A quantitative case study assessment of biophysical and economic effects from altering season of calving in temperate pasture-based dairy systems.

In theory, a late winter-early spring calving date in temperate grazing systems best matches pasture supply and herd demand, thereby minimizing the need for nonpasture feeds and maximizing profitability. We used a quantitative case study approach to define the effects of season of calving on biophysical and financial performance in a grazing system without the confounding effects of imported feeds (i.e., milk production directly from grazed pasture). A 2-yr production system experiment was established to quantify the effects of changing onset of seasonal calving (i.e., planned start of calving; PSC) from winter (July in the Southern Hemisphere) to spring (October), summer, (January), or autumn (April) on pasture and animal production and profitability. Eighty Holstein-Friesian cows were randomly allocated to 1 of 4 PSC treatments, each of which had a different PSC [mean calving date of January 10 (JAN), April 10 (APR), July 10 (JUL), or October 10 (OCT)]. Data were analyzed for consistency of treatment response over years using ANOVA procedures with year, PSC treatment, and year × PSC treatment interactions as fixed effects. Collated biological data and financial data extracted from a national economic database were used as fixed variables to model the financial performance for the different treatments. A stochastic risk analysis was undertaken, where historical pasture growth and milk price data were used to estimate the probability distributions for stochastic input variables. Gross farm revenue and operating profit per hectare were modeled under 2 scenarios: (A) milk price did not include a premium for milk supplied during the winter, and (B) milk price included a realistic premium for milk supplied in winter. Annual and seasonal pasture growth did not differ between treatments, but the pasture growth (kg of dry matter/ha) and profile of the JUL treatment best matched the lactation nutrient demand profile. In comparison, profiles for JAN, APR, and OCT calving treatments had periods of greater surplus and deficit due to the time of calving and herd demand relative to the pasture growth profile. As a result, the JAN and OCT treatments conserved more pasture as silage and cows consumed a larger proportion of their annual diet as silage. Although the amount of silage conserved and consumed did not differ between the JUL and APR calving treatments, the timing of the silage consumption was different, with silage making up a greater proportion of the diets in the APR treatment 1 to 90 and 91 to 180 d postcalving and being offered to the JUL calving treatment only 271 to 365 d postcalving. As a result of differences in the quantity and proportion of pasture and pasture silage in the lactating diet, the JUL treatment herd tended to produce greater milk, 4% fat-corrected milk, fat, protein, and lactose yields (kg/cow) than the other PSC treatments, which did not differ from each other. Operating expenses per hectare did not differ materially between calving date scenarios, but operating expenses per kilogram of fat-corrected milk and kilogram of fat and protein were 15 to 20% less in the JUL treatment. With or without a realistic winter milk premium, gross farm revenue and operating profit per hectare were greater in the JUL treatment than in the APR treatment, which had greater revenue and profitability than the remaining 2 calving date treatments. In summary, our results indicate that a PSC in late winter is most profitable in a grazing system not importing feed, with or without a realistic price incentive scheme.

Dairy cow breed interacts with stocking rate in temperate pasture-based dairy production systems.

Economic optimum stocking rates for grazing dairy systems have been defined by accounting for the pasture production potential of the farm [t of dry matter (DM)/ha], the amount of feed imported from outside the farm (t of DM/ha), and the size of the cow (kg). These variables were combined into the comparative stocking rate [CSR; kg of body weight (BW)/t of feed DM available] measure. However, CSR assumes no effect of cow genetics beyond BW, and there is increasing evidence of within-breed differences in residual feed intake and between-breed differences in the gross efficiency with which cows use metabolizable energy for milk production. A multiyear production system experiment was established to determine whether Jersey (J) and Holstein-Friesian (HF) breeds performed similarly at the same CSR. Fifty-nine J cows and 51 HF cows were randomly allocated to 1 of 2 CSR in a 2 × 2 factorial arrangement; systems were designed to have a CSR of either 80 or 100 kg of BW/t of feed DM (J-CSR80, J-CSR100, HF-CSR80, and HF-CSR100 treatment groups). Data were analyzed for consistency of farmlet response over years using ANOVA procedures, with year and farmlet as fixed effects and the interaction of farmlet with year as a random effect. The collated biological data and financial data extracted from a national economic database were used to model the financial performance for the different breed and CSR treatments. On average, annual and individual season pasture DM production was greater for the J farmlets and was less in the CSR100 treatment; however, the effect of CSR was primarily driven by a large decline in pasture DM production in the HF-CSR100 treatment (breed × CSR interaction). This interaction in feed availability resulted in a breed × CSR interaction for the per-cow and per-hectare milk production variables, with HF cows producing more milk and milk components per cow in the CSR80 treatment but the same amount as the J cows in the CSR100 treatment. On a per-hectare basis, HF cows produced the same amount of 4% fat-corrected milk and lactose as J cows in the CSR80 treatment, but less fat; at CSR100, J cows produced more 4% fat-corrected milk, fat, and protein per hectare than HF cows. Our results support a greater gross efficiency for use of metabolizable energy by the J cow; 11% less total metabolizable energy was required to produce 1 kg of fat and protein at a system level. Economic modeling indicated that profitability of both breeds was less at CSR100, but the decline in profitability with increasing stocking rate was much greater in the HF breed. Holstein-Friesian cows were more profitable at CSR80 but were less profitable at CSR100.

Production and economic responses to intensification of pasture-based dairy production systems.

Production from pasture-based dairy farms can be increased through using N fertilizer to increase pasture grown, increasing stocking rate, importing feeds from off farm (i.e., supplementary feeds, such as cereal silages, grains, or co-product feeds), or through a combination of these strategies. Increased production can improve profitability, provided the marginal cost of the additional milk produced is less than the milk price received. A multiyear production system experiment was established to investigate the biological and economic responses to intensification on pasture-based dairy farms; 7 experimental farmlets were established and managed independently for 3 yr. Paddocks and cows were randomly allocated to farmlet, such that 3 farmlets had stocking rates of 3.35 cows/ha (LSR) and 4 farmlets had stocking rates of 4.41 cows/ha (HSR). Of the LSR farmlets, 1 treatment received no N fertilizer, whereas the other 2 received either 200 or 400 kg of N/ha per year (200N and 400N, respectively). No feed was imported from off-farm for the LSR farmlets. Of the 4 HSR farmlets, 3 treatments received 200N and the fourth treatment received 400N; cows on 2 of the HSR-200N farmlet treatments also received 1.3 or 1.1 t of DM/cow per year of either cracked corn grain or corn silage, respectively. Data were analyzed for consistency of farmlet response over years using mixed models, with year and farmlet as fixed effects and the interaction of farmlet with year as a random effect. The biological data and financial data extracted from a national economic database were used to model the statement of financial performance for the farmlets and determine the economic implications of increasing milk production/cow and per ha (i.e., farm intensification). Applying 200N or 400N increased pasture grown per hectare and milk production per cow and per hectare, whereas increasing stocking rate did not affect pasture grown or milk production per hectare, but reduced milk production per cow. Importing feed in the HSR farmlets increased milk production per cow and per hectare. Marginal milk production responses to additional feed (i.e., either pasture or imported supplementary feed) were between 0.8 and 1.2 kg of milk/kg of DM offered (73 to 97 g of fat and protein/kg of feed DM) and marginal response differences between feeds were explained by metabolizable energy content differences (0.08 kg of milk/MJ of metabolizable energy offered). The marginal milk production response to additional feed was quadratic, with the greatest milk production generated from the initial investment in feed; 119, 99, and 55 g of fat and protein were produced per kilogram of feed DM by reducing the annual feed deficit from 1.6 to 1.0, 1.0 to 0.5, and 0.5 to 0 t of DM, respectively. Economic modeling indicated that the marginal cost of milk produced from pasture resulting from applied N fertilizer was less than the milk price; therefore, strategic use of N fertilizer to increase pasture grown increased farm operating profit per hectare. In comparison, operating profit declined with purchased feed, despite high marginal milk production responses. The results have implications for the strategic direction of grazing dairy farms, particularly in export-oriented industries, where the prices of milk and feed inputs are subject to the considerable volatility of commodity markets.

Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Health related quality of life following the treatment of oropharyngeal cancer by transoral laser.

In 2006, our Institution changed the treatment strategy for small volume primary oropharyngeal tumours to transoral laser microsurgery (TOLM). The main aim of this cohort study was to report the health related quality of life (HRQOL) at around 2 years following TOLM in consecutive patients treated from July 2006 through April 2013. The University of Washington Quality of Life (UW-QOL) questionnaire was administered annually up to Spring 2014 and adjusting for mortality the overall response rate was 71 % (108/153). Tonsil primary site characterised 60 % (98) of patients, base of tongue 25 % (40), soft palate 13 % (21) and others 2 %, (3). Most patients had TOLM, neck dissection and adjuvant radiotherapy, with 21 % (34) of tumours at stage 1 or 2, 25 % (40) at stage 3 and 54 % (88) at stage 4. Kaplan-Meier estimates of overall survival were 94 % at 1 year, 88 % at 2 years and 68 % at 5 years after TOLM. Three-quarters (76 %) reported their overall QOL as being good, very good or outstanding, and by domain a clear majority of patients (range 57-94 %, median 79 %) reported none or only minor problems, most notably for swallowing, chewing and speech. The main dysfunction was in saliva (39 %). In conclusion, the outcomes in TOLM for oropharyngeal squamous cell carcinoma are very encouraging. The data supports the current treatment strategy in the Unit. Further outcomes research is required to help refine patient selection to help optimise the survival and HRQOL benefit of TOLM.

The use of Tisseel™ fibrin sealant in selective neck dissection--a retrospective study in a tertiary Head and Neck Surgery centre.

OBJECTIVES: To determine the feasibility of drain-free surgery in selective neck dissection (SND) by investigating the effects of the use of synthetic fibrin glue Tisseel™ on the drain output and overall wound healing. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral unit in Head and Neck surgery. PARTICIPANTS: The case notes of 30 patients who had undergone SND in levels I to IV were examined and compared. Tisseel was applied prior to wound closure in fifteen patients only. MAIN OUTCOME MEASURES: Drain output, number of days of drain in situ and total number of days of hospitalisation as well as complications rate and type between the Tisseel and non-Tisseel groups. RESULTS: Patients who had Tisseel applied in the wound had a mean drain output of 67.1 ml, which was significantly lower than 174.4 ml in patients who did not have it. Patients in the Tisseel group had the drain in situ for a shorter period and were hospitalised for fewer days than the ones in the non-Tisseel group. CONCLUSIONS: The use of Tisseel in SND resulted in lower drain output and shorter period of drain in situ and hospitalisation. There was no additional morbidity or complication associated with its use, and the initial conclusion is that this technique may have benefits not only to patient recovery but also for healthcare providers as they could potentially reduce the overall costs of surgery by reducing the length of hospital stay.

Prognostic implications of pathologically determined tumour volume in glottic carcinomas treated by transoral laser microsurgery.

OBJECTIVES: The TNM classification system for squamous cell carcinoma (SCC) of the head and neck neglects to incorporate volumetric analysis of the primary tumour. Tumour volume (TV) has been implicated prognostically in laryngeal SCC treated by primary radiotherapy (RT), but data for patients treated surgically are lacking. We evaluated such for glottic SCCs resected by transoral laser microsurgery (TLM). DESIGN: Retrospective cohort study utilising TVs calculated as the product of tumour resection dimensions and time-to-event analyses using the Kaplan-Meier method. The prognostic ability of variables was estimated using log-rank statistics, univariate Cox regression and receiver-operating characteristics analysis where appropriate. SETTING: Tertiary referral head and neck cancer centre. PARTICIPANTS: Patients undergoing primary TLM for glottic SCC with curative intent (2007-2011) with at least 12 months follow-up data. MAIN OUTCOME MEASURES: Prognostic impact of TV on local control (LC), overall survival (OS) and disease-specific survival (DSS). RESULTS: Eligible patients (n = 129) had a median follow-up of 40 months (range 14-79 months). Median TV for all cases was 300 mm(3) (range 2-19800 mm(3)). Three-year LC, OS and DSS were 92%, 92% and 98%, respectively. Tumour volume was not a significant predictor of any oncological outcome measure. Otherwise, a significant influence of pT stage on DSS was observed and of age on OS. CONCLUSIONS: In contrast to laryngeal SCC treated by RT, TV does not appear to portend oncological outcome in glottic SCC managed specifically by TLM and consequently does not warrant incorporation into current prognostic models for such patients.

Modes of delivery of genetic testing services and the uptake of cancer risk management strategies in BRCA1 and BRCA2 carriers.

BRCA testing services are now offered by various healthcare providers, thus it is important to evaluate whether the implementation of cancer risk management (CRM) strategies varies by service provider. Using a registry-based sample of 795 female BRCA mutation carriers, we explored the association between uptake of CRM strategies with duration of genetic counseling (GC) sessions, provider type, and other demographic and clinical variables. All participants completed a baseline questionnaire. Information about uptake of CRM strategies was collected for a subset of 438 participants who completed additional questions. Summary statistics and Pearson chi-squared analysis were used to examine the associations between demographic and clinical variables with service delivery factors and with the uptake of various CRM strategies. Overall uptake of CRM strategies was high across all provider types. However, GC sessions were longer when provided by a genetics professional than by another provider (p < 0.001). Furthermore, higher frequencies of uptake of most CRM strategies were associated with longer GC sessions and when testing was performed by a genetics professional. Identification of factors to optimize delivery of these specialized GC services is important to maximize implementation of CRM strategies in BRCA carriers.

Tabalumab in rheumatoid arthritis patients with an inadequate response to methotrexate and naive to biologic therapy: a phase II, randomized, placebo-controlled trial.

OBJECTIVE: Tabalumab, a fully human IgG4 monoclonal antibody, neutralizes soluble and membrane-bound BAFF. The aim of this study was to examine the tolerability and efficacy of tabalumab in patients with active rheumatoid arthritis receiving methotrexate. METHODS: In this randomized, double-blind, placebo-controlled, parallel, multiple-dose study, patients who were naive to biologic therapy received infusions of tabalumab (30, 60, or 160 mg) or placebo at weeks 0, 3, and 6 in combination with methotrexate and were evaluated for 24 weeks. The primary efficacy end point was the percentage of patients meeting American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16. RESULTS: At week 16, the percentages of patients achieving an ACR20 response in the 30-mg (57.6%), 60-mg (67.6%), and 160-mg (51.5%) groups were significantly greater than the percentage of patients achieving an ACR20 response in the placebo group (29.4%; P<0.05). There were initial transient increases from baseline in the frequency of CD20+ and IgD+/CD27- B cells, followed by reductions, although B cells were not completely depleted. Also, the frequency of IgD-/CD27+ B cells increased in all tabalumab groups compared with the placebo group and returned toward baseline levels by the end of the study. The incidence of adverse events was similar across all treatment groups; no deaths occurred. Serum IgM levels decreased significantly in all tabalumab groups combined compared with the placebo group. There were no significant decreases in serum IgG or IgA levels in the tabalumab groups compared with the placebo group. CONCLUSION: Tabalumab treatment significantly reduces the signs and symptoms of rheumatoid arthritis and has a safety profile similar to that seen with placebo treatment.

Transoral laser resection versus lip-split mandibulotomy in the management of oropharyngeal squamous cell carcinoma (OPSCC): a case match study.

The objective of this study was to compare transoral laser microsurgery (TLM) with lip-split mandibulotomy (LSM) and radial forearm free-flap reconstruction, for the resection of squamous cell carcinoma of the oropharynx (SCCOP). This study is designed as a case-control study matching 24 patients treated with TLM for SCCOP with those treated with LSM. Patients were matched by age (in 5-year epochs), sex, TNM stage, tumour sub site and type of neck dissection. Each group comprised 20 males and 4 females (mean age 56 years). Seven patients treated with TLM had an elective tracheostomy compared with all patients undergoing LSM. Moreover, the time for decanulation was reduced in patients undergoing tracheostomy for TLM. Although similar rates of patients were able to swallow to some degree on discharge, 29% of patients having LSM were discharged requiring enterostomy feeding compared with 4% of patients treated using TLM. Of those able to swallow on discharge, patients who had TLM resumed swallowing in half the time taken for those having LSM. Moreover, those treated with TLM remained in hospital for half the length of time than those treated with LSM. Due to these factors, overall cost for TLM is reduced in comparison with LSM. In comparison with LSM, TLM for the treatment of SCCOP results in fewer tracheostomies and shorter time to decanulation; a quicker recovery of swallowing function and a reduced length of hospital stay. As a result of this, treatment with TLM is on average cheaper. These factors should be considered when deciding on the surgical treatment of a patient with SCCOP.

Relationship between fractional anisotropy of cerebral white matter and metabolite concentrations measured using (1)H magnetic resonance spectroscopy in healthy adults.

Fractional anisotropy (FA) of water diffusion in cerebral white matter (WM), derived from diffusion tensor imaging (DTI), is a sensitive index of microscopic WM integrity. Physiological and metabolic factors that explain intersubject variability in FA values were evaluated in two cohorts of healthy adults of different age spans (N=65, range: 28-50years; and N=25, age=66.6±6.2, range: 57-80years). Single voxel magnetic resonance spectroscopy (MRS) was used to measure N-acetylaspartate (NAA), total choline-containing compounds, and total creatine, bilaterally in an associative WM tract: anterior corona radiata (ACR). FA values were calculated for the underlying, proximal and two distal WM regions. Two-stage regression analysis was used to calculate the proportion of variability in FA values explained by spectroscopy measurements, at the first stage, and subject's age, at the second stage. WM NAA concentration explained 23% and 66% of intersubject variability (p<0.001) in the FA of the underlying WM in the younger and older cohorts, respectively. WM NAA concentration also explained a significant proportion of variability in FA of the genu of corpus callosum (CC), a proximal WM tract where some of the fibers contained within the spectroscopic voxel decussate. NAA concentrations also explained a significant proportion of variability in the FA values in the splenium of CC, a distal WM tract that also carries associative fibers, in both cohorts. These results suggest that MRS measurements explained a significant proportion of variability in FA values in both proximal and distal WM tracts that carry similar fiber-types.

Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families.

The hereditary breast cancer gene BRCA2 was recently cloned and is believed to account for almost half of site-specific breast cancer families and the majority of male breast cancer families. We screened 49 site-specific breast cancer families for mutations in the BRCA2 gene using single strand conformation analysis (SSCA) followed by direct sequencing. We found mutations in eight families, including all four families with male breast cancer. The eight mutations were small deletions with the exception of a single nonsense mutation, an all were predicted to interrupt the BRCA2 coding sequence and to lead to a truncated protein product. Other factors which predicted the presence of a BRCA2 mutation included a case of breast cancer diagnosed at age 35 or below (P = 0.01) and a family history of pancreatic cancer (P = 0.03). Two mutations were seen twice, including a 8535delAG, which was detected in two French Canadian families. Our results suggest the possibility that the proportion of site-specific breast cancer families attributable to BRCA2 may be overestimated.

BRCA2 mutations in primary breast and ovarian cancers.

The second hereditary breast cancer gene, BRCA2, was recently isolated. Germline mutations of this gene predispose carriers to breast cancer, and, to a lesser extent, ovarian cancer. Loss of heterozygosity (LOH) at the BRCA2 locus has been observed in 30-40% of sporadic breast and ovarian tumours, implying that BRCA2 may act as a tumour suppressor gene in a proportion of sporadic cases. To define the role of BRCA2 in sporadic breast and ovarian cancer, we screened the entire gene for mutations using a combination of techniques in 70 primary breast carcinomas and in 55 primary epithelial ovarian carcinomas. Our analysis revealed alterations in 2/70 breast tumours and none of the ovarian carcinomas. One alteration found in the breast cancers was a 2-basepair (bp) deletion (4710delAG) which was subsequently shown to be a germline mutation, the other was a somatic missense mutation (Asp3095Glu) of unknown significance. Our results suggest that BRCA2 is a very infrequent target for somatic inactivation in breast and ovarian carcinomas, similar to the results obtained for BRCA1.

Biologically derived epicardial patch induces macrophage mediated pathophysiologic repair in chronically infarcted swine hearts.

There are nearly 65 million people with chronic heart failure (CHF) globally, with no treatment directed at the pathologic cause of the disease, the loss of functioning cardiomyocytes. We have an allogeneic cardiac patch comprised of cardiomyocytes and human fibroblasts on a bioresorbable matrix. This patch increases blood flow to the damaged heart and improves left ventricular (LV) function in an immune competent rat model of ischemic CHF. After 6 months of treatment in an immune competent Yucatan mini swine ischemic CHF model, this patch restores LV contractility without constrictive physiology, partially reversing maladaptive LV and right ventricular remodeling, increases exercise tolerance, without inducing any cardiac arrhythmias or a change in myocardial oxygen consumption. Digital spatial profiling in mice with patch placement 3 weeks after a myocardial infarction shows that the patch induces a CD45pos immune cell response that results in an infiltration of dendritic cells and macrophages with high expression of macrophages polarization to the anti-inflammatory reparative M2 phenotype. Leveraging the host native immune system allows for the potential use of immunomodulatory therapies for treatment of chronic inflammatory diseases not limited to ischemic CHF.

In vitro analysis of ovarian cancer response to cisplatin, carboplatin, and paclitaxel identifies common pathways that are also associated with overall patient survival.

BACKGROUND: Carboplatin and cisplatin, alone or in combination with paclitaxel, have similar efficacies against ovarian cancer (OVCA) yet exhibit different toxicity profiles. We characterised the common and unique cellular pathways that underlie OVCA response to these drugs and analyse whether they have a role in OVCA survival. METHODS: Ovarian cancer cell lines (n=36) were treated with carboplatin, cisplatin, paclitaxel, or carboplatin-paclitaxel (CPTX). For each cell line, IC(50) levels were quantified and pre-treatment gene expression analyses were performed. Genes demonstrating expression/IC(50) correlations (measured by Pearson; P<0.01) were subjected to biological pathway analysis. An independent OVCA clinico-genomic data set (n=142) was evaluated for clinical features associated with represented pathways. RESULTS: Cell line sensitivity to carboplatin, cisplatin, paclitaxel, and CPTX was associated with the expression of 77, 68, 64, and 25 biological pathways (P<0.01), respectively. We found three common pathways when drug combinations were compared. Expression of one pathway ('Transcription/CREB pathway') was associated with OVCA overall survival. CONCLUSION: The identification of the Transcription/CREB pathway (associated with OVCA cell line platinum sensitivity and overall survival) could improve patient stratification for treatment with current therapies and the rational selection of future OVCA therapy agents targeted to these pathways.

Fractional anisotropy of cerebral white matter and thickness of cortical gray matter across the lifespan.

We examined age trajectories of fractional anisotropy (FA) of cerebral white matter (WM) and thickness of cortical gray matter (GM) in 1031 healthy human subjects (aged 11-90 years). Whole-brain FA and GM thickness values followed quadratic trajectories with age but the relationship between them was linear, indicating that a putative biological mechanism may explain the non-linearity of their age trajectories. Inclusion of the FA values into the quadratic model of the whole-brain and regional GM thickness changes with age made the effect of the age(2) term no longer significant for the whole-brain GM thickness and greatly reduced its significance for regional GM thickness measurements. The phylogenetic order of cerebral myelination helped to further explain the intersubject variability in GM thickness. FA values for the early maturing WM were significantly better (p=10(-6)) at explaining variability in GM thickness in maturing (aged 11-20) subjects than FA values for the late maturing WM. The opposite trend was observed for aging subjects (aged 40-90) where FA values for the late maturing WM were better (p=10(-16)) at explaining the variability in GM thickness. We concluded that the non-linearity of the age trajectory for GM thickness, measured from T1-weighted MRI, was partially explained by the heterogeneity and the heterochronicity of the age-related changes in the microintegrity of cerebral WM. We consider these findings as the evidence that the measurements of age-related changes in GM thickness and FA are driven, in part, by a common biological mechanism, presumed to be related to changes in cerebral myelination.

LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study.

OBJECTIVE: We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti-interleukin-17 (anti-IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs). METHODS: This randomized, double-blind, placebo-controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10. RESULTS: Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821-combined groups (-2.3, -2.4, and -2.3, respectively) than in the placebo group (-1.7) at week 10 (P < or = 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events. CONCLUSION: LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA.

Short communication: Effect of stocking rate on the economics of pasture-based dairy farms.

Data from a multiyear farm systems study evaluating the effect of stocking rate (SR) on pasture production and utilization, milk production per cow and per hectare, reproduction, and cow health were used to determine the economic implications of altering SR. The effect of SR was also evaluated relative to cow size and total feed available (comparative stocking rate; CSR), to account for differences in cow size and feed supplement availability. Milk production, gross revenue, operating expenses, and operating profit per cow all declined with increasing SR and CSR. In comparison, milk production, gross revenue, and operating expenses per hectare increased with increasing SR and CSR. These effects were irrespective of milk price. The effect of SR on operating profit and return on assets, however, was dependent on milk payment system. When payment was based on the economic value of milk fat and protein, operating profit and return on assets were quadratically associated with both SR and CSR, declining at an SR greater or less than 3.3 cows/ha and a CSR greater or less than 77 kg of body weight/t of feed dry matter available. In comparison, when milk payment was based on a fluid milk pricing system, profit per hectare increased linearly with increasing SR and CSR, but return on assets was not affected by SR or CSR.

Processing speed is correlated with cerebral health markers in the frontal lobes as quantified by neuroimaging.

We explored relationships between decline in cognitive processing speed (CPS) and change in frontal lobe MRI/MRS-based indices of cerebral integrity in 38 healthy adults (age 57-90 years). CPS was assessed using a battery of four timed neuropsychological tests: Grooved Pegboard, Coding, Symbol Digit Modalities Test and Category Fluency (Fruits and Furniture). The neuropsychological tests were factor analyzed to extract two components of CPS: psychomotor (PM) and psychophysical (PP). MRI-based indices of cerebral integrity included three cortical measurements per hemisphere (GM thickness, intergyral and sulcal spans) and two subcortical indices (fractional anisotropy (FA), measured using track-based spatial statistics (TBSS), and the volume of hyperintense WM (HWM)). MRS indices included levels of choline-containing compounds (GPC+PC), phosphocreatine plus creatine (PCr+Cr), and N-acetylaspartate (NAA), measured bilaterally in the frontal WM bundles. A substantial fraction of the variance in the PM-CPS (58%) was attributed to atrophic changes in frontal WM, observed as increases in sulcal span, declines in FA values and reductions in concentrations of NAA and choline-containing compounds. A smaller proportion (20%) of variance in the PP-CPS could be explained by bilateral increases in frontal sulcal span and increases in HWM volumes.