Safety and efficacy of subcutaneous tanezumab in patients with knee or hip osteoarthritis

Background/objective: The objective of this study was to investigate the safety and efficacy of subcutaneous (SC) and intravenous (IV) tanezumab administration in osteoarthritis (OA) patients. Materials and methods: Study 1027 (NCT01089725), a placebo-controlled trial, evaluated the efficacy of SC tanezumab (ie, 2.5, 5, and 10 mg) and the therapeutic equivalence of 10 mg tanezumab given subcutaneously versus intravenously every 8 weeks in the symptomatic treatment of OA. Coprimary endpoints were: change from baseline in Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) Pain and Physical Function indices, and Patient\u27s Global Assessment (PGA) of OA. Study 1043 (NCT00994890) was a long-term, noncontrolled safety study of tanezumab (ie, 2.5, 5, and 10 mg) subcutaneously administered every 8 weeks. Both studies were discontinued prematurely due to a US Food and Drug Administration partial clinical hold. Results: Due to the clinical hold, Study 1027 was underpowered, and no statistical analyses were performed. Mean (standard error [SE]) change from baseline to week 8 in WOMAC Pain in tanezumab groups ranged from -3.59 (0.26) to -3.89 (0.32), versus -2.74 (0.25) with placebo. Mean (SE) change from baseline to week 8 in WOMAC Physical Function ranged from -3.13 (0.25) to -3.51 (0.28) with tanezumab and was -2.26 (0.24) with placebo. PGA mean (SE) change from baseline to week 8 ranged from -0.90 (0.11) to -1.08 (0.12) with tanezumab and was -0.78 (0.10) with placebo. Similar effectiveness was associated with tanezumab in Study 1043. Few patients in either study (1.4%-5.2%) discontinued due to adverse events. Five patients required total joint replacements in Study 1027 (placebo, n=2 [2.8%]; tanezumab 2.5 mg, n=3 [4.1%]) and 34 patients in Study 1043 (tanezumab 2.5 mg, n=11 [4.8%]; tanezumab 5 mg, n=8 [3.6%]; tanezumab 10 mg, n=15 [6.6%]). Conclusion: Preliminary results show similar efficacy and safety for both SC and IV administration of tanezumab based on the direct comparisons reported here and indirect comparisons with published results, confirming pharmacokinetic/pharmacodynamic modeling predictions

Gastrointestinal tissue‐based molecular biomarkers: A practical categorization based on the 2019 WHO Classification of Epithelial Digestive Tumours

Molecular biomarkers have come to constitute one of the cornerstones of oncological pathology. The method of classification not only directly affects the manner in which patients are diagnosed and treated, but also guides the development of drugs and of artificial intelligence tools. The aim of this article is to organise and update gastrointestinal molecular biomarkers in order to produce an easy-to-use guide for routine diagnostics. For this purpose, we have extracted and reorganised the molecular information on epithelial neoplasms included in the 2019 World Health Organization classification of tumours. Digestive system tumours, 5th edn

Cell populations in lesions of cutaneous leishmaniasis of leishmania (L.) amazonensis- infected rhesus macaques, Macaca mulatta

The cellular nature of the infiltrate in cutaneous lesion of rhesus monkeys experimentally infected with Leishmania (L.) amazonensis was characterized by immunohistochemistry. Skin biopsies from infected animals with active or healing lesions were compared to non-infected controls (three of each type) to quantitate inflammatory cell types. Inflammatory cells (composed of a mixture of T lymphocyte subpopulations, macrophages and a small number of natural killer cells and granulocytes) were more numerous in active lesions than in healing ones. T-cells accounted for 44.7 ± 13.1% of the infiltrate in active lesions (versus CD2+= 40.3 ± 5.7% in healing lesions) and T-cell ratios favor CD8+ cells in both lesion types. The percentage of cells expressing class II antigen (HLA-DR+) in active lesions (95 ± 7.1%) was significantly higher (P < 0.005) from the healing lesions (42.7 ± 12.7%). Moreover, the expression of the activation molecules CD25 (@ 16%), the receptor for interleukin-2, suggests that many T cells are primed and proliferating in active lesions. Distinct histopathological patterns were observed in lesions at biopsy, but healing lesions contained more organized epithelioid granulomas and activated macrophages, followed by fibrotic substitution. The progression and resolution of skin lesions appears to be very similar to that observed in humans, confirming the potential for this to be used as a viable model to study the immune response in human cutaneous leishmaniasis

The Anatomy of the bill Tip of Kiwi and Associated Somatosensory Regions of the Brain: Comparisons with Shorebirds

Three families of probe-foraging birds, Scolopacidae (sandpipers and snipes), Apterygidae (kiwi), and Threskiornithidae (ibises, including spoonbills) have independently evolved long, narrow bills containing clusters of vibration-sensitive mechanoreceptors (Herbst corpuscles) within pits in the bill-tip. These ‘bill-tip organs’ allow birds to detect buried or submerged prey via substrate-borne vibrations and/or interstitial pressure gradients. Shorebirds, kiwi and ibises are only distantly related, with the phylogenetic divide between kiwi and the other two taxa being particularly deep. We compared the bill-tip structure and associated somatosensory regions in the brains of kiwi and shorebirds to understand the degree of convergence of these systems between the two taxa. For comparison, we also included data from other taxa including waterfowl (Anatidae) and parrots (Psittaculidae and Cacatuidae), non-apterygid ratites, and other probe-foraging and non probe-foraging birds including non-scolopacid shorebirds (Charadriidae, Haematopodidae, Recurvirostridae and Sternidae). We show that the bill-tip organ structure was broadly similar between the Apterygidae and Scolopacidae, however some inter-specific variation was found in the number, shape and orientation of sensory pits between the two groups. Kiwi, scolopacid shorebirds, waterfowl and parrots all shared hypertrophy or near-hypertrophy of the principal sensory trigeminal nucleus. Hypertrophy of the nucleus basorostralis, however, occurred only in waterfowl, kiwi, three of the scolopacid species examined and a species of oystercatcher (Charadriiformes: Haematopodidae). Hypertrophy of the principal sensory trigeminal nucleus in kiwi, Scolopacidae, and other tactile specialists appears to have co-evolved alongside bill-tip specializations, whereas hypertrophy of nucleus basorostralis may be influenced to a greater extent by other sensory inputs. We suggest that similarities between kiwi and scolopacid bill-tip organs and associated somatosensory brain regions are likely a result of similar ecological selective pressures, with inter-specific variations reflecting finer-scale niche differentiation

Abdominal Wound Dehiscence in Adults: Development and Validation of a Risk Model

Background: Several studies have been performed to identify risk factors for abdominal wound dehiscence. No risk model had yet been developed for the general surgical population. The objective of the present study was to identify independent risk factors for abdominal wound dehiscence and to develop a risk model to recognize high-risk patients. Identification of high-risk patients offers opportunities for intervention strategies. Methods: Medical registers from January 1985 to December 2005 were searched. Patients who had primarily undergone appendectomies or nonsurgical (e.g., urological) operations were excluded. Each patient with abdominal wound dehiscence was matched with three controls by systematic random sampling. Putative relevant patient-related, operation-related, and postoperative variables were evaluated in univariate analysis and subsequently entered in multivariate stepwise logistic regression models to delineate major independent predictors of abdominal wound dehiscence. A risk model was developed, which was validated in a population of patients who had undergone operation between January and December 2006. Results: A total of 363 cases and 1,089 controls were analyzed. Major independent risk factors were age, gender, chronic pulmonary disease, ascites, jaundice, anemia, emergency surgery, type of surgery, postoperative coughing, and wound infection. In the validation population, risk scores were significantly higher (P < 0.001) for patients with abdominal wound dehiscence (n = 19) compared to those without (n = 677). Resulting scores ranged from 0 to 8.5, and the risk for abdominal wound dehiscence over this range increased exponentially from 0.02% to 70.1%. Conclusions: The validated risk model shows high predictive value for abdominal wound dehiscence and may help to identify patients at increased risk

Bivariate random-effects meta-analysis and the estimation of between-study correlation

BACKGROUND: When multiple endpoints are of interest in evidence synthesis, a multivariate meta-analysis can jointly synthesise those endpoints and utilise their correlation. A multivariate random-effects meta-analysis must incorporate and estimate the between-study correlation (ρ(B)). METHODS: In this paper we assess maximum likelihood estimation of a general normal model and a generalised model for bivariate random-effects meta-analysis (BRMA). We consider two applied examples, one involving a diagnostic marker and the other a surrogate outcome. These motivate a simulation study where estimation properties from BRMA are compared with those from two separate univariate random-effects meta-analyses (URMAs), the traditional approach. RESULTS: The normal BRMA model estimates ρ(B )as -1 in both applied examples. Analytically we show this is due to the maximum likelihood estimator sensibly truncating the between-study covariance matrix on the boundary of its parameter space. Our simulations reveal this commonly occurs when the number of studies is small or the within-study variation is relatively large; it also causes upwardly biased between-study variance estimates, which are inflated to compensate for the restriction on [Formula: see text] (B). Importantly, this does not induce any systematic bias in the pooled estimates and produces conservative standard errors and mean-square errors. Furthermore, the normal BRMA is preferable to two normal URMAs; the mean-square error and standard error of pooled estimates is generally smaller in the BRMA, especially given data missing at random. For meta-analysis of proportions we then show that a generalised BRMA model is better still. This correctly uses a binomial rather than normal distribution, and produces better estimates than the normal BRMA and also two generalised URMAs; however the model may sometimes not converge due to difficulties estimating ρ(B). CONCLUSION: A BRMA model offers numerous advantages over separate univariate synthesises; this paper highlights some of these benefits in both a normal and generalised modelling framework, and examines the estimation of between-study correlation to aid practitioners

Efficacy of aerobic exercise and a prudent diet for improving selected lipids and lipoproteins in adults: a meta-analysis of randomized controlled trials

Background Studies addressing the effects of aerobic exercise and a prudent diet on lipid and lipoprotein concentrations in adults have reached conflicting conclusions. The purpose of this study was to determine the effects of aerobic exercise combined with a prudent diet on lipid and lipoprotein concentrations in adults. Methods Studies were located by searching nine electronic databases, cross-referencing, and expert review. Two independent reviewers selected studies that met the following criteria: (1) randomized controlled trials, (2) aerobic exercise combined with diet recommendations (saturated/trans fat intake less than 10% of total calories and cholesterol less than 300 mg/day and/or fiber intake ≥25 g/day in women and ≥35 grams per day in men), (3) intervention ≥4 weeks, (4) humans ≥18 years of age, (5) published studies, including dissertations and Master\u27s theses, (6) studies published in any language, (7) studies published between January 1, 1955 and May 1, 2009, (8) assessment of one or more of the following lipid and lipoprotein concentrations: total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), ratio of TC to HDL-C, non-HDL-C, low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Two reviewers independently extracted all data. Random-effects models that account for heterogeneity and 95% confidence intervals were used to pool findings. Results Of the 1,401 citations reviewed, six studies representing 16 groups (8 intervention, 8 control) and up to 559 men and women (282 intervention, 277 control) met the criteria for analysis. Statistically significant intervention minus control reductions were found for TC (-15.5 mg/dl, 95% CI, -20.3 to -10.7), TC:HDL-C (-0.4 mg/dl, 95% CI, -0.7 to -0.2), LDL-C (-9.2 mg/dl, 95% CI, -12.7 to -5.8) and TG (-10.6 mg/dl, 95% CI, -17.2 to -4.0) but not HDL-C (-0.5 mg/dl, 95% CI, -4.0 to 3.1). Changes were equivalent to reductions of 7.5%, 6.6%, 7.2% and 18.2% respectively, for TC, TC:HDL-C, LDL-C and TG. Because of missing variance statistics, non-HDL-C was excluded. Conclusions Aerobic exercise combined with a prudent diet is highly efficacious for improving TC, TC:HDL-C, LDL-C and TG, but not HDL-C concentrations, in adults. However, additional studies are needed, including effectiveness studies using intention-to-treat analysis

Presence of activating KRAS mutations correlates significantly with expression of tumour suppressor genes DCN and TPM1 in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Despite identification of the major genes and pathways involved in the development of colorectal cancer (CRC), it has become obvious that several steps in these pathways might be bypassed by other as yet unknown genetic events that lead towards CRC. Therefore we wanted to improve our understanding of the genetic mechanisms of CRC development.</p> <p>Methods</p> <p>We used microarrays to identify novel genes involved in the development of CRC. Real time PCR was used for mRNA expression as well as to search for chromosomal abnormalities within candidate genes. The correlation between the expression obtained by real time PCR and the presence of the <it>KRAS </it>mutation was investigated.</p> <p>Results</p> <p>We detected significant previously undescribed underexpression in CRC for genes <it>SLC26A3</it>, <it>TPM1 </it>and <it>DCN</it>, with a suggested tumour suppressor role. We also describe the correlation between <it>TPM1 </it>and <it>DCN </it>expression and the presence of <it>KRAS </it>mutations in CRC. When searching for chromosomal abnormalities, we found deletion of the <it>TPM1 </it>gene in one case of CRC, but no deletions of <it>DCN </it>and <it>SLC26A3 </it>were found.</p> <p>Conclusion</p> <p>Our study provides further evidence of decreased mRNA expression of three important tumour suppressor genes in cases of CRC, thus implicating them in the development of this type of cancer. Moreover, we found underexpression of the <it>TPM1 </it>gene in a case of CRCs without <it>KRAS </it>mutations, showing that <it>TPM1 </it>might serve as an alternative path of development of CRC. This downregulation could in some cases be mediated by deletion of the <it>TPM1 </it>gene. On the other hand, the correlation of <it>DCN </it>underexpression with the presence of <it>KRAS </it>mutations suggests that <it>DCN </it>expression is affected by the presence of activating <it>KRAS </it>mutations, lowering the amount of the important tumour suppressor protein decorin.</p