Development of a disease-specific health utility score for chronic obstructive pulmonary disease from a discrete choice experiment patient preference study.

OBJECTIVES: While patient input to health technology assessment (HTA) has traditionally been of a qualitative nature, there is increasing interest to integrate quantitative evidence from patient preference studies into HTA decision making. Preference data can be used to generate disease-specific health utility data. We generated a health utility score for patients with chronic obstructive pulmonary disease (COPD) and consider its use within HTAs. METHODS: Based on qualitative research, six symptoms were identified as important to COPD patients: shortness of breath, exacerbations, chronic cough, mucus secretion, sleep disturbance, and urinary incontinence. We employed a discrete choice experiment (DCE) and the random parameter logistic regression technique to estimate utility scores for all COPD health states. The relationship between patients' COPD health utility scores, self-perceived COPD severity, and EQ-5D-3L utility scores was analyzed, with data stratified according to disease severity and comorbidity subgroups. RESULTS: The COPD health utility score had face validity, with utility scores negatively correlated with patients' self-perceived COPD severity. The correlation between the COPD health utility scores and EQ-5D-3L values was only moderate. While patient EQ-5D-3L scores were impacted by comorbidities, the COPD health utility score was less impacted by comorbid conditions. CONCLUSIONS: Our COPD utility measure, derived from a DCE, provides a patient-centered health utility score and is more sensitive to the COPD health of the individual and less sensitive to other comorbidities. This disease-specific instrument should be considered alongside generic health-related quality of life instruments when valuing new COPD therapies in submissions to licensing and reimbursement agencies.

Magmatic-hydrothermal fluid evolution of the tin-polymetallic metallogenic systems from the Weilasituo ore district, Northeast China.

The large Weilasituo Sn-polymetallic deposit is a recent exploration discovery in the southern Great Xing'an Range, northeast China. The ore cluster area shows horizontal mineralization zoning, from the inner granite body outward, consisting of high-T Sn-W-Li mineralization, middle-T Cu-Zn mineralization and peripheral low-T Pb-Zn-Ag mineralization. However, the intrinsic genetic relationship between Sn-W-Li mineralization and peripheral vein-type Pb-Zn-Ag-Cu mineralization, the formation mechanism and the deep geological background are still insufficiently understood. Here, we use fluid inclusions, trace elements concentrations in quartz and sphalerite, and H-O isotope studies to determine the genetic mechanism and establish a metallogenic model. Fluid inclusion microthermometry and Laser Raman spectroscopic analysis results demonstrates that the aqueous ore-forming fluids evolved from low-medium salinity, medium-high temperature to low salinity, low-medium temperature fluids. Laser Raman spectroscopic analysis shows that CH4 is ubiquitous in fluid inclusions of all ore stages. Early ore fluids have δ18OH2O (v-SMOW) values from + 5.5 to + 6.2‰ and δD values of approximately - 67‰, concordant with a magmatic origin. However, the late ore fluids shifted toward lower δ18OH2O (v-SMOW) (as low as 0.3‰) and δD values (~ - 136‰), suggesting mixing between external fluids derived from the wall rocks and a contribution from meteoric water. Ti-in-quartz thermometry indicates a magmatic crystallization temperature of around 700 °C at a pressure of 1.5 kbar for the magmatic ore stage. Cathodoluminescence (CL) imaging and trace element analysis of quartz from a hydrothermal vug highlight at least three growth episodes that relate to different fluid pulses; each episode begins with CL-bright, Al-Li-rich quartz, and ends with CL-dark quartz with low Al and Li contents. Quartz from Episode 1 formed from early Sn-(Zn)-rich fluids which were likely derived from the quartz porphyry. Quartz from episodes 2 and 3 formed from Zn-(Sn)-Cu-rich fluid. The early magmatic fluid is characterized by low fS2. The SO2 produced by magma degassing reacted with heated water to form SO42-, causing the shift from low fS2 to high fS2. The SO42- generated was converted to S2- by mixing with CH4-rich, Fe and Zn-bearing external fluid which led to late-stage alteration and dissolution of micas in vein walls, thus promoting crystallization of pyrrhotite, Fe-rich sphalerite and chalcopyrite and inhibiting the precipitation of anhydrite. This study shows that ore formation encompassed multiple episodes involving steadily evolved fluids, and that the addition of external fluids plays an important role in the formation of the later Cu-Zn and Ag-Pb-Zn mineralization in the Weilasituo ore district.

Perspective: Prolonged cow-calf contact-A dilemma or simply another step in the evolution of the dairy industry?

The contentious issue of cow-calf separation at birth is incongruent with many views on acceptable farming practices, and carries the risk of eroding public trust in the dairy industry if it is not addressed. The available evidence provides little support for the practice, but research on best practices for maintaining cow-calf contact in a way that enhances animal welfare while preserving farm profitability is nascent. In this article, the authors address the research questions that require answers to better inform producers and facilitate their decision-making and prepare the dairy industry to take another evolutionary step forward.

Ab initio crystal structures and relative phase stabilities for the aleksite series, PbnBi4Te4Sn+2.

Density functional theory methods are applied to crystal structures and stabilities of phases from the aleksite homologous series, PbnBi4Te4Sn+2 (n = homologue number). The seven phases investigated correspond to n = 0 (tetradymite), 2 (aleksite-21R and -42R), 4 (saddlebackite-9H and -18H), 6 (unnamed Pb6Bi4Te4S8), 8 (unnamed Pb8Bi4Te4S10), 10 (hitachiite) and 12 (unnamed Pb12Bi4Te4S14). These seven phases correspond to nine single- or double-module structures, each comprising an odd number of atom layers, 5, 7, (5.9), 9, (7.11), 11, 13, 15 and 17, expressed by the formula: S(MpXp+1)·L(Mp+1Xp+2), where M = Pb, Bi and X = Te, S, p ≥ 2, and S and L = number of short and long modules, respectively. Relaxed structures show a and c values within 1.5% of experimental data; a and the interlayer distance dsub decrease with increasing PbS content. Variable Pb-S bond lengths contrast with constant Pb-S bond lengths in galena. All phases are n-fold superstructures of a rhombohedral subcell with c/3 = dsub*. Electron diffraction patterns show two brightest reflections at the centre of dsub*, described by the modulation vector qF = (i/N) ·â€…dsub*, i = S + L. A second modulation vector, q = γ ·â€…csub*, shows a decrease in γ, from 1.8 to 1.588, across the n = 0 to n = 12 interval. The linear relationship between γ and dsub allows the prediction of any theoretical phases beyond the studied compositional range. The upper PbS-rich limit of the series is postulated as n = 398 (Pb398Bi4Te4S400), a phase with dsub (1.726 Å) identical to that of trigonal PbS within experimental error. The aleksite series is a prime example of mixed layer compounds built with accretional homology principles.

Effect of different air speeds at cow resting height in freestalls on heat stress responses and resting behavior in lactating cows in Wisconsin.

Heat abatement (e.g., soakers, fans) effectively reduces the negative physiological and production effects of heat stress, but no previous studies have documented effective interventions for the reduced lying times observed in response to hot weather. Although likely adaptive for heat dissipation, the reduction in motivated lying behavior may be an animal welfare concern. We evaluated the effect of air speed from fans with variable frequency drives on the heat stress responses of cows in a naturally ventilated freestall barn. Eight groups of lactating Holsteins (16 cows/group) were exposed to 3 treatments in a replicated crossover design: control (fans off, 0.4 ± 0.2 m/s, measured 0.5 m above the stall surface to represent cow resting height) versus 60% (1.7 ± 0.5 m/s; ≥1 m/s in all stalls) and 100% (2.4 ± 0.8 m/s) fan power. Each treatment was applied for 3 d of acclimation and 4 d of data collection. The effects of treatment on daily maximum vaginal temperature (VT) and lying time (LT; both measured with data loggers), respiration rate (RR; recorded from video), unshaved scapular skin temperature (ST), milk yield (MY), and dry matter intake (DMI) were analyzed using linear mixed models. All models included the fixed effect of treatment and a repeated term for treatment day within group of cows, with group as the subject. The models for LT, VT, and RR also included a fixed effect for same-day temperature-humidity index (THI; recorded in the pens with data loggers) and the THI × treatment interaction. The models for DMI and MY, using data from the latter 3 d of each treatment period, also included a fixed effect for the previous day's THI and the -1 d THI × treatment interaction. Lying time differed among treatments (100% vs. 60% fan power vs. control: 14.2 vs. 13.9 vs. 13.2 h/d, respectively, SEM = 0.15 h/d), but both fan treatments prevented the reduction in LT observed in the control treatment as THI increased. Relative to the control, both fan treatments effectively reduced ST, RR, and VT and increased DMI and MY. In the control, average values were elevated for both RR (68.7 ± 1.5 breaths/min, mean ± SEM, greater than a common benchmark of 60 breaths/min) and VT (39.3 ± 0.05°C) but remained in the normal range in both fan treatments (54.2 vs. 50.7 breaths/min in the 60% vs. 100% fan power treatments; 39.0°C in both fan treatments). Both fan treatments resulted in greater overall MY (42.6 vs. 43.0 ± 0.4 kg/d in the 60% vs. 100% fan power treatments) relative to the control (41.0 kg/d) and similarly avoided the reduction in MY when -1 d THI increased. Compared with natural ventilation alone, fans delivering air speeds of at least 1 m/s at cow resting height were effective not only for reducing thermoregulatory responses, but also for maintaining lying time, DMI, and MY in heat stress conditions. This is the first study to demonstrate an intervention to improve animal welfare by maintaining lying times during periods of heat stress.

Milking time behavior of dairy cows in a free-flow automated milking system.

The objective of this preliminary observational study was to determine milking time behavior of cows in a free-flow automated (robotic) milking system (AMS) and identify potential factors that influenced the time waiting to be milked. Milking time behavior of 40 cows from 1 pen on a commercial dairy farm with a free-flow AMS was evaluated using video analysis over 2 d. For each study cow, data were assessed for waiting time to access the milking robot, the use of the fetch pen, robot refusals, and their lying behavior. On average, cows visited the robot to wait to be milked 6 times per day, for 15 min per visit, for a total daily waiting time of 88 min per cow (range 5 to 322 min). Daily waiting time was longer for primiparous cows and decreased with increasing days in milk, but this effect interacted with parity. Daily waiting time and number of visits to the robot were associated with voluntary use of the fetch pen. Furthermore, cows with long daily waiting times had shorter daily lying times compared with cows with short daily waiting times (9.5 vs. 11.1 h/d). It is possible that factors related to the design and layout of the AMS entry and fetch pen had an effect on waiting behavior. We inferred that adoption of grouping strategies intended to reduce competitive behavior, especially toward primiparous cows, could improve milking time behavior in a free-flow AMS. This preliminary observational data from a single herd highlights the need to confirm the findings across multiple AMS herds, both with free-flow and guided-flow systems.

Pentavalent Uranium Incorporated in the Structure of Proterozoic Hematite.

Characterizing the chemical state and physical disposition of uranium that has persisted over geologic time scales is key for modeling the long-term geologic sequestration of nuclear waste, accurate uranium-lead dating, and the use of uranium isotopes as paleo redox proxies. X-ray absorption spectroscopy coupled with molecular dynamics modeling demonstrated that pentavalent uranium is incorporated in the structure of 1.6 billion year old hematite (α-Fe2O3), attesting to the robustness of Fe oxides as waste forms and revealing the reason for the great success in using hematite for petrogenic dating. The extreme antiquity of this specimen suggests that the pentavalent state of uranium, considered a transient, is stable when incorporated into hematite, a ubiquitous phase that spans the crustal continuum. Thus, it would appear overly simplistic to assume that only the tetravalent and hexavalent states are relevant when interpreting the uranium isotopic record from ancient crust and contained ore systems.

People living with moderate-to-severe COPD prefer improvement of daily symptoms over the improvement of exacerbations: a multicountry patient preference study.

Introduction: This patient preference study sought to quantify the preferences of people living with COPD regarding symptom improvement in the UK, USA, France, Australia and Japan. Methods: The inclusion criteria were people living with COPD aged 40 years or older who experienced ≥1 exacerbation in the previous year with daily symptoms of cough and excess mucus production. The study design included: 1) development of an attributes and levels grid through qualitative patient interviews; and 2) implementation of the main online quantitative survey, which included a discrete choice experiment (DCE) to allow assessment of attributes and levels using hypothetical health state profiles. Preference weights (utilities) were derived from the DCE using hierarchical Bayesian analysis. A preference simulator was developed that enabled different health state scenarios to be evaluated based on the predicted patient preferences. Results: 1050 people living with moderate-to-severe COPD completed the survey. All attributes were considered important when patients determined their preferences in the DCE. In a health state preference simulation, two hypothetical health states (comprising attribute levels) with qualitatively equivalent improvements in A) cough and mucus and B) shortness of breath (SOB) resulted in a clear preference for cough and mucus improved profile. When comparing two profiles with C) daily symptoms improved and D) exacerbations improved, there was a clear preference for the daily symptoms improved profile. Conclusions: People living with moderate-to-severe COPD prefer to reduce cough and mucus production together over improvement of SOB and would prefer to reduce combined daily symptoms over an improvement in exacerbations.

Real-Time PCR-Based Methods for Detection of Hepatitis E Virus in Pork Products: A Critical Review.

Standard methods for detection of hepatitis A virus and norovirus in at-risk foodstuffs are available, but currently there is no standard method for detection of hepatitis E virus (HEV) in pork products or other foods that can be contaminated with the virus. Detection assays for HEV are mainly based on nucleic acid amplification, particularly the reverse transcription polymerase chain reaction (RTPCR) in real-time format. RTPCR-based methods can be sensitive and specific, but they require a suite of controls to verify that they have performed correctly. There have been several RTPCR methods developed to detect HEV in pork products, varying in details of sample preparation and RTPCR target sequences. This review critically discusses published HEV detection methods, with emphasis on those that have been successfully used in subsequent studies and surveys. RTPCR assays have been used both qualitatively and quantitatively, although in the latter case the data acquired are only reliable if appropriate assay calibration has been performed. One particular RTPCR assay appears to be ideal for incorporation in a standard method, as it has been demonstrated to be highly specific and sensitive, and an appropriate control and calibration standard is available. The review focuses on the detection of HEV in pork products and similar foodstuffs (e.g., boar). The information may be useful to inform standardisation activities.

The Special Issue: Transmission and Detection of Food and Environmental Pathogens.

To progress towards a full comprehension of the risk caused by pathogenic microorganisms transmitted via food and environmental routes, extensive information on the prevalence, the mechanisms of contamination, and the survival of pathogens is required, particularly to assist with the development of effective systems to reduce contamination, and to formulate procedural control measures, such as the implementation of food safety criteria [...].

Assessing Patient Preferences in Rare Diseases: Direct Preference Elicitation in the Rare Chronic Kidney Disease, Immunoglobulin A Nephropathy.

BACKGROUND: Patient preference information is increasingly being used to inform decision making; however, further work is required to support the collection of preference information in rare diseases. This study illustrates the use of direct preference elicitation methods to collect preference data from small samples in the context of early decision making to inform the development of a product for the treatment of immunoglobulin A nephropathy. METHOD: An interview-based swing weighting approach was used to elicit preferences from 40 patients in the US and China. Attributes were identified through a background review, expert engagement and patient focus groups. Participants completed a series of tasks that involved ranking, rating and scoring improvements in the attributes to obtain attribute swing weights and partial value functions. The preference results were then incorporated into a benefit-risk assessment simulation tool. RESULTS: Participants placed the greatest value on avoiding end-stage renal/kidney disease. Similar weight was given to short-term quality-of-life improvements and avoiding infections. Treatment burden (number of vaccinations) received the least weight. Heterogeneity in preferences was also observed. Consistency tests did not identify statistically significant variation in preferences, and qualitative data suggested that the elicitation exercise was sensitive to participants' interpretation of attributes and that participants were able to express their preferences. CONCLUSION: Direct preference elicitation methods can be used to collect preference data from small samples. Further work should continue to test the validity of the estimate generated by such methods.

Development of an international template to support patient submissions in Health Technology Assessments.

OBJECTIVES: To develop an international template to support patient submissions in Health Technology Assessments (HTAs). This was to be based on the experience and feedback from the implementation and use of the Scottish Medicines Consortium's (SMC) Summary Information for Patient Groups (SIP). METHODS: To gather feedback on the SMC experience, web-based surveys were conducted with pharmaceutical companies and patient groups familiar with the SMC SIP. Semistructured interviews with representatives from HTA bodies were undertaken, along with patient group discussions with those less familiar with the SIP, to explore issues around the approach. These qualitative data informed the development of an international SIP template. RESULTS: Survey data indicated that 82 percent (18 of 22 respondents) of pharmaceutical company representatives felt that the SIP was worthwhile; 88 percent (15/17) of patient group respondents found the SIP helpful. Both groups highlighted the need for additional support and guidance around plain language summaries. Further suggestions included provision of a glossary of terms and cost-effectiveness information. Patient group interviews supported the survey findings and led to the development of a new template. HTA bodies raised potential challenges around buy-in, timing, and bias connected to the SIP approach. CONCLUSIONS: The international SIP template is another approach to support deliberative processes in HTA. Although challenges remain around writing summaries for lay audiences, along with feasibility considerations for HTA bodies, the SIP approach should support more meaningful patient involvement in HTAs.

How to integrate evidence from patient preference studies into health technology assessment: a critical review and recommendations.

Health technology assessment (HTA) agencies vary in their use of quantitative patient preference data (PP) and the extent to which they have formalized this use in their guidelines. Based on the authors' knowledge of the literature, we identified six different PP "use cases" that integrate PP into HTA in five different ways: through endpoint selection, clinical benefit rating, predicting uptake, input into economic evaluation, and a means to weight all HTA criteria. Five types of insight are distinguished across the use cases: understanding what matters to patients, predicting patient choices, estimating the utility generated by treatment benefits, estimating the willingness to pay for treatment benefits, and informing distributional considerations. Summarizing the literature on these use cases, we recommend circumstances in which PP can add value to HTA and the further research and guidance that is required to support the integration of PP in HTA. Where HTA places more emphasis on clinical outcomes, novel endpoints are available; or where there are already many treatment options, PP can add value by helping decision makers to understand what matters to patients. Where uptake is uncertain, PP can be used to estimate uptake probability. Where indication-specific utility functions are required or where existing utility measures fail to capture the value of treatments, PP can be used to generate or supplement existing utility estimates. Where patients are paying out of pocket, PP can be used to estimate willingness to pay.

Quantification of radionuclide distribution and migration during Cu-(Fe)-sulphide mineral processing by alpha particle autoradiography.

Understanding the movement of radionuclides (RNs) between different mineral hosts during processing of base metal ores is critical for accurate modelling of RN deportment and optimisation of processes designed to reduce or eliminate RNs. Here, we demonstrate that spatially resolving quantitative alpha particle autoradiography combined with backscatter electron imaging and energy dispersive X-ray spectroscopy (EDS) can establish the correlation between alpha-emitting RNs (notably 226Ra and 210Po, daughters of the abundant 238U decay series) and certain minerals, in different stages of processing. This is achieved by locating the RNs to a specific mineral grain, the species of which can subsequently be identified using EDS. The mineralogy of RN-associated grains can then be compared with the mineral suite and relative abundances of the species within the sample, by relating how often each mineral is associated with alpha decay-events. In the processing of uranium-bearing copper ores, migration of alpha-emitting RN daughters of the 238U series were observed, and these RNs were demonstrated to correlate strongly with barite, bornite and covellite over other coexisting minerals.

Understanding the mobility and retention of uranium and its daughter products.

Knowledge of the behavior of technologically enhanced naturally occurring radioactive materials derived through the decay of U and its daughter products, and their subsequent fractionation, mobilization and retention, is essential to develop effective mitigation strategies and long-term radiological risk prediction. In the present study, multiple state-of-the-art, spatially resolved micro-analytical characterization techniques were combined to systematically track the liberation and migration of radionuclides (RN) from U-bearing phases in an Olympic Dam Cu flotation concentrate following sulfuric-acid-leach processing. The results highlighted the progressive dissolution of U-bearing minerals (mainly uraninite) leading to the release, disequilibrium and ultimately upgrade of daughter RN from the parent U. This occurred in conjunction with primary Cu-Fe-sulfide minerals undergoing coupled-dissolution reprecipitation to the porous secondary Cu-mineral, covellite. The budget of RN remaining in the leached concentrate was split between RN still hosted in the original U-bearing minerals, and RN that were mobilized and subsequently sorbed/precipitated onto porous covellite and auxiliary gangue mineral phases (e.g. barite). Further grinding of the flotation concentrate prior to sulfuric-acid-leach led to dissolution of U-bearing minerals previously encapsulated within Cu-Fe-sulfide minerals, resulting in increased release and disequilibrium of daughter RN, and causing further RN upgrade. The various processes that affect RN (mobility, sorption, precipitation) and sulfide minerals (coupled-dissolution reprecipitation and associated porosity generation) occur continuously within the hydrometallurgical circuit, and their interplay controls the rapid and highly localized enrichment of RN. The innovative combination of tools developed here reveal the heterogeneous distribution and fractionation of the RN in the ores following hydrometallurgical treatment at nm to cm-scales in exquisite detail. This approach provides an effective blueprint for understanding of the mobility and retention of U and its daughter products in complex anthropogenic and natural processes in the mining and energy industries.

Radiated temperature from thermal imaging is related to feed consumption, growth rate and feed efficiency in grower pigs.

Individual feed consumption and animal weight were continuously recorded in grower pigs using an automated feeding system. Infrared images were recorded each time a pig entered the feeding system and infrared thermography provided radiated thermal measurements of the dorsal surface of each animal. Feed was withdrawn and the animals fasted for a period of 24 h three times during the growth of the animals at body weights of approximately 35, 65 and 105 kg. There was a significant reduction of 0.28 °C in the maximum surface temperature (Tmax), and 0.48 °C in the average surface temperature (Tmean) during the periods of fasting. Maximum and average pig temperatures exhibited negative correlations to feed consumption and growth variables. There were negative correlations of residual feed intake (RFI) to Tmax and Tmean radiated temperatures. There were positive correlations of residual gain (RG) and residual intake and gain (RIG) with Tmax and Tmean. The Tmax and Tmean temperature responses to fasting were negatively associated with feed consumption and growth variables. Absolute temperature and temperature response variables were positively associated with RFI and negatively associated with residual intake and gain (RIG). These findings provide support for the concept of radiated heat losses as a measure of metabolic activity and a predictor of growth performance.

Identification of Patient Needs and Preferences in Pigmented Villonodular Synovitis (PVNS) Using a Qualitative Online Bulletin Board Study.

INTRODUCTION: Pigmented villonodular synovitis (PVNS), also known as giant-cell tumour of the tendon sheath (GCTT), is a rare, benign proliferative tumour affecting the inner lining of synovial joints and tendon sheets. Information on treatment needs of PVNS patients to inform drug development is currently scarce. We conducted an exploratory qualitative study with PVNS patients to generate insights into the objective and emotional aspects related to their medical journey and experiences of living with this disease. METHODS: A 4-day study using an online bulletin board (OBB), an asynchronous, online qualitative research platform, was conducted with patients recruited via physician referral who underwent screening questions to ensure eligibility for the study and willingness to participate. The discussion was moderated, was structured and allowed open answers in response to other participants' posts. RESULTS: Eleven patients (4 from the USA, 4 from the UK and 3 from Canada; 45% female), aged 28-57 years, suffering from PVNS for 2-27 years participated in the study. Key patient insights from the study were: (1) pain was the topmost, spontaneous thought that the participants associated with PVNS, constituting a significant emotional and psychological burden; (2) surgery (arthroscopy) did not completely ameliorate symptoms associated with PVNS, as the relapse rate was high in these patients; (3) PVNS has a substantial negative financial impact on patients, their families and the healthcare system; (4) orthopaedic specialists/surgeons predominantly managed PVNS, as surgery is currently the only therapeutic option. CONCLUSION: PVNS patients expressed an urgent need for a medical drug treatment, which can reduce pain, avoid relapses and provide an alternative to surgery, the current standard of care.