A core outcome set for trials in miscarriage management and prevention: An international consensus development study.

OBJECTIVE: To develop core outcome sets (COS) for miscarriage management and prevention. DESIGN: Modified Delphi survey combined with a consensus development meeting. SETTING: International. POPULATION: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes. CONCLUSIONS: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage.

Benchmarking calf health: Assessment tools for dairy herd health consultancy based on reference values from 730 German dairies with respect to seasonal, farm type, and herd size effects.

Good calf health is crucial for a successfully operating farm business and animal welfare on dairy farms. To evaluate calf health on farms and to identify potential problem areas, benchmarking tools can be used by farmers, herd managers, veterinarians, and other advisory persons in the field. However, for calves, benchmarking tools are not yet widely established in practice. This study provides hands-on application for on-farm benchmarking of calf health. Reference values were generated from a large dataset of the "PraeRi" study, including 730 dairy farms with a total of 13,658 examined preweaned dairy calves. At herd level, omphalitis (O, median 15.9%) was the most common disorder, followed by diarrhea (D, 15.4%) and respiratory disease (RD, 2.9%). Abnormal weight bearing (AWB) was rarely detected (median, 0.0%). Calves with symptoms of more than one disorder at the same time (multimorbidity, M) were observed with a prevalence of 2.3%. The enrolled farms varied in herd size, farm operating systems, and management practices and thus represented a wide diversity in dairy farming, enabling a comparison with similar managed farms in Germany and beyond. To ensure comparability of the data in practice, the reference values were calculated for the whole data set, clustered according to farm size (1-40 dairy cows (n = 130), 41-60 dairy cows (n = 99), 61-120 dairy cows (n = 180), 121-240 dairy cows (n = 119) and farms with more than 240 dairy cows (n = 138), farm operating systems (conventional (n = 666), organic (n = 64)) and month of the year of the farm visit. There was a slight tendency for smaller farms to have a lower prevalence of disorders. A statistically significant herd-size effect was detected for RD (p = 0.008) and D (p < 0.001). For practical application of these reference values, tables, diagrams, and an Excel® (Microsoft®) based calf health calculator were developed as tools for on-farm benchmarking (https://doi.org/10.6084/m9.figshare.c.6172753). In addition, this study provides a detailed description of the colostrum, feeding and housing management of preweaned calves in German dairy farms of different herd sizes and farm type (e.g., conventional and organic).

Predictors and Outcomes of Cardiac Events following Thoracic Endovascular Aortic Repair in Descending Thoracic Aortic Aneurysm and Dissection.

BACKGROUND: Cardiac events following thoracic endovascular aortic repair (TEVAR) have been associated with significant morbidity and mortality. However, predictors of post-TEVAR cardiac events in descending thoracic aortic aneurysm or dissection are poorly understood. METHODS: A retrospective analysis of completed TEVAR procedures performed from 2010 to 2016 was conducted using the ACS-NSQIP (American College of Surgeons National Surgical Quality Improvement Program) participant user file database. Adult patients (≥18 years) who underwent TEVAR for descending thoracic aortic aneurysm or dissection were identified and 30-day outcomes were examined. An initial univariate analysis was performed to determine associations between all patient variables and cardiac events, defined as myocardial infarction or cardiac arrest that occurred ≤30 days of surgery. Multivariate logistic regression was subsequently performed to identify independent risk factors for cardiac events following TEVAR. RESULTS: The study identified 150 out of 2,905 (5.2%) patients who underwent TEVAR for descending thoracic aortic aneurysm or dissection who developed cardiac events. No significant difference in incidence of cardiac events was noted among patients presenting with aortic aneurysm or dissection (p = 0.339). The overall 30-day mortality rate for all patients was 9.1%. Independent preoperative predictors of post-TEVAR cardiac events included emergency procedure (odds ratio [OR] 2.80, 95% confidence interval [CI] 1.9-4.1, p < 0.01); American Society of Anesthesiologists score >3 (OR 1.71, 95% CI 1.1-2.6, p = 0.01), ventilator dependence (OR 2.33, 95% CI 1.3-4.2, p < 0.01), renal failure (OR 2.53, 95% CI 1.50-4.3, p < 0.01), blood transfusion (OR 1.84, 95% CI 1.1-3.2, p = 0.03), and preoperative leukocytosis (OR 2.45, 1.6-3.8, p < 0.01). After TEVAR, unplanned reintubation (OR 5.52, 95% CI 3.5-8.8, p < 0.01), prolonged mechanical ventilation (OR 1.94, 95% CI 1.2-3.2, p = 0.011), and postoperative blood transfusion (OR 4.02, 95% CI 2.70-6.0, p < 0.01) were independent predictors of cardiac events. Cardiac events greatly increased mortality (60.7 vs. 5.5%), total length of hospital stay (13.2 ± 14.7 days vs. 8.3 ± 9.3 days), and readmission rates (19.3 vs. 8.2%, p < 0.01). CONCLUSIONS: Cardiac events following TEVAR are associated with significant mortality. Patients with these risk factors should be appropriately monitored to improve outcomes.

Effect of Resident Involvement on Morbidity and Mortality Following Thoracic Endovascular Aortic Repair.

OBJECTIVE: To evaluate the effect of resident involvement in thoracic endovascular aortic repair (TEVAR). SUMMARY OF BACKGROUND DATA: Although the influence of resident intraoperative involvement in several types of surgical procedures has been reported, the effect of resident participation in TEVAR is unknown. We evaluated patient outcomes in resident-involved TEVAR procedures. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was analyzed for TEVAR performed from 2010 to 2012. Current procedural terminology codes were used to identify adult patients (≥18 y) who underwent TEVAR. Patients were grouped into those with and without resident involvement. Descriptive and binomial logistic statistics were used to determine the effect of resident involvement on post-TEVAR outcomes. p values < 0.05 were considered statistically significant. RESULTS: A total of 676 patients met inclusion criteria for this study. Of these, 517 (76.5%) had residents involved. Overall mortality was 9.8%, with no significant difference between the 2 groups (p = 0.88). Resident involvement was not a significant predictor of any post-TEVAR complication. Postoperative pneumonia (3.5% vs 6.9%, p = 0.06), prolonged mechanical ventilation (11.8% vs 11.9%, p = 0.96), stroke (2.7% vs 5.7%, p = 0.07), urinary tract infection (3.3% vs 4.4%, p = 0.50), progressive renal insufficiency (1.2% vs 2.5%, p = 0.22), acute renal failure (4.1% vs 5.0%, p = 0.60), cardiac arrest (2.9% vs 5.0%, p = 0.20), myocardial infarction (1.7% vs 1.9%, p = 0.91), deep venous thrombosis (1.7% vs 1.3%, p = 0.67), red blood cells transfusions (29.2% vs 36.5%, p = 0.08), sepsis (2.9% vs 4.4%, p = 0.35), septic shock (1.9% vs 3.8%, p = 0.18), and unplanned reintubation (8.7% vs 9.4%, p = 0.78) were not significantly affected. Additionally, resident involvement did not significantly affect operative time (176.1 ± 122.8 min vs 180.3 ± 119.1 min, p = 0.71) and anesthesia time (282.1 ± 146.6 min vs 278.3 ± 140.5 min, p = 0.78). CONCLUSIONS: The participation of residents in TEVAR did not significantly affect all 30-day patient outcomes. Resident involvement in TEVAR is safe and should be encouraged. MINI ABSTRACT: This study evaluated the effect of resident participation on postoperative outcomes of thoracic endovascular aortic repair (TEVAR) using the American College of Surgeons National Surgical Quality Improvement (ACS-NSQIP) database. Results showed that resident involvement in TEVAR does not negatively affect patient outcomes.

Graft preservation solutions in cardiovascular surgery.

Vein grafts are still the most commonly used graft material in cardiovascular surgery and much effort has been spent in recent years on investigating the optimal harvesting technique. One other related topic of similar importance remained more or less an incidental one. The storage solutions of vein grafts following procurement and prior to implantation are, despite their assumed impact, a relatively neglected theme. There is no doubt that the endothelium plays a key role in long-term patency of vein grafts, but the effects of the different storage solutions on the endothelium remain unclear : In a review of the literature, we could find 20 specific papers that addressed the question, of which the currently available preservation solutions are superior, harmless, damaging or ineffective. The focus lies on saline and autologous whole blood. Besides these two storage media, novel or alternative solutions have been investigated with surprising findings. In addition, a few words will be spent on potential alternatives and novel solutions on the market. As there is currently no randomized clinical trial regarding saline versus autologous whole blood available, this review compares all previous studies and methods of analysis to provide a certain level of evidence on this topic. In summary, saline has negative effects on the endothelial layers and therefore may compromise graft patency. Related factors, such as distension pressure, may outbalance the initial benefit of autologous whole blood or storage solutions and intensify the harmful effects of warm saline. In addition, there is no uniform consent on the superiority of autologous whole blood for vein graft storage. This may open the door to alternatives such as the University of Wisconsin solution or one of the specific designed storage solutions like TiProtec™ or Somaluthion™. Whether these preservation solutions are superior or advantageous remains the subject of further studies.

Thermal probe maskless lithography for 27.5 nm half-pitch Si technology.

Thermal scanning probe lithography is used for creating lithographic patterns with 27.5 nm half-pitch line density in a 50 nm thick high carbon content organic resist on a Si substrate. The as-written patterns in the poly phthaladehyde thermal resist layer have a depth of 8 nm, and they are transformed into high-aspect ratio binary patterns in the high carbon content resist using a SiO2 hard-mask layer with a thickness of merely 4 nm and a sequence of selective reactive ion etching steps. Using this process, a line-edge roughness after transfer of 2.7 nm (3σ) has been achieved. The patterns have also been transferred into 50 nm deep structures in the Si substrate with excellent conformal accuracy. The demonstrated process capabilities in terms of feature density and line-edge roughness are in accordance with today's requirements for maskless lithography, for example for the fabrication of extreme ultraviolet (EUV) masks.

Complement fragment 3a priming of umbilical cord blood progenitors: safety profile.

Preclinical data showed that priming CD34(+) hematopoietic progenitor cells with complement fragment 3a (C3a) improved homing and engraftment. Thus, we hypothesized that priming of umbilical cord blood (UCB) hematopoietic progenitors with C3a would facilitate homing and could potentially be used to address the need for improved engraftment after UCB transplantation. We primed 1 of 2 UCB units for double UCB transplantation after nonmyeloablative conditioning. This design provided adequate safety and the potential to observe skewed long-term chimerism in favor of the C3a-primed unit as a surrogate measure of efficacy. C3a priming of 1 UCB unit did not result in infusional toxicity. Increased grades 1 to 3 hypertension were the only infusional adverse events observed in 9 (30%) patients. We observed no activation of inflammatory or coagulation pathways downstream of C3a. As tested, C3a priming did not impair engraftment, but did not skew chimerism toward the treated unit. As compared with historical controls, mortality and survival were not adversely affected. Thus, before any additional clinical studies, C3a priming to promote engraftment will require further preclinical optimization.

Inkjet-printed graphene electronics.

We demonstrate inkjet printing as a viable method for large-area fabrication of graphene devices. We produce a graphene-based ink by liquid phase exfoliation of graphite in N-methylpyrrolidone. We use it to print thin-film transistors, with mobilities up to ∼95 cm(2) V(-1) s(-1), as well as transparent and conductive patterns, with ∼80% transmittance and ∼30 kΩ/□ sheet resistance. This paves the way to all-printed, flexible, and transparent graphene devices on arbitrary substrates.

Directed placement of gold nanorods using a removable template for guided assembly.

We have used a temperature sensitive polymer film as a removable template to position, and align, gold nanorods onto an underlying target substrate. Shape-matching guiding structures for the assembly of nanorods of size 80 nm × 25 nm have been written by thermal scanning probe lithography. The nanorods were assembled into the guiding structures, which determine both the position and the orientation of single nanorods, by means of capillary interactions. Following particle assembly, the polymer was removed cleanly by thermal decomposition and the nanorods are transferred to the underlying substrate. We have thus demonstrated both the placement and orientation of nanorods with an overall positioning accuracy of ≈10 nm onto an unstructured target substrate.

Rapid turnaround scanning probe nanolithography.

Scanning probe nanolithography (SPL) has demonstrated its potential in a variety of applications like 3D nanopatterning, 'direct development' lithography, dip-pen deposition or patterning of self-assembled monolayers. One of the main issues holding back SPL has been the limited throughput for patterning and imaging. Here we present a complete lithography and metrology system based on thermomechanical writing into organic resists. Metrology is carried out using a thermoelectric topography sensing method. More specifically, we demonstrate a system with a patterning pixel clock of 500 kHz, 20 mm s(-1) linear scan speed, a positioning accuracy of 10 nm, a read-back frequency bandwidth of 100, 000 line-pairs s(-1) and a turnaround time from patterning to qualifying metrology of 1 min. Thus, we demonstrate a nanolithography system capable of implementing rapid turnaround.

Systemic activation of integrin alphaVbeta3 in donors with spontaneous intracerebral hemorrhage is associated with subsequent development of vasculopathy in the heart transplant recipient.

BACKGROUND: Recipients of hearts from donors with spontaneous intracerebral hemorrhage (ICH) are at increased risk of allograft vasculopathy compared with trauma donors. We have recently shown that the vitronectin receptor (integrin alpha(V)beta3) is upregulated in transplant vasculopathy. We hypothesized that donor ICH is associated with systemic activation of alpha(V)beta3 in the donor before transplantation. METHODS: We evaluated mRNA expressions of alpha(V)beta3 (TaqMan PCR) in endomyocardial biopsy samples at 1-week post-transplant in 20 recipients from ICH donors and 20 recipients from trauma donors. To investigate whether systemic activation of alpha(V)beta3 was present in the donor before transplantation, alpha(V)beta3 expression was also evaluated in the corresponding donor spleen lymphocytes. All patients underwent serial coronary intravascular ultrasound to evaluate for coronary vasculopathy. The baseline characteristics were similar except for increased donor age in the ICH Group. RESULTS: The ICH Group showed significant increased mRNA expression of alpha(V)beta3 in the heart biopsy samples (3.8-fold, p = 0.012) and in the corresponding donor spleen lymphocytes (3.5-fold, p = 0.014) compared with the Trauma Group. At 1 year, the ICH Group also showed increased progression of coronary vasculopathy. Multivariate regression analysis found that donor lymphocytic alpha(V)beta3 mRNA expression was independently associated with increased risk of vasculopathy (odds ratio, 1.9; 95% CI, 1.21-3.98, p = 0.03). CONCLUSIONS: Our report demonstrates the presence of systemic activation of alpha(V)beta3 in donors with spontaneous intracerebral hemorrhage and its association with the subsequent development of allograft vasculopathy in the recipient.

Single-molecule dilution and multiple displacement amplification for molecular haplotyping.

Separate haploid analysis is frequently required for heterozygous genotyping to resolve phase ambiguity or confirm allelic sequence. We demonstrate a technique of single-molecule dilution followed by multiple strand displacement amplification to haplotype polymorphic alleles. Dilution of DNA to haploid equivalency, or a single molecule, is a simple method for separating di-allelic DNA. Strand displacement amplification is a robust method for non-specific DNA expansion that employs random hexamers and phage polymerase Phi29 for double-stranded DNA displacement and primer extension, resulting in high processivity and exceptional product length. Single-molecule dilution was followed by strand displacement amplification to expand separated alleles to microgram quantities of DNA for more efficient haplotype analysis of heterozygous genes.

Microchip separations of protein biotoxins using an integrated hand-held device.

We report the development of a hand-held instrument capable of performing two simultaneous microchip separations (gel and zone electrophoresis), and demonstrate this instrument for the detection of protein biotoxins. Two orthogonal analysis methods are chosen over a single method in order to improve the probability of positive identification of the biotoxin in an unknown mixture. Separations are performed on a single fused-silica wafer containing two separation channels. The chip is housed in a microfluidic manifold that utilizes o-ring sealed fittings to enable facile and reproducible fluidic connection to the chip. Sample is introduced by syringe injection into a septum-sealed port on the device exterior that connects to a sample loop etched onto the chip. Detection of low nanomolar concentrations of fluorescamine-labeled proteins is achieved using a miniaturized laser-induced fluorescence detection module employing two diode lasers, one per separation channel. Independently controlled miniature high-voltage power supplies enable fully programmable electrokinetic sample injection and analysis. As a demonstration of the portability of this instrument, we evaluated its performance in a laboratory field test at the Defence Science and Technology Laboratory with a series of biotoxin variants. The two separation methods cleanly distinguish between members of a biotoxin test set. Analysis of naturally occurring variants of ricin and two closely related staphylococcal enterotoxins indicates the two methods can be used to readily identify ricin in its different forms and can discriminate between two enterotoxin isoforms.

Systemic up-regulation of angiotensin II type 1 receptor in cardiac donors with spontaneous intracerebral hemorrhage.

Donor spontaneous intracerebral hemorrhage (ICH) is a potential risk factor for morbidity and mortality after cardiac transplantation. We hypothesized that donor ICH is associated with systemic up-regulation of angiotensin II receptor type 1 (AT1R). We evaluated mRNA expression of AT1R and AT2R in donor spleen lymphocytes and in heart biopsies from 20 recipients of hearts from donors with spontaneous ICH which were compared with 20 recipients from trauma donors. Heart biopsies showed 4.7-fold increased mRNA expression of AT1R (p < 0.0001) in the ICH group compared with the Trauma group. The ICH group also showed 2.6-fold (p < 0.01) increased mRNA expression of AT1R in the donor spleen lymphocytes, suggesting the presence of systemic activation before transplantation. At 1 year, the ICH group had increased coronary vasculopathy by vascular ultrasound. Using multivariate regression analysis, mRNA expression of AT1R in the donor spleen lymphocytes was found to be a strong independent predictor of transplant vasculopathy (odds ratio = 4.397, CI = 1.243-15.553, adjusted p = 0.02). This is the first report to describe splenic up-regulation of AT1R in the presence of spontaneous ICH and its association with subsequent development of transplant vasculopathy.

Angiotensin II receptors from peritransplantation through first-year post-transplantation and the risk of transplant coronary artery disease.

OBJECTIVES: We evaluated whether the angiotensin II (Ang II) receptors from perioperation through one-year post-transplantation predict the transplant coronary artery disease (TCAD) progression. BACKGROUND: The role of Ang II receptors (type 1: AT(1)R; type 2: AT(2)R) in TCAD is uncertain. METHODS: We investigated 28 heart donors and the corresponding recipients. The levels of AT(1)R and AT(2)R messenger ribonucleic acid (mRNA) were examined in lymphocytes from the donor spleen and in the donor heart at one-week and one-year posttransplantation to determine their association with the progression of TCAD, measured as changes in maximal intimal thickness (CMIT) and plaque volume (CPV) by intravascular ultrasound (IVUS) examinations. RESULTS: The AT(1)R mRNA in lymphocytes from the donor spleen (CMIT: r = 0.73, p < 0.0001; CPV: r = 0.69, p < 0.0001) and in the donor hearts at one-week (CMIT: r = 0.52, p = 0.005; CPV: r = 0.56, p = 0.002) and at one-year (CMIT: r = 0.63, p < 0.0001; CPV: r = 0.43, p = 0.004) post-transplantation along with AT(2)R mRNA in the donor hearts at one-year post-transplantation (CMIT: r = 0.3, p < 0.0001; CPV: r = 0.53, p = 0.009) were univariate predictors, whereas AT(1)R mRNA in lymphocytes and in the donor hearts at one-year post-transplantation proved to be multivariate predictors of the progression of TCAD. CONCLUSIONS: These data suggest a role for Ang II receptors in the pathogenesis of TCAD and support a novel concept that TCAD may have its origin in the donor per se and may be modulated by the recipient's inherent biological factors.

Donor spontaneous intracerebral hemorrhage is associated with systemic activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 and subsequent development of coronary vasculopathy in the heart transplant recipient.

BACKGROUND: Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the progression of hemorrhagic stroke. We hypothesized that donor intracerebral hemorrhage (ICH) is associated with activation of the metalloproteinases before transplantation that play a key role in the subsequent development of transplant vasculopathy. METHODS AND RESULTS: We evaluated mRNA expressions of MMP-2 and MMP-9 in donor spleen lymphocytes (before transplantation) and in heart biopsies at 1 week after transplantation in 20 recipients from ICH donors and 20 recipients from trauma donors. Patients underwent serial coronary intravascular ultrasound, and interstitial myocardial fibrosis was quantified at 1 year. The baseline characteristics were similar except for increased donor age in the ICH group. Heart biopsies from the ICH group showed significant increased expression of MMP-2 (17-fold, P<0.0001) and MMP-9 (20-fold, P<0.0001) compared with the trauma group. Furthermore, the ICH group showed 1.8-fold (P=0.016) increased mRNA expression of MMP-2 and 1.7-fold (P=0.015) increased mRNA expression of MMP-9 in the donor spleen lymphocytes, suggesting the presence of systemic activation of metalloproteinases before transplantation. At 1 year, the ICH group showed increased myocardial fibrosis and accelerated coronary vasculopathy. Using multivariate regression analysis, MMP-9 was found to be associated with increased risk for vasculopathy independent of donor age (OR, 2.41; P=0.01; 95% CI, 1.24 to 4.69). CONCLUSIONS: This is the first report to describe systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of allograft vasculopathy.