Japanese value set for the EORTC QLU-C10D: A multi-attribute utility instrument based on the EORTC QLQ-C30 cancer-specific quality-of-life questionnaire.

PURPOSE: This study aimed to develop a Japanese value set for the EORTC QLU-C10D, a multi-attribute utility measure derived from the cancer-specific health-related quality-of-life (HRQL) questionnaire, the EORTC QLQ-C30. The QLU-C10D contains ten HRQL dimensions: physical, role, social and emotional functioning, pain, fatigue, sleep, appetite, nausea, and bowel problems. METHODS: Quota sampling of a Japanese online panel was used to achieve representativeness of the Japanese general population by sex and age (≥ 18 years). The valuation method was an online discrete choice experiment. Each participant considered 16 choice pairs, randomly assigned from 960 choice pairs. Each pair included two QLU-C10D health states and life expectancy. Data were analyzed using conditional logistic regression, parameterized to fit the quality-adjusted life-year framework. Preference weights were calculated as the ratio of each dimension-level coefficient to the coefficient for life expectancy. RESULTS: A total of 2809 eligible panel members consented, 2662/2809 (95%) completed at least one choice pair, and 2435/2662 (91%) completed all choice pairs. Within dimensions, preference weights were generally monotonic. Physical functioning, role functioning, and pain were associated with the largest utility weights. Intermediate utility weights were associated with social functioning and nausea; the remaining symptoms and emotional functioning were associated with smaller utility decrements. The value of the worst health state was - 0.221, lower than that seen in most other existing QLU-C10D country-specific value sets. CONCLUSIONS: The Japan-specific QLU-C10D value set is suitable for evaluating the cost and utility of oncology treatments for Japanese health technology assessment and decision-making.

Farm-level factors associated with lameness prevalence, productivity, and milk quality in farms with automated milking systems.

Impaired locomotion (lameness) may negatively affect the ability and desire of cows to milk voluntarily, which is a key factor in success of automated milking systems (AMS). The objective of this study was to identify factors associated with herd-level lameness prevalence and associations of lameness and other farm-level factors with milking activity, milk yield, and milk quality in herds with AMS. From April to September 2019, 75 herds with AMS in Ontario, Canada, were visited, and data on barn design and farm management practices were collected. Data from AMS were collected, along with milk recording data, for the 6-mo period before farm visits. Farms averaged 98 ± 71 lactating cows, 2.3 ± 1.5 robot units/farm, 43.6 ± 9.4 cows/robot, 36.4 ± 4.9 kg/d of milk, a milking frequency of 3.01 ± 0.33 milkings/d, and a herd average geometric mean SCC of 179.3 ± 74.6 (× 1,000) cells/mL. Thirty percent of cows/farm (minimum of 30 cows/farm) were scored for body condition (1 = underconditioned to 5 = over conditioned) and locomotion (1 = sound to 5 = lame; clinically lame ≥3 out of 5 = 28.3 ± 11.7%, and severely lame ≥4 out of 5 = 3.0 ± 3.2%). Clinical lameness (locomotion score ≥3) was less prevalent on farms with sand bedding, with increased feed bunk space per cow, and on farms with non-Holstein breeds versus Holsteins, and tended to be less prevalent with lesser proportion of underconditioned cows (with body condition score ≤2.5). Severe lameness occurrence (farms with any cows with locomotion score ≥4) was associated with a greater proportion of underconditioned cows and in farms with stalls with greater curb heights. Herd average milk yield/cow per day increased with lesser prevalence of clinical lameness (each 10-percentage-point decrease in clinical lameness prevalence was associated with 2.0 kg/cow per day greater milk yield) and greater milking visit frequency per day, and tended to be greater with increased feed push-up frequency. Lesser herd average somatic cell count was associated with lesser clinical lameness prevalence, herd average days in milk, and proportion of overconditioned cows, and somatic cell count tended to be lesser for farms with sand bedding versus those with organic bedding substrates. The results highlight the importance of minimizing lameness prevalence, using of sand bedding, ensuring adequate feed access and feed bunk space, and maintaining proper cow body condition to optimize herd-level productivity and milk quality in AMS herds.

Benchmarking of farms with automated milking systems in Canada and associations with milk production and quality.

The objective of this study was to benchmark the herd-level housing and management strategies of automated milking system (AMS) farms across Canada and assess the associations of these herd-level housing factors and management practices with milk production and quality. Canadian AMS farms (n = 197; Western Canada: n = 50, Ontario: n = 77, Quebec: n = 59, Atlantic Canada: n = 11) were each visited once from April to September 2019, and details were collected related to barn design and herd management practices. Milk-recording data for the 6 mo before farm visits were collected. Farms averaged (± standard deviation) 110 ± 102 lactating cows, 2.4 ± 1.9 AMS units/farm, 47.5 ± 14.9 cows/AMS, 36.7 ± 5.0 kg/d of milk, 4.13 ± 0.34% fat, 3.40 ± 0.16% protein, and a herd-average somatic cell count of 186,400 ± 80,800 cells/mL. Farms mainly used freestall housing systems (92.5%), organic bedding substrates (73.6%), and free flow cow traffic systems (87.8%); farms predominantly milked Holsteins (90.4%). Multivariable regression models were used to associate herd-level housing factors and management practices with milk production and quality. At the herd level, feed push-up frequency (mean = 12.8 ± 8.3 times per day) and feed bunk space (mean = 64 ± 21.5 cm/cow) were positively associated with milk yield. Greater milk yield was associated with herds using inorganic (sand) versus organic bedding, milking Holsteins versus non-Holsteins, and using a form of mechanical ventilation versus natural ventilation alone. Milk fat and milk protein content were only associated with breed. Herds with lower somatic cell counts had more frequent alley cleaning (mean = 12.1 ± 7.5 times per day), wider lying alleys (mean = 304.5 ± 40.0 cm), and sand bedding. The results highlight the importance of using sand bedding, using mechanical ventilation, keeping feed pushed up, ensuring alleys are clean, and ensuring adequate space at the feed bunk for maintaining herd-level productivity and milk quality in farms with AMS.

Behavior, health, and productivity of early-lactation dairy cows supplemented with molasses in automated milking systems.

The objective of this study was to determine the effect of molasses-based liquid feed (LF) supplementation within automated milking systems (AMS) on the behavior, health, and production of early-lactation dairy cows. In 6 commercial AMS dairy herds, 390 dairy cows were randomly assigned before calving to 1 of 2 treatments, within farm, balanced by parity: (1) control group (CON) receiving a standard AMS pellet [mean = 3.9 kg/d on a dry matter (DM) basis, n = 188], or (2) same amount of standard AMS pellet (mean = 3.6 kg/d on a DM basis, n = 202) plus 1 kg/d DM of LF for multiparous cows (1.6 kg/d as fed) and 0.88 kg/d DM for primiparous cows (1.4 kg/d as fed). Across farms, cows were fed partial mixed rations similar in ingredient and nutrient composition. Cows on the LF treatment received supplementation for the first 60 d in milk (DIM). Blood samples were taken 2 times/wk for the first 3 wk postcalving to assess ß-hydroxybutyrate (BHB). Samples with BHB ≥1.2 mmol/L were classified as a positive case of subclinical ketosis (SCK). Cow body condition and lameness were scored every 10 d postcalving until 60 DIM. No differences were detected between treatments for milk yield (average milk yield = 37.4 ± 1.98 kg/d) and milking frequency (average milking frequency = 3.2 ± 0.01 times/d). Similarly, no difference between treatments in daily AMS visits was detected (average AMS visits = 5.3 ± 0.3 times/d). However, CON cows experienced more AMS refusals/d than LF cows (LF = 1.6 refusals/d, CON = 2.1 refusals/d). No difference between treatments in daily rumination time was detected (average rumination time = 476 ± 10.8 min/d). Treatment was associated with the number of times cows tested positive for SCK; cows on LF had fewer repeated diagnoses of SCK, such that 15% of cows on LF had ≥3 diagnoses of SCK out of 5 tests, compared with 27% of CON cows. Cows receiving molasses tended to have lower blood BHB values at ∼15 DIM. Molasses supplementation also allowed cows to maintain a more stable body condition score, as LF cows tended to lose less body condition over the first 60 DIM compared with CON cows. Overall, the results of this study demonstrate that supplementing a molasses-based LF to AMS cows may help support the energy demands of milk production in early lactation and, thus, reduce the incidence of repeat positive SCK tests during that time period.

Minimally important differences for interpreting the EORTC QLQ-C30 in patients with advanced colorectal cancer treated with chemotherapy.

AIM: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) assesses the health-related quality of life of patients in cancer trials. There are currently no minimally important difference (MID) guidelines for the EORTC QLQ-C30 for colorectal cancer (CRC). This study aims to estimate MIDs for the EORTC QLQ-C30 scales in patients with advanced CRC treated with chemotherapy and enrolled in clinical trials. METHOD: The data were obtained from three published EORTC trials that treated CRC patients using chemotherapy. Potential anchors were selected from clinical variables based on their correlation with EORTC QLQ-C30 scales. Anchor-based MIDs for within-group change and between-group change were estimated via the mean change method and linear regression, respectively, and summarized using weighted correlation. Distribution-based MIDs were also examined. RESULTS: Anchor-based MIDs were determined for deterioration in 8 of the 14 EORTC QLQ-C30 scales and in 9 scales for improvement, and varied by scale, direction of change and anchor. MIDs for improvement (deterioration) ranged from 6 to 18 (-11 to -5) points for within-group change and 5 to 15 (-10 to -4) for between-group change. Summarized MIDs (in absolute values) per scale mostly ranged from 5 to 10 points. CONCLUSIONS: These findings have clinical relevance for the interpretation of treatment efficacy and the design of clinical trials by informing sample size requirements.

EORTC QLU-C10D value sets for Austria, Italy, and Poland.

OBJECTIVE: To develop Austrian, Italian, and Polish general population value sets for the EORTC QLU-C10D, a cancer-specific utility instrument based on the EORTC QLQ-C30, and to descriptively compare their index scores for distinct health states. METHODS: The QLU-C10D descriptive system comprises 10 health attributes and each can take on 4 levels. A standardised and pre-tested methodology has been applied for valuations including a web-based discrete choice experiment (DCE). It was administered in 1000 general population respondents per country recruited via online panels, aiming at representativeness for core socio-demographic variables. RESULTS: In all three countries, the attributes with the largest impact on utility were physical functioning, pain, and role functioning. Cancer-specific dimensions with the largest impact were nausea and fatigue or bowel problems. Utility values of the worst health state (i.e. severe problems on all 10 dimension) were -0.111 (Austria), 0.025 (Italy), and 0.048 (Poland). Country-specific utilities differed for a selection of health states across the continuum. Austrian utilities were systematically lower for moderately and severely impaired health states. CONCLUSION: QLU-C10D cancer-specific utilities can now be calculated in three more countries. Differences between countries indicate that careful consideration is required when using non-country-specific value sets in economic evaluations.

Systematic review of clinical practice guidelines for colorectal and anal cancer: the extent of recommendations for managing long-term symptoms and functional impairments.

PURPOSE: Due to increasing numbers of colorectal and anal cancer survivors, more individuals are living with long-term symptoms after treatment. A systematic review was undertaken to assess the extent to which practice guidelines for colorectal and anal cancer provide recommendations for managing long-term symptoms and functioning impairments. METHODS: Four electronic databases and websites of 30 international cancer societies were searched for clinical practice guidelines, consensus statements, or best practice recommendations for colorectal or anal cancer. Quality of included guidelines was evaluated with the Appraisal of Guidelines for Research & Evaluation II tool. Results were narratively summarized. RESULTS: We included 51 guidelines or consensus statements. Recommendations for managing long-term symptoms or functioning impairments were reported in 13 guidelines (25.4%). All 13 recommend a healthy lifestyle, diet, body weight, and physical activity. The ASCO Colorectal Cancer Survivorship Care Guideline is the most comprehensive, including interventions targeting sexual and bowel function to pain and cognitive issues, and also highlights limited evidence for informing management strategies. Other guidelines recommend treating incontinence, chronic diarrhea, and distress, and stress the need for greater awareness for sexual dysfunction, survivorship clinics, and referrals to specific supportive care interventions. CONCLUSIONS: Few clinical practice guidelines include recommendations for managing long-term symptoms and functioning impairments. It is unclear if this is due to limited evidence or absence of management strategies and interventions. Clear recommendations for managing long-term symptoms and functioning to help health professionals in supporting colorectal and anal cancer survivors are needed.

Predictors of progression free survival, overall survival and early cessation of chemotherapy in women with potentially platinum sensitive (PPS) recurrent ovarian cancer (ROC) starting third or subsequent line(≥3) chemotherapy - The GCIG symptom benefit study (SBS).

BACKGROUND: Potentially platinum sensitive recurrent ovarian cancer (PPS ROC) is defined by a platinum-free interval of >6 months, and usually treated with platinum-based chemotherapy with variable response and benefit in women who have had 3 or more lines of chemotherapy(≥3). We identified baseline characteristics (health-related quality of life[HRQL] and clinicopathological factors), associated with PFS, OS and early progression (within 8 weeks). The goal is to improve patient selection for chemotherapy based on a nomogram predicting PFS. METHODS: HRQL was assessed with EORTC QLQ-C30/QLQ-OV28. Associations with PFS and OS were assessed with Cox proportional hazards regression. Variables significant in univariable analysis were included in multivariable analyses using backward elimination to select those significant. Associations with stopping chemotherapy early were assessed with logistic regression. RESULTS: 378 women were enrolled, with median(m)OS and PFS of 16.6 months and 5.3 months, respectively. The majority had ECOGPS 0-1. Chemotherapy was stopped early in 45/378 participants (12%); with mOS 3.4 months (95% CI: 1.7-7.2). Physical function(PF), role function(RF), cognitive function(CF), social function(SF), Global Health Status(GHS) and abdominal/GI symptoms(AGIS) were significant univariable predictors of PFS(p < 0.030). SF remained significant after adjusting for clinicopathological factors; p = 0.03. PF, RF, CF, SF, GHS and AGIS were significant univariable predictors of OS (p < 0.007); PF, RF, SF and GHS remained significant predictors of OS in multivariable models; p < 0.007. Poor baseline PF and GHS were significant univariable predictors of stopping chemotherapy early (p < 0.007) but neither remained significant after adjusting for clinicopathological factors. CONCLUSION: Baseline HRQL is simple to measure, is predictive of PFS and OS and when used in conjunction with clinicopathological prognostic factors, can assist with clinical decision making and treatment recommendations for women with PPSROC≥3.

Short communication: Assessing the accuracy of inline milk fat-to-protein ratio data as an indicator of hyperketonemia in dairy cows in herds with automated milking systems.

The objective of this study was to evaluate the accuracy of inline milk fat-to-protein (F:P) data to detect hyperketonemia (HYK) in herds with automated milking systems (AMS). The F:P ratio has been investigated as a tool for detecting HYK with moderate accuracy in past studies, but inline F:P data in AMS may also be useful for HYK screening. To assess the accuracy of these data in commercial settings, we monitored 484 cows from 9 AMS herds for their first 3 wk of lactation, taking blood samples once per week (n = 1,427). Positive cases of HYK were defined by whole-blood ß-hydroxybutyrate (BHB) concentrations ≥1.2 or ≥1.4 mmol/L. Milk data were collected from the AMS software on each farm for each cow and converted into 4 different F:P values: (1) value from the same day as the BHB test; (2) 5-d centered-moving average (CMA); (3) 5-d backward-moving average (BMA); (4) 5-d forward-moving average (FMA). In linear regression models, all 4 values were associated with BHB, but slope estimates varied and R2 were low: same day (slope = 0.95, R2 = 0.07), CMA (slope = 1.05, R2 = 0.07), BMA (slope = 0.65, R2 = 0.04), and FMA (slope = 1.23, R2 = 0.09). In logistic regression models, the odds of having HYK (BHB ≥1.2 mmol/L) increased with every 0.1-unit increase from the mean F:P ratio (1.16) using same-day values (odds ratio = 1.35, 95% confidence interval = 1.25-1.47) and CMA (odds ratio = 1.39, 95% confidence interval = 1.27-1.51). The same increase in F:P from mean BMA (1.14) and FMA (1.17) was associated with 1.22 and 1.49 times the odds of HYK, respectively. For all 4 F:P variations, we evaluated the sensitivity, specificity, positive predictive value, and negative predictive value of different F:P thresholds with HYK status. As the F:P threshold increased from 1.17 to 1.50, sensitivity decreased (range: 77 to 9%) but specificity increased (range: 58 to 96%). Same-day and CMA F:P cutoffs at which a balance was reached between sensitivity and specificity ranged from 1.18 to 1.22; however, even at these values we found high rates of false positives and negatives (range: 31-39%). These results suggest that inline milk F:P data from inconsistently calibrated sensors should not be used alone to detect HYK in AMS herds.

Milk yield relative to supplement intake and rumination time differs by health status for fresh cows milked with automated systems.

Automated milking systems (AMS) provide the capability of adjusting the amount of supplemental concentrate offered to cows based on parity, days in milk, and milk yield; in many situations, more supplement is provided to those cows with higher production demands. To determine associations of subclinical ketosis (SCK) and blood ß-hydroxybutyrate (BHB) with milk yield, supplement consumed in the AMS, rumination time, and the ratios of milk yield to supplement intake and milk yield to rumination time, we monitored 605 cows from 9 AMS herds, testing blood BHB concentrations 1×/wk for the first 3 wk of lactation. Milk yield, supplement intake, and rumination data were collected from the AMS computer on each farm. For analyses, only multiparous cows from 8 herds were included (n = 172 total) and were matched, within farm, to include an equal number of cows in each of 4 health status groups (n = 43 per group): SCK (BHB ≥1.2 mmol/L at ≥1 of 3 tests, with no other disorder in the first 30 d in milk), SCK+ (BHB ≥1.2 mmol/L at ≥1 of 3 tests, with another health disorder), HLT (BHB always <1.2 mmol/L, with no other disorder), or OTH (BHB always <1.2 mmol/L, with a health disorder). Milk yield and rumination time varied by health status, but we found no difference in supplement intake by health status group. As a result, milk yield relative to supplement intake and milk yield relative to rumination time differed by health status and were both positively associated with BHB. Cows in SCK had the highest milk yield and ratio of milk yield to supplement intake, but SCK+ cows had the lowest rumination time and the highest milk yield to rumination ratio. These results highlight the differences in milk production (per day and relative to supplement consumption or rumination time) associated with blood BHB and health status. Therefore, potential exists to modify supplementation in AMS to reduce negative energy balance by accounting for milk production of fresh cows.

Graduate Student Literature Review: Detecting health disorders using data from automatic milking systems and associated technologies.

This review synthesizes a range of research findings regarding behavioral and production responses to health disorders and subsequent illness detection for herds using automatic (robotic) milking systems (AMS). We discuss the effects of health disorders on cow behavior and production, specifically those variables that are routinely recorded by AMS and associated technologies. This information is used to inform the resultant use of behavior and production variables and to summarize and critique current illness detection studies. For conventional and AMS herds separately, we examined research from the past 20 yr and those variables recorded automatically on-farm that may respond to development of illness and lameness. The main variables identified were milk yield, rumination time, activity, and body weight, in addition to frequency of successful, refused, and fetched (involuntary) milkings in AMS herds. Whether making comparisons within cow or between sick and healthy cows, consistent reductions in activity, rumination time, and milk yield are observed. Lameness, however, had obvious negative effects on milk yield but not necessarily on rumination time or activity. Finally, we discuss detection models for identifying lameness and other health disorders using routinely collected data in AMS, specifically focusing on their scientific validation and any study limitations that create a need for further research. Of the current studies that have worked toward disease detection, many data have been excluded or separated for isolated models (i.e., fresh cows, certain lactation groups, and cows with multiple illnesses or moderate cases). Thus, future studies should (1) incorporate the entire lactating herd while accounting for stage of lactation and parity of each animal; (2) evaluate the deviations that cows exhibit from their own baseline trajectories and relative to healthy contemporaries; (3) combine the use of several variables into health alerts; and (4) differentiate the probable type of health disorder. Most importantly, no model or software currently exists to integrate data and directly support decision-making, which requires further research to bridge the gap between technology and herd health management.

Determining optimal eluter design by modeling physical dose enhancement in brachytherapy.

PURPOSE: In situ drug release concurrent with radiation therapy has been proposed to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release compounds, such as nanoparticles or chemotherapeutic agents. The relative effectiveness of the approaches has not been compared yet. This work models the physical dose enhancement of implantable eluters in conjunction with brachytherapy to determine which delivery mechanism provides greatest opportunity to enhance the therapeutic ratio. MATERIALS AND METHODS: The combined effect of implanted eluters and radioactive sources were modeled in a manner that allowed the comparison of the relative effectiveness of different types of implantable eluters over a range of parameters. Prostate geometry, source, and spacer positions were extracted from treatment plans used for 125 I permanent prostate implants. Compound concentrations were calculated using steady-state solution to the diffusion equation including an elimination term characterized by the diffusion-elimination modulus (ϕb ). Does enhancement was assumed to be dependent on compound concentration up to a saturation concentration (csat ). Equivalent uniform dose (EUD) was used as an objective to determine the optimal configuration of eluters for a range of diffusion-elimination moduli, concentrations, and number of eluters. The compound delivery vehicle that produced the greatest enhanced dose was tallied for points in parameter space mentioned to determine the conditions under whether there are situations where one approach is preferable to the other. RESULTS: The enhanced effect of implanted eluters was calculated for prostate volumes from 14 to 45 cm3 , ϕb from 0.01 to 4 mm-1 , csat from 0.05 to 7.5 times the steady-state compound concentration released from the surface of the eluter. The number of used eluters (ne ) was simulated from 10 to 60 eluters. For the region of (csat , Φ)-space that results in a large fraction of the gland being maximally sensitized, compound eluting spacers or sources produce equal increase in EUD. In the majority of the remaining (csat , Φ)-space, eluting spacers result in a greater EUD than sources even where sources often produce greater maximal physical dose enhancement. Placing eluting implants in planned locations throughout the prostate results in even greater enhancement than using only source or spacer locations. CONCLUSIONS: Eluting brachytherapy spacers offer an opportunity to increase EUD during the routine brachytherapy process. Incorporating additional needle placements permits compound eluting spacer placement independent of source placement and thereby allowing a further increase in the therapeutic ratio. Additional work is needed to understand the in vivo spatial distribution of compound around eluters, and to incorporate time dependence of both compound release and radiation dose.

Behavior and productivity of cows milked in automated systems before diagnosis of health disorders in early lactation.

Associations of electronically recorded data were examined before diagnosis of health disorders in early-lactation cows in herds with automated milking systems (AMS). Rumination time, activity, and milk yield data were collected for 8 mo for 605 early-lactation cows in 9 commercial AMS herds. Using multivariable generalized linear regression models controlling for parity and days in milk, data were examined relative to the day of diagnosis for health disorders occurring in absence of, or at least 14 d before, another disorder: mastitis (n = 13), new cases of lameness (n = 45), subclinical ketosis (SCK; n = 113), and purulent vaginal discharge (n = 49). All cases of displaced abomasum (DA; n = 8) occurred in conjunction with other disorders. Deviations from baseline among affected cows were examined, as well as differences compared with a group of healthy cows and an average group of all cows, who were given mock diagnosis days using the mean days in milk at diagnosis for each disorder. On 6 to 14 d of the 2 wk before diagnosis, cows with DA or mastitis had lower milk yield, rumination time, milking frequency, activity, and milk temperature compared with healthy cows as well as deviations from their own baseline rumination time and milk data starting 4 to 12 d before diagnosis. Cows with DA had lower AMS supplement intake than healthy cows and deviations from their baseline activity and milk temperature starting 6 and 4 d before diagnosis, respectively. Cows with mastitis had greater milk conductivity than healthy cows and deviated from their baseline milking frequency and conductivity 8 and 12 d before diagnosis, respectively. Compared with healthy cows, those with SCK or new cases of lameness generally had lower milk yield, rumination time, milk temperature, supplement intake, and milking and refusal frequencies. Only the milk temperature of lame cows deviated from baseline. Thus, acute health disorders (i.e., DA and mastitis) were associated with deviations from those cows' baseline AMS data, whereas more chronic disorders (i.e., SCK and lameness) were associated with significant but subtle longer term changes in milk production and behavior. Because cows with health disorders deviated from a group of healthy cows before they deviated from their own baseline and from the average of all other cows, including a healthy reference group in health alerts could refine the ability of detection models to identify subtle deviations in early lactation.

Quality of life in patients with advanced epithelial ovarian cancer (EOC) randomized to maintenance pazopanib or placebo after first-line chemotherapy in the AGO-OVAR 16 trial. Measuring what matters-patient-centered end points in trials of maintenance therapy.

Background: Health-related quality of life (HRQoL) was a secondary end point in AGO-OVAR 16, which randomized 940 patients with EOC after first-line chemotherapy to maintenance pazopanib (PZ) or placebo (P). Additional post hoc analyses were carried out to investigate additional patient-centered end points. Patients and methods: HRQoL was measured with EORTC-QLQ-C30, QLQ-OV28 and EQ-5D-3L. Pre-specified end points included mean differences in HRQoL between treatment arms. Exploratory analyses included quality-adjusted progression-free survival (QAPFS), impact of specific symptoms and progressive disease (PD) on HRQoL and time to second-line chemotherapy. The objective was to provide clinical perspective to the significant median PFS gain of 5.6 months with PZ. Results: There were statistically significant differences between PZ and P in QLQ-C30 global health status [5.5 points; 95% confidence interval (CI), 0.7-10.4, P = 0.024] from baseline to 25 months, but not EQ-5D-3L (0.018 points; 95% CI - 0.033 to 0.069, P = 0.485). The impact of diarrhea was captured in QLQ-OV28 Abdominal/GI-Symptoms scale (8.1 points; 95% CI 3.6-12.5, P = 0.001). QAPFS was 386 days (95% CI 366-404 days) with PZ versus 359 days (95% CI 338-379 days) with placebo (P = 0.052). PD was associated with a decline in HRQoL (P < 0.0001). Median time to second-line chemotherapy was 19.7 months with PZ and 15.0 months with P [hazard ratio (HR) 0.72, 95% CI 0.69-0.86, P = 0.0001]. Conclusions: There were small to no significant mean score differences in global HRQoL and EQ5D-3L between PZ and placebo, respectively, despite the increased toxicity of PZ. Exploratory end points including QAPFS, impact of specific symptoms on HRQoL during treatment and at PD help place the PFS gain with PZ in context and interpret the results. Additional patient-centered end points should be considered in trials of maintenance therapy in EOC beyond mean differences in HRQoL scores alone, to support the benefit to patients of prolongation of PFS. Clinical Trials Registration Number: NCT00866697.

International validation of the European Organisation for Research and Treatment of Cancer QLQ-BRECON23 quality-of-life questionnaire for women undergoing breast reconstruction.

BACKGROUND: The aim was to carry out phase 4 international field-testing of the European Organisation for Research and Treatment of Cancer (EORTC) breast reconstruction (BRECON) module. The primary objective was finalization of its scale structure. Secondary objectives were evaluation of its reliability, validity, responsiveness, acceptability and interpretability in patients with breast cancer undergoing mastectomy and reconstruction. METHODS: The EORTC module development guidelines were followed. Patients were recruited from 28 centres in seven countries. A prospective cohort completed the QLQ-BRECON15 before mastectomy and the QLQ-BRECON24 at 4-8 months after reconstruction. The cross-sectional cohort completed the QLQ-BRECON24 at 1-5 years after reconstruction, and repeated this 2-8 weeks later (test-retest reliability). All participants completed debriefing questionnaires. RESULTS: A total of 438 patients were recruited, 234 in the prospective cohort and 204 in the cross-sectional cohort. A total of 414 reconstructions were immediate, with a comparable number of implants (176) and donor-site flaps (166). Control groups comprised patients who underwent two-stage implant procedures (72, 75 per cent) or delayed reconstruction (24, 25 per cent). Psychometric scale validity was supported by moderate to high item-own scale and item-total correlations (over 0·5). Questionnaire validity was confirmed by good scale-to-sample targeting, and computable scale scores exceeding 50 per cent, except nipple cosmesis (over 40 per cent). In known-group comparisons, QLQ-BRECON24 scales and items differentiated between patient groups defined by clinical criteria, such as type and timing of reconstruction, postmastectomy radiotherapy and surgical complications, with moderate effect sizes. Prospectively, sexuality and surgical side-effects scales showed significant responsiveness over time (P < 0·001). Scale reliability was supported by high Cronbach's α coefficients (over 0·7) and test-retest (intraclass correlation more than 0·8). One item (finding a well fitting bra) was excluded based on high floor/ceiling effects, poor test-retest and weak correlations in factor analysis (below 0·3), thus generating the QLQ-BRECON23 questionnaire. CONCLUSION: The QLQ-BRECON23 is an internationally validated tool to be used alongside the EORTC QLQ-C30 (cancer) and QLQ-BR23 (breast cancer) questionnaires for evaluating quality of life and satisfaction after breast reconstruction.

Deviations in behavior and productivity data before diagnosis of health disorders in cows milked with an automated system.

To explore potential changes in behavior and productivity useful for early detection of health disorders in cows milked with automated milking systems (AMS), we collected longitudinal data throughout lactation of 57 dairy cows housed in a freestall barn with an AMS. Health problems were recorded, including subclinical ketosis (SCK; n = 19), metritis (n = 11), hoof disorders (n = 14), pneumonia (n = 7), and displaced abomasum (DA; n = 5). Data on rumination, activity, milking frequency and yield, and lying behavior were recorded electronically. Using repeated-measures mixed linear regression models, these data were analyzed for the days before the day of diagnosis/treatment (d 0) for each disorder separately, controlling for days in milk and parity. Analyses were performed between the day on which each outcome variable deviated significantly from baseline (up to d -14) and the day before diagnosis (nadir at d -1, before treatment and recovery). Outcomes tested were 3-d rolling averages of milk yield, milking frequency, and AMS supplement intake, in addition to daily rumination time (DRT), body weight, milk temperature, activity (measure of head/neck motion), and 3 lying behavior variables. From d -8, -6, and -5 before diagnosis of DA, SCK, or pneumonia, respectively, DRT declined by 45, 25, and 50 min/d. From d -14 to -1 before diagnosis of hoof disorders, DRT declined by 3 min/d. Body weight declined from d -4 before pneumonia (-14 kg/d) and metritis (-13 kg/d), from d -6 before SCK (-10 kg/d), and from d -5 before hoof disorders (-5 kg/d). Milk yield declined by 4.4 and 4.1 kg/d from d -4 before DA and pneumonia diagnoses, respectively, and by 1.2 kg/d from d -5 before SCK diagnosis. Activity levels declined before diagnosis of DA, pneumonia, SCK, or metritis. Lying behavior changed before diagnosis of DA, pneumonia, or metritis. Our results provide evidence that rumination behavior often deviated before milk yield and that several variables could contribute to earlier or automated identification of disorders. Behavior and productivity changed differently in association with various health disorders, suggesting the potential to distinguish among health problems. These variables merit further investigation in larger studies of cows milked with AMS.

Cow-level associations of lameness, behavior, and milk yield of cows milked in automated systems.

This study evaluated differences in behavior and productivity between lame and nonlame cows in herds with automated milking systems (AMS). We monitored 30 cows per herd on 41 farms with AMS in Canada (26 herds in Ontario and 15 herds in Alberta). During a 6-d period, milking data (n = 1,184) and lying behavior data (n = 1,209) were collected from cows on 41 farms. Rumination behavior (n = 569) and activity (n = 615) data were available for cows at 22 farms. Locomotion was scored using a numerical rating system (NRS; 1 = sound; 5 = extremely lame). Cows were defined as clinically lame with NRS ≥ 3 (n = 353, 29%) and nonlame with NRS < 3 (n = 865, 71%). Greater parity, lower body condition, and lower environmental temperature were factors associated with lameness. When accounting for other factors, lame cows produced 1.6 kg/d less milk in 0.3 fewer milkings/d. Lame cows were 2.2 times more likely to be fetched more than 1 time during the 6-d period and spent 38 min/d more time lying down in bouts that were 3.5 min longer in comparison with nonlame cows. As the number of cows per AMS unit increased, the frequency of milkings and refusals per cow per day decreased and cow activity increased. For each 13.3-percentage-point increase in freestall stocking density (cows per stall), daily lying time decreased by 13 min/d and cows were 1.6 times more likely to be fetched more than 1 time during the 6-d period. There was no difference in daily rumination or activity between lame and nonlame cows or in night:day rumination time, but lame cows had greater night:day activity ratios. This study supports the growing knowledge that lameness has negative effects on milk production, voluntary milking behavior, and lying behavior of cows in herds with AMS. These results may help dairy producers gain a better appreciation of the negative effects of even moderate cases of lameness and may help motivate them to improve their lameness monitoring and treatment protocols.

Associations of herd-level housing, management, and lameness prevalence with productivity and cow behavior in herds with automated milking systems.

Lameness is problematic for herds with automated milking systems (AMS) due to negative effects on milking frequency and productivity. The objective of this study was to evaluate how management, barn design, and the prevalence of lameness relate to productivity and behavior at the herd level in AMS. Details about barn design, stocking density, and management were collected from 41 AMS farms in Canada (Ontario: n=26; Alberta: n=15). We collected milking data for all cows on each farm, plus lying behavior data for 30 cows/farm during a 6-d period. Farms averaged 105±56 lactating cows and 2.2±1.3 AMS units. Forty cows/farm were gait scored (or 30% of cows for herds with >130 cows) using a numerical rating system (NRS; 1=sound to 5=extremely lame). Cows were defined as clinically lame with NRS ≥3 (mean=26.2±13.0%/herd) and severely lame with NRS ≥4 (mean=2.2±3.1%/herd). The prevalence of both clinical and severe lameness were negatively associated with environmental temperature. Clinical lameness tended to be less prevalent with more frequent scraping of manure alleys. The prevalence of severe lameness was positively associated with stocking density and curb height of the lying stalls. Milking frequency/cow per day was negatively related to the ratio of cows to AMS units. Doubling the prevalence of severe lameness (i.e., from 2.5 to 5%) was associated with reductions in milk production of 0.7kg/cow per day and 39kg/AMS per day. Milk/AMS was positively associated with more cows/AMS (+32kg/cow). Fewer cows were fetched to the AMS with more frequent alley scraping. Lying behavior was associated with the frequency of feed push-ups, stall base, and environmental temperature. These results highlight the need for AMS producers to identify and reduce clinical lameness because 26% of cows/herd were clinically lame. Further, the results indicate that more frequently scraped alleys and optimal stocking densities are associated with improved cow mobility, productivity, and voluntary milking behavior.