Validity of outcome measures used in randomized clinical trials and observational studies in degenerative lumbar spinal stenosis.

It is unclear whether outcome measures used in degenerative lumbar spinal stenosis (DLSS) have been validated for this condition. Cross-sectional analysis of studies for DLSS included in systematic reviews (SA) and meta-analyses (MA) indexed in the Cochrane Library. We extracted all outcome measures for pain and disability. We assessed whether the studies provided external references for the validity of the outcome measures and the quality of the validation studies. Out of 20 SA/MA, 95 primary studies used 242 outcome measures for pain and/or disability. Most commonly used were the VAS (n = 69), the Oswestry Disability Index (n = 53) and the Zurich Claudication Questionnaire (n = 22). Although validation references were provided in 45 (47.3%) primary studies, only 14 validation studies for 9 measures (disability n = 7, pain and disability combined n = 2) were specifically validated in a DLSS population. The quality of the validation studies was mainly poor. The Zurich Claudication Questionnaire was the only disease specific tool with adequate validation for assessing treatment response in DLSS. To compare results from clinical studies, outcome measures need to be validated in a disease specific population. The quality of validation studies need to be improved and the validity in studies adequately cited.

Association between depression and anxiety on symptom and function after surgery for lumbar spinal stenosis.

Evidence on the role of depression and anxiety in patients undergoing surgical treatment for symptomatic degenerative lumbar spinal stenosis (DLSS) is conflicting. We aimed to assess the association between depression and anxiety with symptoms and function in patients undergoing surgery for DLSS. Included were patients with symptomatic DLSS participating in a prospective multicentre cohort study who underwent surgery and completed the 24-month follow-up. We used the hospital anxiety and depression scale (HADS) to assess depression/anxiety. We used mixed-effects models to quantify the impact on the primary outcome change in the spinal stenosis measure (SSM) symptoms/function subscale from baseline to 12- and 24-months. Logistic regression analysis was used to quantify the odds of the SSM to reach a minimal clinically important difference (MCID) at 24 months follow-up. The robustness of the results in the presence of unmeasured confounding was quantified using a benchmarking method based on a multiple linear model. Out of 401 patients 72 (17.95%) were depressed and 80 anxious (19.05%). Depression was associated with more symptoms (ß = 0.36, 95% confidence interval (CI) 0.20 to 0.51, p < 0.001) and worse function (ß = 0.37, 95% CI 0.24 to 0.50, p < 0.001) at 12- and 24-months. Only the association between baseline depression and SSM symptoms/function was robust at 12 and 24 months. There was no evidence for baseline depression/anxiety decreasing odds for a MCID in SSM symptoms and function over time. In patients undergoing surgery for symptomatic DLSS, preoperative depression but not anxiety was associated with more severe symptoms and disability at 12 and 24 months.

Measurement of oxygen concentration for detection of subclinical mastitis.

INTRODUCTION: Subclinical mastitis is a frequent and economically important disease in cattle. Since the milk appears macroscopically normal the diagnosis depends on indirect parameters. In automatic milking systems ideally the measurements have to be automatized and completed during milking process. Oxygen concentration of the milk is a parameter which has not been used widely to date. Oxygen is consumed by cells in the milk, hence an increased number of cells results in decreased oxygen concentration. The main objectives of the study were to study the association of milk oxygen concentration with the number of cells and the electric conductivity and to assess the feasibility of oxygen concentration for detection of subclinical mastitis. The study was performed on five dairy farms using 690 macroscopically normal quarter milk samples. Oxygen concentrations (OC), somatic cell count (SCC) and electric conductivity (EC) were measured. The associations between the parameters were calculated and the diagnostic value of OC for detection of subclinical mastitis was estimated. Significant correlations were found between OC and SCC (rs =-0.28) and between OC and EC (rs = -0.20). SCC of the samples varied between 1,000 and 21,602,000 cells/ml. Out of the 690 milk samples 404 had SCC 200,000 cells/ml (subclinical mastitis). OC decreased whereas EC increased significantly with increasing SCC (P < 0.001). The threshold for OC to diagnose subclinical mastitis was 5.22% (sensitivity 84%, specificity 46%). The area under the curve describing the diagnostic value of OC was 0.72 (confidence interval 0.68-0.76). In conclusion OC has potential to be used as parameter to detect subclinical mastitis in dairy cattle. Currently the application is not suitable for routine use. Further research is necessary to improve measurement technology and diagnostic value of the parameter.

INTRODUCTION: La mammite subclinique est une maladie fréquente et économiquement importante chez les bovins. Puisque le lait apparaît macroscopiquement normal, le diagnostic dépend des paramètres indirects. Dans les systèmes de traite automatique, les mesures doivent idéalement être automatisées et effectuées pendant le processus de traite. La concentration en oxygène du lait est un paramètre qui n'a pas été largement utilisé à ce jour. L'oxygène est consommé par les cellules dans le lait, un nombre accru de cellules entraînant donc une diminution de la concentration en oxygène. Les principaux objectifs de l'étude étaient d'étudier l'association de la concentration d'oxygène du lait avec le nombre de cellules et la conductivité électrique et d'évaluer la praticabilité de la mesure de la concentration en oxygène pour la détection de la mammite subclinique. L'étude a été réalisée dans cinq fermes laitières à l'aide de 690 échantillons de lait de quartier macroscopiquement normaux. Des concentrations d'oxygène (OC), le nombre de cellules somatiques (SCC) et la conductivité électrique (EC) ont été mesurés. Les associations entre les paramètres ont été calculées et la valeur diagnostique de l'OC pour la détection de la mammite subclinique a été estimée. Des corrélations significatives ont été trouvées entre OC et SCC (rs= -0,28) et entre OC et EC (rs = -0,20). Le SCC des échantillons variait entre 1'000 et 21'602'000 cellules/ml. Sur les 690 échantillons de lait, 404 avaient un SCC de 200 000 cellules/ml (mammite subclinique). L'OC a diminué alors que l'EC a augmenté de façon significative avec l'augmentation du SCC (P - 0,001). Le seuil pour que l'OC permette un diagnostic de mammite subclinique était de 5,22 % (sensibilité 84 %, spécificité 46 %). La zone sous la courbe décrivant la valeur diagnostique de CO était 0.72 (intervalle de confiance 0.68-0.76). En conclusion, l'OC pourrait être utilisée comme paramètre pour détecter la mammite subclinique chez les bovins laitiers. Actuellement, l'application n'est pas adaptée à une utilisation de routine. D'autres recherches sont nécessaires pour améliorer la technologie de mesure et la valeur diagnostique du paramètre.

Short communication: Use of lameness scoring to genetically improve claw health in Austrian Fleckvieh, Brown Swiss, and Holstein cattle.

The specific objective of this study was to evaluate the use of lameness scoring to genetically improve claw health in Austrian Fleckvieh, Brown Swiss, and Holstein cows based on data from the "Efficient Cow" project. In 2014, a 1-yr data collection was carried out. Data from 6,519 cows kept on 161 farms were recorded. At each time of milk recording, lameness scores were assessed by trained staff of the milk recording organizations. Hoof trimming on these farms was documented and recorded as well. Veterinarian diagnoses and culling due to foot and leg problems from these farms were available from the routine recording system. As repeated lameness records per cow and lactation were available, an overall lactation lameness score was calculated. Estimated heritabilities for lameness were 0.11, 0.05, and 0.09 for Fleckvieh, Brown Swiss, and Holstein, respectively; however, only heritability estimates for Fleckvieh were significantly different from zero. Breeding values for lameness were obtained, reversed in sign, and cows were ranked according to their breeding value. A low breeding value for lameness resistance (the bottom 10% of the cows) was associated with a significantly higher frequency of trimmed cows, which indicates that the cows selected by the farmer to be trimmed are not completely random. Additionally, a high breeding value for lameness resistance (the top 10% of the cows) was associated with lower frequencies of claw diseases recorded at trimming, claw and leg diagnoses, and culling due to foot and leg problems, which highlights the usefulness of lameness scoring for genetic improvement of claw health. Overall, selecting for a better lameness score has the potential to reduce claw diseases, especially the frequency of severe claw diseases that lead to culling.

Rapid Discovery of De Novo Deleterious Mutations in Cattle Enhances the Value of Livestock as Model Species.

In humans, the clinical and molecular characterization of sporadic syndromes is often hindered by the small number of patients and the difficulty in developing animal models for severe dominant conditions. Here we show that the availability of large data sets of whole-genome sequences, high-density SNP chip genotypes and extensive recording of phenotype offers an unprecedented opportunity to quickly dissect the genetic architecture of severe dominant conditions in livestock. We report on the identification of seven dominant de novo mutations in CHD7, COL1A1, COL2A1, COPA, and MITF and exploit the structure of cattle populations to describe their clinical consequences and map modifier loci. Moreover, we demonstrate that the emergence of recessive genetic defects can be monitored by detecting de novo deleterious mutations in the genome of bulls used for artificial insemination. These results demonstrate the attractiveness of cattle as a model species in the post genomic era, particularly to confirm the genetic aetiology of isolated clinical case reports in humans.

Cost-effectiveness of conservative versus surgical treatment strategies of lumbar spinal stenosis in the Swiss setting: analysis of the prospective multicenter Lumbar Stenosis Outcome Study (LSOS).

PURPOSE: To evaluate the cost-effectiveness of conservative versus surgical treatment strategies for lumbar spinal stenosis (LSS). METHODS: Patients prospectively enrolled in the multicenter Lumbar Stenosis Outcome Study (LSOS) with a minimum follow-up of 12 months were included. Quality adjusted life years (QALY) were calculated based on EQ-5D data. Cost data were retrieved retrospectively. Cost-effectiveness was calculated via decision tree analysis. RESULTS: A total of 434 patients were included, treated surgically (n = 170) or conservatively (n = 264) for LSS. The majority of surgically treated patients underwent decompression (n = 141, 82.9%), and 17.1% (n = 29) additionally underwent fusion. A reoperation was required in 13 (7.6%) surgically treated patients. In 27 (10.2%) conservatively treated patients, a single infiltration was successful, with no further infiltration or surgery within the follow-up. However, 46 patients (17.4%) required multiple infiltrations, and in 191 (72.4%) initially conservatively treated patients a subsequent surgery was needed. The area under the curve was 0.776 QALY in the surgical arm (0.776 and 0.790, decompression or additional fusion, respectively), compared to 0.778 in the conservative arm. Treatment costs were estimated at CHF 12,958 and 13,637 (USD 13,465 and 14,169) in surgically and initially conservatively treated patients, respectively [base-case incremental cost-effectiveness ratio (ICER): CHF 392,145, USD 407,831], per QALY gained. Probabilistic sensitivity analysis identified surgery as the preferred strategy in 67.1%. CONCLUSIONS: Both the surgical and the conservative treatment approach resulted in a comparable health-related quality of life within the first year after study inclusion. Due to slightly higher costs, mostly because the majority of initially conservatively treated patients underwent multiple infiltrations or a subsequent surgery, decompressive surgery was identified as the most cost-effective approach for LSS in this setting.

Claw health and prevalence of lameness in cows from compost bedded and cubicle freestall dairy barns in Austria.

Claw health and lameness data from five dairies with compost bedded barns (n = 201 data sets) were evaluated and compared with data from five dairy herds housed in freestall cubicle barns (n = 297 data sets). They were matched for having the same cow numbers, flooring type and similar milk yield. The prevalence of lameness, claw lesions and their severity grades were analysed. Two claw health indicators, the cow claw score (CCS) and the farm claw score (FCS), were calculated using a computerised claw trimming database programme; there was no significant difference in overall lameness prevalence in cows from five compost bedded barns (18.7%) compared to cows from five freestall cubicle herds (14.9%). A cumulative link mixed model (CLMM) did not show significant differences in locomotion between different types of bedding material, flooring system, breed, visit number, observer and time since last trimming, but locomotion was significantly influenced by CCS. Another CLMM tested the impact of parameters mentioned on CCS and showed significant influence of flooring type, visit number and cattle breed. Statistically significant differences in the prevalence of claw disorders between compost bedded and freestall cubicle barns were found for white line disease (WLD; 20.4% and 46.6%, respectively), heel horn erosion (HHE; 26.9% and 59.9%, respectively), concave dorsal wall as a result of chronic laminitis (6.5% and 15.9%, respectively) and for interdigital hyperplasia (0.2% and 3.1%, respectively). The results of this study indicate that compost dairy barns are a good alternative to common cubicle housing systems in terms of lameness, claw health and animal welfare.

mtDNA diversity in human populations highlights the merit of haplotype matching in gene therapies.

STUDY QUESTION: Does mitochondrial DNA (mtDNA) diversity in modern human populations potentially pose a challenge, via mtDNA segregation, to mitochondrial replacement therapies? SUMMARY ANSWER: The magnitude of mtDNA diversity in modern human populations is as high as in mammalian model systems where strong mtDNA segregation is observed; consideration of haplotype pairs and/or haplotype matching can help avoid these potentially deleterious effects. WHAT IS KNOWN ALREADY: In mammalian models, substantial proliferative differences are observed between different mtDNA haplotypes in cellular admixtures, with larger proliferative differences arising from more diverse haplotype pairings. If maternal mtDNA is 'carried over' in human gene therapies, these proliferative differences could lead to its amplification in the resulting offspring, potentially leading to manifestation of the disease that the therapy was designed to avoid-but existing studies have not investigated whether mtDNA diversity in modern human populations is sufficient to permit significant amplification. STUDY DESIGN, SIZE, DURATION: This theoretical study used over 7500 human mtDNA sequences from The National Center for Biotechnology Information (NCBI), a range of international and British mtDNA surveys, and 2011 census data. PARTICIPANTS/MATERIALS, SETTING, METHODS: A stochastic simulation approach was used to model random haplotype pairings from within different regions. In total, 1000 simulated pairings were analysed using the basic local alignment search tool (BLAST) for each region. Previous data from mouse models were used to estimate proliferative differences. MAIN RESULTS AND THE ROLE OF CHANCE: Even within the same haplogroup, differences of around 20-80 single-nucleotide polymorphisms (SNPs) are common between mtDNAs admixed in random pairings. These values are sufficient to lead to substantial segregation in mouse models over an organismal lifetime, even given low starting heteroplasmy, inducing increases from 5% to 35% over 1 year. Substantial population mixing in modern UK cities increases the expected genetic differences. Hence, the likely genetic differences between humans randomly sampled from a population may well allow substantial amplification of a disease-carrying mtDNA haplotype over the timescale of a human lifetime. We report ranges and mean differences for all statistics to quantify uncertainty in our results. LIMITATIONS/REASONS FOR CAUTION: The mapping from mouse and other mammalian models to the human system is challenging, as timescales and mechanisms may differ. Reporting biases in NCBI mtDNA data, if present, may affect the statistics we compute. We discuss the robustness of our findings in the light of these concerns. WIDER IMPLICATIONS OF THE FINDINGS: Matching the mtDNA haplotypes of the mother and third-party donor in mitochondrial replacement therapies is supported as a means of ameliorating the potentially deleterious results of human mtDNA diversity. We present a chart of expected SNP differences between mtDNA haplogroups, allowing the selection of optimal partners for therapies. LARGE SCALE DATA: N/A STUDY FUNDING/COMPETING INTERESTS: The authors report no external funding sources or conflicts of interest.

Consistent detection of bovine papillomavirus in lesions, intact skin and peripheral blood mononuclear cells of horses affected by hoof canker.

REASONS FOR PERFORMING THE STUDY: Equine hoof canker is a chronic proliferative pododermatitis of as yet unknown aetiology. Like equine sarcoid disease, canker is a therapy-resistant disorder characterised by hyperkeratosis, acanthosis and a marked tendency to recur. HYPOTHESIS: There is an association of sarcoid-inducing bovine papillomaviruses of types 1 and 2 (BPV-1, BPV-2) with hoof canker disease. METHODS: Using PCR-based techniques, we assessed canker tissue, intact skin and/or peripheral blood mononuclear cells (PBMCs) of 25 canker-affected horses for the presence of sarcoid-associated BPV-1 and -2. RESULTS: Conventional PCR revealed BPV-1/-2 DNA in 24/24 canker, 12/13 skin and 10/11 PBMC DNA isolates. Using inverse PCR, full-length BPV episomes were detected in 1/5 canker specimens. Sequencing of viral early and late genes amplified from canker, intact skin and PBMC DNA of 2 cases revealed an overall identity of 98% to BPV-1. Viral DNA loads amounted to ≤16 copies per cell in canker tissue and intact skin, and to ≤0.35 copies per PBMC, as determined by quantitative PCR. Using RT-PCR, the viral major oncogene E5 was shown to be transcribed in 2/4 canker tissue specimens and 5/7 PBMC isolates. Immunocapture PCR from 7 canker and 6 skin extract supernatants revealed capsomere-associated viral DNA in one canker and one skin sample. Hoof tissue, skin and PBMCs collected from 13 individuals with no signs of canker or BPV-related malignancies scored negative throughout the experiments. CONCLUSION: These findings suggest that the observed presence of BPV-1/-2 in canker-affected horses is not coincidental but indicative of an active contribution to hoof canker disease. POTENTIAL RELEVANCE: The use of antivirals and/or immune modulators may help improving canker therapy.

Intralesional bovine papillomavirus DNA loads reflect severity of equine sarcoid disease.

REASONS FOR PERFORMING STUDY: Sarcoids are nonmetastasising, yet locally aggressive skin tumours that constitute the most frequent neoplasm in equids. Infection by bovine papillomaviruses types 1 and 2 (BPV-1, BPV-2) has been recognised as major causative factor in sarcoid pathogenesis, but a possible correlation of intralesional virus load with disease severity has not been established thus far. HYPOTHESIS: Given the pathogenic role of BPV-1 and BPV-2 in sarcoid disease, we suggest that intralesional viral DNA concentration may reflect the degree of affection. METHODS: Severity of disease was addressed by recording the tumour growth kinetics, lesion number and tumour type for 37 sarcoid-bearing horses and one donkey. Viral load was estimated via quantitative real-time PCR (qPCR) of the E2, E5, L1 and L2 genes from the BPV-1/-2 genome for one randomly selected lesion per horse and correlated with disease severity. RESULTS: Quantitative PCR against E2 identified viral DNA concentrations ranging from 0-556 copies/tumour cell. Of 16 horses affected by quiescent, slowly growing single tumours or multiple mild-type lesions, 15 showed a viral load up to 1.4 copies per cell. In stark contrast, all equids (22/22) bearing rapidly growing and/or multiple aggressive sarcoids had a viral load between 3 and 569 copies per cell. Consistent results were obtained with qPCR against E5, L1 and L2. CONCLUSIONS: While tumours of the same clinical type carried variable virus load, confirming that viral titre does not determine clinical appearance, we identified a highly significant correlation between intralesional viral load and disease severity. POTENTIAL RELEVANCE: The rapid determination of BPV viral load will give a reliable marker for disease severity and may also be considered when establishing a therapeutic strategy.

Ticks and haemoparasites of dogs from Praia, Cape Verde.

In February 2008 an epidemiological field study on arthropod-borne infections in dogs was carried out in Praia, the capital city of Cape Verde. For this purpose 130 dogs were included in the study. Of these, 94.6% were infested with ticks. Altogether, 1293 ticks of the genus Rhipicephalus (in all evaluated cases R. sanguineus) were collected. Examination for haemotropic parasites was performed via polymerase chain reaction (PCR). Lymph node fine-needle aspirates were screened by PCR for Leishmania infantum infections in 20 dogs with enlarged lymph nodes. Our investigation revealed two species of protozoa (Babesia canis vogeli and Hepatozoon canis) and two species of rickettsiae (Anaplasma platys and Ehrlichia canis). In 101 dogs (77.7%) DNA of one or more pathogens was detected. The PCR examination for H. canis was positive in 83 dogs (63.8%), for E. canis in 34 dogs (26.2%), for A. platys in 10 dogs (7.7%) and for B. canis in five dogs (3.8%), whereas neither B. gibsoni nor L. infantum DNA could be detected. Of the infected dogs, 71.3% had a monoinfection, 27.7% had infections with two pathogens and 1.0% with three pathogens. B. canis, H. canis, E. canis, A. platys and their vector tick R. sanguineus are endemic to Cape Verde and can be present in dogs in high prevalences. These results outline the risk of importing tropical canine diseases when Capeverdian stray dogs are taken to Europe.