Sea ice limits the interaction of the land and ocean water in the Arctic winter and influences this interaction in the summer by governing the fetch. In many parts of the Arctic, the open-water ...season is increasing in duration and summertime sea-ice extents are decreasing. Sea ice provides a first-order control on the physical vulnerability of Arctic coasts to erosion, inundation, and damage to settlements and infrastructures by ocean water. We ask how the changing sea-ice cover has influenced coastal erosion over the satellite record. First, we present a pan-Arctic analysis of satellite-based sea-ice concentration specifically along the Arctic coasts. The median length of the 2012 open-water season, in comparison to 1979, expanded by between 1.5 and 3-fold by Arctic Sea sector, which allows for open water during the stormy Arctic fall. Second, we present a case study of Drew Point, Alaska, a site on the Beaufort Sea, characterized by ice-rich permafrost and rapid coastal-erosion rates, where both the duration of the open-water season and distance to the sea-ice edge, particularly towards the northwest, have increased. At Drew Point, winds from the northwest result in increased water levels at the coast and control the process of submarine notch incision, the rate-limiting step of coastal retreat. When open-water conditions exist, the distance to the sea ice edge exerts control on the water level and wave field through its control on fetch. We find that the extreme values of water-level setup have increased consistently with increasing fetch.
Medical management of an unruptured ectopic pregnancy with intramuscular methotrexate is common and cost-effective. Two treatment protocols, the "single dose" and the "multidose," have been advocated ...and independently reported in the medical literature. This analysis systematically compares the success and prevalence of side effects of these two regimens.
Published data on women with an ectopic pregnancy medically managed were identified using a MEDLINE search from 1966 to 2001 using key words and review of the references of each manuscript.
Studies were selected based on dosing regimen, number of subjects, and study quality. Data regarding outcome, number of doses administered, side effects, and baseline characteristics were extracted. Data were summarized, and the associations of failed management and the presence of side effects with treatment protocol were calculated. Baseline serum chorionic gonadotropin values and the presence of embryonic fetal actively were controlled for with multivariable logistic regression.
The overall success rate for women treated with methotrexate for an ectopic pregnancy was 89% (1181 of 1327). The single dose was much more commonly used. The use of single dose was associated with a significantly greater chance of failed medical management than the use of the multidose in both crude (odds ratio OR 1.71; 1.04, 2.82) and adjusted analyses (OR 4.74; 1.77, 12.62). The single-dose regimen was associated with fewer side effects (OR 0.44; 0.31, 0.63). Women who experienced side effects were more likely to have successful treatment regardless of regimen.
The multidose regimen is more effective than the single-dose regimen.
Liver transplantation is an effective treatment for liver failure. There is a large unmet demand, even as not all donated livers are transplanted. The clinical selection criteria for donor livers ...based on histopathological evaluation and liver function tests are variable. We integrated transcriptomics and histopathology to characterize donor liver biopsies obtained at the time of organ recovery. We performed RNA sequencing as well as manual and artificial intelligence-based histopathology (10 accepted and 21 rejected for transplantation).
We identified two transcriptomically distinct rejected subsets (termed rejected-1 and rejected-2), where rejected-2 exhibited a near-complete transcriptomic overlap with the accepted livers, suggesting acceptability from a molecular standpoint. Liver metabolic functional genes were similarly upregulated, and extracellular matrix genes were similarly downregulated in the accepted and rejected-2 groups compared to rejected-1. The transcriptomic pattern of the rejected-2 subset was enriched for a gene expression signature of graft success post-transplantation. Serum AST, ALT, and total bilirubin levels showed similar overlapping patterns. Additional histopathological filtering identified cases with borderline scores and extensive molecular overlap with accepted donor livers.
Our integrated approach identified a subset of rejected donor livers that are likely suitable for transplantation, demonstrating the potential to expand the pool of transplantable livers.
Liver resection is an important surgical technique in the treatment of cancers and transplantation. We used ultrasound imaging to study the dynamics of liver regeneration following two-thirds partial ...hepatectomy (PHx) in male and female rats fed
Lieber-deCarli liquid diet protocol of ethanol or isocaloric control or chow for 5-7 weeks. Ethanol-fed male rats did not recover liver volume to the pre-surgery levels over the course of 2 weeks after surgery. By contrast, ethanol-fed female rats as well as controls of both sexes showed normal volume recovery. Contrary to expectations, transient increases in both portal and hepatic artery blood flow rates were seen in most animals, with ethanol-fed males showing higher peak portal flow than any other experimental group. A computational model of liver regeneration was used to evaluate the contribution of physiological stimuli and estimate the animal-specific parameter intervals. The results implicate lower metabolic load, over a wide range of cell death sensitivity, in matching the model simulations to experimental data of ethanol-fed male rats. However, in the ethanol-fed female rats and controls of both sexes, metabolic load was higher and in combination with cell death sensitivity matched the observed volume recovery dynamics. We conclude that adaptation to chronic ethanol intake has a sex-dependent impact on liver volume recovery following liver resection, likely mediated by differences in the physiological stimuli or cell death responses that govern the regeneration process. Immunohistochemical analysis of pre- and post-resection liver tissue validated the results of computational modeling by associating lack of sensitivity to cell death with lower rates of cell death in ethanol-fed male rats
Our results illustrate the potential for non-invasive ultrasound imaging to assess liver volume recovery towards supporting development of clinically relevant computational models of liver regeneration.
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.
Background Women with polycystic ovarian syndrome have a high prevalence of metabolic syndrome and type 2 diabetes mellitus. Blacks and Hispanics have a high morbidity and mortality due to ...cardiovascular disease and diabetes mellitus in the general population. Since metabolic syndrome is a risk factor for development of type 2 diabetes and cardiovascular disease, understanding any racial and ethnic differences in metabolic syndrome among women with polycystic ovarian syndrome is important for prevention strategies. However, data regarding racial/ethnic differences in metabolic phenotype among women with polycystic ovary syndrome are inconsistent. Objective We sought to determine if there are racial/ethnic differences in insulin resistance, metabolic syndrome, and hyperandrogenemia in women with polycystic ovarian syndrome. Study Design We conducted secondary data analysis of a prospective multicenter, double-blind controlled clinical trial, the Pregnancy in Polycystic Ovary Syndrome II study, conducted in 11 academic health centers. Data on 702 women with polycystic ovarian syndrome aged 18-40 years who met modified Rotterdam criteria for the syndrome and wished to conceive were included in the study. Women were grouped into racial/ethnic categories: non-Hispanic whites, non-Hispanic blacks, and Hispanic. The main outcomes were the prevalence of insulin resistance, metabolic syndrome, and hyperandrogenemia in the different racial/ethnic groups. Results Body mass index (35.1 ± 9.8 vs 35.7 ± 7.9 vs 36.4 ± 7.9 kg/m2 ) and waist circumference (106.5 ± 21.6 vs 104.9 ± 16.4 vs 108.7 ± 7.3 cm) did not differ significantly between non-Hispanic white, non-Hispanic black, and Hispanic women. Hispanic women with polycystic ovarian syndrome had a significantly higher prevalence of hirsutism (93.8% vs 86.8%), abnormal free androgen index (75.8% vs 56.5%), abnormal homeostasis model assessment (52.3% vs 38.4%), and hyperglycemia (14.8% vs 6.5%), as well as lower sex hormone binding globulin compared to non-Hispanic whites. Non-Hispanic black women had a significantly lower prevalence of metabolic syndrome (24.5% vs 42.2%) compared with Hispanic women, and lower serum triglyceride levels compared to both Hispanics and non-Hispanic whites (85.7 ± 37.3 vs 130.2 ± 57.0 vs 120.1 ± 60.5 mg/dL, P < .01), with a markedly lower prevalence of hypertriglyceridemia (5.1% vs 28.3% vs 30.5%, P < .01) compared to the other 2 groups. Conclusion Hispanic women with polycystic ovarian syndrome have the most severe phenotype, both in terms of hyperandrogenism and metabolic criteria. Non-Hispanic black women have an overall milder polycystic ovarian syndrome phenotype than Hispanics and in some respects, than non-Hispanic white women.
Hazard assessment for post‐wildfire debris flows, which are common in the steep terrain of the western United States, has focused on the susceptibility of upstream basins to generate debris flows. ...However, reducing public exposure to this hazard also requires an assessment of hazards in downstream areas that might be inundated during debris flow runout. Debris flow runout models are widely available, but their application to hazard assessment for post‐wildfire debris flows has not been extensively tested. Necessary inputs to these models include the total volume of the mobilized flow, flow properties (either inherent material properties or calibration coefficients), and site topography. Estimates of volume are possible in post‐event (“back calculation”) studies, yet before an event, volume is an uncertain quantity. We simulated debris flow runout for the well‐constrained 9 January 2018 Montecito event using three models (RAMMS, FLO2D, and D‐Claw) to determine the relative importance of volume and flow properties. We broke the impacted area into three domains, and for each model‐domain combination, we performed a numerical sampling study in which volume and flow properties varied within a wide, but plausible range. We assessed model performance based on inundation patterns and peak flow depths. We found all models could simulate the event with comparable results. Simulation performance was most sensitive to flow volume and less sensitive to flow properties. Our results emphasize the importance of reducing uncertainty in pre‐event estimates of flow volume for hazard assessment.
Plain Language Summary
Changes in soil properties after fire mean rain can more easily erode the surface and initiate debris flows—mixtures of water, soil, and rock that rapidly move from steep source areas to downstream regions. The combination of frequent fire, steep landscapes, dense population, and intense rain makes southern California prone to debris flows. The scientific community has established methods linking debris flow likelihood and volume to rainfall intensity and burned area characteristics. We presently lack a basis for understanding how flow volume, flow material properties, representation of flow physics, and site topography all combine to produce an inundation hazard. We begin to address this by using observations from the 9 January 2018 Montecito, California, debris flow event to test three candidate models for debris flow inundation. We found that all models can simulate the event and that the largest source of uncertainty in inundated area is the flow volume.
Key Points
The 2018 Montecito event was successfully simulated with three debris flow inundation models that vary in model physics
Model performance was more sensitive to flow volume and site morphology than to flow properties
Estimated volumes were lower than rainfall‐based predictions, and observed inundation areas were larger than volume‐based predictions
A snapshot of biologic drug development Andrews, L; Ralston, S; Blomme, E ...
Human & experimental toxicology,
12/2015, Letnik:
34, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Since the approval of insulin as the first recombinant therapeutic protein, the prominence of biologic therapies in drug development has grown significantly. Many modalities beyond traditional ...biologics are now being developed or explored for various indications with significant unmet medical needs. From early traditional replacement proteins to more recent, highly engineered antibodies, oligonucleotides, fusion proteins, and gene constructs, biologic agents have delivered life-changing therapies, despite often having scientifically and technically challenging development programs. This brief review outlines some of the major biotherapeutic classes and identifies the advantages and challenges with the development of these products.
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