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STUDY QUESTION Are novel circulating placental markers prokineticin-1 (PK-1), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PlGF) associated with late miscarriage in asymptomatic first trimester pregnant women? SUMMARY ANSWER Increased serum sFlt-1 or PlGF, but not sEng or PK-1, were significantly associated with reduced miscarriage risk after adjustment for age, BMI, gestational age, smoking and blood pressure. WHAT IS KNOWN ALREADY Abnormal placental development is observed in two-thirds of miscarriages. Identifying women at high risk of late miscarriage could help diagnose potentially treatable causes of miscarriage such as infection, thrombosis or immunological disease. Recently, the circulating placental markers PK-1, sFlt-1, sEng and PlGF have been identified; however, it is not known if circulating levels of these markers are associated with late miscarriage. STUDY DESIGN, SIZE, DURATION A single-centre observational cohort study with prospectively collected data was carried out at a tertiary care centre 2010-2012, in 993 asymptomatic pregnant women. Plasma PK-1, and serum sEng, sFlt-1 and PlGF were measured once in each patient during the antenatal booking visit, and pregnancy outcome was monitored prospectively. Less than 1% of patients were lost to follow-up. Multiples of median (MOM) levels were calculated to adjust for gestational age. PARTICIPANTS/MATERIALS, SETTING, METHODS Nine-hundred and ninety-three asymptomatic pregnant women attending antenatal clinic for a routine booking antenatal appointment were recruited to the study, of whom 12 were lost to follow-up and excluded from analysis. Of the cohort, 50 of the remaining 981 women suffered late miscarriage. MAIN RESULTS AND THE ROLE OF CHANCE Gestation-adjusted sEng, sFlt-1 and PlGF levels were 11% (P

Background Because of improved surgical expertise and intraoperative management, pleural disease (PD+) represents a relatively minor contraindication to lung transplantation (LTx). The presence of pleural abnormalities from previous procedures or pleural involvement from fungal or bacterial disease is not considered a limiting factor for LTx. However there are no studies available to assess the impact of pleural diseases on short- and midterm outcomes after LTx. Methods We retrospectively reviewed 163 consecutive patients who underwent LTx between 2010 and 2013. Patients were divided according to the presence of pleural abnormalities before the operation (PD+ versus PD–). The primary end point of the study was primary graft dysfunction (PGD; grade 3) and overall survival. To avoid possible selection bias and to heck the robustness of the results, a propensity score–matching analysis (1:3) was performed. Results A total of 26 patients (16%) had pleural abnormalities before transplantation. Intra- and postoperative variables were comparable. PD+ was associated with a significantly higher incidence of PGD at 0 and 48 hours postoperatively ( p = 0.037 and p = 0.032, respectively). Moreover, PD+ was associated with significantly worse survival at 3 months ( p = 0.021). Although there was a trend toward worse early overall survival in the Kaplan-Meier estimate (Breslow p = 0.050), midterm survival was comparable (log-rank p = 0.240). Conclusions LTx in patients with preoperative pleural abnormalities is feasible. Identifying higher-risk recipients with pleural abnormalities might have important clinical relevance because of a higher incidence of PGD and worse early survival, even though midterm survival is comparable.

Male testosterone levels decline by 1% per year from the age of 40 years. Whilst a primary testicular deficit occurs, hypothalamic or pituitary dysregulation may also coexist. This study aimed to compare the hypothalamic response to kisspeptin-54 and the pituitary response to gonadotropin-releasing hormone (GnRH) of older men with those of young men.Following 1 h of baseline sampling, healthy older men (n = 5, mean age 59.3 ± 2.9 years) received a 3-h intravenous infusion of either vehicle, kisspeptin-54 0.1, 0.3, or 1.0 nmol/kg/h or GnRH 0.1 nmol/kg/h, on five different study days. Serum gonadotropins and total testosterone were measured every 10 min and compared to those of young men (n = 5/group) (mean age 28.9 ± 2.0 years) with a similar body mass index (24 kg/m2) who underwent the same protocol.Kisspeptin-54 and GnRH significantly stimulated serum gonadotropin release in older men compared to vehicle (p0.001 for all groups). Gonadotropin response to kisspeptin-54 was at least preserved in older men when compared to young men. At the highest dose of kisspeptin-54 (1.0 nmol/kg/h), a significantly greater luteinising hormone (LH) (p = 0.003) response was observed in older men. The follicle-stimulating hormone (FSH) response to GnRH was increased in older men (p = 0.002), but the LH response was similar (p = 0.38). Serum testosterone rises following all doses of kisspeptin-54 (p ≤ 0.009) were reduced in older men.Our data suggest that healthy older men without late-onset hypo-gonadism (LOH) have preserved hypothalamic response to kisspeptin-54 and pituitary response to GnRH, but impaired testicular response. Further work is required to investigate the use of kisspeptin-54 to identify hypothalamic deficits in men with LOH.

Arterial endothelial cells maintain vascular homeostasis and vessel tone in part through the secretion of nitric oxide (NO). In this study, we determined how aortic valve endothelial cells (VEC) regulate aortic valve interstitial cell (VIC) phenotype and matrix calcification through NO. Using an anchored in vitro collagen hydrogel culture system, we demonstrate that three-dimensionally cultured porcine VIC do not calcify in osteogenic medium unless under mechanical stress. Co-culture with porcine VEC, however, significantly attenuated VIC calcification through inhibition of myofibroblastic activation, osteogenic differentiation, and calcium deposition. Incubation with the NO donor DETA-NO inhibited VIC osteogenic differentiation and matrix calcification, whereas incubation with the NO blocker l-NAME augmented calcification even in 3D VIC–VEC co-culture. Aortic VEC, but not VIC, expressed endothelial NO synthase (eNOS) in both porcine and human valves, which was reduced in osteogenic medium. eNOS expression was reduced in calcified human aortic valves in a side-specific manner. Porcine leaflets exposed to the soluble guanylyl cyclase inhibitor ODQ increased osteocalcin and α-smooth muscle actin expression. Finally, side-specific shear stress applied to porcine aortic valve leaflet endothelial surfaces increased cGMP production in VEC. Valve endothelial-derived NO is a natural inhibitor of the early phases of valve calcification and therefore may be an important regulator of valve homeostasis and pathology.

Objectives The aims of this study were to compare long-term results after homograft versus Freestyle (Medtronic Inc., Minneapolis, Minnesota) aortic root replacement. Background The ideal substitute for aortic root replacement remains undetermined. Methods Between 1997 and 2005, 166 patients (age 65 ± 8 years) undergoing total aortic root replacement were randomized to receive a homograft (n = 76) or a Freestyle bioprosthesis (n = 90). Six patients randomly assigned to homograft crossed over to Freestyle because of unavailability of suitably sized homografts. Median follow-up was 7.6 years (maximum 11 years; 1,035 patient-years). “Evolving” aortic valve dysfunction was defined as aortic regurgitation ≥2/4 and/or peak gradient >20 mm Hg. Results Patient characteristics were comparable between groups. Concomitant procedures were performed in 44% and 47% of Freestyle and homograft patients, respectively (p = 0.5). Overall hospital mortality was 4.8% (1% for isolated root replacement). Eight-year survival was 80 ± 5% in the Freestyle group versus 77 ± 6% in the homograft group (p = 0.9). Freedom from need for reoperation at 8 years was significantly higher after Freestyle root replacement (100 ± 0% vs. 90 ± 5% after homograft replacement; p = 0.02). All reoperations were secondary to structural valve deterioration (n = 6). At last echocardiographic follow-up, actuarial freedom from evolving aortic valve dysfunction was 86 ± 5% for Freestyle bioprostheses versus 37 ± 7% for homografts (p Conclusions In this patient group, late survival is similar after homograft versus Freestyle root replacement. However, Freestyle aortic root replacement is associated with significantly less progressive aortic valve dysfunction and a lower need for reoperations.

Background The management of patients in a cardiothoracic centre requires effective interaction between clinical care groups. CRRISiS (Clinical Risk Reduction in Simulated Settings) was developed to support this. These high-fidelity, simulation sessions involve the multidisciplinary-team across departments. A debrief structure focussing on human factors and clinical outcomes facilitates a ‘common debrief language’ across departments. We report participant feedback from our first 2 years. Methodology 43 training sessions were delivered across cardiology, transplant, intensive care and cardiothoracic departments. All staff were encouraged to attend and signed consent forms. Sessions commenced with an introduction to crisis resource management principles. A structured, step-wise, immersive simulation followed with events occurring in real time, with staff participating in their clinical roles. Scenarios were based on a previously challenging clinical situation or “never events”. These included cardiac tamponade and fluoroscopic failure during primary angioplasty. Each scenario was followed by a debrief, facilitated by a simulation instructor, reflecting on both clinical and human factors. The simulation team included teaching fellows, resuscitation officers, allied healthcare professionals and consultants. Feedback was collected using Likert Scale. Results 202 responses were analysed (16 physiologists, 13 radiographers, 8 students, 3 healthcare assistants, 7 physiotherapists, 50 nurses, 30 junior doctors, 6 registrars, 6 consultants, 68 other/unknown). Group sizes varied from 4–23 staff. 99.5% agreed/strongly agreed that the scenario felt realistic and they had increased awareness of human factors. 99.2% felt they had increased their clinical knowledge and enhanced inter-professional relationships. 99.5% would recommend to colleagues and like to attend more sessions. Conclusions Implementation of a formal simulation-training programme across a specialist centre is possible. Although it is difficult to assess whether attendance at CRRISiS sessions impacts upon clinical outcomes, candidates have reported improvements in awareness of human factors, clinical knowledge and inter-professional relationships. Moving forward, this may have positive implications for patient care.

Neurokinin B (NKB) is a hypothalamic neuropeptide binding preferentially to the neurokinin 3 receptor. Expression of the gene encoding NKB is elevated in postmenopausal women. Furthermore, rodent studies suggest that NKB signalling may mediate menopausal hot flushes. However, the effects of NKB administration on hot flushes have not been investigated in humans. To address this, we performed a randomised, double-blinded, placebo-controlled, 2-way cross-over study. Ten healthy women were admitted to a temperature and humidity-controlled research unit. Participants received 30 minute intravenous infusions of NKB and vehicle in random order. Symptoms, heart rate, blood pressure, sweating and skin temperature were compared between NKB and vehicle in a double-blinded manner. Eight of ten participants experienced flushing during NKB infusion with none experiencing flushing during vehicle infusion (P = 0.0007). Significant elevations in heart rate (P = 0.0106 vs. pre-symptoms) and skin temperature measured using skin probe (P = 0.0258 vs. pre-symptoms) and thermal imaging (P = 0.0491 vs. pre-symptoms) characteristic of menopausal flushing were observed during hot flush episodes. Our findings provide evidence that NKB administration can cause hot flushes in women. Further studies are required to determine if pharmacological blockade of NKB signalling could inhibit hot flushes during the menopause and during treatment for sex-steroid dependent cancers.

Context: Kisspeptin is a recently identified hormone encoded by the KISS1 gene, playing a critical role in human reproduction. Plasma kisspeptin levels rise dramatically during normal pregnancy due to placental synthesis, which implicates it as a potential tool for assessing risks of pregnancy complications. No previous prospective study has investigated the association between plasma kisspeptin and risk of miscarriage. Objective: The objective of the study was to determine whether a single plasma kisspeptin or serum human chorionic gonadotropin (hCG) measurement in asymptomatic women attending their booking antenatal visit is associated with miscarriage. Design: This was a prospective cohort study. Setting: The study was conducted at a tertiary obstetric center. Participants: A total of 993 asymptomatic pregnant women with a gestation of 6 weeks or longer attending routine antenatal booking visit were recruited between January 2010 and December 2012. Main Outcome Measures: Plasma kisspeptin and serum hCG were measured during the antenatal booking visit. Pregnancy outcome was recorded prospectively. Results: Plasma kisspeptin correlated with gestation (r2 = 0.57; P < .0001). Gestational age-corrected (multiples of median) plasma kisspeptin was 60.4% lower (P < .001), and multiples of median-hCG was 36.1% lower (P < .001) in women later diagnosed with miscarriage compared with women without miscarriage. Increased plasma kisspeptin was associated with reduced miscarriage risk, even after adjusting for age, body mass index, gestational age, smoking, and blood pressure [odds ratio 0.13 (95% confidence interval 0.08–0.22), P = .0001]. Kisspeptin had a higher diagnostic performance for miscarriage than hCG (receiver-operator characteristic-area under the curve 0.899 ± 0.025 plasma kisspeptin; 0.775 ± 0.040, serum hCG, P < .01 vs plasma kisspeptin). Conclusion: Our data suggest for the first time that a single plasma kisspeptin measurement taken during the antenatal booking visit provides a potential novel marker for identifying asymptomatic pregnant women at a gestation of 6 weeks or greater at increased risk of miscarriage.

The choice of the graft conduit for coronary artery bypass grafting (CABG) has significant implications both in the short- and long-term. The patency of a coronary conduit is closely associated with an uneventful postoperative course, better long-term patient survival and superior freedom from re-intervention. The internal mammary artery is regarded as the primary conduit for CABG patients, given its association with long-term patency and survival. However, long saphenous vein (LSV) continues to be utilized universally as patients presenting for CABG often have multiple coronary territories requiring revascularization. Traditionally, the LSV has been harvested by creating incisions from the ankle up to the groin termed open vein harvesting (OVH). However, such harvesting methods are associated with incisional pain and leg wound infections. In addition, patients find such large incisions to be cosmetically unappealing. These concerns regarding wound morbidity and patient satisfaction led to the emergence of endoscopic vein harvesting (EVH). Published experience comparing OVH with EVH suggests decreased wound related complications, improved patient satisfaction, shorter hospital stay, and reduced postoperative pain at the harvest site following EVH. Despite these reported advantages concerns regarding risk of injury at the time of harvest with its potential detrimental effect on vein graft patency and clinical outcomes have prevented universal adoption of EVH. This review article provides a detailed insight into the technical aspects, outcomes, concerns, and controversies associated with EVH.

Arterial endothelial cells maintain vascular homeostasis and vessel tone in part through the secretion of nitric oxide (NO). In this study, we determined how aortic valve endothelial cells (VEC) regulate aortic valve interstitial cell (VIC) phenotype and matrix calcification through NO. Using an anchored in vitro collagen hydrogel culture system, we demonstrate that three-dimensionally cultured porcine VIC do not calcify in osteogenic medium unless under mechanical stress. Co-culture with porcine VEC, however, significantly attenuated VIC calcification through inhibition of myofibroblastic activation, osteogenic differentiation, and calcium deposition. Incubation with the NO donor DETA-NO inhibited VIC osteogenic differentiation and matrix calcification, whereas incubation with the NO blocker l-NAME augmented calcification even in 3D VIC–VEC co-culture. Aortic VEC, but not VIC, expressed endothelial NO synthase (eNOS) in both porcine and human valves, which was reduced in osteogenic medium. eNOS expression was reduced in calcified human aortic valves in a side-specific manner. Porcine leaflets exposed to the soluble guanylyl cyclase inhibitor ODQ increased osteocalcin and α-smooth muscle actin expression. Finally, side-specific shear stress applied to porcine aortic valve leaflet endothelial surfaces increased cGMP production in VEC. Valve endothelial-derived NO is a natural inhibitor of the early phases of valve calcification and therefore may be an important regulator of valve homeostasis and pathology.

Background The ideal substitute for aortic valve replacement in patients with aortic valve disease is not known. Our hypothesis was that the regulatory and adaptive properties of a living valve substitute could improve the long-term outcomes in patients. We therefore compared these outcomes after autograft aortic root replacement (Ross procedure) versus homograft aortic root replacement in adults. Methods Male and female patients (

The aims of this study were to compare long-term results after homograft versus Freestyle (Medtronic Inc., Minneapolis, Minnesota) aortic root replacement.The ideal substitute for aortic root replacement remains undetermined.Between 1997 and 2005, 166 patients (age 65 +/- 8 years) undergoing total aortic root replacement were randomized to receive a homograft (n = 76) or a Freestyle bioprosthesis (n = 90). Six patients randomly assigned to homograft crossed over to Freestyle because of unavailability of suitably sized homografts. Median follow-up was 7.6 years (maximum 11 years; 1,035 patient-years). "Evolving" aortic valve dysfunction was defined as aortic regurgitation/=2/4 and/or peak gradient20 mm Hg.Patient characteristics were comparable between groups. Concomitant procedures were performed in 44% and 47% of Freestyle and homograft patients, respectively (p = 0.5). Overall hospital mortality was 4.8% (1% for isolated root replacement). Eight-year survival was 80 +/- 5% in the Freestyle group versus 77 +/- 6% in the homograft group (p = 0.9). Freedom from need for reoperation at 8 years was significantly higher after Freestyle root replacement (100 +/- 0% vs. 90 +/- 5% after homograft replacement; p = 0.02). All reoperations were secondary to structural valve deterioration (n = 6). At last echocardiographic follow-up, actuarial freedom from evolving aortic valve dysfunction was 86 +/- 5% for Freestyle bioprostheses versus 37 +/- 7% for homografts (p0.001). Clinically, freedom from New York Heart Association functional class III to IV and freedom from valve-related complications were similar between groups (p = 0.7 and p = 0.9, respectively).In this patient group, late survival is similar after homograft versus Freestyle root replacement. However, Freestyle aortic root replacement is associated with significantly less progressive aortic valve dysfunction and a lower need for reoperations.