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.

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.

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.

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.

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.

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.

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.

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.

Evaluating risk of ESRD in the urban poor.

The capacity of risk prediction to guide management of CKD in underserved health settings is unknown. We conducted a retrospective cohort study of 28,779 adults with nondialysis-requiring CKD who received health care in two large safety net health systems during 1996-2009 and were followed for ESRD through September of 2011. We developed and evaluated the performance of ESRD risk prediction models using recently proposed criteria designed to inform population health approaches to disease management: proportion of cases followed and proportion that needs to be followed. Overall, 1730 persons progressed to ESRD during follow-up (median follow-up=6.6 years). ESRD risk for time frames up to 5 years was highly concentrated among relatively few individuals. A predictive model using five common variables (age, sex, race, eGFR, and dipstick proteinuria) performed similarly to more complex models incorporating extensive sociodemographic and clinical data. Using this model, 80% of individuals who eventually developed ESRD were among the 5% of cohort members at the highest estimated risk for ESRD at 1 year. Similarly, a program that followed 8% and 13% of individuals at the highest ESRD risk would have included 80% of those who eventually progressed to ESRD at 3 and 5 years, respectively. In this underserved health setting, a simple five-variable model accurately predicts most cases of ESRD that develop within 5 years. Applying risk prediction using a population health approach may improve CKD surveillance and management of vulnerable groups by directing resources to a small subpopulation at highest risk for progressing to ESRD.

The Video Interaction Guidance approach applied to teaching communication skills in dentistry.

PURPOSE: To examine dentists' views of a novel video review technique to improve communication skills in complex clinical situations. MATERIALS AND METHODS: Dentists (n = 3) participated in a video review known as Video Interaction Guidance to encourage more attuned interactions with their patients (n = 4). Part of this process is to identify where dentists and patients reacted positively and effectively. Each dentist was presented with short segments of video footage taken during an appointment with a patient with intellectual disabilities and communication difficulties. Having observed their interactions with patients, dentists were asked to reflect on their communication strategies with the assistance of a trained VIG specialist. RESULTS: Dentists reflected that their VIG session had been insightful and considered the review process as beneficial to communication skills training in dentistry. They believed that this technique could significantly improve the way dentists interact and communicate with patients. The VIG sessions increased their awareness of the communication strategies they use with their patients and were perceived as neither uncomfortable nor threatening. DISCUSSION: The VIG session was beneficial in this exploratory investigation because the dentists could identify when their interactions were most effective. Awareness of their non-verbal communication strategies and the need to adopt these behaviours frequently were identified as key benefits of this training approach. One dentist suggested that the video review method was supportive because it was undertaken by a behavioural scientist rather than a professional counterpart. CONCLUSION: Some evidence supports the VIG approach in this specialist area of communication skills and dental training.

Updated investigations of cancer excesses in individuals born or resident in the vicinity of Sellafield and Dounreay.

BACKGROUND: Earlier studies have shown raised risks of leukaemia and non-Hodgkin lymphoma in children, teenagers and young adults resident either at birth or diagnosis in Seascale. Some increases in cancer risk in these age groups have also been noted among those living around Dounreay. We aimed to update previous analyses relating to areas close to these nuclear installations by considering data from an additional 16 years of follow-up. METHODS: Cross-sectional analyses compared cancer incidence rates for 1963-2006 among those aged 0-24 years at diagnosis living in geographically specified areas around either Sellafield or Dounreay with general population rates. Cancer incidence for the period 1971-2006 among the cohort of Cumbrian births between 1950 and 2006 was compared to national incidence for 1971-2006 using person-years analysis. Cancer among those born in the postcode sector closest to Dounreay was compared with that among those born in the three adjoining postcode sectors. Analyses considered both cancer overall and ICD-O-3 defined diagnostic subgroups including leukaemia, central nervous system tumours and other malignancies. RESULTS: Apart from previously reported raised risks, no new significantly increased risks for cancer overall or any diagnostic subgroup were found among children or teenagers and young adults living around either nuclear installation. Individuals born close to the installations from 1950 to 2006 were not shown to be at any increased risk of cancer during the period 1971 to date. CONCLUSIONS: Analysis of recent data suggests that children, teenagers and young adults currently living close to Sellafield and Dounreay are not at an increased risk of developing cancer. Equally, there is no evidence of any increased cancer risk later in life among those resident in these areas at birth.

Toll-like receptor 1 polymorphisms and associated outcomes in sepsis after traumatic injury: a candidate gene association study.

OBJECTIVE: To determine whether single nucleotide polymorphisms (SNPs) in TLR1 are associated with mortality, specifically sepsis-associated mortality, in a traumatically injured population. BACKGROUND: Innate immune responses mediated by toll-like receptors (TLRs) induce early inflammatory responses to pathogen and damage-associated molecular patterns. Genetic variation in TLRs has been associated with susceptibility and outcomes in a number of infectious and noninfectious disease states. METHODS: Patients admitted to the trauma intensive care unit at a level 1 trauma center serving 4 states were enrolled and followed for development of infection, sepsis, and death. Genomic DNA was genotyped and logistic regression analysis was performed to determine associations between TLR1 SNPs and mortality. We further examined for associations between TLR1 SNPs and mortality in subgroups on the basis of the presence of sepsis and the type of sepsis-associated organism. RESULTS: We enrolled 1961 patients. TLR1-7202G (rs5743551) was associated with increased mortality after traumatic injury and this association was primarily observed in the subset of patients who developed sepsis [adjusted odds ratio (OR): 3.16; 95% confidence interval (CI): 1.43-6.97, P=0.004]. This association persisted after further restriction to gram-positive sepsis. TLR1(742A/G(Asn248Ser)) (rs4833095), a coding SNP in LD with TLR1-7202G, was also associated with mortality in gram-positive sepsis (adjusted OR: 4.16; 95% CI: 1.22-14.19, P=0.023). CONCLUSIONS: Genetic variation in TLR1 is associated with increased mortality in patients with sepsis after traumatic injury and may represent a novel marker of risk for death in critically injured patients.

Epidemiology of biopsy-proven giant cell arteritis in South Australia.

BACKGROUND/AIM: To determine the epidemiology and clinical features of biopsy-proven giant cell arteritis (GCA) in South Australia (SA). METHODS: Patients with biopsy-proven GCA were identified from pathology reports of temporal artery biopsies at SA Pathology laboratories, from 1 January 1992, to 31 July 2011. Epidemiological data were collected through patient questionnaires and standardised case note reviews. Incidence was estimated using Australian Bureau of Statistics population data for SA. Seasonality was analysed by Cosinor analysis, and time-to- event analysis was performed for the duration of steroid use. RESULTS: There were 314 cases of biopsy-proven GCA (72% female). The mean age at diagnosis of GCA was 78 years (interquartile range 72-82). The estimated population incidence for people over 50 was 3.2 per 100,000 person years. The female : male incidence ratio was 2.3 (P < 0.001), and incidence increased with each age decade. There was evidence of seasonal variation (P = 0.015), with higher rates observed in the summer months. Clinical data were available for 163 patients (68% female, median age 78 years). The most common presenting clinical features were temporal headache (74%), visual disturbance (68.4%), jaw claudication (59.3%) and symptoms of polymyalgia rheumatica (56%). The median initial steroid dose was 60 mg, with median duration of steroid use 4.5 years. Corticosteroid side-effects were common, affecting 89%, with 34% reporting five or more. CONCLUSIONS: This is the first epidemiological study of Australian biopsy-proven GCA patients. Age at onset and gender associations were similar to other Western populations. There was a high burden of steroid use in these patients.

The relationship between compost bedded pack performance, management, and bacterial counts.

The objective of this study was to assess the relationships among temperature, moisture, carbon-to-nitrogen (C:N) ratio, space per cow, and bacterial counts from bedding material collected from compost bedded pack (CBP) barns. A field survey of 42 routinely aerated CBP barns was conducted in Kentucky between October 2010 and March 2011. Two bedding material samples of 1,064.7 cm(3) each were collected during a single site visit from 9 evenly distributed locations throughout each barn and thoroughly mixed to create a composite sample representative of the entire CBP. Bacterial counts were determined for coliforms, Escherichia coli, streptococci, staphylococci, and Bacillus spp. University of Kentucky Regulatory Services (Lexington) laboratory personnel performed nutrient analyses to determine moisture, carbon, and nitrogen contents. Surface and 10.2-cm pack depth temperatures were collected for each of the 9 evenly distributed locations and the mean calculated to produce a composite temperature. Space per cow was calculated as the total CBP area divided by number of cows housed on the CBP. The GLM procedure of SAS (SAS Institute Inc., Cary, NC) generated models to describe factors affecting bacterial counts. Bacterial counts were 6.3 ± 0.6, 6.0 ± 0.6, 7.2 ± 0.7, 7.9 ± 0.5, and 7.6 ± 0.5 log 10 cfu/g of dry matter for coliform, Escherichia coli, streptococci, staphylococci, and Bacillus spp., respectively. Composite temperature, CBP moisture, C:N ratio, and space per cow had no effect on coliform counts. Escherichia coli reached a peak concentration when the C:N ratio was between 30:1 and 35:1. Staphylococci counts increased as ambient temperature increased. Streptococci counts decreased with increased space per cow and composite temperature and increased with increasing ambient temperature and moisture. Streptococci counts peaked at a C:N ratio ranging from 16:1 to 18:1. Bacillus spp. counts were reduced with increasing moisture, C:N ratio, and ambient temperature. Mastitis-causing bacteria thrive in similar conditions to that of composting bacteria and microbes, making elimination of these at higher temperatures (55 to 65°C) difficult in an active composting environment. Producers must use recommended milking procedures and other preventative practices to maintain low somatic cell count in herds with a CBP barn.

Risk of cancer following primary total hip replacement or primary resurfacing arthroplasty of the hip: a retrospective cohort study in Scotland.

BACKGROUND: Release and dispersion of particles arising from corrosion and wear of total hip arthroplasty (THA) components has raised concerns about a possible increased risk of cancer. Concerns have been heightened by a recent revival in the use of metal-on-metal (MoM) hip prostheses. METHODS: From a linked database of hospital discharge, cancer registration, and mortality records, we selected a cohort of patients who underwent primary THA (1990-2009) or primary resurfacing arthroplasty (mainly 2000-2009) in Scotland, with follow-up to the end of 2010. Available operation codes did not enable us to distinguish MoM THAs. Indirectly standardised incidence ratios (SIRs) were calculated for selected cancers with standardisation for age, sex, deprivation, and calendar period. RESULTS: The study cohort included 71 990 patients yielding 547 001 person-years at risk (PYAR) and 13 946 cancers diagnosed during follow-up. For the total period of observation combined, the risks of all cancers (SIR: 1.05; 95% CI: confidence interval 1.04-1.07), prostate cancer (SIR: 1.07; 95% CI: 1.01-1.14), and multiple myeloma (SIR: 1.22; 95% CI: 1.06-1.41) were increased. These modest increases in risk emerged in the context of effectively multiple tests of statistical significance, and may reflect inadequate adjustment for confounding factors. For 1317 patients undergoing primary resurfacing arthroplasty between 2000 and 2009 (PYAR=5698), the SIR for all cancers (n=39) was 1.23 (95% CI: 0.87-1.68). CONCLUSION: In the context of previous research, these results do not suggest a major cause for concern. However, the duration of follow-up of patients receiving recently introduced, new-generation MoM prostheses is too short to rule out a genuinely increased risk of cancer entirely.