacillus cell-free culture supernatants modulate chicken macrophage activities.

Lactobacilli are commensal microbes that reside in the intestines of several species, including chickens. Structural constituents of lactobacilli are able to stimulate the host immune system. Macrophages are crucial players in both innate and adaptive immune systems. Here, we investigated the effects of Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus salivarius and their cell-free culture supernatants on the pro-inflammatory gene expression profile, nitric oxide (NO) production and phagocytosis by chicken macrophages. Substantial differences were found among Lactobacillus strains in their capacity to induce pro-inflammatory cytokines. L. acidophilus only up-regulated interferon (IFN)-γ, while L. reuteri and L. salivarius up-regulated interleukin (IL)-1ß, IL-6, IL-8 and IL-12 expression. Supernatant of L. salivarius up-regulated IL-1ß, IL-8 and IFN-γ expression, while the other cell-free supernatants did not induce significant changes. Moreover, L. reuteri and L. salivarius increased macrophage phagocytosis, but all cell-free supernatants increased macrophage NO production and did not change phagocytosis activity.

Investigation of a commercial ELISA for the detection of canine procalcitonin.

BACKGROUND: Rapid identification of sepsis enables prompt administration of antibiotics and is essential to improve patient survival. Procalcitonin (PCT) is a biomarker used to diagnose sepsis in people. Commercial assays to measure canine PCT peptide have not been validated. OBJECTIVE: To investigate the validity of a commercially available enzyme-linked immunosorbent assay (ELISA) marketed for the measurement of canine PCT. ANIMALS: Three dogs with sepsis, 1 healthy dog, 1 dog with thyroid carcinoma. METHODS: Experimental study. The ELISA's ability to detect recombinant and native canine PCT was investigated and intra-assay and interassay coefficients of variability were calculated. Assay validation including mass spectrometry of the kit standard solution was performed. RESULTS: The ELISA did not consistently detect recombinant canine PCT. Thyroid lysate yielded a positive ELISA signal. Intra-assay variability ranged from 18.9 to 77.4%, while interassay variability ranged from 56.1 to 79.5%. Mass spectrometry of the standard solution provided with the evaluated ELISA kit did not indicate presence of PCT. CONCLUSIONS AND CLINICAL IMPORTANCE: The results of this investigation do not support the use of this ELISA for the detection of PCT in dogs.

Factors associated with morbidity, mortality, and growth of dairy heifer calves up to 3 months of age.

Calfhood disease is an important problem on many dairy operations that can have substantial effects on heifer survival and productivity, and has economic and welfare impacts. Neonatal calf diarrhea (NCD) and bovine respiratory disease (BRD) are the most common causes of morbidity and mortality in young dairy cattle. The objective of this observational study was to investigate factors associated with the risks of morbidity and mortality, and with growth, in commercial dairy heifers calves. A total of 2874 heifer calves from 19 commercial dairy farms in Minnesota and Ontario were enrolled at 1-7 days of age and followed for approximately 3 months. Using cut-points of serum total protein of 5.2 and 5.7 g/dl, the incidences of failure of transfer of passive immunity (FTPI) were 11 and 32%, respectively. A cut-point of 5.7 g/dl was the most predictive of BRD before 5 weeks of age (sensitivity=40%, specificity=69%). The positive predictive value was poor (PPV=18%), but the negative predictive value was good (NPV=87%). A cut-point of 5.2g/dl was most predictive of death before 5 weeks of age (sensitivity=27%, specificity=89%, PPV=5%, NPV=98%). Serum total protein during the first week of life was a poor predictor of NCD. Over 23% of calves were treated for diarrhea. Risk factors were weight at enrollment, other diseases before 2 weeks of age, and an interaction between season of birth and herd-level incidence of NCD. Almost 22% of calves were treated at least once for BRD. Factors associated with an increased risk of BRD included herd-level incidence of BRD, season of birth, navel dipping, other diseases before 2 weeks of age, failure of transfer of passive immunity, and manual control of temperature in pre-weaning housing. Administration of supplemental antibody products at birth was associated with a reduced incidence of BRD. Overall mortality was 3.5%. Risk of mortality was increased by treatment for BRD and other diseases. The mean average weight gain was 0.95 kg/day (range: 0.11-1.62 kg/day; SD=0.2). Twinning status, FTP, treatment for NCD or other diseases, and month of birth influenced body weight. This study illustrated relationships among various diseases, mortality, and growth. Furthermore, it demonstrated the importance of colostrum for protection against BRD and improved growth performance, while bringing into question the optimal method of determining failure of transfer of passive immunity.

The effects of viral vaccination of dairy heifer calves on the incidence of respiratory disease, mortality, and growth.

Bovine respiratory disease (BRD) is one of the most common infectious causes of morbidity and mortality in young dairy cattle. The objective of this randomized clinical trial was to determine the effectiveness of 1 or 2 doses of a 5-way, modified-live viral vaccine, administered to heifer calves before weaning to aid in the prevention of BRD. The hypotheses were that vaccination would reduce the incidence of BRD and mortality, and that 2 doses would be more effective than 1. A total of 2,874 heifer calves from 19 commercial dairy farms in Minnesota and Ontario were enrolled at 1 to 7d of age and were followed until 3 mo of age. Calves were randomly assigned to receive a commercial, intramuscular, modified-live vaccine against bovine viral diarrhea virus types 1 and 2, bovine respiratory syncytial virus, bovine herpesvirus type 1, and parainfluenza virus type 3 at 15 to 21 d of age (2 wk only), 35 to 42 d (5 wk only), both 2 and 5 wk, or sterile saline at both times (unvaccinated controls). The incidence of failure of passive transfer was 11 or 32%, using cut-points of serum total protein of 5.2 and 5.7 g/dL, respectively. Overall, 22% of calves were treated at least once for BRD. The incidence risk of naturally occurring BRD was 7.7% before 2 wk of age, 8.0% between 2 and 5 wk, and 9.5% between 5 wk and 3 mo of age, and was not different between vaccination groups. Overall mortality throughout the 3-mo study period was 3.5%. Mortality was 1.6% before 2 wk of age, 0.5% between 2 and 5 wk, and 1.2% between 5 wk and 3 mo of age. The risk of mortality was not affected by vaccination. Mean average daily gain of 1.07 kg/d from 5 wk to 3 mo of age was not different between vaccine groups. In this population of commercial, home-raised calves, with an overall low incidence of failure of passive transfer, intramuscular vaccination with a multivalent, modified live viral vaccine at 2 or 5 wk of age or both was not associated with a decreased risk of BRD or mortality, or with growth until 3 mo of age. Reasons for these findings may include interference by maternal antibodies, unresponsiveness of the neonatal immune system, timing of immunity relative to pathogen exposure, disease caused by pathogens other than the viruses in the vaccine, or herd immunity. However, in populations with higher incidence of failure of passive transfer or risk of BRD, calves with low levels of specific antibodies may respond differently to vaccination.

Disordered gambling among higher-frequency gamblers: who is at risk?

BACKGROUND: When gambling opportunities are made available to the public in a given jurisdiction, some individuals participate occasionally and others more frequently. Among frequent gamblers, some individuals develop problematic involvement and some do not. This study addresses the association among demographic and social risk factors, frequency of gambling and gambling disorders. METHOD: Data from an adult community sample (n=1372) were used to identify risk factors for higher-frequency gambling and disordered gambling involvement. RESULTS: Individuals with higher intelligence, older individuals and more religious individuals were less frequent gamblers. Males, single individuals and those exposed to gambling environments (friends and family who gamble) and those who started to gamble at a younger age were more frequent gamblers. Excitement-seeking personality traits were also higher among more frequent gamblers. A different set of risk factors was associated with the likelihood of gambling disorder among these higher-frequency gamblers. These variables included mental health indicators, childhood maltreatment and parental gambling involvement. Among higher-frequency gamblers, individuals who smoke cigarettes, those with a diagnosis of alcohol or drug dependence or obsessive-compulsive disorder, those with higher anxiety or depression and those with higher impulsivity and antisocial personality traits were more likely to report gambling-related problems. These individuals were also more likely to report gambling on electronic gambling machines (e.g. slot machines). CONCLUSIONS: These data suggest a model in which higher-frequency gambling, particularly with electronic gambling machines, when combined with any type of emotional vulnerability increased the likelihood of gambling disorder.

Incorporation of antigens from Mannheimia haemolytica culture supernatant, and recombinant bovine C3d into ISCOM matrix using neutravidin-biotin interaction.

The aim of this study was to incorporate antigens from Mannheimia haemolytica culture supernatant, and an immune modulatory molecule, recombinant bovine C3d (rBoC3d), into immune stimulating complexes (ISCOMs) using neutravidin-biotin interaction. Biotinylated ISCOM matrix was generated using a commercial kit. The biotinylated ISCOM matrix was incubated with neutravidin and then centrifuged in a sucrose density gradient. The rBoC3d was expressed as an in vivo biotinylated protein and with a c-Myc tag (EQKLISEEDL) engineered to facilitate detection. The neutravidin-coated ISCOM matrix was incubated with biotinylated antigens from M. haemolytica culture supernatants and rBoC3d. To test the association among the neutravidin-coated ISCOM matrix, biotinylated antigens and rBoC3d, an analytical sucrose density gradient (10-40%, w/w) was performed. The experimental formulations were run in SDS-PAGE gels under reducing conditions. For Western immunoblot analysis, polyclonal bovine antiavidin, monoclonal anti-c-Myc, monoclonal antileukotoxin, and anti-GS60 antibodies were used to detect the presence of neutravidin, rBoC3d, leukotoxin, and GS60 antigens, respectively. By taking advantage of the biotin-neutravidin interaction, not only leukotoxin but also the recombinant immunomodulatory molecule, rBoC3d, was incorporated into ISCOM particles.

Challenges in mucosal vaccination of cattle.

Recognition of the mucosal portal of entry for many infectious diseases and of the relevance of mucosal immune response to protection has encouraged the development of vaccines administered by mucosal routes, principally oral and intranasal, for stimulation of intestinal and nasopharyngeal lymphoid tissues respectively. The oral route is problematic in cattle and other ruminants where antigen degradation in the rumen is likely, prior to transit to the intestine. On the other hand, rumination can be exploited for exposure of nasopharyngeal tissues during cudding if vaccine antigen is expressed by a fibrous feed like alfalfa. An increase in anti-leukotoxin (Lkt) IgA was demonstrated in nasal secretions of calves following feeding of alfalfa expressing a truncated Lkt50 from Mannheimia haemolytica, and there is evidence suggesting that such vaccination may protect against experimentally induced pneumonia. Intranasal vaccination is an alternative approach for use in pre-ruminating calves. Intranasal administration of ISCOMs carrying soluble antigens of M. haemolytica, including native Lkt, induced Lkt specific IgA in nasal secretions after vaccination at 4 and 6 weeks of age. Subcutaneous (s.c.) administration of the same vaccine induced Lkt specific IgG in both serum and nasal secretions, whereas s.c. administration of a commercial M. haemolytica vaccine did not. Regardless of the vaccination strategy employed it is difficult to assess the immunogenicity of mucosally administered vaccines because production of secreted antibodies tends to be transient, and they do not persist on the mucosal surface in the absence of ongoing antigenic stimulation. An additional challenge is demonstration of vaccine efficacy in response to experimental infection. Protection of the mucosally vaccinated animal will most probably result from recall response, which may not amplify sufficiently to counter the effects of experimental pulmonary delivery of a large bolus of virulent bacteria, even though the response would suffice over the more prolonged and gradual infection that occurs in natural induction of pneumonia.

Developments in sensor systems.

Healthy Aims is a large European Union Sixth Framework project. It has the overall goal to produce new intelligent medical implants, sensor systems and relevant technologies for clinical applications. Developments on some of the sensor systems are reported here.

Mannheimia haemolytica and bovine respiratory disease.

Mannheimia haemolytica is the principal bacterium isolated from respiratory disease in feedlot cattle and is a significant component of enzootic pneumonia in all neonatal calves. A commensal of the nasopharynx, M. haemolytica is an opportunist, gaining access to the lungs when host defenses are compromised by stress or infection with respiratory viruses or mycoplasma. Although several serotypes act as commensals, A1 and A6 are the most frequent isolates from pneumonic lungs. Potential virulence factors include adhesin, capsular polysaccharide, fimbriae, iron-regulated outer membrane proteins, leukotoxin (Lkt), lipopolysaccharide (LPS), lipoproteins, neuraminidase, sialoglycoprotease and transferrin-binding proteins. Of these, Lkt is pivotal in induction of pneumonia. Lkt-mediated infiltration and destruction of neutrophils and other leukocytes impairs bacterial clearance and contributes to development of fibrinous pneumonia. LPS may act synergistically with Lkt, enhancing its effects and contributing endotoxic activity. Antibiotics are employed extensively in the feedlot industry, both prophylactically and therapeutically, but their efficacy varies because of inconsistencies in diagnosis and treatment regimes and development of antibiotic resistance. Vaccines have been used for many decades, even though traditional bacterins failed to demonstrate protection and their use often enhanced disease in vaccinated animals. Modern vaccines use culture supernatants containing Lkt and other soluble antigens, or bacterial extracts, alone or combined with bacterins. These vaccines have 50-70% efficacy in prevention of M. haemolytica pneumonia. Effective control of M. haemolytica pneumonia is likely to require a combination of more definitive diagnosis, efficacious vaccines, therapeutic intervention and improved management practices.

Human motion analysis.

Huge market potential exists for products that will help the growing elderly population live independent lives for as long as possible. Sensors play an essential role in many of the diagnosis, monitoring and treatment devices to be used in the home. Some of the innovations in this area are reported.