Factors associated with successful median arcuate ligament release in an international, multi-institutional cohort.

OBJECTIVE: Prior research on median arcuate ligament syndrome has been limited to institutional case series, making the optimal approach to median arcuate ligament release (MALR) and resulting outcomes unclear. In the present study, we compared the outcomes of different approaches to MALR and determined the predictors of long-term treatment failure. METHODS: The Vascular Low Frequency Disease Consortium is an international, multi-institutional research consortium. Data on open, laparoscopic, and robotic MALR performed from 2000 to 2020 were gathered. The primary outcome was treatment failure, defined as no improvement in median arcuate ligament syndrome symptoms after MALR or symptom recurrence between MALR and the last clinical follow-up. RESULTS: For 516 patients treated at 24 institutions, open, laparoscopic, and robotic MALR had been performed in 227 (44.0%), 235 (45.5%), and 54 (10.5%) patients, respectively. Perioperative complications (ileus, cardiac, and wound complications; readmissions; unplanned procedures) occurred in 19.2% (open, 30.0%; laparoscopic, 8.9%; robotic, 18.5%; P < .001). The median follow-up was 1.59 years (interquartile range, 0.38-4.35 years). For the 488 patients with follow-up data available, 287 (58.8%) had had full relief, 119 (24.4%) had had partial relief, and 82 (16.8%) had derived no benefit from MALR. The 1- and 3-year freedom from treatment failure for the overall cohort was 63.8% (95% confidence interval [CI], 59.0%-68.3%) and 51.9% (95% CI, 46.1%-57.3%), respectively. The factors associated with an increased hazard of treatment failure on multivariable analysis included robotic MALR (hazard ratio [HR], 1.73; 95% CI, 1.16-2.59; P = .007), a history of gastroparesis (HR, 1.83; 95% CI, 1.09-3.09; P = .023), abdominal cancer (HR, 10.3; 95% CI, 3.06-34.6; P < .001), dysphagia and/or odynophagia (HR, 2.44; 95% CI, 1.27-4.69; P = .008), no relief from a celiac plexus block (HR, 2.18; 95% CI, 1.00-4.72; P = .049), and an increasing number of preoperative pain locations (HR, 1.12 per location; 95% CI, 1.00-1.25; P = .042). The factors associated with a lower hazard included increasing age (HR, 0.99 per increasing year; 95% CI, 0.98-1.0; P = .012) and an increasing number of preoperative diagnostic gastrointestinal studies (HR, 0.84 per study; 95% CI, 0.74-0.96; P = .012) Open and laparoscopic MALR resulted in similar long-term freedom from treatment failure. No radiographic parameters were associated with differences in treatment failure. CONCLUSIONS: No difference was found in long-term failure after open vs laparoscopic MALR; however, open release was associated with higher perioperative morbidity. These results support the use of a preoperative celiac plexus block to aid in patient selection. Operative candidates for MALR should be counseled regarding the factors associated with treatment failure and the relatively high overall rate of treatment failure.

Land use and climate change impacts on global soil erosion by water (2015-2070).

Soil erosion is a major global soil degradation threat to land, freshwater, and oceans. Wind and water are the major drivers, with water erosion over land being the focus of this work; excluding gullying and river bank erosion. Improving knowledge of the probable future rates of soil erosion, accelerated by human activity, is important both for policy makers engaged in land use decision-making and for earth-system modelers seeking to reduce uncertainty on global predictions. Here we predict future rates of erosion by modeling change in potential global soil erosion by water using three alternative (2.6, 4.5, and 8.5) Shared Socioeconomic Pathway and Representative Concentration Pathway (SSP-RCP) scenarios. Global predictions rely on a high spatial resolution Revised Universal Soil Loss Equation (RUSLE)-based semiempirical modeling approach (GloSEM). The baseline model (2015) predicts global potential soil erosion rates of [Formula: see text] Pg yr-1, with current conservation agriculture (CA) practices estimated to reduce this by ∼5%. Our future scenarios suggest that socioeconomic developments impacting land use will either decrease (SSP1-RCP2.6-10%) or increase (SSP2-RCP4.5 +2%, SSP5-RCP8.5 +10%) water erosion by 2070. Climate projections, for all global dynamics scenarios, indicate a trend, moving toward a more vigorous hydrological cycle, which could increase global water erosion (+30 to +66%). Accepting some degrees of uncertainty, our findings provide insights into how possible future socioeconomic development will affect soil erosion by water using a globally consistent approach. This preliminary evidence seeks to inform efforts such as those of the United Nations to assess global soil erosion and inform decision makers developing national strategies for soil conservation.

Sex, Endothelial Cell Functions, and Peripheral Artery Disease.

Peripheral artery disease (PAD) is caused by blocked arteries due to atherosclerosis and/or thrombosis which reduce blood flow to the lower limbs. It results in major morbidity, including ischemic limb, claudication, and amputation, with patients also suffering a heightened risk of heart attack, stroke, and death. Recent studies suggest women have a higher prevalence of PAD than men, and with worse outcomes after intervention. In addition to a potential unconscious bias faced by women with PAD in the health system, with underdiagnosis, and lower rates of guideline-based therapy, fundamental biological differences between men and women may be important. In this review, we highlight sexual dimorphisms in endothelial cell functions and how they may impact PAD pathophysiology in women. Understanding sex-specific mechanisms in PAD is essential for the development of new therapies and personalized care for patients with PAD.

Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis.

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.

Targeting a critical step in fungal hexosamine biosynthesis.

Aspergillus fumigatus is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment including host defenses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. As this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N-acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. GNA1 deletion resulted in loss of fungal viability and disruption of the cell wall, phenotypes that could be rescued by exogenous GlcNAc, the product of the Gna1 enzyme. In a murine model of aspergillosis, the Δgna1 mutant strain exhibited attenuated virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the Gna1 active site and can be optimized to a selective submicromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an antifungal target in A. fumigatus.

Spatial co-localisation of extreme weather events: a clear and present danger.

Extreme weather events have become a dominant feature of the narrative surrounding changes in global climate with large impacts on ecosystem stability, functioning and resilience; however, understanding of their risk of co-occurrence at the regional scale is lacking. Based on the UK Met Office's long-term temperature and rainfall records, we present the first evidence demonstrating significant increases in the magnitude, direction of change and spatial co-localisation of extreme weather events since 1961. Combining this new understanding with land-use data sets allowed us to assess the likely consequences on future agricultural production and conservation priority areas. All land-uses are impacted by the increasing risk of at least one extreme event and conservation areas were identified as the hotspots of risk for the co-occurrence of multiple event types. Our findings provide a basis to regionally guide land-use optimisation, land management practices and regulatory actions preserving ecosystem services against multiple climate threats.

A 'debt' based approach to land degradation as an indicator of global change.

We propose a way to synthesize different approaches to globally map land degradation by combining vegetation and soil indicators into a consistent framework for assessing land degradation as an environmental 'debt'. our combined approach reveals a broader lens for land degradation through global change, in particular, identifying hot-spots for the different kinds of land degradation.

Dielectric Spectroscopy and Application of Mixing Models Describing Dielectric Dispersion in Clay Minerals and Clayey Soils.

The number of sensors, ground-based and remote, exploiting the relationship between soil dielectric response and soil water content continues to grow. Empirical expressions for this relationship generally work well in coarse-textured soils but can break down for high-surface area and intricate materials such as clayey soils. Dielectric mixing models are helpful for exploring mechanisms and developing new understanding of the dielectric response in porous media that do not conform to a simple empirical approach, such as clayey soils. Here, we explore the dielectric response of clay minerals and clayey soils using the mixing model approach in the frequency domain. Our modeling focuses on the use of mixing models to explore geometrical effects. New spectroscopic data are presented for clay minerals (talc, kaolinite, illite and montmorillonite) and soils dominated by these clay minerals in the 1 MHz-6 GHz bandwidth. We also present a new typology for the way water is held in soils that we hope will act as a framework for furthering discussion on sensor design. We found that the frequency-domain response can be mostly accounted for by adjusting model structural parameters, which needs to be conducted to describe the Maxwell-Wagner (MW) relaxation effects. The work supports the importance of accounting for soil structural properties to understand and predict soil dielectric response and ultimately to find models that can describe the dielectric-water content relationship in fine-textured soils measured with sensors.

Global environmental changes impact soil hydraulic functions through biophysical feedbacks.

Although only representing 0.05% of global freshwater, or 0.001% of all global water, soil water supports all terrestrial biological life. Soil moisture behaviour in most models is constrained by hydraulic parameters that do not change. Here we argue that biological feedbacks from plants, macro-fauna and the microbiome influence soil structure, and thus the soil hydraulic parameters and the soil water content signals we observe. Incorporating biological feedbacks into soil hydrological models is therefore important for understanding environmental change and its impacts on ecosystems. We anticipate that environmental change will accelerate and modify soil hydraulic function. Increasingly, we understand the vital role that soil moisture exerts on the carbon cycle and other environmental threats such as heatwaves, droughts and floods, wildfires, regional precipitation patterns, disease regulation and infrastructure stability, in addition to agricultural production. Biological feedbacks may result in changes to soil hydraulic function that could be irreversible, resulting in alternative stable states (ASS) of soil moisture. To explore this, we need models that consider all the major feedbacks between soil properties and soil-plant-faunal-microbial-atmospheric processes, which is something we currently do not have. Therefore, a new direction is required to incorporate a dynamic description of soil structure and hydraulic property evolution into soil-plant-atmosphere, or land surface, models that consider feedbacks from land use and climate drivers of change, so as to better model ecosystem dynamics.

Zones of influence for soil organic matter dynamics: A conceptual framework for data and models.

Soil organic matter (SOM) is an indicator of sustainable land management as stated in the global indicator framework of the United Nations Sustainable Development Goals (SDG Indicator 15.3.1). Improved forecasting of future changes in SOM is needed to support the development of more sustainable land management under a changing climate. Current models fail to reproduce historical trends in SOM both within and during transition between ecosystems. More realistic spatio-temporal SOM dynamics require inclusion of the recent paradigm shift from SOM recalcitrance as an 'intrinsic property' to SOM persistence as an 'ecosystem interaction'. We present a soil profile, or pedon-explicit, ecosystem-scale framework for data and models of SOM distribution and dynamics which can better represent land use transitions. Ecosystem-scale drivers are integrated with pedon-scale processes in two zones of influence. In the upper vegetation zone, SOM is affected primarily by plant inputs (above- and belowground), climate, microbial activity and physical aggregation and is prone to destabilization. In the lower mineral matrix zone, SOM inputs from the vegetation zone are controlled primarily by mineral phase and chemical interactions, resulting in more favourable conditions for SOM persistence. Vegetation zone boundary conditions vary spatially at landscape scales (vegetation cover) and temporally at decadal scales (climate). Mineral matrix zone boundary conditions vary spatially at landscape scales (geology, topography) but change only slowly. The thicknesses of the two zones and their transport connectivity are dynamic and affected by plant cover, land use practices, climate and feedbacks from current SOM stock in each layer. Using this framework, we identify several areas where greater knowledge is needed to advance the emerging paradigm of SOM dynamics-improved representation of plant-derived carbon inputs, contributions of soil biota to SOM storage and effect of dynamic soil structure on SOM storage-and how this can be combined with robust and efficient soil monitoring.

Faith and Global Health Practice in Ebola and HIV Emergencies.

We examined the relationship between religion and health by highlighting the influences of religion on the response to the 2014 to 2016 Ebola outbreak and the global HIV epidemic. We recounted the influences of religion on burial practices developed as an infection control measure during the Ebola outbreak in West Africa. We also explored the influence of religion on community outreach and health education. We examined faith-based responses to the global HIV/AIDS pandemic, noting that religion conflicted with public health responses to HIV (e.g., justification for HIV-related stigma) or aligned with public health as a force for improved HIV responses (e.g., providing HIV services or providing social capital and cohesion to support advocacy efforts). We further discussed the similarities and differences between the influence of religion during the HIV/AIDS pandemic and the 2014 to 2016 Ebola outbreak. We then described lessons learned from Ebola and HIV/AIDS to better inform collaboration with religious actors.

Utility of Culturing Marginal Bone in Patients Undergoing Lower Limb Amputation for Infection.

Guidelines suggest culturing clinically uninfected bone at the margin after surgical resection for osteomyelitis, but little published evidence supports this procedure. To investigate whether culturing marginal bone after completing resection of infected bone affected antibiotic use or further surgical intervention, we collected data on sequential patients undergoing amputation for a foot infection at our tertiary care hospital between January 2014 and May 2015. We recorded patient age, sex, presence of diabetes mellitus, level of amputation, whether marginal bone was sent for culture, microbiology of any marginal bone specimens, type and duration of antibiotic therapy, and any further surgical resection. Among 132 patients, the mean age was 71.9 years, 103 (78.0%) were male, and 79 (59.8%) had diabetes. Treating surgeons sent marginal bone in 58 (43.9%) of these patients, 50 (86.2%) of which were culture positive. Patients with a positive bone culture were significantly more likely to undergo further surgical intervention (20.0% vs 6.1%, p = .047). For patients with diabetes, compared with those without, surgeons did not send marginal bone for culture more often (46% vs 42%, p = .72), nor did they undertake further surgical interventions more frequently (13.4% vs 10.1%, p = .89). Our results suggest that the clinicians used the marginal bone culture findings to make clinical decisions but do not clarify if there is a benefit to performing this procedure. Although patients whose proximal bone specimens were culture positive were more likely to undergo a surgical intervention, the reasons for, and benefit of, this additional surgery were unclear.

Lateral carbon transfer from erosion in noncroplands matters.

This study combines two unprecedentedly high resolution (250 × 250 m) maps of soil erosion (inter-rill and rill processes) and soil organic carbon to calculate a global estimate of erosion-induced organic carbon (C) displacement. The results indicate a gross C displacement by soil erosion of 2.5-0.3+0.5 Pg C/year. The greatest share of displaced C (64%) comes from seminatural lands and forests. This suggests that lateral C transfer from erosion in noncroplands may play a more important role than previously assumed.

Factors Predicting Noncompliance with Follow-up after Endovascular Aneurysm Repair.

BACKGROUND: Although the potential for complications after endovascular aneurysm repair (EVAR) mandates lifetime follow-up, noncompliance with follow-up has been shown to be as high as 57%. We sought to investigate the incidence of noncompliance with follow-up in our patient population and to identify risk factors associated with this to allow implementation of targeted strategies to prevent loss to follow-up. METHODS: We carried out a review of consecutive patients undergoing EVAR at 2 Sydney hospitals between 1995 and 2015. Patients noncompliant with standard follow-up were compared with a control group of compliant patients. Data collected included baseline clinical characteristics, perioperative complications, and postoperative complications, as well as distance from treating centers. RESULTS: During the study period, 1,482 patients underwent EVAR, of which 338 patients (22.8%) were not compliant with follow-up. Patients noncompliant with follow-up were significantly more likely to be younger, have hypertension, and be current smokers. Patients who did not attend follow-up were also significantly more likely to be from a non-English-speaking background (28.4 vs. 17.9%; P = 0.01) and live closer to the treating institution (109 ± 151.5 vs. 150 ± 208.34 km; P = 0.01). CONCLUSIONS: Follow-up after EVAR remains suboptimal. The present study serves to demonstrate that several factors, especially current smoking and a non-English-speaking background, are associated with poor compliance with follow-up after EVAR in our patient population and represent a potential area of intervention to improve compliance.

N-myristoyltransferase inhibitors as new leads to treat sleeping sickness.

African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for approximately 30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target-T. brucei N-myristoyltransferase-leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.

The histone chaperones Vps75 and Nap1 form ring-like, tetrameric structures in solution.

NAP-1 fold histone chaperones play an important role in escorting histones to and from sites of nucleosome assembly and disassembly. The two NAP-1 fold histone chaperones in budding yeast, Vps75 and Nap1, have previously been crystalized in a characteristic homodimeric conformation. In this study, a combination of small angle X-ray scattering, multi angle light scattering and pulsed electron-electron double resonance approaches were used to show that both Vps75 and Nap1 adopt ring-shaped tetrameric conformations in solution. This suggests that the formation of homotetramers is a common feature of NAP-1 fold histone chaperones. The tetramerisation of NAP-1 fold histone chaperones may act to shield acidic surfaces in the absence of histone cargo thus providing a 'self-chaperoning' type mechanism.

Bisubstrate UDP-peptide conjugates as human O-GlcNAc transferase inhibitors.

Inhibitors of OGT (O-GlcNAc transferase) are valuable tools to study the cell biology of protein O-GlcNAcylation. We report OGT bisubstrate-linked inhibitors (goblins) in which the acceptor serine in the peptide VTPVSTA is covalently linked to UDP, eliminating the GlcNAc pyranoside ring. Goblin1 co-crystallizes with OGT, revealing an ordered C3 linker and retained substrate-binding modes, and binds the enzyme with micromolar affinity, inhibiting glycosyltransfer on to protein and peptide substrates.