Antifibrinolytics for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding (HMB) is an important physical and social problem for women. Oral treatment for HMB includes antifibrinolytic drugs, which are designed to reduce bleeding by inhibiting clot-dissolving enzymes in the endometrium.Historically, there has been some concern that using the antifibrinolytic tranexamic acid (TXA) for HMB may increase the risk of venous thromboembolic disease. This is an umbrella term for deep venous thrombosis (blood clots in the blood vessels in the legs) and pulmonary emboli (blood clots in the blood vessels in the lungs). OBJECTIVES: To determine the effectiveness and safety of antifibrinolytic medications as a treatment for heavy menstrual bleeding. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO and two trials registers in November 2017, together with reference checking and contact with study authors and experts in the field. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing antifibrinolytic agents versus placebo, no treatment or other medical treatment in women of reproductive age with HMB. Twelve studies utilised TXA and one utilised a prodrug of TXA (Kabi). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary review outcomes were menstrual blood loss (MBL), improvement in HMB, and thromboembolic events. MAIN RESULTS: We included 13 RCTs (1312 participants analysed). The evidence was very low to moderate quality: the main limitations were risk of bias (associated with lack of blinding, and poor reporting of study methods), imprecision and inconsistency.Antifibrinolytics (TXA or Kabi) versus no treatment or placeboWhen compared with a placebo, antifibrinolytics were associated with reduced mean blood loss (MD -53.20 mL per cycle, 95% CI -62.70 to -43.70; I² = 8%; 4 RCTs, participants = 565; moderate-quality evidence) and higher rates of improvement (RR 3.34, 95% CI 1.84 to 6.09; 3 RCTS, participants = 271; moderate-quality evidence). This suggests that if 11% of women improve without treatment, 43% to 63% of women taking antifibrinolytics will do so. There was no clear evidence of a difference between the groups in adverse events (RR 1.05, 95% CI 0.93 to 1.18; 1 RCT, participants = 297; low-quality evidence). Only one thromboembolic event occurred in the two studies that reported this outcome.TXA versus progestogensThere was no clear evidence of a difference between the groups in mean blood loss measured using the Pictorial Blood Assessment Chart (PBAC) (MD -12.22 points per cycle, 95% CI -30.8 to 6.36; I² = 0%; 3 RCTs, participants = 312; very low quality evidence), but TXA was associated with a higher likelihood of improvement (RR 1.54, 95% CI 1.31 to 1.80; I² = 32%; 5 RCTs, participants = 422; low-quality evidence). This suggests that if 46% of women improve with progestogens, 61% to 83% of women will do so with TXA.Adverse events were less common in the TXA group (RR 0.66, 95% CI 0.46 to 0.94; I² = 28%; 4 RCTs, participants = 349; low-quality evidence). No thromboembolic events were reported in any group.TXA versus non-steroidal anti-inflammatory drugs (NSAIDs)TXA was associated with reduced mean blood loss (MD -73.00 mL per cycle, 95% CI -123.35 to -22.65; 1 RCT, participants = 49; low-quality evidence) and higher likelihood of improvement (RR 1.43, 95% CI 1.18 to 1.74; 12 = 0%; 2 RCTs, participants = 161; low-quality evidence). This suggests that if 61% of women improve with NSAIDs, 71% to 100% of women will do so with TXA. Adverse events were uncommon and no comparative data were available. No thromboembolic events were reported.TXA versus ethamsylateTXA was associated with reduced mean blood loss (MD 100 mL per cycle, 95% CI -141.82 to -58.18; 1 RCT, participants = 53; low-quality evidence), but there was insufficient evidence to determine whether the groups differed in rates of improvement (RR 1.56, 95% CI 0.95 to 2.55; 1 RCT, participants = 53; very low quality evidence) or withdrawal due to adverse events (RR 0.78, 95% CI 0.19 to 3.15; 1 RCT, participants = 53; very low quality evidence).TXA versus herbal medicines (Safoof Habis and Punica granatum)TXA was associated with a reduced mean PBAC score after three months' treatment (MD -23.90 pts per cycle, 95% CI -31.92 to -15.88; I² = 0%; 2 RCTs, participants = 121; low-quality evidence). No data were available for rates of improvement. TXA was associated with a reduced mean PBAC score three months after the end of the treatment phase (MD -10.40 points per cycle, 95% CI -19.20 to -1.60; I² not applicable; 1 RCT, participants = 84; very low quality evidence). There was insufficient evidence to determine whether the groups differed in rates of adverse events (RR 2.25, 95% CI 0.74 to 6.80; 1 RCT, participants = 94; very low quality evidence). No thromboembolic events were reported.TXA versus levonorgestrel intrauterine system (LIUS)TXA was associated with a higher median PBAC score than TXA (median difference 125.5 points; 1 RCT, participants = 42; very low quality evidence) and a lower likelihood of improvement (RR 0.43, 95% CI 0.24 to 0.77; 1 RCT, participants = 42; very low quality evidence). This suggests that if 85% of women improve with LIUS, 20% to 65% of women will do so with TXA. There was insufficient evidence to determine whether the groups differed in rates of adverse events (RR 0.83, 95% CI 0.25 to 2.80; 1 RCT, participants = 42; very low quality evidence). No thromboembolic events were reported. AUTHORS' CONCLUSIONS: Antifibrinolytic treatment (such as TXA) appears effective for treating HMB compared to placebo, NSAIDs, oral luteal progestogens, ethamsylate, or herbal remedies, but may be less effective than LIUS. There were too few data for most comparisons to determine whether antifibrinolytics were associated with increased risk of adverse events, and most studies did not specifically include thromboembolism as an outcome.

Sustainable pathways towards climate and biodiversity goals in the UK: the importance of managing land-use synergies and trade-offs.

Agricultural and environmental policies are being fundamentally reviewed and redesigned in the UK following its exit from the European Union. The UK government and the Devolved Administrations recognise that current land use is not sustainable and that there is now an unprecedented opportunity to define a better land strategy that responds fully to the interconnected challenges of climate change, biodiversity loss and sustainable development. This paper presents evidence from three pathways (current trends, sustainable medium ambition, and sustainable high ambition) to mid-century that were co-created with UK policymakers. The pathways were applied to a national integrated food and land-use model (the FABLE calculator) to explore potential synergies and trade-offs between achieving multiple sustainability targets under limited land availability and constraints to balance food supply and demand at national and global levels. Results show that under the Current Trends pathway all unprotected open natural land would be converted to urban, agriculture and afforested land, with the consequence that from 2030 onwards tree planting targets could not be met. In contrast, the two sustainable pathways illustrate how dietary change, agricultural productivity improvements and waste reduction can free up land for nature recovery and carbon sequestration. This enables a transition to a sustainable food and land-use system that provides a net carbon sink with up to 44% of land able to support biodiversity conservation. We highlight key trade-offs and synergies, which are important to consider for designing and implementing emerging national policies. These include the strong dependence of climate, food and biodiversity targets on dietary shifts, sustainable improvements in agricultural productivity, improved land-use design for protecting and restoring nature, and rapid reductions in food loss and waste. Supplementary Information: The online version contains supplementary material available at 10.1007/s11625-022-01242-8.

Mulberry Heart Disease and Hepatosis Dietetica in Farm Pigs (Sus scrofa domesticus) in a Research Setting.

Perioperative complications and deaths occurred while developing a novel surgical model of pediatric kyphosis in 10 to 12 kg male farm-raised Yorkshire piglets. All piglets appeared clinically normal preoperatively. Intraoperative complications included tachycardia, respiratory acidosis, and death. Postoperatively, clinical signs included posterior paresis, head pressing, prolonged anesthetic recovery, difficulty rising, and sudden death. Necropsies were performed on all piglets. Some morbidity and mortality were accurately attributed to the spinal surgery. However, the index piglet for this report died suddenly approximately 16 to 18 h after surgery. Necropsy of this animal revealed clear, serosanguineous pleural and pericardial effusions along with myocardial hemorrhage and hepatic lesions, consistent with mulberry heart disease and hepatosis dietetica, respectively. Serum vitamin E and selenium levels from this animal were below age-specific lab reference ranges. Clinical signs of vitamin E and selenium deficiency are most common in fast-growing weaner piglets. The added stress of major surgery may exacerbate the condition in young piglets. Resolution of morbidity and mortality in both juvenile and adult pigs occurred upon the use of an alternate vendor able to provide feed analyses meeting industry standards, although serum levels of vitamin E and selenium in similar ages and breed of swine were still occasionally slightly below reference ranges.

Multiscale socio-ecological networks in the age of information.

Interactions between people and ecological systems, through leisure or tourism activities, form a complex socio-ecological spatial network. The analysis of the benefits people derive from their interactions with nature-also referred to as cultural ecosystem services (CES)-enables a better understanding of these socio-ecological systems. In the age of information, the increasing availability of large social media databases enables a better understanding of complex socio-ecological interactions at an unprecedented spatio-temporal resolution. Within this context, we model and analyze these interactions based on information extracted from geotagged photographs embedded into a multiscale socio-ecological network. We apply this approach to 16 case study sites in Europe using a social media database (Flickr) containing more than 150,000 validated and classified photographs. After evaluating the representativeness of the network, we investigate the impact of visitors' origin on the distribution of socio-ecological interactions at different scales. First at a global scale, we develop a spatial measure of attractiveness and use this to identify four groups of sites. Then, at a local scale, we explore how the distance traveled by the users to reach a site affects the way they interact with this site in space and time. The approach developed here, integrating social media data into a network-based framework, offers a new way of visualizing and modeling interactions between humans and landscapes. Results provide valuable insights for understanding relationships between social demands for CES and the places of their realization, thus allowing for the development of more efficient conservation and planning strategies.

Preparation of swine for the laboratory.

Swine are an important model in many areas of biomedical research. These animals have been used predominantly as preclinical models involving surgical and interventional protocols. The systems most commonly studied include cardiovascular, integumentary, digestive, and urological. Swine are intelligent social animals and require species-specific socialization and handling techniques. It is important to acclimate the animals to the facility and to personnel before they are placed on chronic protocols. Gentle handling techniques instead of forceful procedures are essential to their socialization. They require sturdy caging with specific construction standards, and toys for environmental enrichment. Because the species is covered by both the Animal Welfare Act and the US Department of Agriculture, interstate transport requires a health certificate with destination state-specific disease screening standards. This manuscript provides an overview of best practices that have been utilized in the authors' facility.

Fire Usage and Ancient Hominin Detoxification Genes: Protective Ancestral Variants Dominate While Additional Derived Risk Variants Appear in Modern Humans.

Studies of the defence capacity of ancient hominins against toxic substances may contribute importantly to the reconstruction of their niche, including their diets and use of fire. Fire usage implies frequent exposure to hazardous compounds from smoke and heated food, known to affect general health and fertility, probably resulting in genetic selection for improved detoxification. To investigate whether such genetic selection occurred, we investigated the alleles in Neanderthals, Denisovans and modern humans at gene polymorphisms well-known to be relevant from modern human epidemiological studies of habitual tobacco smoke exposure and mechanistic evidence. We compared these with the alleles in chimpanzees and gorillas. Neanderthal and Denisovan hominins predominantly possess gene variants conferring increased resistance to these toxic compounds. Surprisingly, we observed the same in chimpanzees and gorillas, implying that less efficient variants are derived and mainly evolved in modern humans. Less efficient variants are observable from the first early Upper Palaeolithic hunter-gatherers onwards. While not clarifying the deep history of fire use, our results highlight the long-term stability of the genes under consideration despite major changes in the hominin dietary niche. Specifically for detoxification gene variants characterised as deleterious by epidemiological studies, our results confirm the predominantly recent appearance reported for deleterious human gene variants, suggesting substantial impact of recent human population history, including pre-Holocene expansions.

Vascular access port (VAP) usage in large animal species.

Intravascular catheterization access for injection and sampling is one of the most common experimental surgical procedures. The vascular access port (VAP) was developed as an alternative to externalization of catheters. A VAP typically is implanted subcutaneously, with an attached catheter that is tunneled to a blood vessel for chronic catheterization. Catheters and ports have been designed to reduce the problems of occlusion, venous thrombosis, and infection. Key issues involve the use of meticulous aseptic technique for implantation of the devices and a "locking" solution that prevents clotting and retention of residues within the catheter. There are species-specific differences to be considered when planning the surgical implantation and maintenance of these devices. This manuscript reviews the procedures that have been used in the implantation of VAPs in large animal species and makes recommendations for procedures that will decrease complication rates associated with long-term catheterization.

Ecosystem service provision in a changing Europe: adapting to the impacts of combined climate and socio-economic change.

CONTEXT: Future patterns of European ecosystem services provision are likely to vary significantly as a result of climatic and socio-economic change and the implementation of adaptation strategies. However, there is little research in mapping future ecosystem services and no integrated assessment approach to map the combined impacts of these drivers. OBJECTIVE: Map changing patterns in ecosystem services for different European futures and (a) identify the role of driving forces; (b) explore the potential influence of different adaptation options. METHODS: The CLIMSAVE integrated assessment platform is used to map spatial patterns in services (food, water and timber provision, atmospheric regulation, biodiversity existence/bequest, landscape experience and land use diversity) for a number of combined climatic and socio-economic scenarios. Eight adaptation strategies are explored within each scenario. RESULTS: Future service provision (particularly water provision) will be significantly impacted by climate change. Socio-economic changes shift patterns of service provision: more dystopian societies focus on food provision at the expense of other services. Adaptation options offer significant opportunities, but may necessitate trade-offs between services, particularly between agriculture- and forestry-related services. Unavoidable trade-offs between regions (particularly South-North) are also identified in some scenarios. CONCLUSIONS: Coordinating adaptation across regions and sectors will be essential to ensure that all needs are met: a factor that will become increasingly pressing under dystopian futures where inter-regional cooperation breaks down. Integrated assessment enables exploration of interactions and trade-offs between ecosystem services, highlighting the importance of taking account of complex cross-sectoral interactions under different future scenarios of planning adaptation responses.

The tachykinin peptide neurokinin B binds copper(I) and silver(I) and undergoes quasi-reversible electrochemistry: towards a new function for the peptide in the brain.

The tachykinin neuropeptide family, which includes substance P and neurokinin B, is involved in a wide array of biological functions. Among these is the ability to protect against the neurotoxic processes in Alzheimer's Disease, but the mechanisms driving neuroprotection remain unclear. Dysregulation of metal ions, particularly copper, iron and zinc is a common feature of Alzheimer's Disease, and other amyloidogenic disorders. Copper is known to be released from neurons and recent work has shown that some tachykinins can bind Cu(II) ions, and that neurokinin B can inhibit copper uptake into astrocytes. We have now examined whether neurokinin B is capable of binding Cu(I), which is predicted to be available in the synapse. Using a combination of spectroscopic techniques including cyclic voltammetry and magnetic resonance we show that neurokinin B can bind Cu(I) either directly from added CuCl or by reduction of Cu(II)-bound neurokinin B. The results showed that the Cu(I) binding site differs greatly to that of Cu(II) and involves thioether coordination via Met2 and Met10 and an imidazole nitrogen ligand from His3. The Cu(I) coordination is also different to the site adopted by Ag(I). During changes in oxidation state, copper remains bound to neurokinin B despite large changes to the inner coordination sphere. We predict that neurokinin B may be involved in synaptic copper homeostasis.

Best practices for performing experimental surgery in swine.

The authors have extensive experience in surgery, anesthesia, and perioperative care in both miniature and domestic swine in the research setting. This manuscript describes the techniques that have been developed over the last four decades while developing porcine surgical models and their use in translational research. Swine are conditioned and socialized during a seven-day period prior to entering into a survival surgical protocol. Housing is designed to be nonstressful and accommodate the needs of the species. Induction of anesthesia is generally performed in the animal's pen. Injectable agents are administered sc in the neck using a butterfly catheter technique. The anesthetic protocol is designed to consider the physiologic effects of the agents and their potential effects on the research being performed. Complete aseptic technique is performed and includes final application of adhesive iodine impregnated drapes over the surgical site. Preemptive analgesia is performed using parenteral analgesics, local anesthetics, and/or epidural analgesics. Animals are monitored intensively intraoperatively and during the postoperative period with frequent recordings of physiologic parameters. Observation during the postoperative period is continuous until the animal fully recovers the righting reflex. Observations of the animals in the postoperative period are performed at least daily until surgical incisions are healed. In protocols which create defects or impede physiologic function daily monitoring may have to be performed in conjunction with specific therapies or tests throughout the duration of the protocol.

Conduct and its consequences: attempts at debiasing jury judgments.

Jurors in negligence cases are supposed to judge a defendant by the reasonableness of his or her conduct and not by the consequences of that conduct. But several studies have shown that a cognitive heuristic known as hindsight bias can skew post hoc judgments of some prior behavior. Thus, jurors who must evaluate the actions of a defendant may be influenced inappropriately by the consequences of those actions. A complementary problem arises when jurors must evaluate the injuries incurred by the plaintiff. Here, jurors' knowledge about the defendant's allegedly negligent conduct can proactively influence their assessment of the plaintiff's injuries and determination of damages. The purpose of the present study was to examine the effectiveness of two procedural techniques intended to reduce or eliminate the impact of hindsight bias in negligence cases--multiple admonitions from a judge about the proper use of evidence--and bifurcation (actually withholding irrelevant evidence from jurors). We presented a re-enacted automobile negligence trial to 355 jury-eligible adults drawn from the community, varied the evidence and instructions that they heard, and measured liability judgments and damage awards from individual jurors both before and after deliberating, and from juries. Results showed that admonitions were generally ineffective in guiding jurors to the proper use of evidence but that bifurcation was relatively more effective. Deliberations had no curative effect on jurors' misapplication of evidence.