Adverse perinatal outcomes are strongly associated with degree of abnormality in uterine artery Doppler pulsatility index.

OBJECTIVES: To investigate the association between varying degrees of abnormality in the uterine artery Doppler pulsatility index (UtA-PI) and adverse perinatal outcomes. METHODS: Prospective study of 33,364 women who gave birth to singleton, non-anomalous babies in Oxford, following universal measurement of UtA-PI in mid-pregnancy. Relative risk ratios for the primary outcomes of extended perinatal mortality and live birth with severe small-for-gestational-age (SGA) were calculated by multinomial logistic regression, for early preterm birth (<34+0) and late preterm/term birth (≥34+0). The risks were also investigated for iatrogenic preterm birth or a composite adverse outcome before 34+0 weeks. RESULTS: Compared with women with normal UtA-PI, the risk of extended perinatal mortality before 34+0 weeks was higher in women with UtA-PI >90th centile (RRR 4.7, 95% CI 2.7-8.0, p<0.001), but this was not demonstrated in later births. The risk of severe SGA birth was strongly associated with abnormal UtA-PI for both early births (RRR 26.0, 95% CI 11.6-58.2, p<0.001), and later births (RRR 2.3, 95% CI 1.8-2.9, p<0.001). Women with a raised UtA-PI were more likely to undergo early iatrogenic birth (RRR 7.8, 95% CI 5.5-11.2, p<0.001). For each of the outcomes and the composite outcome, the risk increased significantly in association with the degree of abnormality, through the 90th, 90-94th, 95-99th and >99th centiles (ptrend<0.001). CONCLUSIONS: An elevated UtA-PI is a key predictor of iatrogenic preterm birth, severe SGA and perinatal loss up to 34+0 weeks. It is the 90th centile that should be used, and management should be further tailored to the degree of abnormality, as pregnancies with very raised UtA-PI measurements constitute a group at extreme risk. This article is protected by copyright. All rights reserved.

HA-1-targeted T cell receptor (TCR) T cell therapy for recurrent leukemia after hematopoietic stem cell transplantation.

Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective anti-leukemic effect post-HCT. We conducted a phase I clinical trial employing a novel TCR-T product targeting the minor H antigen HA-1 to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T post-HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8-co-receptor were successfully manufactured from HA-1 disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to nine HCT recipients who had developed disease recurrence post-HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, four patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with one ongoing at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial is registered at clinicaltrials.gov as NCT03326921.

B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model.

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3-specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3-specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.

Meeting Report: WHO Workshop on modelling global mortality and aetiology estimates of enteric pathogens in children under five. Cape Town, 28-29th November 2018.

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates.

Development of a Bioactive Polymeric Drug Eluting Coronary Stent Coating Using Electrospraying.

Drug-eluting stents are now routinely used in the treatment of acute coronary syndromes caused by coronary artery disease. Whilst the sustained release of anti-proliferative drugs from these devices has greatly reduced the need for repeat revascularisation procedures, this approach is not suitable for all patients and appears to delay regrowth of the endothelium, necessitating the use of prolonged dual anti-platelet therapy. Although the development of more advanced stent platforms and drug coatings has produced modest improvements in performance, these devices have not fully addressed the limitations experienced with their first-generation counterparts. In the present study, we developed a novel stent coating that provides controlled sirolimus release from a bioactive polymer (accelerate™ AT) that has previously been shown to support endothelial cell growth in vitro. A bespoke electrospray deposition process provided control over the coating thickness, surface roughness, drug load, and release kinetics. The resultant optimised coating combines rapid release of an anti-proliferative agent from a bioactive polymer coating that promotes re-endothelialisation, thereby offering potential protection against in-stent restenosis and thrombosis. This novel, dual-action coating therefore has significant therapeutic potential, with the enhanced control of drug load and release kinetics offered by electrospray deposition also opening up opportunities for more personalised treatment approaches. Further development and evaluation of these technologies in vitro and in vivo is therefore warranted.

Strong toll-like receptor responses in cystic fibrosis patients are associated with higher lung function.

BACKGROUND: Cystic fibrosis (CF) airways disease varies widely among patients with identical cystic fibrosis transmembrane conductance regulator (CFTR) genotypes. Robust airway inflammation is thought to be deleterious in CF; inter-individual variation in Toll-like receptor (TLR)-mediated innate immune inflammatory responses (TMIIR) might account for a portion of the phenotypic variation. We tested if TMIIR in people with CF are different than those of healthy controls, and whether higher TMIIR in people with CF are associated with reduced lung function. METHODS: We cultured whole blood from clinically stable subjects with CF (n = 76) and healthy controls (n = 45) with TLR agonists, and measured cytokine production and expression of TLR-associated genes. We tested for differences in TLR-stimulated cytokine levels between subjects with CF and healthy subjects, and for associations between cytokine and gene expression levels with baseline lung function (forced expiratory volume in one second percent predicted (FEV1%)) and decline in FEV1% over time. RESULTS: TMIIR in blood from subjects with CF were lower than in healthy controls. Expression of TLR regulators SARM1, TOLLIP, and AKT1 were downregulated in CF. In subjects with CF we found that lower TLR4-agonist-induced IL-8 was associated with lower FEV1% at enrollment (p<0.001) and with greater five year FEV1% decline (p<0.001). CONCLUSIONS: TMIIR were lower in people with CF relative to healthy controls; however, unexpectedly, greater whole blood TMIIR were positively associated with lung function in people with CF. These findings suggest a complex interaction between inflammation and disease in people with CF.

Dexamethasone: chondroprotective corticosteroid or catabolic killer?

While glucocorticoids have been used for over 50 years to treat rheumatoid and osteoarthritis pain, the prescription of glucocorticoids remains controversial because of potentially harmful side effects at the molecular, cellular and tissue levels. One member of the glucocorticoid family, dexamethasone (DEX) has recently been demonstrated to rescue cartilage matrix loss and chondrocyte viability in animal studies and cartilage explant models of tissue injury and post-traumatic osteoarthritis, suggesting the possibility of DEX as a disease-modifying drug if used appropriately. However, the literature on the effects of DEX on cartilage reveals conflicting results on the drug's safety, depending on the dose and duration of DEX exposure as well as the model system used. Overall, DEX has been shown to protect against arthritis-related changes in cartilage structure and function, including matrix loss, inflammation and cartilage viability. These beneficial effects are not always observed in model systems using initially healthy cartilage or isolated chondrocytes, where many studies have reported significant increases in chondrocyte apoptosis. It is crucially important to understand under what conditions DEX may be beneficial or harmful to cartilage and other joint tissues and to determine potential for safe use of this glucocorticoid in the clinic as a disease-modifying drug.

Effect of prepartum exercise on lying behavior, labor length, and cortisol concentrations.

The objective of this study was to assess the effect of exercise and pasture turnout on lying behavior, labor length, and cortisol concentrations around the time of parturition in dairy cows. Twenty-nine primiparous and 31 multiparous, pregnant, nonlactating Holstein (n = 58) and Jersey × Holstein cross (n = 2) dairy cows were assigned to control (n = 20), exercise (n = 20), or pasture (n = 20) treatments at dry-off using rolling enrollment. Control cows remained in the dry cow group pen. Exercise cows were removed from the dry cow group pen 5 times per week and walked for 1.4 ± 0.1 h at 1.88 ± 0.58 km/h. Pasture cows were moved to an outdoor paddock 5 times per week for 1.8 ± 0.3 h/d. Cows were housed in deep-bedded sand freestalls in a naturally ventilated, 4-row freestall barn. Cows were moved into maternity pens on the day of projected calving or when cows displayed signs that calving was imminent (restlessness, raised or lifted tail, ruptured amniotic sac, or swollen vulva), and treatments were discontinued. Cameras continuously recorded cows from entry into the pen until farm staff noted a calf, and one observer continuously watched video for two visually observable periods throughout the calving process: time from initial observation of amniotic sac to initial observation of calf's feet, and time from initial observation of calf's feet to full expulsion of calf. Assisted calvings were excluded. Accelerometers were attached to the rear fetlocks of cows 3 d before dry-off and removed 14 d postpartum. Activity was summarized by day for the 7 d before and after delivery time recorded from video observation into lying time (hours per day), lying bout frequency (bouts per day), lying bout duration (minutes per bout), and steps (number per day). Plasma total cortisol concentration was measured on d 0 and 3 postpartum and determined by a radioimmunoassay procedure using a commercially available kit. Data were analyzed using mixed linear model. During calving, time from appearance of the amniotic sac to appearance of the calf's feet was longer for pasture cows compared with control. Control cows engaged in fewer lying bouts and less overall lying time compared with pasture and exercise cows. Cortisol concentrations were higher on the day of calving compared with 3 d later, regardless of treatment. Understanding the effects of lying alterations around calving and increases in labor period length may allow for physical activity recommendations for late-gestation dairy cows.

From biology to behavior: a cross-disciplinary seminar series surrounding added sugar and low-calorie sweetener consumption.

INTRODUCTION: This report presents a synopsis of a three-part, cross-sector, seminar series held at the George Washington University (GWU) in Washington, DC from February-April, 2018. The overarching goal of the seminar series was to provide a neutral forum for diverse stakeholders to discuss and critically evaluate approaches to address added sugar intake, with a key focus on the role of low-calorie sweeteners (LCS). METHODS: During three seminars, twelve speakers from academic institutions, federal agencies, non-profit organizations, and the food and beverage industries participated in six interactive panel discussions to address: 1) Do Farm Bill Policies Impact Population Sugar Intake? 2) What is the Impact of Sugar-sweetened Beverage (SSB) Taxes on Health and Business? 3) Is Sugar Addictive? 4) Product Reformulation Efforts: Progress, Challenges, and Concerns? 5) Low-calorie Sweeteners: Helpful or Harmful, and 6) Are Novel Sweeteners a Plausible Solution? Discussion of each topic involved brief 15-minute presentations from the speakers, which were followed by a 25-minute panel discussion moderated by GWU faculty members and addressed questions generated by the audience. Sessions were designed to represent opposing views and stimulate meaningful debate. Given the provocative nature of the seminar series, attendee questions were gathered anonymously using Pigeonhole™, an interactive, online, question and answer platform. RESULTS: This report summarizes each presentation and recapitulates key perspectives offered by the speakers and moderators. CONCLUSIONS: The seminar series set the foundation for robust cross-sector dialogue necessary to inform meaningful future research, and ultimately, effective policies for lowering added sugar intakes.

Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial.

Interferon-γ (IFNγ) has been studied as a cancer treatment with limited evidence of clinical benefit. However, it could play a role in cancer immunotherapy combination treatments. Despite high expression of immunogenic cancer-testis antigens, synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) have a cold tumor microenvironment (TME), with few infiltrating T cells and low expression of major histocompatibility complex class I (MHC-I). We hypothesized that IFNγ treatment could drive inflammation in a cold TME, facilitating further immunotherapy. We conducted a phase 0 clinical trial treating 8 SS or MRCL patients with weekly systemic IFNγ. We performed pre- and posttreatment biopsies. IFNγ changed the SS and MRCL TME, inducing tumor-surface MHC-I expression and significant T-cell infiltration (P < 0.05). Gene-expression analysis suggested increased tumor antigen presentation and less exhausted phenotypes of the tumor-infiltrating T cells. Newly emergent antigen-specific humoral and/or T-cell responses were found in 3 of 7 evaluable patients. However, increased expression of PD-L1 was observed on tumor-infiltrating myeloid cells and in some cases tumor cells. These findings suggest that systemic IFNγ used to convert SS and MRCL into "hot" tumors will work in concert with anti-PD-1 therapy to provide patient benefit.

A multicentre, UK, retrospective, observational study to assess the effectiveness of insulin glargine 300 units/ml in treating people with Type 1 diabetes mellitus in routine clinical practice (SPARTA).

AIM: To conduct an open-label study to provide UK real-world evidence regarding the use of insulin glargine 300 units/ml (U300) in people with Type 1 diabetes mellitus. METHODS: People with Type 1 diabetes who had been prescribed U300 ≥6 months before data collection and had HbA1c levels recorded within 3 months prior to U300 (baseline) were included. The primary endpoint was change in HbA1c from baseline to month 6 after U300 initiation. Other endpoints included number of documented hypoglycaemic and diabetic ketoacidosis episodes, and change in daily basal insulin dose. RESULTS: A total of 298 people with Type 1 diabetes were included [mean age 42.1 years, mean HbA1c 79 mmol/mol (9.4%)]. After U300 initiation, the mean reduction in HbA1c from baseline to month 6 was -4 mmol/mol (-0.4%; P<0.001; n=188). The total daily basal insulin dose at 6 months was 1.3 units higher than at the time of U300 initiation (P<0.001; n=275) but was not significantly different from the prior basal insulin dose. There was no clinically significant difference in weight between baseline and month 6 [mean difference +0.7 kg, 95% CI -0.1, 1.5; P=0.084; n=115). During the 6 months before and after U300 initiation, severe hypoglycaemic episodes were documented for 6/298 and 4/298 participants. Diabetic ketoacidosis episodes requiring Accident and Emergency department visits or hospitalization were documented for 4/298 and 6/298 participants, before and after U300 initiation, respectively. CONCLUSIONS: In people with Type 1 diabetes, a change in basal insulin to U300 was associated with clinically and statistically significant HbA1c improvements, without significant changes in basal insulin dose and weight. Documented severe hypoglycaemia episodes and diabetic ketoacidosis requiring Accident and Emergency department visits or hospitalization were low and similar before and after U300 initiation.

Genetic Variation in MAP3K1 Associates with Ventilator-Free Days in Acute Respiratory Distress Syndrome.

Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) regulates numerous intracellular signaling pathways involved in inflammation and apoptosis. We hypothesized that genetic variation in MAP3K1 might be associated with outcomes in patients with acute respiratory distress syndrome (ARDS), and that these variants would alter MAP3K1-mediated changes in inflammation and transcriptional regulation. To test this hypothesis, we genotyped single-nucleotide polymorphisms covering linkage disequilibrium bins in MAP3K1 in 306 subjects with ARDS from the ARDSNet FACTT (Fluid and Catheter Treatment Trial) study, and tested for associations between MAP3K1 single-nucleotide polymorphisms and ventilator-free days (VFDs) and mortality. We then validated these associations in a separate cohort of 241 patients with ARDS from Harborview Medical Center (Seattle, WA). We found the variant allele of rs832582 (MAP3K1906Val) was significantly associated with decreased VFDs using multivariate linear regression (-6.1 d, false discovery rate = 0.06) in the FACTT cohort. In the Harborview Medical Center cohort, subjects homozygous for MAP3K1906Val also had decreased VFDs (-15.1 d, false discovery rate < 0.01), and increased 28-day mortality (all subjects homozygous for the rare allele died). In whole blood stimulated with various innate immune agonists ex vivo, MAP3K1906Val was associated with increased IL-1ß, IL-6, IL-8, monocyte chemoattractant protein 1, and TNF-α production. Transcriptome analysis of whole blood stimulated with Toll-like receptor 4 agonist ex vivo demonstrated enrichment of inflammatory gene sets in subjects homozygous for MAP3K1906Val. Our findings show a robust association between the variant allele of rs832582 (MAP3K1906Val) and decreased VFDs in patients with ARDS and suggest that this variant may predispose individuals to a greater inflammatory response.

Small-for-gestational-age babies after 37 weeks: impact study of risk-stratification protocol.

OBJECTIVE: Although no clear evidence exists, many international guidelines advocate early-term delivery of small-for-gestational-age (SGA) fetuses. The aim of this study was to determine whether a risk-stratification protocol in which low-risk SGA fetuses are managed expectantly beyond 37 weeks affects perinatal and maternal outcomes. METHODS: This was an impact study examining data collected over a 39-month period (1 January 2013 to 30 April 2016) at a tertiary referral unit. The study included women who were referred to the fetal medicine unit with a singleton non-anomalous fetus diagnosed antenatally as SGA (estimated fetal weight < 10th centile) from 36 + 0 weeks' gestation. In 2014, a protocol for management of SGA was introduced, which included risk stratification with surveillance and expectant management after 37 weeks for lower-risk babies (protocol group). This was compared with the previous strategy, which recommended delivery at around 37 weeks (pre-protocol group). Primary outcome was neonatal composite adverse outcome. RESULTS: In the pre-protocol group, there were 138 SGA babies; in the protocol group there were 143. Mean gestational ages at delivery were 37.4 weeks in the pre-protocol group and 38.2 weeks in the protocol group (P = 0.04). The incidence of neonatal composite adverse outcome was lower in the protocol group (9% vs 22%; P < 0.01), as was neonatal unit admission (13% vs 39%; P < 0.01). Induction of labor and Cesarean section rates were lower, and vaginal delivery rate (83% vs 60%; P < 0.01) was higher, in the protocol group. Most of the differences were as a result of delayed delivery of SGA babies that were stratified as low risk. CONCLUSIONS: The findings of this study suggest that protocol-based management of SGA babies may improve outcome, and that identification of moderate SGA should not in isolation prompt delivery. Larger numbers are required to assess any impact on perinatal mortality. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Effect of prepartum exercise, pasture turnout, or total confinement on hoof health.

Lameness is a major welfare concern in the dairy industry, and access to physical activity during the dry period may improve hoof health. The objective of this study was to determine the effects of forced exercise, pasture turnout, or total confinement of dry cows on horn growth and wear and sole thickness. Twenty-nine primiparous and 31 multiparous, pregnant, nonlactating Holstein (n = 58) and Jersey-Holstein crossbred (n = 2) dairy cows were assigned to either total confinement (n = 20), exercise (n = 20), or pasture (n = 20) treatments at dry-off using rolling enrollment from January to November 2015. Cows were managed with a 60-d dry period (58.5 ± 5.4 d) divided into far-off (dry-off to 2 wk before parturition) and close-up periods (2 wk before projected parturition). Cows were housed in a naturally ventilated, 4-row freestall barn at the University of Tennessee's Little River Animal and Environmental Unit (Walland, TN) with concrete flooring and deep-bedded sand freestalls. Cows assigned to confinement remained in the housing pen. Exercise cows were walked for a targeted 1.5 h at 3.25 km/h, 5 times/wk until calving. Pasture cows were turned out for a targeted 1.5 h, 5 times/wk until calving. Hoof growth and wear and sole thickness of the rear hooves were measured on d 2 and 44, relative to dry-off. Data were analyzed using the MIXED procedure of SAS (SAS Institute Inc., Cary, NC). Cranial and caudal horn wear was greater for exercise cows than confinement and pasture cows. Exercise cows experienced more equal rates of horn growth and wear cranially. Confined cows tended to increase sole thickness from d 2 to 44, relative to dry-off. Frequent, short duration exercise on concrete did not impair the hoof health of late-gestation dry cows. Further, exercise may improve overall hoof health, potentially improving cow welfare.

Effect of maternal exercise on calf dry matter intake, weight gain, behavior, and cortisol concentrations at disbudding and weaning.

The objective of this study was to determine the effect of maternal physical activity during late gestation on calf dry matter intake, weight gain, behavior, and cortisol concentration during disbudding and weaning. Fifty-five Holstein and 5 Jersey × Holstein crossbred calves were enrolled into the study during gestation. Calves were born from pregnant, nonlactating Holstein (n = 58) and Jersey × Holstein crossbred (n = 2) dairy cows. Cows were assigned to either confinement (n = 20 cows; 13 female calves, 7 male calves), exercise (n = 20 cows; 8 female calves, 12 male calves), or pasture (n = 20 cows; 11 female calves, 9 male calves) treatments at dry-off from January to November 2015. Enrollment in treatment was balanced by parity (1.8 ± 0.9), projected mature-equivalent fat-corrected milk (13,831 ± 2,028 kg/lactation), dam breed, and projected calving date. Cows assigned to confinement remained in the pen throughout the dry period. Cows assigned to exercise were walked 5 times/wk at a targeted 1.5 h at 3.25 km/h. Cows assigned to pasture were turned out 5 times/wk for a targeted 1.5 h/d. Treatments were terminated on the expected due date or at signs of calving. Calves were removed from cows immediately once observed by farm staff and subsequently weighed and moved into a straw deep-bedded hutch. Data loggers were attached to the rear fetlock of each calf -3 d to +6 d relative to disbudding and weaning to monitor changes in lying behavior. Calves were weighed on d -7, -5, -3, -1, 0, 1, 3, 5, and 7, and grain was weighed the 7 d preceding and following disbudding and weaning. Blood was collected 24 h before and 0, 1, and 4 h after disbudding and d -1, 0, 1, and 2 relative to weaning to determine cortisol concentrations. Data were analyzed using mixed linear model in SAS (SAS Institute Inc., Cary, NC). Calf weight gain decreased the day after disbudding and calves tended to have elevated cortisol concentrations 1 h after disbudding, regardless of maternal treatment. Calf weight gain decreased the day of and after weaning; calves had elevated cortisol concentrations the day after weaning, regardless of treatment. Behavior did not differ by treatment at disbudding, but calves from pasture cows lay down for less time compared with confinement and exercise maternal treatments and less frequently than exercise maternal treatments at weaning. More research investigating the significance of lying time and restlessness around stressful events is needed to further understand the implications of such behavioral responses.

Milking time and risk of over-milking can be decreased with early teat cup removal based on udder quarter milk flow without loss in milk yield.

Increasing the milk flow rate at which milking is terminated can shorten milking time and increase milking efficiency. The effects on milk yield and composition have not been fully investigated when the take-off is set at the udder quarter level and independent of feeding during milking. The objective of this study was to investigate the effect of 3 take-off levels at the udder quarter level (0.06, 0.3, and 0.48 kg/min) applied with or without feeding during milking on milking time, milk yield, the degree of udder emptying, milk composition, and free fatty acids. In this study, 30 cows were allocated into 6 groups, balanced by lactation number, lactation stage, and milk yield, and subjected to a 3 × 2 factorial arrangement of treatments using a Latin square design. Treatments were applied for 1 wk each. This study demonstrated milking time could be reduced by applying up to a take-off level of 0.48 kg/min on udder quarter level without losing milk yield or compromising milk composition or udder health.

Effects of bedding with recycled sand on lying behaviors, udder hygiene, and preference of lactating Holstein dairy cows.

Effects of bedding with recycled sand and season on lying behaviors, hygiene, and preferences of late-lactation Holstein cows were studied. It was hypothesized that recycled sand will decrease lying time and increase hygiene scores due to increased moisture content and organic matter, and thus a preference for the control sand will be evident. Cows (n = 64) were divided into 4 groups (n = 8 per group) per season. In summer (August to September), cows were balanced by days in milk (268.1 ± 11.9 d) and parity (2.0 ± 0.2). In winter (January to February), mean DIM was 265.5 ± 34.1 d. Cows were assigned to 1 of 2 treatments using a crossover design with each treatment lasting 7 d (no-choice phase): bedding with recycled sand (RS; n = 32) or control (CO; clean sand; n = 32). Stocking density was maintained at 100%. The choice phase allowed cows to have access to either treatment with stocking density at 50%. Accelerometers recorded daily lying time, number of lying bouts per day, lying bout duration (min/bout), and total steps per day. Teat swabs, milk, sand samples, and udder hygiene scores were collected on d 0, 3, and 7 of each experimental week. Samples were cultured for streptococci, staphylococci, and gram-negative bacteria. Video data were used to assess bedding preferences. All data were analyzed using the MIXED and GLIMMIX procedures of SAS 9.4 (SAS Institute Inc., Cary, NC). Lying time was not affected by treatment, but cows did take more steps during winter. Bacterial counts were elevated for cows on recycled sand. A preference was observed for clean sand during the summer, but no preference was observed for sand during the winter. Regardless of bedding, the most commonly observed behavior was lying in the stalls, which suggested either bedding might be suitable. Caution should be used with this interpretation of preference, as sand was recycled only once. This limited reclamation was still sufficient to potentially alter the composition of sand, driving the observed preference. If these changes in composition continue, then the strength of the preference may also change. However, considering all variables within the current study, recycled sand is a viable bedding source to use for dairy cows.

A survey of practices for the use of electronic health records to support research recruitment.

Electronic health records (EHRs) provide great promise for identifying cohorts and enhancing research recruitment. Such approaches are sorely needed, but there are few descriptions in the literature of prevailing practices to guide their use. A multidisciplinary workgroup was formed to examine current practices in the use of EHRs in recruitment and to propose future directions. The group surveyed consortium members regarding current practices. Over 98% of the Clinical and Translational Science Award Consortium responded to the survey. Brokered and self-service data warehouse access are in early or full operation at 94% and 92% of institutions, respectively, whereas, EHR alerts to providers and to research teams are at 45% and 48%, respectively, and use of patient portals for research is at 20%. However, these percentages increase significantly to 88% and above if planning and exploratory work were considered cumulatively. For most approaches, implementation reflected perceived demand. Regulatory and workflow processes were similarly varied, and many respondents described substantive restrictions arising from logistical constraints and limitations on collaboration and data sharing. Survey results reflect wide variation in implementation and approach, and point to strong need for comparative research and development of best practices to protect patients and facilitate interinstitutional collaboration and multisite research.

Short communication: Short-term changes in stocking density did not alter meal characteristics of lactating Holstein dairy cattle.

The study objectives were to determine the effect of short-term increases in stocking density and milking on meal duration, meal frequency, and time between meals and to determine the bioequivalence of different meal criterions in a competitive environment. Forty-eight Holstein dairy cows were allotted to 1 of 4 groups (n=12 per group). Stocking density treatments of 100 (one cow per freestall and headlock), 113, 131, and 142% were assigned to groups using a 4×4 Latin square with treatments imposed for 14-d periods. On d 11 of each period, feeding time was recorded for 24h using 10-min scan samples from direct observation. Meals were defined as repeated observations of eating with a maximum of 20, 30, or 40min of not eating between observations constituting the same meal. A new meal was established when a cow was observed feeding and then not feeding for greater than 2 (20min), 3 (30min), or 4 (40min) observations. To evaluate diurnal effects, the 24-h period of data was divided into 8-h intervals (based on milking time); morning (0400-1200h), afternoon (1200-2000h), and night (2000-0400h). Feed delivery occurred daily at 0430h, with feed pushed up throughout the day. A mixed linear model was used to determine the effect of stocking density and time of day on meals per day, meals per hour, meal duration, time between meals, and meal duration 2h before and after milking. Regardless of stocking density, meal duration, meal frequency, meals per hour, and time between meals did not differ. Regardless of stocking density, mean meal duration was longer during the morning and afternoon compared with night. Meal duration was also greater after milking compared with before milking, regardless of stocking density. These results suggest meal length decreased throughout the day, relative to feed delivery, with periodic increases in length due to return from milking. Meals per hour, meal duration before and after milking, and meal frequency established bioequivalence for the 20-, 30-, and 40-min meal criteria. Bioequivalence was not met for meal duration when the meal criterion was increased from 20 to 40min. Short-term increases in stocking density of 14-d duration did not affect the feeding pattern of lactating dairy cows, indicating that mid-lactation dairy cows can compensate for reduced feed bunk access during short-term overstocking. When calculating feeding behaviors, including meal frequency and time between meals, using a meal criterion of 20, 30, or 40min resulted in similar outcomes when using 10-min scan samples. Future studies should investigate changes in other behaviors, such as resting, which may be altered to compensate for reduced access to the feed bunk.