Time toxicity associated with early phase clinical trial participation.

BACKGROUND: Early phase cancer clinical trials (EPCTs) involve experimental drugs being used for the first time in humans. These studies are designed for dose determination and safety, and represent the most time intensive of all clinical trials for both clinicians and patients. We sought to quantify the amount of patient time consumed through EPCT participation. PATIENTS AND METHODS: A retrospective audit of patients treated in the EPCT unit at Liverpool Hospital, Sydney was carried out from 2013 to 2023. We defined 'time toxicity' (TT) as a composite measure where time-toxic days were considered days with any health care system contact, including clinic visits, infusions, procedures or blood work. RESULTS: A total of 219 patients across 36 EPCTs were included. The median age was 65 years (range 31-81 years). Patients spent a median of 29% (range 4%-100%) of their days in direct contact with the health care system during their study. Protocol-specified visits accounted for the greatest contribution to total TT in 101 (46%) patients. In 7% (n = 16) of patients, unscheduled visits due to either adverse events or cancer-related symptoms accounted for the greatest TT. TT reduced as patients completed additional cycles of treatment. Patients who completed >10 cycles spent 14% of their days interacting with health care systems compared with 35% for those who completed ≤2 cycles. No statistically significant difference in TT was noted between dose-expansion and dose-escalation studies or trials focusing on immune-oncology versus targeted therapy. CONCLUSIONS: Our study is the first to report TT in EPCTs with an extended follow-up. Clinicians should be aware of TT when discussing risks and benefits. TT also may not be the appropriate term when describing the time patients invest during EPCTs. Toxicity implies a negative impact, but for many patients, trial participation would be seen as positive. There should be efforts to streamline health care visits to limit TT in EPCTs.

Fatty acid concentration of plasma, muscle, adipose and liver from beef heifers fed an encapsulated n-3 polyunsaturated fatty acid supplement.

Increasing the content of polyunsaturated fat in the human diet is a priority for reducing cardiovascular disease and cancer risks. Beef has the potential to contribute to the polyunsaturated fat content in the human diet; however, ruminants cannot synthesise many long-chain fatty acids de novo; they require dietary supplementation. The objectives of the current study were to evaluate (i) the effect of a partially rumen protected n-3 long-chain polyunsaturated fatty acid (LC-PUFA) dietary supplement on the fatty acid composition of muscle (Longissimus dorsi), adipose and liver tissues of beef heifers and (ii) the usefulness of blood plasma as a predictor of tissue concentrations of specific fatty acids. Charolais crossbred heifers (n = 20) were assigned to one of two isolipid dietary treatments namely palmitic acid (control) or an n-3 LC-PUFA supplement for a 91-day period. Blood plasma and adipose tissue samples were taken to determine the temporal effect of these diets on fatty acid composition (days 0, 10, 35 and 91), while liver and muscle samples were taken following slaughter. Dietary lipid source did not influence animal growth rate or body condition score. At day 91, the percentage differences between control and n-3 LC-PUFA heifers in concentrations of eicosapentaenoic acid were +61, +176 and +133 % in liver, muscle and adipose, respectively. For docosahexaenoic acid, at the same time point, the percentage differences were +57, +73 and +138 % for liver, muscle and adipose, respectively. Medium-to-strong positive correlation coefficients were evident for liver and plasma fatty acids, in particular, there were positive relationships with concentrations of total saturated fatty acid (SFA), total n-6 PUFA and total n-3 PUFA. This trend also extended to both the ratio of PUFA to SFA (slope (ß1) = 0.56 ±â€¯0.167, intercept (ß0) = 0.56, R2 = 0.61, P < 0.05) and the ratio of n-6 to n-3 PUFA (ß1 = 0.15 ±â€¯0.054, ß0 = 0.24, R2 = 0.52, P < 0.05). A strong correlation was also detected in the ratio of n-6 to n-3 in plasma and muscle tissue of heifers fed the n-3 LC-PUFA diet (ß1 = 0.53 ±â€¯0.089, ß0 = -0.31, R2 = 0.83, P < 0.001). The results of this study show that the n-3 LC-PUFA can be readily increased through targeted supplementation and that plasma concentrations of n-3 LC-PUFA are useful predictors of their concentrations in a number of economically important tissues.

Leveraging legacy archaeological collections as proxies for climate and environmental research.

Understanding the causes and consequences of previous climate changes is essential for testing present-day climate models and projections. Archaeological sites are paleoenvironmental archives containing unique ecological baselines with data on paleoclimate transformations at a human timescale. Anthropogenic and nonanthropogenic forces have destroyed many sites, and others are under immediate threat. In the face of this loss, previously excavated collections from these sites-referred to as legacy collections-offer a source of climate and other paleoenvironmental information that may no longer exist elsewhere. Here, we 1) review obstacles to systematically using data from legacy archaeological collections, such as inconsistent or unreported field methods, inadequate records, unsatisfactory curation, and insufficient public knowledge of relevant collections; 2) suggest best practices for integrating archaeological data into climate and environmental research; and 3) summarize several studies to demonstrate the benefits and challenges of using legacy collections as archives of local and regional environmental proxies. Data from archaeological legacy collections contribute regional ecological baselines as well as serve to correct shifting baselines. They also enable regional climate reconstructions at various timescales and corroborate or refine radiocarbon dates. Such uses of legacy collections raise ethical concerns regarding ownership of and responsibility for cultural resources and highlight the importance of Indigenous involvement in planning and executing fieldwork and stewardship of cultural heritage. Finally, we discuss methodologies, practices, and policies pertaining to archaeological legacy collections and support calls for discipline-wide shifts in collections management to ensure their long-term utility in multidisciplinary research and public engagement.

An improved temporal formulation of pupal transpiration in Glossina.

The temporal aspect of a model of pupal dehydration is improved upon. The observed dependence of pupal transpiration on time is attributed to an alternation between two, essential modes, for which the deposition of a thin, pupal skin inside the puparium and its subsequent demise are thought to be responsible. For each mode of transpiration, the results of the Bursell investigation into pupal dehydration are used as a rudimentary data set. These data are generalised to all temperatures and humidities by invoking the property of multiplicative separability. The problem, then, is that as the temperature varies with time, so does the metabolism and the developmental stages to which the model data pertain, must necessarily warp. The puparial-duration formula of Phelps and Burrows and Hargrove is exploited to facilitate a mapping between the constant-temperature time domain of the data and that of some, more general case at hand. The resulting, Glossina morsitans model is extrapolated to other species using their relative surface areas, their relative protected and unprotected transpiration rates and their different fourth instar excretions (drawing, to a lesser extent, from the data of Buxton and Lewis). In this way the problem of pupal dehydration is formulated as a series of integrals and the consequent survival can be predicted. The discovery of a distinct definition for hygrophilic species, within the formulation, prompts the investigation of the hypothetical effect of a two-day heat wave on pupae. This leads to the conclusion that the classification of species as hygrophilic, mesophilic and xerophilic is largely true only in so much as their third and fourth instars are and, possibly, the hours shortly before eclosion.

A model of teneral dehydration in Glossina.

The results of a long-established investigation into teneral transpiration are used as a rudimentary data set. These data are not complete in that all are at 25°C and the temperature-dependence cannot, therefore, be resolved. An allowance is, nonetheless, made for the outstanding temperature-dependent data. The data are generalised to all humidities, levels of activity and, in theory, temperatures, by invoking the property of multiplicative separability. In this way a formulation, which is a very simple, first order, ordinary differential equation, is devised. The model is extended to include a variety of Glossina species by resorting to their relative, resting water loss rates in dry air. The calculated, total water loss is converted to the relevant humidity, at 24°C, that which produced an equivalent water loss in the pupa, in order to exploit an adaption of an established survival relationship. The resulting computational model calculates total, teneral water loss, consequent mortality and adult recruitment. Surprisingly, the postulated race against time, to feed, applies more to the mesophilic and xerophilic species, in that increasing order. So much so that it is reasonable to conclude that, should Glossina brevipalpis survive the pupal phase, it will almost certainly survive to locate a host, without there being any significant prospect of death from dehydration. With the conclusion of this work comes the revelation that the classification of species as hygrophilic, mesophilic and xerophilic is largely true only in so much as their third and fourth instars are and, possibly, the hours shortly before eclosion.

Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of Bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1.

Although the ability of bioactive lipid sphingosine-1-phosphate (S1P) to positively regulate anti-apoptotic/pro-survival responses by binding to S1P1 is well known, the molecular mechanisms remain unclear. Here we demonstrate that expression of S1P1 renders CCL39 lung fibroblasts resistant to apoptosis following growth factor withdrawal. Resistance to apoptosis was associated with attenuated accumulation of pro-apoptotic BH3-only protein Bim. However, although blockade of extracellular signal-regulated kinase (ERK) activation could reverse S1P1-mediated suppression of Bim accumulation, inhibition of caspase-3 cleavage was unaffected. Instead S1P1-mediated inhibition of caspase-3 cleavage was reversed by inhibition of phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC), which had no effect on S1P1 regulation of Bim. However, S1P1 suppression of caspase-3 was associated with increased expression of anti-apoptotic protein Mcl-1, the expression of which was also reduced by inhibition of PI3K and PKC. A role for the induction of Mcl-1 in regulating endogenous S1P receptor-dependent pro-survival responses in human umbilical vein endothelial cells was confirmed using S1P receptor agonist FTY720-phosphate (FTY720P). FTY720P induced a transient accumulation of Mcl-1 that was associated with a delayed onset of caspase-3 cleavage following growth factor withdrawal, whereas Mcl-1 knockdown was sufficient to enhance caspase-3 cleavage even in the presence of FTY720P. Consistent with a pro-survival role of S1P1 in disease, analysis of tissue microarrays from ER(+) breast cancer patients revealed a significant correlation between S1P1 expression and tumour cell survival. In these tumours, S1P1 expression and cancer cell survival were correlated with increased activation of ERK, but not the PI3K/PKB pathway. In summary, pro-survival/anti-apoptotic signalling from S1P1 is intimately linked to its ability to promote the accumulation of pro-survival protein Mcl-1 and downregulation of pro-apoptotic BH3-only protein Bim via distinct signalling pathways. However, the functional importance of each pathway is dependent on the specific cellular context.

A set of discrete formulae for the performance of a tsetse population during aerial spraying.

A set of discrete formulae that calculates the hypothetical impact of aerial spraying on a tsetse population is derived and the work is thought to be novel. Both the original population and the subsequent generations which survive the aerial spraying, may ultimately be thought of as deriving from two, distinct sources. These origins are, however, neither distinct, nor relevant by the third generation. It is for this reason that the female population is considered to be composed of the following four categories for the purposes of derivation: Original flies which existed as such at the commencement of spraying; original pupae which existed as such at the commencement of spraying; the immediate descendants of both the aforementioned categories, during spraying; third and higher generation descendants. In theory, the latter category is a recurrence relation. In practice, the third generation's pupal stage has hardly come into existence, even by the end of a completed operation. Implicit in the formulae is the assumption of one, temperature-dependent mortality rate for the entire pupal stage, a second for the period between eclosion and ovulation and yet a third for the entire, adult life-span. Gravid female resistance to the insecticide is assumed to be inconsequential. A further assumption of the formulae is that at least one male is always available (degree of sterility variable).

Neuronal expression of class 6 semaphorins in zebrafish.

Semaphorins are a large family of guidance molecules identified by an extracellular SEMA domain. Classes 1 and 2 are derived from invertebrates, classes 3-7 are vertebrate and class 8 (v) are viral semaphorins. Class 6 semaphorins are reported to have a wide variety of roles including in axon guidance, transcriptional regulation and cancer. Here we report the identification and expression of four class 6 semaphorins (6A, 6Ba, 6Bb and 6Dl) in three stages of larval development in zebrafish (24, 48 and 72 hours postfertilization). Our data indicate that each of the class 6 semaphorins shows a distinct pattern of expression in the developing nervous system that is dynamic over the first 3 days of embryonic development. These data suggest that the individual class 6 semaphorins have diverse roles in nervous system development.

A prevalence study of errors in opioid prescribing in a large teaching hospital.

AIM: In 2007, the National Patient Safety Agency performed a study demonstrating that errors in prescribing led to nearly 12,000 adverse clinical incidents a year. The following year, they issued a rapid response report entitled 'Reducing Dosing Errors with Opioid Medicines' designed to be implemented by all NHS trusts. We performed a prevalence study to assess opioid prescribing errors in our large multi-speciality teaching hospital prior to implementation of these recommendations. METHODOLOGY: We conducted a 1 day snapshot of opioid prescriptions on inpatient drug charts. For every chart, all opioid information was entered into the study proforma. All data were reviewed by consensus group and errors categorised by quality and whether they were potentially lethal, serious, significant or minor. RESULTS: A total of 330/722 (46%) charts were found to have opioid prescriptions. On the study day, there were 74 charts with errors and on expert review another 16 erroneous charts were found giving a total of 90/330 (27.2%). The largest quality statement error group was 'unclear prescription, missing information'. There were 4 potentially lethal, 26 serious, 38 significant and 22 minor errors. DISCUSSION: Previous studies have reported opioid prescription error rates of 51.2-70%. Compared with the opioid literature, our trust fares well with an error rate of 27%- four of these errors being potentially lethal. This study has identified where there are weaknesses in our hospital opioid prescribing practice and has aided us in rewriting our acute and chronic pain guidelines with the explicit inclusion of the National Patient Safety Agency recommendations. We have also disseminated the study results at the Trust academic meeting and developed an opioid e-learning package which will be mandatory for all new staff.

Theoretical levels of control as a function of mean temperature and spray efficacy in the aerial spraying of tsetse fly.

The hypothetical impact of aerial spraying on tsetse fly populations is investigated. Spray cycles are scheduled at intervals two days short of the first interlarval period and halted once the last of the female flies that originated from pre-spray-deposited pupae have been sprayed twice. The effect of temperature on the aerial spraying of tsetse, through its reproductive cycle and general population dynamics, is of particular interest, given that cooler weather is preferred for the settling of insecticidal droplets. Spray efficacy is found to come at a price due to the greater number of cycles necessitated by cooler weather. The extra cost is argued to be worth while. Pupae, still in the ground at the end of spraying, are identified as the main threat to a successful operation. They are slightly more vulnerable at the low temperature extreme of tsetse habitat (16°C), when the cumulative, natural pupal mortality is high. One can otherwise base one's expectations on the closeness with which the time to the third last spray approaches one puparial duration. A disparity of anything close to the length of a spray cycle advocates caution, whereas one which comes close to vanishing should be interpreted as being auspicious. Three such key temperatures, just below which one can anticipate an improved outcome and just above which caution should be exercised, are 17.146°C, 19.278°C and 23.645°C. A refinement of the existing formulae for the puparial duration and the first interlarval period might be prudent in the South African context of a sympatric Glossina brevipalpis-Glossina austeni, tsetse population. The resulting aerial spraying strategy would then be formulated using a G. brevipalpis puparial duration and a G. austeni first interlarval period.

The finite element implementation of a K.P.P. equation for the simulation of tsetse control measures in the vicinity of a game reserve.

An equation, strongly reminiscent of Fisher's equation, is used to model the response of tsetse populations to proposed control measures in the vicinity of a game reserve. The model assumes movement is by diffusion and that growth is logistic. This logistic growth is dependent on an historical population, in contrast to Fisher's equation which bases it on the present population. The model therefore takes into account the fact that new additions to the adult fly population are, in actual fact, the descendents of a population which existed one puparial duration ago, furthermore, that this puparial duration is temperature dependent. Artificially imposed mortality is modelled as a proportion at a constant rate. Fisher's equation is also solved as a formality. The temporary imposition of a 2% day(-1) mortality everywhere outside the reserve for a period of 2years will have no lasting effect on the influence of the reserve on either the Glossina austeni or the G. brevipalpis populations, although it certainly will eradicate tsetse from poor habitat, outside the reserve. A 5km-wide barrier with a minimum mortality of 4% day(-1), throughout, will succeed in isolating a worst-case, G. austeni population and its associated trypanosomiasis from the surrounding areas. A more optimistic estimate of its mobility suggests a mortality of 2% day(-1) will suffice. For a given target-related mortality, more mobile species are found to be more vulnerable to eradication than more sedentary species, while the opposite is true for containment.

The relationship between periovulatory endocrine and follicular activity on corpus luteum size, function, and subsequent embryo survival.

The objectives of this study were to examine the relationships between periovulatory endocrine events, ovarian activity, and embryo survival after artificial insemination (AI) in cattle (Bos taurus). Eighty-four reproductively normal beef heifers were estrus synchronized using a prostaglandin-based regimen. Artificial insemination was performed between 5 and 21h after heat onset. Ultrasonic examination of ovarian structures began 12h after the onset of heat and continued every 6h until confirmed ovulation. Blood samples were collected for measurement of estradiol, progesterone, and insulin-like growth factor-1 (IGF-1). Pregnancy diagnosis was conducted on Days 30 and 100 after AI. Embryo survival was defined as the presence of an embryo with a detectable heartbeat in a clear amniotic sac at Day 30 postinsemination. There was no effect of the intervals from the onset of heat to AI or ovulation or from AI to ovulation on embryo survival (P>0.10). There was a tendency (P=0.09) of an inverse relationship between preovulatory follicle size and embryo survival that was unrelated to concentrations of estradiol or IGF-1 during the periovulatory period (P>0.05). There was evidence (P=0.08) of a positive association between embryo survival and concentrations of progesterone on Day 7; however, this relationship was independent (P<0.05) of hormonal and follicular measurements during the periovulatory period. This study shows that heifers could be inseminated up to 31.5h before ovulation without compromising the probability of embryo survival. This study suggests that there is an optimum range of follicle size within which high embryo survival rates can be achieved.

A model of pupal water loss in Glossina.

The results of a long-established investigation into pupal transpiration are used as a rudimentary data set. These data are then generalised to all temperatures and humidities by invoking the property of multiplicative separability, as well as by converting established relationships in terms of constant humidity at fixed temperature, to alternatives in terms of a calculated water loss. In this way a formulation which is a series of very simple, first order, ordinary differential equations is devised. The model is extended to include a variety of Glossina species using their relative surface areas, their relative pupal and puparial loss rates and their different 4th instar excretions. The resulting computational model calculates total, pupal water loss, consequent mortality and emergence. Remaining fat reserves are a more tenuous result. The model suggests that, while conventional wisdom is often correct in dismissing variability in transpiration-related pupal mortality as insignificant, the effects of transpiration can be profound under adverse conditions and for some species, in general. The model demonstrates how two gender effects, the more significant one at the drier extremes of tsetse fly habitat, might arise. The agreement between calculated and measured critical water losses suggests very little difference in the behaviour of the different species.

Embryo yield and quality following dietary supplementation of beef heifers with n-3 polyunsaturated fatty acids (PUFA).

The objective of this study was to examine the effects of dietary n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation on embryo yield and quality in heifers. Animals were individually offered barley straw and concentrate diets supplemented with either palmitic acid (C16:0; CON) or a partially rumen protected n-3 PUFA-enriched supplement. Following oestrous cycle synchronisation, superovulation was induced using FSH. Blood samples were collected for the measurement of fatty acids, metabolites, insulin and IGF-1. On day 7 post-insemination the number of ovulations was estimated and embryos recovered non-surgically and quality graded. At embryo recovery 50 ml of the uterine flushing was collected from each horn for fatty acid analysis. Grade 1 embryos were isolated, snap frozen in liquid nitrogen and stored at -80 degrees C. mRNA expression for six genes, LIF, BAX, Cx43 and E-CAD associated with embryo development, and PPAR-alpha and -delta, associated with lipid metabolism was analysed. The n-3 PUFA supplementation increased plasma n-3 PUFA concentration (P<0.05) and reduced n-6:n-3 PUFA ratio (P<0.05). Uterine concentration of the n-3 PUFA, eicosapentaenoic acid was increased (P<0.05) and the concentration of arachidonic acid decreased (P<0.05) following n-3 PUFA supplementation. While CON increased triglyceride concentrations, diet did not affect the other plasma metabolites, insulin or IGF-1 (P>0.05). Similarly, there was no effect of diet on superovulation rate, embryo recovery rate, embryo quality (P>0.05) or mRNA expression of the genes examined (P>0.05).

Effect of level of dietary n-3 polyunsaturated fatty acid supplementation on systemic and tissue fatty acid concentrations and on selected reproductive variables in cattle.

Reproductively normal crossbred beef heifers were individually offered a diet of barley straw and concentrate supplemented with one of four levels of a fish oil (FO) enriched supplement. Following oestrous cycle synchronisation, blood samples were collected at appropriate intervals for the measurement of progesterone (P(4)), oestradiol (E(2)), fatty acids, insulin-like growth factor 1 (IGF-1) and metabolites. On days 15 and 16 of the cycle, oxytocin was administered intravenously and the prostaglandin F(2alpha) (PGF(2alpha)) response was measured as venous concentrations of 13,14-dihydro-15-keto PGF(2alpha) (PGFM). The heifers were slaughtered on days 17 or 18 of the oestrous cycle and endometrial tissue, rumen fluid and follicular fluid were collected for determination of fatty acid concentrations. In general there was no effect (P>0.05) of diet on plasma P(4) or E(2) concentrations. Increasing FO supplementation increased CL diameter on day 7 post-oestrus (P<0.0001) but had no effect on diameter on day of slaughter (P>0.05). On day 15, PGFM concentration was greater on the highest level of FO supplementation compared to controls (P<0.05), however, there were no differences between other diet comparisons (P>0.05). There was no effect of diet on PGFM concentration on day 16 (P>0.05). There was a strong positive relationship between plasma and uterine endometrial concentrations of both EPA (R(2)=0.86; P<0.0001) and total n-3 PUFA (R(2)=0.77; P<0.0001). IGF-1 concentrations increased on all diets and were greatest at the highest level of n-3 PUFA supplementation (P<0.05).

Dietary n-3 polyunsaturated fatty acids alter the expression of genes involved in prostaglandin biosynthesis in the bovine uterus.

Nutrition plays a critical role in the regulation of cow fertility. There is emerging evidence that dietary long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) may act as specific regulators of some reproductive processes. In vitro studies suggest that the n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may play pivotal roles by suppressing the synthesis of uterine prostaglandin F(2alpha) (PGF(2alpha)) which is centrally involved in the control of the bovine oestrous cycle and in early embryo survival. The objective of the current study was to determine the effect of dietary inclusion of n-3 PUFA on uterine endometrial mRNA expression of key genes regulating PGF(2alpha) biosynthesis. Beef heifers were fed either a low (CON; n=10) or high (HIGH PUFA; n=10) n-3 PUFA diet for 45 days and endometrial tissues were harvested following slaughter. Following analysis, tissues within each dietary group were ranked on the basis of their PUFA concentrations and the highest (n=7) and lowest (n=7) within each of HIGH PUFA and CON, respectively, were used in gene expression studies. Endometrial n-3 PUFA concentrations were more than two-fold higher (P<0.05) and EPA concentrations alone more than seven-fold higher (P<0.01) in the HIGH PUFA than the CON group. Endometrial concentrations of arachidonic acid, were lower (P<0.001) in the tissues from HIGH PUFA than those from the CON group. Total RNA was isolated from all endometrial tissues and real-time reverse transcription (RT) PCR conducted to compare the relative expression of 11 genes with known involvement in uterine biosynthesis of 2-series prostaglandins. Expression of mRNA for prostaglandin E synthase (PGES) and peroxisome proliferator-activated receptors, PPAR alpha and delta was increased (P<0.05) while mRNA expression of phospholipase A(2) (PLA(2)) was decreased (P=0.06) in the HIGH PUFA endometrial tissues. Expression of genes coding for the oxytocin receptor (OTR), phospholipase C (PLC), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), PGE(2) 9-ketoreductase (9-KPR), prostaglandin F synthase (PGFS), and the nuclear transcription factor, PPAR gamma was not different (P>0.05) between HIGH PUFA and CON tissues. Overall the results indicate that key genes regulating uterine PGF(2alpha) biosynthesis can be regulated by dietary inclusion of LC n-3 PUFA which may influence uterine function and embryo survival.

Effect of dietary enrichment with either n-3 or n-6 fatty acids on systemic metabolite and hormone concentration and ovarian function in heifers.

The objective of this experiment was to examine the effects of dietary n-3 or n-6 fatty acid (FA) supplementation on blood FA, metabolite and hormone concentrations, follicle size and dynamics and corpus luteum (CL) size. Reproductively normal heifers (n = 24) were individually fed diets of chopped straw and concentrate containing either (i) no added lipid (CON; n = 8); (ii) 2% added fat as whole raw soya beans (WSB, n-6; n = 8); or (iii) 2% added fat as fish oil (FO, n-3; n = 8). Following oestrous cycle synchronisation, blood samples were collected at appropriate times and intervals for the measurement of hormones, FAs and metabolites. On days 15 and 16 of the cycle, animals were subjected to an intravenous oxytocin challenge and prostaglandin F2α (PGF2α) response, measured as venous concentrations of 13,14-dihydro-15-keto PGF2α (PGFM). Dry matter intake and average daily gain were similar among treatments (P > 0.05). Plasma concentration of linoleic acid was highest on WSB (P < 0.05), while eicosapentaenoic (EPA, n-3; P < 0.0001) and docosahexaenoic acid (DHA, n-3; P < 0.0001) were greatest in the FO group. Plasma concentrations of arachidonic acid were higher on FO (P < 0.05) compared with CON and WSB. Plasma triglyceride concentrations increased, while ß-hydroxybutyrate (BHBA) decreased with time on all diets (P < 0.05). There was a diet × time interaction (P < 0.01) for non-esterified fatty acid (NEFA) concentrations. Plasma cholesterol was higher on WSB and FO (P < 0.01) compared with CON. Progesterone (P4) and oestradiol (E2) concentrations, as well as follicle growth rate and CL diameter were similar across diets (P > 0.05). There was a diet × day interaction for PGFM (P < 0.01). When corrected for systemic E2 : P4 ratio, day 15 concentrations of PGFM were higher in the WSB group at 15 and 30 min (P < 0.01) post oxytocin administration compared with CON and FO, which were similar (P > 0.05). Concentrations of PGFM on day 16 were similar for WSB and FO and were greater than CON at 15 (P < 0.01) and 45 min (P < 0.05) post oxytocin administration, and at 30 min for FO (P < 0.05). With the exception of PGFM, dietary lipid source did not affect the reproductive variables measured.

Effects of interventions aimed at changing the length of primary care physicians' consultation.

BACKGROUND: Observational studies have shown differences in process and outcome between the consultations of primary care physicians whose average consultation lengths differ. These differences may be due to self selection. OBJECTIVES: To assess the effectiveness and efficiency of interventions to alter the length of primary care physicians' consultations. SEARCH STRATEGY: The following electronic databases were searched: Cochrane Effective Practice and Organisation of Care Group (EPOC) Specialised Register (October 2002); CENTRAL (The Cochrane Library June 2003); MEDLINE (1966 to October 2002);EMBASE (1981 to October 2002); NHS National Research Register (June 2003). The search strategies combined subject terms for 'general practice', 'consultation' and 'length' with methodological filters. SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) of interventions to alter the length of primary care physicians' consultations. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two authors using agreed criteria. Disagreements were resolved by discussion. Where data were missing attempts were made to contact authors. Given the heterogeneity of studies meta-analysis was not attempted, and results are presented as a narrative summary. MAIN RESULTS: Six articles describing four UK trials met the inclusion criteria. All tested short term changes in the consultation time allocated to each patient and all had methodological weaknesses, particularly due to non-random allocation of patients. Altering appointment length resulted in modest changes in average length of consultation. There were no consistent differences in problem recognition, examination, prescribing, referral or investigation rates. There was some evidence that blood pressure was checked and smoking discussed more often when more time was available. None of the interventions were associated with differences in patient satisfaction. No trials examined efficiency. AUTHORS' CONCLUSIONS: The findings of this review do not provide sufficient evidence to support or resist a policy of altering the lengths of primary care physicians' consultations. Further trials are needed that focus on health outcomes and cost effectiveness.

Systematic review: the effect of Helicobacter pylori and its eradication on gastro-oesophageal reflux disease in patients with duodenal ulcers or reflux oesophagitis.

BACKGROUND: The effect of Helicobacter pylori in provoking or protecting against gastro-oesophageal reflux disease is unclear and studies have given conflicting results. Recent guidelines recommend H. pylori eradication in patients on long-term proton pump inhibitors. AIM: To ascertain the effect of H. pylori eradication on gastro-oesophageal reflux disease outcomes (reflux oesophagitis and heartburn) in patients with duodenal ulcer disease, and to ascertain the effect of H. pylori infection on reflux oesophagitis concerning heartburn, pH, severity, healing and relapse rates. METHODS: A systematic review of electronic databases was undertaken to September 2003. Experts in the field, pharmaceutical companies and journals were contacted about unpublished trials. Studies were reviewed according to predefined eligibility and quality criteria. Twenty-seven studies/trials were included in the systematic review. RESULTS: Study variation rather than therapy-influenced results in relation to the presence or absence of oesophagitis in patients with duodenal ulcer who underwent H. pylori eradication at 6-48 months follow-up. In patients with reflux oesophagitis no obvious differences were discovered in heartburn scores, 24-h pH values, healing and relapse rates between H. pylori-positive and -negative cases. CONCLUSION: There is no evidence to indicate that H. pylori eradication in duodenal ulcer disease provokes reflux oesophagitis or worsens heartburn; (ii) there are insufficient data to draw firm conclusions about the impact of H. pylori in patients with reflux oesophagitis.

Fibroblast reaction to island topography: changes in cytoskeleton and morphology with time.

In order to develop next-generation tissue engineering materials, the understanding of cell responses to novel material surfaces needs to be better understood. Topography presents powerful cues for cells, and it is becoming clear that cells will react to nanometric, as well as micrometric, scale surface features. Polymer-demixing of polystyrene and polybromostyrene has been found to produce nanoscale islands of reproducible height, and is very cheap and fast compared to techniques such as electron beam lithography. This study observed temporal changes in cell morphology and actin and tubulin cytoskeleton using scanning electron and fluorescence microscopy. The results show large differences in cell response to 95 nm high islands from 5 min to 3 weeks of culture. The results also show a change in cell response from initial fast organisation of cytoskeleton in reaction to the islands, through to lack of cell spreading and low recruitment of cell numbers on the islands.