Attenuated psychosis symptoms are related to working alliance between therapist and service user.

AIM: Many trials have demonstrated the efficacy of specific therapy modalities for individuals with attenuated psychosis symptoms (APS). Less is known regarding mechanisms behind positive outcomes, including the role of nonspecific therapeutic factors. This study explored working alliance (WA) in a clinic serving individuals with APS to see how WA changed across the course of treatment and its relation to APS. METHODS: Session level APS and WA data was available for 12 individuals of diverse racial and gender identity, (M = 48 sessions each). Multilevel models with random intercepts tested change in WA and APS over time, and cross-sectional and prospective relations. RESULTS: WA increased and APS decreased over time. Cross sectionally, WA and APS were inversely related. Prospective relations were non-significant. CONCLUSION: When symptoms increase, therapists for individuals with APS should be attentive to potential disruptions in WA, though strong WA may be a cross-sectional protective factor.

Evaluation of delayed timing of artificial insemination with sex-sorted sperm on pregnancy per artificial insemination in seasonal-calving, pasture-based lactating dairy cows.

The objective was to use ovulation synchronization with timed artificial insemination (TAI) to evaluate the effect of timing of artificial insemination (AI) with frozen sex-sorted sperm on fertility performance in pasture-based compact calving herds. Ejaculates from 3 Holstein-Friesian bulls were split and processed to provide frozen sex-sorted sperm (SS) at 4 × 106 sperm per straw, and frozen conventional sperm at 15 × 106 sperm per straw (CONV). A modified Progesterone-Ovsynch protocol was used for estrous synchronization, with TAI occurring 16 h after the second GnRH injection for cows assigned to CONV, and either 16 h (SS-16) or 22 h (SS-22) for cows assigned to SS. Pregnancy diagnosis was conducted by transrectal ultrasound scanning of the uterus 35 to 40 d after TAI (n = 2,175 records available for analysis). Generalized linear mixed models were used to examine the effects of treatment on pregnancy per artificial insemination (P/AI). Fixed effects included treatment (n = 3), bull (n = 3), treatment by bull interaction, parity (n = 4), days-in-milk category (n = 3), and treatment by days-in-milk category, with herd (n = 24) included as a random effect. Pregnancy per AI was greater for CONV compared with both SS-16 and SS-22 (61.1%, 49.0%, and 51.3%, respectively), and the SS treatments did not differ from each other (relative P/AI for SS-16 and SS-22 vs. CONV were 80.2% and 84.0%, respectively). There were significant bull and treatment by bull interaction effects. Additional analysis was undertaken using a model that included herd as a fixed effect. This analysis identified marked herd-to-herd variation (within-herd relative P/AI for the combined SS treatments vs. CONV ranged from 48-121%). The tertile of herds with the best performance achieved a mean relative P/AI of 100% (range = 91-121%), indicating that P/AI equivalent to CONV is achievable with SS. Conversely, the tertile of herds with the poorest performance achieved a mean relative P/AI of 67% (range = 48-77%). We found that SS resulted in poorer overall P/AI compared with CONV sperm regardless of timing of AI. Marked variation existed between herds; however, one-third of herds achieved P/AI results equal to CONV. Identification of factors responsible for the large herd-to-herd variation in P/AI with SS, and development of strategies to reduce this variation, warrant further research.

Safety of direct oral anticoagulants in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular dysplasia resulting in visceral arteriovenous malformations and smaller mucocutaneous telangiectasia. Most patients experience recurrent nosebleeds and become anemic without iron supplementation. However, thousands may require anticoagulation for conditions such as venous thromboembolism and/or atrial fibrillation. Over decades, tolerance data has been published for almost 200 HHT-affected users of warfarin and heparins, but there are no published data for the newer direct oral anticoagulants (DOACs) in HHT. METHODS: To provide such data, a retrospective audit was conducted across the eight HHT centres of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), in Denmark, France, Germany, Italy, the Netherlands and the UK. RESULTS: Although HHT Centres had not specifically recommended the use of DOACs, 32 treatment episodes had been initiated by other clinicians in 28 patients reviewed at the Centres, at median age 65 years (range 30-84). Indications were for atrial fibrillation (16 treatment episodes) and venous thromboembolism (16 episodes). The 32 treatment episodes used Apixaban (n = 15), Rivaroxaban (n = 14), and Dabigatran (n = 3). HHT nosebleeds increased in severity in 24/32 treatment episodes (75%), leading to treatment discontinuation in 11 (34.4%). Treatment discontinuation was required for 4/15 (26.7%) Apixaban episodes and 7/14 (50%) Rivaroxaban episodes. By a 4 point scale of increasing severity, there was a trend for Rivaroxaban to be associated with a greater bleeding risk both including and excluding patients who had used more than one agent (age-adjusted coefficients 0.61 (95% confidence intervals 0.11, 1.20) and 0.74 (95% confidence intervals 0.12, 1.36) respectively. Associations were maintained after adjustment for gender and treatment indication. Extreme hemorrhagic responses, worse than anything experienced previously, with individual nosebleeds lasting hours requiring hospital admissions, blood transfusions and in all cases treatment discontinuation, occurred in 5/14 (35.7%) Rivaroxaban episodes compared to 3/15 (20%) Apixaban episodes and published rates of ~ 5% for warfarin and heparin. CONCLUSIONS: Currently, conventional heparin and warfarin remain first choice anticoagulants in HHT. If newer anticoagulants are considered, although study numbers are small, at this stage Apixaban appears to be associated with lesser bleeding risk than Rivaroxaban.

Across rather than between river genetic structure in Atlantic salmon Salmo salar in north-east Scotland, UK: potential causes and management implications.

The aim of this study was to examine the genetic structuring, based on c. 4300 single nucleotide polymorphic markers, of juvenile Atlantic salmon Salmo salar sampled from 11 rivers in north-east Scotland, which form part of a radial drainage system. Within this area, sites in the upper mountainous and lower coastal sections of the different rivers were more closely related than sites from the upper and lower sections of the same river. Differentiation between fish from upper and lower sections was related to both distance from the sea and elevation, which were themselves correlated. The occurrence of such cross-river genetic grouping appears to be the result of both similar selective pressures resulting in homologous adaptive differences within each river and also recent common ancestry between rivers. Examination of historical tagging information showed high rates (27·4%) of between-river straying in this region that may help to maintain the across rather than between-river structure. The existence of cross-river groupings highlights the complex structuring of S. salar populations and may confound genetic identification of single-river stocks. Furthermore, the results presented show that cross-river structuring should also be an important consideration in managing S. salar stocks.

Long term effects of gestational hypertension and pre-eclampsia on kidney function: Record linkage study.

OBJECTIVE: To assess the long term effects of hypertensive disorders of pregnancy on renal function. DESIGN: Cohort study where exposure was gestational hypertension or preeclampsia in the first pregnancy. Normotensive women formed the comparison group. SETTING: Aberdeen, Scotland. PARTICIPANTS: All women with date of birth on or before 30th June 1969 and at least their first singleton delivery recorded in the Aberdeen Maternity and Neonatal Databank. METHODS: Participants were linked to the Renal Biochemistry Register, Scottish Morbidity Records, Scottish Renal Registry and National Register for deaths. MAIN OUTCOME MEASURES: Occurrence of chronic kidney disease (CKD) as identified from renal function tests in later life, hospital admissions or death from kidney disease or recorded as receiving renal replacement therapy. RESULTS: CKD was diagnosed in 7.5% and 5.2% of women who previously had GH and PE respectively compared to 3.9% in normotensive women. The unadjusted odds ratio (95% confidence interval) of having CKD in PE was 2.04 (1.53, 2.71) and that for GH was 1.37 (1.15, 1.65), while the adjusted odds ratio (95% confidence interval) of CKD was 1.93 (1.44, 2.57) and 1.36 (1.13, 1.63) in women with PE and GH respectively. Kaplan-Meier curves of survival time to development of chronic kidney disease revealed that women with preeclampsia were susceptible to kidney function impairment earliest, followed by those with gestational hypertension. CONCLUSIONS: There was an increased subsequent risk of CKD associated with hypertensive disorders of pregnancy. Women with GH and PE were also found to have CKD earlier than normotensive women.

Experience of a new high-purity factor X concentrate in subjects with hereditary factor X deficiency undergoing surgery.

INTRODUCTION: Maintaining haemostasis in surgery is challenging for hereditary rare bleeding disorders in which multi-coagulation-factor concentrates are the only therapeutic option. Hereditary factor X (FX) deficiency affects 1:500 000 to 1:1 000 000 individuals, and no specific replacement FX concentrate has been available. A high-purity, plasma-derived FX concentrate (pdFX) has been developed for patients with hereditary FX deficiency. AIM: Our objective was to assess the safety and efficacy of pdFX in subjects with FX deficiency undergoing surgery. METHODS: Subjects with hereditary mild-to-severe FX deficiency (basal plasma FX activity [FX:C] <20 IU dL(-1) ) undergoing surgery received pdFX preoperatively to raise FX:C to 70-90 IU dL(-1) and postoperatively to maintain levels >50 IU dL(-1) until the subject was no longer at risk of bleeding due to surgery. Efficacy of pdFX was assessed by blood loss during surgery, requirement for blood transfusion, postoperative bleeding from the surgical or other sites, and changes in haemoglobin levels. Safety was assessed by adverse events (AEs), development of inhibitors, and clinically significant changes in laboratory parameters. RESULTS: Five subjects (aged 14-59 years) underwent seven surgical procedures (four major and three minor). Treatment duration was 1-15 days. For each procedure, pdFX treatment was assessed as "excellent" in preventing bleeding and achieving haemostasis. No blood transfusions were required, no AEs related to pdFX were observed, and no clinically significant trends were found in any laboratory parameters. CONCLUSION: These data demonstrate that pdFX is safe and effective as replacement therapy in five subjects with mild-to-severe FX deficiency undergoing surgery on seven occasions.

Bucking the trend: genetic analysis reveals high diversity, large population size and low differentiation in a deep ocean cetacean.

Understanding the genetic structure of a population is essential to its conservation and management. We report the level of genetic diversity and determine the population structure of a cryptic deep ocean cetacean, the Gray's beaked whale (Mesoplodon grayi). We analysed 530 bp of mitochondrial control region and 12 microsatellite loci from 94 individuals stranded around New Zealand and Australia. The samples cover a large area of the species distribution (~6000 km) and were collected over a 22-year period. We show high genetic diversity (h=0.933-0.987, π=0.763-0.996% and Rs=4.22-4.37, He=0.624-0.675), and, in contrast to other cetaceans, we found a complete lack of genetic structure in both maternally and biparentally inherited markers. The oceanic habitats around New Zealand are diverse with extremely deep waters, seamounts and submarine canyons that are suitable for Gray's beaked whales and their prey. We propose that the abundance of this rich habitat has promoted genetic homogeneity in this species. Furthermore, it has been suggested that the lack of beaked whale sightings is the result of their low abundance, but this is in contrast to our estimates of female effective population size based on mitochondrial data. In conclusion, the high diversity and lack of genetic structure can be explained by a historically large population size, in combination with no known exploitation, few apparent behavioural barriers and abundant habitat.

Ancient population genomics and the study of evolution.

Recently, the study of ancient DNA (aDNA) has been greatly enhanced by the development of second-generation DNA sequencing technologies and targeted enrichment strategies. These developments have allowed the recovery of several complete ancient genomes, a result that would have been considered virtually impossible only a decade ago. Prior to these developments, aDNA research was largely focused on the recovery of short DNA sequences and their use in the study of phylogenetic relationships, molecular rates, species identification and population structure. However, it is now possible to sequence a large number of modern and ancient complete genomes from a single species and thereby study the genomic patterns of evolutionary change over time. Such a study would herald the beginnings of ancient population genomics and its use in the study of evolution. Species that are amenable to such large-scale studies warrant increased research effort. We report here progress on a population genomic study of the Adélie penguin (Pygoscelis adeliae). This species is ideally suited to ancient population genomic research because both modern and ancient samples are abundant in the permafrost conditions of Antarctica. This species will enable us to directly address many of the fundamental questions in ecology and evolution.

Measurement of factor IX activity in plasma-derived and recombinant concentrates: insights from thrombin generation and activation-based assays.

BACKGROUND: Hemophilia B, resulting from a deficiency of coagulation factor IX, is treated effectively with either recombinant FIX (r-FIX) or plasma-derived FIX (pd-FIX) concentrates, although differences in pharmacokinetics are observed. FIX is activated in vivo by both activated FXI (FXIa) and tissue factor (TF)-activated FVII (FVIIa); however, conventional activated partial thromboplastin time (APTT)-based assays assess only activation by FXIa. OBJECTIVES: To examine the differences between pd-FIX and r-FIX concentrates with respect to their thrombogenicity and activation. METHODS AND RESULTS: FIX ELISA was used to quantify antigenic FIX. Calibrated automated thrombography was performed to evaluate the effect of FIX on thrombin generation. FIXa was quantified by the cleavage of FIXa-specific chromogenic substrate. FIX activation was studied in a purified system. RESULTS: We found that r-FIX had ~ 1.6-fold greater specific activity than pd-FIX. r-FIX generated a markedly higher thrombin peak than pd-FIX at an equivalent antigen level when coagulation was initiated by TF, but this was not seen in contact activation-triggered thrombin generation (TG). Interestingly, the amount of FIXa in r-FIX concentrate was 10 times higher than that in pd-FIX concentrate. In a purified system, the amount of r-FIXa generated by FXIa in the first 10 min of activation was 1.37-fold that of pd-FIXa, whereas no difference between the concentrates was observed when triggered by TF-FVIIa. CONCLUSIONS: Clear differences were observed between pd-FIX and r-FIX concentrates, including the proportion of FIXa and the activation by FXIa. These may explain some of the discrepancies observed clinically, and suggest that the APTT may not reflect their resultant in vivo properties.

Refractory cachexia and truth-telling about terminal prognosis: a qualitative study.

The purpose of this paper is to examine the consequences that medical practitioners' decisions about whether or not to be candid about terminal prognosis have for those suffering from refractory cachexia and their families. It presents the findings of a qualitative study that used focus groups and semi-structured interviews of a volunteer sample of doctors, nurses and dieticians in a cancer centre of a large teaching hospital in Northern Ireland. Respondents reported that some physicians tended to avoid discussing terminal prognosis in a direct manner with their patients. Nurses and dieticians tended to be reluctant to engage in conversations about weight loss with patients with cachexia. One of the reasons they reported for their lack of acknowledgement of weight loss concerned the close association between refractory cachexia and terminal prognosis. Because they viewed the telling of bad news as an exclusive prerogative of medical practitioners, they did not feel in a position to discuss cachexia because they were concerned that this had the potential to raise end-of-life issues that lay outside the boundaries of their professional role. This meant patients and their families were provided with little information about how to cope with the distressing consequences of cachexia.

Characterisation of von Willebrand factor A1 domain mutants I1416N and I1416T: correlation of clinical phenotype with flow-based platelet adhesion.

BACKGROUND: Type 2M von Willebrand disease (VWD) results from mutations in the A1 domain of von Willebrand factor (VWF) that reduce its platelet-binding function. However, currently employed VWF functional static assays may not distinguish between clinical phenotype. METHODS: Fifteen individuals from five kindreds with VWF-A1 domain mutations I1416T or I1416N, correlated with mild and moderate clinical phenotypes, respectively, were investigated. The mutations were reproduced by site-directed mutagenesis and expressed in HEK293T cells; functional studies of the recombinant mutants, including GPIbα binding using a flow-based assay, were performed. RESULTS: Plasma from all individuals demonstrated discordant reductions in VWF antigen and platelet-binding function in the presence of high-molecular-weight VWF multimers consistent with VWD type 2M. There was lowered expression and secretion of both mutants compared with wild type (WT) recombinant (r)VWF as well as a significant reduction in GPIbα binding. Binding to collagen was normal and electrophoretic analysis demonstrated a similar multimer distribution between the mutant proteins and wt-rVWF. GPIbα binding under flow was also significantly reduced for I1416N and I1416T rVWF. Impairment of GPIbα binding was more marked for I1416N rVWF than I1416T under both static and flow conditions: this was in spite of similar VWF:Ristocetin cofactor (RCo) activities in patient plasma and is consistent with a respective clinical phenotype. CONCLUSIONS: Our findings have established for the first time that I1416N and I1416T are responsible for a type 2M VWD phenotype and demonstrate that quantification of VWF function under shear stress may provide a more accurate measure of clinical severity than the static functional measurements in current diagnostic use.

PP038. Are women with gestational hypertension or preeclampsia at an increased long term risk of kidney function impairment?

INTRODUCTION: Preeclampsia is known to cause impairment of kidney function in pregnancy, which manifests as proteinuria. Previous studies have found an association between preeclampsia and kidney disease but were restricted in their numbers or had a short follow up time. OBJECTIVES: To assess the long term effects of hypertensive disorders of pregnancy on kidney function in later life. METHODS: From the Aberdeen maternity and neonatal databank (AMND), we identified the first singleton pregnancy of all women with date of birth on or before 30th June 1969. These women were linked by means of their identifying information to the local renal biochemistry database (GRBD). GRBD captures all kidney function tests from primary and secondary care in the health region. A cohort study design was used to assess the odds ratios with 95% confidence intervals for chronic kidney disease stage 1-5 (predefined based on internationally accepted KDOQI definition) occurring at least 1year following delivery. Those with gestational hypertension and preeclampsia were compared to normotensive women using multivariate logistic regression to adjust for potential confounders. RESULTS: A total of 14675 women who had been linked to the RBD and had complete information regarding age, socio-economic class, smoking category, and body mass index (BMI) were included in a multivariate model. The unadjusted odds ratio (95% confidence interval) of having chronic kidney disease (according to previously stated definition) in preeclamptic women was 2.04 (1.53,2.71) and that in women with gestational hypertension was 1.37 (1.15,1.65), while the adjusted odds ratio (95% confidence interval) of having chronic kidney disease was 1.93 (1.44,2.57) and 1.36 (1.13,1.63) in preeclamptic women and women with gestational hypertension respectively compared to women who were normotensive in their first pregnancy. CONCLUSION: Women who had gestational hypertension or preeclampsia in their first pregnancy had a higher risk of impairment of renal function compared to women who were normotensive.

Pregnancy in type 2B VWD: a case series.

Type 2B von Willebrand disease (VWD) is a rare, inherited bleeding disorder resulting from a qualitative defect in von Willebrand factor (VWF). There is very little published information on how to quantify bleeding risk and manage haemostasis in type 2B VWD patients during pregnancy. This article presents the changes in VWF parameters and details of patient management and delivery outcomes for four pregnancies in three women with two different mutations causing type 2B VWD. We report an unexpected rise in the VWF:Ag at 37 weeks gestation in two sisters with R1306W associated with significant thrombocytopenia. These patients were supported with platelet transfusions as well as intermediate purity VWF-FVIII plasma concentrates during the peri- and postpartum periods. No thrombocytopenia was observed in our third case with a mutation encoding an R1308C substitution; haemostatic support was with intermediate purity VWF-FVIII plasma concentrates alone. No adverse bleeding events occurred and in all cases a live healthy infant was delivered. One patient was readmitted post partum with bleeding symptoms due to retained placenta; no further haemostatic support was given at this time. This case series is the first to detail the progression of laboratory parameters, management and outcomes of pregnancy in patients with type 2B VWD. The cases illustrate some of the challenges posed by the increased production of a VWF variant with a gain-of-function effect. The rapid coagulation changes observed in this series illustrate the need for continual monitoring of VWF parameters and platelet count throughout pregnancy in women with type 2B VWD.

UKHCDO guidelines on the management of HCV in patients with hereditary bleeding disorders 2011.

Chronic HCV infection continues to be of significant clinical importance in patients with hereditary bleeding disorders. This guideline provides information on the recent advances in the investigation and treatment of HCV infection and gives GRADE system based recommendations on the management of the infection in this patient group.

Ancient DNA recovers the origins of Maori feather cloaks.

Feather cloaks ("kakahu"), particularly those adorned with kiwi feathers, are treasured items or "taonga" to the Maori people of "Aotearoa"/New Zealand. They are considered iconic expression of Maori culture. Despite their status, much of our knowledge of the materials used to construct cloaks, the provenance of cloaks, and the origins of cloak making itself, has been lost. We used ancient DNA methods to recover mitochondrial DNA sequences from 849 feather samples taken from 109 cloaks. We show that almost all (>99%) of the cloaks were constructed using feathers from North Island brown kiwi. Molecular sexing of nuclear DNA recovered from 92 feather cloak samples also revealed that the sex ratio of birds deviated from a ratio of 1:1 observed in reference populations. Additionally, we constructed a database of 185 mitochondrial control region DNA sequences of kiwi feathers comprising samples collected from 26 North Island locations together with data available from the literature. Genetic subdivision (G(ST)), nucleotide subdivision (N(ST)) and Spatial Analysis of Molecular Variants (SAMOVA) analyses revealed high levels of genetic structuring in North Island brown kiwi. Together with sequence data from previously studied ancient and modern kiwi samples, we were able to determine the geographic provenance of 847 cloak feathers from 108 cloaks. A surprising proportion (15%) of cloaks were found to contain feathers from different geographic locations, providing evidence of kiwi trading among Maori tribes or organized hunting trips into other tribal areas. Our data also suggest that the east of the North Island of New Zealand was the most prolific of all kiwi cloak making areas, with over 50% of all cloaks analyzed originating from this region. Similar molecular approaches have the potential to discover a wealth of lost information from artifacts of endemic cultures worldwide.

The risk of variant Creutzfeldt-Jakob disease among UK patients with bleeding disorders, known to have received potentially contaminated plasma products.

The risk of variant Creutzfeldt-Jakob disease (vCJD) from potentially infected plasma products remains unquantified. This risk has been assessed for 787 UK patients with an inherited bleeding disorder prospectively followed-up for 10-20 years through the UK Haemophilia Centre Doctors' Organisation (UKHCDO) Surveillance Study. These patients had been treated with any of 25 'implicated' clotting factor batches from 1987 to 1999, which included in their manufacture, plasma from eight donors who subsequently developed clinical vCJD. Variant CJD infectivity of these batches was estimated using plasma fraction infectivity estimates and batch-manufacturing data. Total potential vCJD infectivity received by each patient has been estimated by cumulating estimated infectivity from all doses received during their lifetime. Of 787 patients, 604 (77%) were followed-up for over 13 years following exposure to an implicated batch. For these 604 patients, the estimated vCJD risk is ≥ 1% for 595, ≥ 50% for 164 and 100% for 51. This is additional to background UK population risk due to dietary exposure. Of 604 patients, 94 (16%) received implicated batches linked to donors who developed clinical vCJD within 6 months of their donations. One hundred and fifty-one (25%) had received their first dose when under 10 years of age. By 1st January 2009, none of these patients had developed clinical vCJD. The absence of clinical vCJD cases in this cohort to date suggests that either plasma fraction infectivity estimates are overly precautionary, or the incubation period is longer for this cohort than for implicated cellular blood product recipients. Further follow-up of this cohort is needed.