Continuous Space-Time Crystal State Driven by Nonreciprocal Optical Forces.

We show that the continuous time crystal state can arise in an ensemble of linear oscillators from nonconservative coupling via optical radiation pressure forces. This new mechanism comprehensively explains observations of the time crystal state in an array of nanowires illuminated with light [T. Liu et al., Nat. Phys. 19, 986 (2023).NPAHAX1745-247310.1038/s41567-023-02023-5]. Being fundamentally different from regimes of nonlinear synchronization, it has relevance to a wide range of interacting many-body systems, including in the realms of chemistry, biology, weather, and nanoscale matter.

Imaging of cerebral venous thrombosis.

The incidence of cerebral venous thrombosis (CVT) is increasing due to the widespread use of computed tomography (CT) and magnetic resonance imaging (MRI) for investigating patients with acute headaches and new onset of seizures. Alternatively referred to as cerebral venous sinus thrombosis (CVST) or dural venous sinus thrombosis (DVST), the terms encompass a broad spectrum of neurological pathologies. These include dural venous sinus thrombosis, cortical vein thrombosis, cavernous sinus thrombosis, venous infarction/haemorrhage, and the rare sequelae of intracranial hypertension or dural arteriovenous fistula. Timely and accurate diagnosis is critical; most patients are young adults and up to 15% will die in the acute phase of the condition. Imaging diagnosis using unenhanced CT or CT venography (CTV) can be readily achieved by the general radiologist. MRI or MRI venography (MRV) are powerful techniques, provided the radiologist is aware of critical diagnostic pitfalls. In selected cases, cerebral digital subtraction angiography (DSA) can facilitate both diagnosis and anticoagulant/transcatheter thrombolytic therapy improving clinical outcome. This article will outline the condition, highlighting cerebral venous anatomy, diagnostic techniques, and pitfalls pertinent to all practising radiologists.

Short communication: Evaluation of an eating time sensor for use in pasture-based dairy systems.

The assessment of grazing behavior is important for research and practice in pasture-grazed dairy farm systems. However, few devices are available that enable assessment of cow grazing behavior at an individual animal level. This study investigated whether commercially available Smarttag "eating time" sensors (Nedap Livestock Management, Groenlo, the Netherlands) were suitable for recording the grazing time of cows. Smarttag sensors were mounted on the neck collars of multiparous Holstein-Friesian cows in a herd in Taranaki, New Zealand. Cows were randomly selected each observation day from the milking herd for 8 separate days across a 1-mo period. Trained observers conducted 90-min observation periods to evaluate the relationship between the sensor eating time measure and grazing time. A set of 5 defined cow behaviors (2 "head up" and 3 "head down" behaviors) were assessed. In total, observations of 37 cows were recorded in 14 sessions over 8 d in the study period, providing 55.5 total hours of observations. Observation data were aligned with sensor data according to the sensor time stamps and grouped into matching 15-min intervals. Interobserver reliability was assessed both before and after the main trial period, and the mean percentage eating time per observer had a coefficient of variation of 0.46% [mean 93.2, standard deviation (SD) 0.425] before and 0.07% (mean 96.3, SD 0.074) after. In the main trial, the relationship between observed (mean 70.8%) and sensor-derived (mean 69.3%) percentage eating time over the observation period gave a Pearson correlation coefficient of 0.971, concordance correlation coefficient 0.968, mean difference 1.50% points, and SD 5.8% points. Therefore, sensor-identified percentage "eating time" and observed percentage active grazing time were shown to be both very well correlated and concordant (in agreement, with high correlation and little bias). Therefore, the relationship between observed and sensor-derived data had a high degree of agreement for identifying cow grazing activity. In conclusion, Smarttag sensors are a valid and useful tool for estimating grazing activity at time periods of 1 h or more.

Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions.

Cell-based therapy with CD4+ FOXP3+ regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-γ and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3+ TBET+ FOXP3+ T helper (Th)1-Tregs. CXCR3 remained expressed after injection in vivo and Th1-Tregs migrated efficiently towards CXCL10 in vitro. To induce tissue-specific migration, addition of retinoic acid (RA) during Treg expansion induced expression of the gut-homing receptors α4ß7-integrin and CCR9. FOXP3+ RA-Tregs had elevated expression of the functional markers latency-associated peptide and glycoprotein A repetitions predominant, increased suppressive capacity in vitro and migrated efficiently to healthy and inflamed intestine after injection into mice. Homing-receptor-tailored Tregs were epigenetically stable even after long-term exposure to inflammatory conditions, suppressive in vivo and characterized by Th1- or gut-homing-specific transcriptomes. Tailoring human thymic Treg homing during in vitro expansion offers a new and clinically applicable approach to improving the potency and specificity of Treg therapy.

Methods to manufacture regulatory T cells for cell therapy.

Regulatory T cell (Treg ) therapy has shown promise in early clinical trials for treating graft-versus-host disease, transplant rejection and autoimmune disorders. A challenge has been to isolate sufficiently pure Tregs and expand them to a clinical dose. However, there has been considerable progress in the development and optimization of these methods, resulting in a variety of manufacturing protocols being tested in clinical trials. In this review, we summarize methods that have been used to manufacture Tregs for clinical trials, including the choice of cell source and protocols for cell isolation and expansion. We also discuss alternative culture or genome editing methods for modulating Treg specificity, function or stability that could be applied to future clinical manufacturing protocols to increase the efficacy of Treg therapy.

Short communication: Milk fat payment affects the relative profitability of Jersey and Holstein-Friesian cows at optimal comparative stocking rate.

Choice of stocking rate and breed of cow are 2 strategic decisions that affect the profitability of pasture-based dairy farm businesses. This study sought to analyze the effects of a range of fat and protein prices on the profitability of the Jersey (J) and Holstein-Friesian (HF) breeds at 2 comparative stocking rates (CSR): 80 kg of body weight (BW) per tonne of dry matter (DM) of feed (CSR80), and 100 kg of BW per tonne of DM of feed (CSR100). Data were obtained from a recently published study, and equations constructed to determine the values for fat and protein at which each breed broke even (profit = NZ$0/ha; at time of writing, NZ$1 = US$0.69 or €0.60), returned equal profit, and exceeded the other breed by 1% or 5%. At CSR100 there were few combinations of fat and protein prices for which HF were more profitable than J. At CSR80, J and HF were equally profitable at a fat price of NZ$5.67 ± NZ$0.20 per kilogram, depending on protein price. The study also highlighted the importance of including volume adjustments in milk price calculations when differences in milk composition exist, as the fat price at which the profitability of HF and J were equal was NZ$1.23/kg lower when volume adjustments were included. The recent increase in the value of fat relative to protein favors J. Farmers should consider the medium- to long-term outlook of fat price when evaluating breed choice for their farm system.

Hot topic: Selecting cattle for low residual feed intake did not affect daily methane production but increased methane yield.

Reducing enteric methane (CH4) production and improving feed conversion efficiency of dairy cows is of high importance. Residual feed intake (RFI) is one measure of feed efficiency, with low RFI animals being more efficient in feed conversion. Enteric CH4 is an important source of digestible energy loss in ruminants and, because research in beef cattle has reported a positive relationship between RFI and daily CH4 production, we hypothesized that low RFI dairy heifers, which are more feed efficient, would produce less CH4/d. We measured the daily methane production (g of CH4/d), methane yield [g of CH4/kg of dry matter intake (DMI)], and CH4 per kilogram of body weight (BW) gain for 56 heifers (20-22 mo old) in a 2 × 2 factorial arrangement: factors included 2 breeds (Holstein-Friesian and Jersey; n = 28/breed), with equal numbers of animals previously determined as being either high [+2.0 kg of dry matter (DM)/d] or low RFI (-2.1 kg of DM/d; n = 28/RFI category). All heifers were commingled and offered unrestricted access to the same diet of dried alfalfa cubes. Between RFI categories, heifers did not differ in BW or BW gain but low RFI heifers had 9.3 and 10.6% lower DMI and DMI/kg of BW, respectively, than high RFI heifers. Similarly, RFI category did not affect CH4/d or CH4/kg of BWg, but CH4/kg of DMI was higher in low RFI heifers because of their lower DMI. These results might reflect more complete digestion of ingested feed in the more efficient, low RFI heifers, consistent with previous reports of greater apparent digestibility of organic matter. Holstein-Friesian heifers were heavier and consumed more total DM than Jersey heifers, but breed did not affect DMI/kg of BW or BWg. Jersey heifers produced less CH4/d, but not CH4/kg of DMI or CH4/kg of BWg. We detected no interaction between breed and RFI category in any of the variables measured. In conclusion, differences in RFI in dairy heifers did not affect daily CH4 production (g/d); however, low RFI heifers had a greater CH4 yield (g/kg of DMI) on a high forage diet.

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.

How do patients trade-off surgeon choice and waiting times for total joint replacement: a discrete choice experiment.

OBJECTIVE: Patients face significant waiting times for hip and knee total joint replacement (TJR) in publicly funded healthcare systems. We aimed to assess how surgeon selection and reputation affect patients' willingness to wait for TJR. DESIGN: We assessed patient preferences using a discrete choice experiment questionnaire with 12 choice scenarios administered to patients referred for TJR. Based on qualitative research, pre- and pilot-testing, we characterized each scenario by five attributes: surgeon reputation, surgeon selection, waiting time to surgeon visit (initial consultation), waiting time to surgery, and travel time to hospital. Preferences were assessed using hierarchical Bayes (HB) analysis and evaluated for goodness-of-fit. We conducted simulation analyses to understand how patients value surgeon reputation and surgeon selection in terms of willingness to wait for surgeon visit and surgery. RESULTS: Of 422 participants, 68% were referred for knee TJR. The most important attribute was surgeon reputation followed by waiting times, surgeon selection process and travel time. Patients appear willing to wait 10 months for a visit with an excellent reputation surgeon before switching to a good reputation surgeon. Patients in the highest pain category were willing to wait 7.3 months before accepting the next available surgeon, compared to 12 months for patients experiencing the least pain. CONCLUSIONS: Our findings confirm that patients value surgeon reputation in the context of wait times and surgeon selection. We suggest opportunities to reduce wait times by explicitly offering the next available surgeon to increase patient choice, and by reporting surgeon performance to reduce potential misinformation about reputation.

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.

A 100-Year Review: A century of change in temperate grazing dairy systems.

From 1917 to 2017, dairy grazing systems have evolved from uncontrolled grazing of unimproved pastures by dual-purpose dairy-beef breeds to an intensive system with a high output per unit of land from a fit-for-purpose cow. The end of World War I signaled significant government investments in agricultural research institutes around the world, which coincided with technological breakthroughs in milk harvesting and a recognition that important traits in both plants and animals could be improved upon relatively rapidly through genetic selection. Uptake of milk recording and herd testing increased rapidly through the 1920s, as did the recognition that pastures that were rested in between grazing events yielded more in a year than those continuously grazed. This, and the invention and refinement of the electric fence, led to the development of "controlled" rotational grazing. This, in itself, facilitated greater stocking rates and a 5 to 10% increase in milk output per hectare but, perhaps more importantly, it allowed a more efficient use of nitrogen fertilizer, further increasing milk output/land area by 20%. Farmer inventions led to the development of the herringbone and rotary milking parlors, which, along with the "unshortable" electric fence and technological breakthroughs in sperm dilution rates, allowed further dairy farm expansion. Simple but effective technological breakthroughs in reproduction ensured that cows were identified in estrus early (a key factor in maintaining the seasonality of milk production) and enabled researchers to quantify the anestrus problem in grazing herds. Genetic improvement of pasture species has lagged its bovine counterpart, but recent developments in multi-trait indices as well as investment in genetic technologies should significantly increase potential milk production per hectare. Decades of research on the use of feeds other than pasture (i.e., supplementary feeds) have provided consistent milk production responses when the reduction in pasture intake associated with the provision of supplementary feed (i.e., substitution rate) is accounted for. A unique feature of grazing systems research over the last 70 yr has been the use of multi-year farm systems experimentation. These studies have allowed the evaluation of strategic changes to a component of the system on all the interacting features of the system. This technique has allowed excellent component research to be "systemized" and is an essential part of the development of the intensive grazing production system that exists today. Future challenges include the provision of skilled labor or specifically designed automation to optimize farm management and both environmental sustainability and animal welfare concerns, particularly relating to the concentration of nitrogen in each urine patch and the associated risk of nitrate leaching, as well as concerns regarding exposure of animals to harsh climatic conditions. These combined challenges could affect farmers' "social license" to farm in the future.

Generating an image that affords slant perception from stereo, without pictorial cues.

This paper describes an algorithm for generating a planar image that when tilted provides stereo cues to slant, without contamination from pictorial gradients. As the stimuli derived from this image are ultimately intended for use in studies of slant perception under magnification, a further requirement is that the generated image be suitable for high-definition printing or display on a monitor. A first stage generates an image consisting of overlapping edges with sufficient density that when zoomed, edges that nearly span the original scale are replaced with newly emergent content that leaves the visible edge statistics unchanged. A second stage reduces intensity clumping while preserving edges by enforcing a broad dynamic range across the image. Spectral analyses demonstrate that the low-frequency content of the resulting image, which would correspond to the pictorial cue of texture gradient changes under slant, (a) has a power fall-off deviating from 1/f noise (to which the visual system is particularly sensitive), and (b) does not offer systematic cues under changes in scale or slant. Two behavioral experiments tested whether the algorithm generates stimuli that offer cues to slant under stereo viewing only, and not when disparities are eliminated. With a particular adjustment of dynamic range (and nearly so with the other version that was tested), participants viewing without stereo cues were essentially unable to discriminate slanted from flat (frontal) stimuli, and when slant was reported, they failed to discriminate its direction. In contrast, non-stereo viewing of a control stimulus with pictorial cues, as well as stereoscopic observation, consistently allowed participants to perceive slant correctly. Experiment 2 further showed that these results generalized across a population of different stimuli from the same generation process and demonstrated that the process did not substitute biased slant cues.

Nasopharyngeal non-intestinal-type adenocarcinoma: a case report and updated review of the literature.

BACKGROUND: Non-intestinal-type adenocarcinoma is a malignancy traditionally found in the sinonasal cavity. To our knowledge, this case is the first reported of this rare condition originating in the nasopharynx. CASE PRESENTATION: A 67-year-old woman with nasopharyngeal non-intestinal-type adenocarcinoma, with an accompanying parapharyngeal mass received primary radiation treatment for both lesions. Her tumour subsequently persisted, with a concomitant conversion in pathology from a low- to a high-grade malignancy. RESULTS: Non-intestinal-type and intestinal-type adenocarcinomas of the nasopharynx are extremely rare tumours and do not appear in the World Health Organization classification system. We review the pathophysiologic features of these malignancies and propose modifications to the current classification system. CONCLUSIONS: Non-intestinal-type adenocarcinoma should be included in the differential diagnosis of nasopharyngeal masses. In our experience, this tumour in this location showed a partial response to primary radiation but later converted from a low- to a high-grade adenocarcinoma.

Predictive modeling of the outcomes of chemotherapy-induced (febrile) neutropenia prophylaxis with biosimilar filgrastim (MONITOR-GCSF study).

BACKGROUND: Risk models of chemotherapy-induced (CIN) and febrile neutropenia (FN) have to date focused on determinants measured at the start of chemotherapy. We extended this static approach with a dynamic approach of CIN/FN risk modeling at the start of each cycle. DESIGN: We applied predictive modeling using multivariate logistic regression to identify determinants of CIN/FN episodes and related hospitalizations and chemotherapy disturbances (CIN/FN consequences) in analyses at the patient ('ever' during the whole period of chemotherapy) and cycle-level (during a given chemotherapy cycle). Statistical dependence of cycle data being 'nested' under patients was managed using generalized estimation equations. Predictive performance of each model was evaluated using bootstrapped c concordance statistics. RESULTS: Static patient-level risk models of 'ever' experiencing CIN/FN adverse events and consequences during a planned chemotherapy regimen included predictors related to history, risk factors, and prophylaxis initiation and intensity. Dynamic cycle-level risk models of experiencing CIN/FN adverse events and consequences in an upcoming cycle included predictors related to history, risk factors, and prophylaxis initiation and intensity; as well as prophylaxis duration, CIN/FN in prior cycle, and treatment center characteristics. CONCLUSIONS: These 'real-world evidence' models provide clinicians with the ability to anticipate CIN/FN adverse events and their consequences at the start of a chemotherapy line (static models); and, innovatively, to assess risk of CIN/FN adverse events and their consequences at the start of each cycle (dynamic models). This enables individualized patient treatment and is consistent with the EORTC recommendation to re-appraise CIN/FN risk at the start of each cycle. Prophylaxis intensity (under-, correctly-, or over-prophylacted relative to current EORTC guidelines) is a major determinant. Under-prophylaxis is clinically unsafe. Over-prophylaxis of patients administered chemotherapy with intermediate or low myelotoxicity levels may be beneficial, both in patients with and without risk factors, and must be validated in future studies.

'Real-life' effectiveness studies of omalizumab in adult patients with severe allergic asthma: systematic review.

We reviewed 24 'real-life' effectiveness studies of omalizumab in the treatment of severe allergic asthma that included 4117 unique patients from 32 countries with significant heterogeneity in patients, clinicians and settings. The evidence underscores the short- and long-term benefit of anti-IgE therapy in terms of the following: improving lung function; achieving asthma control and reducing symptomatology, severe exacerbations and associated work/school days lost; reducing healthcare resource utilizations, in particular hospitalizations, hospital lengths of stay and accident specialist or emergency department visits; reducing or discontinuing other asthma medications; and improving quality of life - thus confirming, complementing and extending evidence from randomized trials. Thus, omalizumab therapy is associated with signal improvements across the full objective and subjective burden of illness chain of severe allergic asthma. Benefits of omalizumab may extend up to 2-4 years, and the majority of omalizumab-treated patients may benefit for many years. Omalizumab has positive short- and long-term safety profiles similar to what is known from randomized clinical trials. Initiated patients should be monitored for treatment response at 16 weeks. Those showing positive response at that time are highly likely to show sustained treatment response and benefit in terms of clinical, quality of life and health resource utilization outcomes.

Increased stocking rate and associated strategic dry-off decision rules reduced the amount of nitrate-N leached under grazing.

The effect of intensive agricultural systems on the environment is of increasing global concern, and recent review articles have highlighted the need for sustainable intensification of food production. In grazing dairy systems, the leaching of nitrate-N (NO3-N) to groundwater is a primary environmental concern. A herd-level factor considered by many to be a key contributor to the amount of NO3-N leached from dairy pastures is stocking rate (SR), and some countries have imposed limits to reduce the risk of NO3-N loss to groundwater. The objective of the current experiment was to determine the effect of dairy cow SR on NO3-N leached in a grazing system that did not import feed from off-farm and had the same N fertilizer input. Five SR were evaluated (2.2, 2.7, 3.1, 3.7, and 4.3 cows/ha) in a completely randomized design (i.e., 2 replicates of each SR as independent farmlets) over 2 y. Pasture utilization, milk production/hectare, and days in milk/hectare increased with SR, but days in milk/cow and milk production/cow declined. The concentration of NO3-N in drainage water and the quantity of NO3-N leached/ha per year declined linearly with increasing SR, and the operating profit/kg NO3-N leached per ha increased. Higher SR was associated with fewer days in milk/cow, resulting in a reduction in estimated urine N excretion/cow (the main source of N leaching) during the climatically sensitive period for NO3-N leaching (i.e., late summer to winter). We hypothesized that the reduction in estimated urine N excretion per cow led to an increase in urinary N spread and reduced losses from urine patches. The results presented indicate that lowering SR may not reduce nitrate leaching and highlight the need for a full farm system-level analysis of any management change to determine its effect on productivity and environmental outcomes.

Short communication: grazing pattern of dairy cows that were selected for divergent residual feed intake as calves.

The aim of this study was to investigate and assess differences in the grazing pattern of 2 groups of mature dairy cows selected as calves for divergent residual feed intake (RFI). Sixteen Holstein-Friesian cows (471±31kg of body weight, 100 d in milk), comprising 8 cows selected as calves (6-8 mo old) for low (most efficient: CSCLowRFI) and 8 cows selected as calves for high (least efficient: CSCHighRFI) RFI, were used for the purpose of this study. Cows (n=16) were managed as a single group, and strip-grazed (24-h pasture allocation at 0800h) a perennial ryegrass sward for 31 d, with measurements taken during the last 21 d. All cows were equipped with motion sensors for the duration of the study, and jaw movements were measured for three 24-h periods during 3 random nonconsecutive days. Measurements included number of steps and jaw movements during grazing and rumination, plus fecal particle size distribution. Jaw movements were analyzed to identify bites, mastication (oral processing of ingesta) during grazing bouts, chewing during rumination, and to calculate grazing and rumination times for 24-h periods. Grazing and walking behavior were also analyzed in relation to the first meal of the day after the new pasture was allocated. Measured variables were subjected to multivariate analysis. Cows selected for low RFI as calves appeared to (a) prioritize grazing and rumination over idling; (b) take fewer steps, but with a higher proportion of grazing steps at the expense of nongrazing steps; and (c) increase the duration of the first meal and commenced their second meal earlier than CSCHighRFI. The CSCLowRFI had fewer jaw movements during eating (39,820 vs. 45,118 for CSCLowRFI and CSCHighRFI, respectively), more intense rumination (i.e., 5 more chews per bolus), and their feces had 30% less large particles than CSCHighRFI. These results suggest that CSCLowRFI concentrate their grazing activity to the time when fresh pasture is allocated, and graze more efficiently by walking and masticating less, hence they are more efficient grazers than CSCHighRFI.

Body condition score at calving affects systemic and hepatic transcriptome indicators of inflammation and nutrient metabolism in grazing dairy cows.

Calving body condition score (BCS) is an important determinant of early-lactation dry matter intake, milk yield, and disease incidence. The current study investigated the metabolic and molecular changes induced by the change in BCS. A group of cows of mixed age and breed were managed from the second half of the previous lactation to achieve mean group BCS (10-point scale) that were high (HBCS, 5.5; n=20), medium (MBCS, 4.5; n=18), or low (LBCS, 3.5; n=19). Blood was sampled at wk -4, -3, -2, 1, 3, 5, and 6 relative to parturition to measure biomarkers of energy balance, inflammation, and liver function. Liver was biopsied on wk 1, 3, and 5 relative to parturition, and 10 cows per BCS group were used for transcript profiling via quantitative PCR. Cows in HBCS and MBCS produced more milk and had greater concentrations of nonesterified fatty acids and ß-hydroxybutyrate postpartum than LBCS. Peak concentrations of nonesterified fatty acids and ß-hydroxybutyrate and greater hepatic triacylglycerol concentrations were recorded in HBCS at wk 3. Consistent with blood biomarkers, HBCS and MBCS had greater expression of genes associated with fatty acid oxidation (CPT1A, ACOX1), ketogenesis (HMGCS2), and hepatokines (FGF21, ANGPTL4), whereas HBCS had the lowest expression of APOB (lipoprotein transport). Greater expression during early lactation of BBOX1 in MBCS and LBCS suggested greater de novo carnitine synthesis. The greater BCS was associated with lower expression of growth hormone/insulin-like growth factor-1 signaling axis genes (GHR1A, IGF1, and IGFALS) and greater expression of gluconeogenic genes. These likely contributed to the higher milk production and greater gluconeogenesis. Despite greater serum haptoglobin around calving, cows in HBCS and MBCS had greater blood albumin. Cows in MBCS, however, had a higher albumin:globulin ratio, probably indicating a less pronounced inflammatory status and better liver function. The marked decrease in expression of NFKB1, STAT3, HP, and SAA3 coupled with the increase in ALB on wk 3 in MBCS cows were consistent with blood measures. Overall, results suggest that the greater milk production of cows with higher calving BCS is associated with a proinflammatory response without negatively affecting expression of genes related to metabolism and the growth hormone/insulin-like growth factor-1 axis. Results highlight the sensitivity of indicators of metabolic health and inflammatory state to subtle changes in calving BCS and, collectively, indicate a suboptimal health status in cows calving at either BCS 3.5 or 5.5 relative to BCS 4.5.

Genomic prediction of dry matter intake in dairy cattle from an international data set consisting of research herds in Europe, North America, and Australasia.

With the aim of increasing the accuracy of genomic estimated breeding values for dry matter intake (DMI) in Holstein-Friesian dairy cattle, data from 10 research herds in Europe, North America, and Australasia were combined. The DMI records were available on 10,701 parity 1 to 5 records from 6,953 cows, as well as on 1,784 growing heifers. Predicted DMI at 70 d in milk was used as the phenotype for the lactating animals, and the average DMI measured during a 60- to 70-d test period at approximately 200 d of age was used as the phenotype for the growing heifers. After editing, there were 583,375 genetic markers obtained from either actual high-density single nucleotide polymorphism (SNP) genotypes or imputed from 54,001 marker SNP genotypes. Genetic correlations between the populations were estimated using genomic REML. The accuracy of genomic prediction was evaluated for the following scenarios: (1) within-country only, by fixing the correlations among populations to zero, (2) using near-unity correlations among populations and assuming the same trait in each population, and (3) a sharing data scenario using estimated genetic correlations among populations. For these 3 scenarios, the data set was divided into 10 sub-populations stratified by progeny group of sires; 9 of these sub-populations were used (in turn) for the genomic prediction and the tenth was used for calculation of the accuracy (correlation adjusted for heritability). A fourth scenario to quantify the benefit for countries that do not record DMI was investigated (i.e., having an entire country as the validation population and excluding this country in the development of the genomic predictions). The optimal scenario, which was sharing data, resulted in a mean prediction accuracy of 0.44, ranging from 0.37 (Denmark) to 0.54 (the Netherlands). Assuming near-unity among-country genetic correlations, the mean accuracy of prediction dropped to 0.40, and the mean within-country accuracy was 0.30. If no records were available in a country, the accuracy based on the other populations ranged from 0.23 to 0.53 for the milking cows, but were only 0.03 and 0.19 for Australian and New Zealand heifers, respectively; the overall mean prediction accuracy was 0.37. Therefore, there is a benefit in collaboration, because phenotypic information for DMI from other countries can be used to augment the accuracy of genomic evaluations of individual countries.