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Background: Psychiatric medications play a vital role in the management of mental health disorders. However, the COVID-19 pandemic and subsequent lockdown limited access to primary care services, leading to an increase in remote assessment and treatment options to maintain social distancing. This study aimed to investigate the impact of the COVID-19 pandemic lockdown on the use of psychiatric medication in primary care settings. Methods: We conducted a retrospective claims-based analysis of anonymized monthly aggregate practice-level data on anxiolytics and hypnotics use from 322 general practitioner (GP) practices in the North East of England, where health disparities are known to be higher. Participants were all residents who took anxiolytics and hypnotics from primary care facilities for two financial years, from 2019/20 to 2020/21. The primary outcome was the volume of Anxiolytics and Hypnotics used as the standardized, average daily quantities (ADQs) per 1000 patients. Based on the OpenPrescribing database, a random-effect model was applied to quantify the change in the level and trend of anxiolytics and hypnotics use after the UK national lockdown in March 2020. Practice characteristics extracted from the Fingertips data were assessed for their association with a reduction in medication use following the lockdown. Results: This study in the North East of England found that GP practices in higher health disparate regions had a lower workload than those in less health disparate areas, potentially due to disparities in healthcare utilization and socioeconomic status. Patients in the region reported higher levels of satisfaction with healthcare services compared to the England average, but there were differences between patients living in higher versus less health disparate areas. The study highlights the need for targeted interventions to address health disparities, particularly in higher health disparate areas. The study also found that psychiatric medication use was significantly more common in residents living in higher health disparate areas. Daily anxiolytics and hypnotics use decreased by 14 items per 1000 patients between the financial years 2019/20 and 2020/21. A further nine items per 1000 decreased for higher health disparate areas during the UK national lockdown. Conclusions: People during the COVID-19 lockdown were associated with an increased risk of unmet psychiatric medication demand, especially for higher health disparate areas that had low-socioeconomic status.

Purpose Hyperaccumulators are plants with the ability to tolerate and accumulate high concentrations of potentially phytotoxic metals. The Australian legume Crotalaria novae-hollandiae accumulates remarkably high concentrations of zinc (Zn), cadmium (Cd) and copper (Cu) in its shoots when growing on metalliferous (Zn-Cd ‘calamine’) soils. This study aimed to investigate zinc-cadmium tolerance in C. novae-hollandiae and to compare it with the closely related, but non-metalliferous, C. cunninghamii. Methods Crotalaria cunninghamii and C. novae-hollandiae were exposed to Zn (3–1000 μM) and Cd (0–60 μM) treatments in hydroponics culture. At the end of the experiment, harvested plants were segmented into roots, old and young stems, old and young leaves for elemental analysis with Inductively coupled plasma atomic emission spectroscopy (ICP-AES). Laboratory-based micro-X-ray fluorescence (μXRF) analysis was used to elucidate elemental distribution in a shoot and in leaflets. Results Crotalaria cunninghamii accumulated up to 1210 μg Zn g−1 and 47.6 μg Cd g−1 in its leaves, with a 75% reduction in biomass in the Zn treatment. Crotalaria novae-hollandiae accumulated up to 16,600 μg Zn g−1 and 1250 μg Cd g−1, with a 70% increase in biomass when exposed to Zn. The species both exhibited chlorosis and stunted growth in the Cd treatments, while only C. cunninghamii exhibited toxicity symptoms in Zn treatment. Conclusions Crotalaria novae-hollandiae has limited tolerance for Cd and based on the accumulation and distribution of foliar Zn and Cd it is suspected that C. novae-hollandiae has different uptake and tolerance mechanisms when compared to other widely studied Zn-Cd hyperaccumulators (such as Noccaea caerulescens and Arabidopsis halleri).

Few longitudinal studies have measured contraceptive continuation past one year in Sub-Saharan Africa. We surveyed 674 women who had been randomized to receive the three-month intramuscular contraceptive injectable (DMPA-IM), levonorgestrel (LNG) implant, or copper IUD during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial in South Africa and Zambia and were subsequently followed for two additional years to explore method continuation, reasons for discontinuation, and access to implant and IUD removal services. We also conducted in-depth qualitative interviews with 39 participants. We estimated cumulative discontinuation probabilities using Kaplan-Meier estimates and assessed factors associated with discontinuation using Cox-proportional hazards models. The LNG implant continuation rate over the maximum 44-month study period was 60%, while rates for the copper IUD and DMPA-IM were 52% and 44%, respectively. Reasons for method discontinuation included side effects, particularly menstrual changes, and method stock-outs. Most implant and IUD users who sought removal were able to access services; however, room for improvement exists. In this cohort randomized to receive a contraceptive method and attend regular study visits, implants and IUDs continued to be highly acceptable over an additional two years, but facilities should continue to ensure that insertions and removals are available as requested.

Context: Root foraging by hyperaccumulator plants in response to patchily distributed metals has been observed in several obligate hyperaccumulators, but it is not known whether facultative hyperaccumulators respond similarly.Aims: This study investigated the root-growth behaviour in the leguminous zinc (Zn) hyperaccumulator Crotalaria novae-hollandiae compared with the non-accumulating Crotalaria cunninghamii in response to localised soil Zn enrichment in the soil to observe foraging versus avoidance responses.Methods: We conducted rhizotron experiments in which we exposed the Crotalaria species pair to juxtaposed treatments, which were either homogenous (each half of the treatments containing same Zn concentrations) or heterogenous (different Zn concentrations in each half of the treatments). The Zn concentrations were 0 μg Zn g−1 (control), 2000 μg Zn g−1 and 5000 μg Zn g−1 in the form of zinc carbonate).Key results: We found that none of the treatments had significantly different rooting density and root biomass, regardless of the Crotalaria species. This finding contrasts with increased root proliferation in Zn-rich patches found for other obligate hyperaccumulator species.Conclusions and implications: The no-preference root response towards Zn in Crotalaria may partly explain the facultative hyperaccumulation mechanism displayed by these species. This root response towards Zn may ultimately affect Zn phytoextraction efficacy when utilising Crotalaria species in a heterogenous Zn soil substrate. These findings highlight the need for rhizosphere investigations prior to field phytoextraction applications.

Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks., Joshi, Gomes et al. employ a chemical modulation approach of the cellular interactome to a hyperconnectivity state and show association with the increased response of pancreatic cancer cell lines to specific drugs, including those that target the MAPK-pathways and PI3K-mTOR pathway. To achieve this, the authors employ chemical modulation of the interactome via epichaperome inhibition with the small molecule PU-H71.

A 67-year-old woman had delayed initial diagnosis of her right low flow carotid cavernous fistula (CCF) during the coronavirus disease (COVID-19) pandemic due to difficulty detecting ocular signs via online virtual examinations. Her right eye conjunctival erythema and proptosis with medial rectus enlargement on computed tomography scan was initially misdiagnosed as euthyroid thyroid-associated orbitopathy without lid retraction. She developed vision loss, and increasing episcleral venous congestion and CCF was suspected. Computed tomographic angiography did not show an obvious fistula. Digital subtraction angiography revealed the right-sided low flow CCF, which was fed from vessels from the contralateral side.

The transient hydrodynamic lubrication model of tilting pad journal bearings (TPJBs) was established by the computational fluid dynamics (CFD) method and the self-developed dynamic grid program. The fluid-structure interaction between the flow field and the rotor motion, the pads rotations was realized. The feasibility of the model is proved by comparing with the experimental data. The dynamic response of TPJBs under the various unbalance, the loading modes and the rotating speeds was studied. The dynamic response of TPJBs is further analyzed through a research of the relationships among the shaft whirl orbits, transient force acting on the shaft, rotation angles of the pads and transient oil film force of the pads. With the increase of unbalance, the whirl orbits expand and whirl orbits centers rise continuously. The whirl orbits and orbit center attitude angles of TPJBs are smaller than those of fixed-pad journal bearings. Compare with the load between pads, the whirl orbits are smaller and whirl orbits centers drop slightly under the load on pads. With the increase of rotating speed, the whirl orbits expand nonlinearly, whirl orbit center rises nonlinearly. The transient force acting on the shaft, the rotation angles of the pads and the transient oil film force of the pads change periodically, and the period and frequency of these changes are the same as that of the shaft rotation. The maximum force acting on the shaft appear before the maximum shaft center position (the vertexes of the whirl orbit).

Rheumatoid arthritis (RA) is a chronic inflammatory disease with fluctuating course of progression. Despite substantial improvement in treatments in recent years, treatment response is still not guaranteed. The aim of this study was to identify variation in Disease Activity Score 28 (DAS28) of RA patients in response to Tocilizumab, and to investigate both molecular and clinical factors influencing response. Clinical and biochemical data for 485 RA patients receiving Tocilizumab in combination with methotrexate were extracted from the LITHE phase III clinical study (NCT00106535), and post-hoc analysis conducted. Latent class mixed models were used to identify statistically distinct trajectories of DAS28 after the initiation of treatment. Biomarker measurements were then analysed cross-sectionally and temporally, to characterise patients by serological biomarkers and clinical factors. We identified three distinct trajectories of drug response: class 1 (n = 85, 17.5%), class 2 (n = 338, 69.7%) and class 3 (n = 62, 12.8%). All groups started with high DAS28 on average (DAS28 > 5.1). Class 1 showed the least reduction in DAS28, with significantly more patients seeking escape therapy (p p

This review article summarizes recent (2014–2019) advances in our understanding of tropical cyclogenesis, stemming from activities at the ninth International Workshop on Tropical Cyclones. Tropical cyclogenesis involves the interaction of dynamic and thermodynamic processes at multiple spatio-temporal scales. Studies have furthered our understanding of how tropical cyclogenesis may be affected by external processes, such as intraseasonal oscillations, monsoon circulations, the intertropical convergence zone, and midlatitude troughs and cutoff lows. Additionally, studies have furthered our understanding of how tropical cyclogenesis may be affected by internal processes, such as the organization of deep convection; the evolution of the “pouch” structure; the role of friction; the development of the moist, warm core; the importance of surface fluxes; and the role of the mid-level vortex. A relatively recent class of idealized, numerical simulations of tropical cyclogenesis in radiative-convective equilibrium have highlighted the potential importance of radiative feedbacks on tropical cyclogenesis. We also offer some recommendations to the community on future directions for tropical cyclogenesis research.

Recovering from major earthquakes is a challenge, especially in mountainous environments where postearthquake hazards may cause substantial impacts for prolonged periods of time. Although such impacts were reported in the 1923 Great Kantō earthquake and the 1999 Chi-Chi earthquake, careless reconstruction in hazard-prone areas and consequently huge losses were witnessed following the 2008 Wenchuan earthquake in the Sichuan province of China, as several reconstructed settlements were severely damaged by mass movements and floods. In order to summarize experiences and identify problems in the reconstruction planning, a monitoring of one of the settlements, the town of Longchi, was carried out by image interpretation and field investigation. Seven inventories containing buildings, farmlands, roads and mitigation measures were made to study the dynamics of elements at risk and exposure over a period of 11 years. It was found that the total economic value of the newly reconstructed buildings was several times more than in the preearthquake situation in 2007, because of enormous governmental investment. Postseismic hazards were not sufficiently taken into consideration in the recovery planning before the catastrophic debris flow disaster in 2010. As a result, the direct economic loss from postseismic disasters was slightly more than the loss caused by the Wenchuan earthquake itself. The society showed an impact-adapt pattern, experiencing losses from disasters and then gaining resistance by abandoning buildings in hazard-prone areas and installing mitigation measures. The locations potentially exposed to postearthquake hazards were summarized, and a possible timetable for reconstruction was proposed. Problems might be encountered in hazard assessment, and possible solutions were discussed.

Extracting the seismic deformation field and analyzing the surface deformation after an earthquake occurs are of great significance for explaining earthquake mechanism and earthquake relief. Through the dual polarization mode of the two-pass method D-InSAR technology, this paper extracted the coseismic deformation fields based on two Sentinel-1A SAR images covering the Yulin earthquake area, and analyzed the surface deformation. The results show that the subsidence area obtained by VV and VH polarization modes are consistent. The uplift center areas are located in Tongxin Village in Rong County and Mapo Town in Luchuan County, and the subsidence center area is located in Fuxin Town of Beiliu City in the northeast. In the earthquake area, the maximum uplift derived by the VV mode SAR data is 12.1 cm, and the maximum subsidence is 5.8 cm. the maximum uplift obtained by the VH mode SAR data is 11.2 cm, and the maximum subsidence is 9 cm. The results obtained by the two polarization modes are consistent. D-InSAR technology can accurately obtain the coseismic deformation field, which provides data guarantee for the follow-up study of the inversion of seismic source parameters in the region.

IntroductionTo enhance health and prevent secondary consequences for patients with cardiovascular disease (CVD), maintenance of an active lifestyle following participation in cardiac rehabilitation (CR) is important. However, levels of physical activity often decrease after completion of a structured CR programme. Models that support long-term behaviour change with a sustained level of physical activity are imperative. The aim of this study is to evaluate the feasibility of a mobile health intervention based on the Health Action Process Approach theoretical model of behaviour change in patients with CVD for 3 months after completion of a CR programme.Methods and analysisIn a feasibility trial design, we will recruit 40 participants from CR programmes at Slagelse Hospital, the City of Slagelse (municipality), or Holbæk Hospital. After completing the standard structured CR programme, each participant will create an action plan for physical activity together with a physiotherapist. Following that, participants are sent 2 weekly text messages for 3 months. The first text message prompts physical activity, and the second will check if the action plan has been followed. If requested by participants, a coordinator will call and guide the physical activities behaviour. The feasibility of this maintenance intervention is evaluated based on predefined progression criteria. Physical activity is measured with accelerometers at baseline and at 3 months follow-up.Ethics and disseminationStudy approval was waived (EMN-2021-00020) by the Research Ethics Committee of Region Zealand, Denmark. Study results will be made public and findings disseminated to patients, health professionals, decision-makers, researchers and the public.Trial registration numberNCT05011994.

Made available in DSpace on 2022-04-29T08:40:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-03-10 Gallinamide A, a metabolite of the marine cyanobacterium Schizothrix sp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated the potency of gallinamide A and 23 synthetic analogues against intracellular Trypanosoma cruzi amastigotes and the cysteine protease, cruzain. We determined the co-crystal structures of cruzain with gallinamide A and two synthetic analogues at ∼2 Å. SAR data revealed that the N-terminal end of gallinamide A is loosely bound and weakly contributes in drug-target interactions. At the C-terminus, the intramolecular π-π stacking interactions between the aromatic substituents at P1′ and P1 restrict the bioactive conformation of the inhibitors, thus minimizing the entropic loss associated with target binding. Molecular dynamics simulations showed that in the absence of an aromatic group at P1, the substituent at P1′ interacts with tryptophan-184. The P1-P1′ interactions had no effect on anti-cruzain activity, whereas anti-T. cruzi potency increased by ∼fivefold, likely due to an increase in solubility/permeability of the analogues. Skaggs School of Pharmacy and Pharmaceutical Sciences Center for Discovery and Innovation in Parasitic Diseases University of California San Diego, La Jolla Departamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista Julio de Mesquita Filho, São José do Rio Preto Center for Marine Biotechnology and Biomedicine Scripps Institution of Oceanography University of California San Diego, La Jolla School of Chemistry The University of Sydney Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science The University of Sydney Departamento de Física Instituto de Biociências Letras e Ciências Exatas Universidade Estadual Paulista Julio de Mesquita Filho, São José do Rio Preto

Critical illness, including sepsis, causes significant pathophysiologic changes that alter the pharmacokinetics (PK) of antibiotics. Ceftriaxone is one of the most prescribed antibiotics in patients admitted to the pediatric intensive care unit (PICU). We sought to develop population PK models of both total ceftriaxone and free ceftriaxone in children admitted to a single-center PICU using a scavenged opportunistic sampling approach. We tested if the presence of sepsis and phase of illness (before or after 48 hours of antibiotic treatment) altered ceftriaxone PK parameters. We performed Monte Carlo simulations to evaluate whether dosing regimens commonly used in PICUs in the United States (50 mg/kg every 12 hours vs. 24 hours) resulted in adequate antimicrobial coverage. We found that a two-compartment model best described both total and free ceftriaxone concentrations. For free concentrations, the population clearance value is 6.54 L/h/70 kg, central volume is 25.4 L/70 kg and the peripheral volume is 19.6 L/70kg. For both models, we found that allometric weight scaling, post-menstrual age, creatinine clearance and daily highest temperature had significant effects on clearance. Presence of sepsis or phase of illness did not have a significant effect on clearance or volume of distribution. Monte Carlo simulations demonstrated that to achieve free concentrations above 1 μg/mL for 100% of the dosing intervals, a dosing regimen of 50 mg/kg every 12 hours is recommended for most patients. A continuous infusion could be considered if the target is to maintain free concentrations four times above the minimum inhibitory concentrations (4 μg/mL).

In this work, we explore the potential of multi-domain multi-branch convolutional neural networks (CNNs) for identifying comparatively rare giant radio galaxies from large volumes of survey data, such as those expected for new-generation radio telescopes like the SKA and its precursors. The approach presented here allows models to learn jointly from multiple survey inputs, in this case NVSS and FIRST, as well as incorporating numerical redshift information. We find that the inclusion of multi-resolution survey data results in correction of 39% of the misclassifications seen from equivalent single domain networks for the classification problem considered in this work. We also show that the inclusion of redshift information can moderately improve the classification of giant radio galaxies., 22 pages, 11 figures, accepted by MNRAS

Objectives To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. Trial design Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial Participants The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; Admitted to hospital for COVID-19; One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: D-Dimer ≥2 times ULN OR D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; > 18 years of age; Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: pregnancy; hemoglobin platelet count 9/L in the last 72 hours; known fibrinogen known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; known bleeding within the last 30 days requiring emergency room presentation or hospitalization; known history of a bleeding disorder of an inherited or active acquired bleeding disorder; known history of heparin-induced thrombocytopenia; known allergy to UFH or LMWH; admitted to the intensive care unit at the time of screening; treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; Imminent death according to the judgement of the most responsible physician; enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients. Intervention and comparator Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician’s discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care. Main outcomes The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): All-cause death Composite of ICU admission or all-cause death Composite of mechanical ventilation or all-cause death Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; Red blood cell transfusion (>1 unit); Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; Renal replacement therapy; Hospital-free days alive; ICU-free days alive; Ventilator-free days alive; Organ support-free days alive; Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); Heparin induced thrombocytopenia; Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers. Randomisation Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment. Blinding (masking) No blinding involved. This is an open-label trial. Numbers to be randomised (sample size) 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05. Trial Status Protocol Version Number 1.4. Recruitment began on May 11th, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing. Trial registration ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Climate change can strongly alter soil microbial functioning via plant–microbe interactions, often with important consequences for ecosystem carbon and nutrient cycling. Given the high degree of intraspecific trait variability in plants, it has been hypothesized that genetic shifts within plant species yield a large potential to control the response of plant–microbe interactions to climate change. Here we examined if sea-level rise and plant genotype interact to affect soil microbial communities in an experimental coastal wetland system, using two known genotypes of the dominant salt-marsh grass Elymus athericus characterized by differences in their sensitivity to flooding stress – i.e., a tolerant genotype from low-marsh environments and an intolerant genotype from high-marsh environments. Plants were exposed to a large range of flooding frequencies in a factorial mesocosm experiment, and soil microbial activity parameters (exo-enzyme activity and litter breakdown) and microbial community structure were assessed. Plant genotype mediated the effect of flooding on soil microbial community structure and determined the presence of flooding effects on exo-enzyme activities and belowground litter breakdown. Larger variability in microbial community structure, enzyme activities, and litter breakdown in soils planted with the intolerant plant genotype supported our general hypothesis that effects of climate change on soil microbial activity and community structure can depend on plant intraspecific genetic variation. In conclusion, our data suggest that adaptive genetic variation in plants could suppress or facilitate the effects of sea-level rise on soil microbial communities. If this finding applies more generally to coastal wetlands, it yields important implications for our understanding of ecosystem–climate feedbacks in the coastal zone.

Objectives-\ud Adenosine hyperemia is an integral component of the physiological assessment of obstructive coronary artery disease in patients with chronic coronary syndrome (CCS). The aim of this study was to compare systemic, coronary and microcirculatory hemodynamics between intravenous (IV) adenosine hyperemia versus physical exercise stress in patients with CCS and coronary stenosis.\ud Methods-\ud Twenty-three patients (mean age, 60.6 ± 8.1 years) with CCS and single-vessel coronary stenosis underwent cardiac catheterization. Continuous trans-stenotic coronary pressure-flow measurements were performed during: i) IV adenosine hyperemia, and ii) physical exercise using a catheter-table-mounted supine ergometer. Systemic, coronary and microcirculatory hemodynamic responses were compared between IV adenosine and exercise stimuli.\ud Results-\ud Mean stenosis diameter was 74.6% ± 10.4. Median (interquartile range) FFR was 0.54 (0.44–0.72). At adenosine hyperemia versus exercise stress, mean aortic pressure (Pa, 91 ± 16 mmHg vs 99 ± 15 mmHg, p < 0.0001), distal coronary pressure (Pd, 58 ± 21 mmHg vs 69 ± 24 mmHg, p < 0.0001), trans-stenotic pressure ratio (Pd/Pa, 0.63 ± 0.18 vs 0.69 ± 0.19, p < 0.0001), microvascular resistance (MR, 2.9 ± 2.2 mmHg.cm−1.sec−1 vs 4.2 ± 1.7 mmHg.cm−1.sec−1, p = 0.001), heart rate (HR, 80 ± 15 bpm vs 85 ± 21 bpm, p = 0.02) and rate-pressure product (RPP, 7522 ± 2335 vs 9077 ± 3200, p = 0.0001) were all lower. Conversely, coronary flow velocity (APV, 23.7 ± 9.5 cm/s vs 18.5 ± 6.8 cm/s, p = 0.02) was higher. Additionally, temporal changes in Pa, Pd, Pd/Pa, MR, HR, RPP and APV during IV adenosine hyperemia versus exercise were all significantly different (p < 0.05 for all).\ud Conclusions-\ud In patients with CCS and coronary stenosis, invasive hemodynamic responses differed markedly between IV adenosine hyperemia versus physical exercise stress. These differences were observed across systemic, coronary and microcirculatory hemodynamics.

The Tibetan Plateau (TP) is the largest alpine plateau on Earth and plays an important role in global climate dynamics. On the TP, climate change is happening particularly fast, with an increase in air temperature twice the global average. The particular sensitivity of this high mountain environment allows observation and tracking of abiotic and biotic feedback mechanisms. Closed lake systems, such as Nam Co on the central TP, represent important natural laboratories for tracking past and recent climatic changes, as well as geobiological processes and interactions within their respective catchments. This review gives an interdisciplinary overview of past and modern environmental changes using Nam Co as a case study. In the catchment area, ongoing rise in air temperature forces glaciers to melt, contributing to a rise in lake level and changes in water chemistry. Some studies base their conclusions on inconsistent glacier inventories, but an ever-increasing deglaciation and thus higher water availability have persisted over the last few decades. Increasing water availability causes translocation of sediments, nutrients and dissolved organic matter to the lake, as well as higher carbon emissions to the atmosphere. The intensity of grazing has an additional and significant effect on CO2 fluxes, with moderate grazing enhancing belowground allocation of carbon while adversely affecting the C sink potential through reduction of above-surface and subsurface biomass at higher grazing intensities. Furthermore, increasing pressure from human activities and livestock grazing are enhancing grassland degradation processes, thus shaping biodiversity patterns in the lake and catchment. The environmental signal provided by taxon-specific analysis (e.g., diatoms and ostracods) in Nam Co revealed profound climatic fluctuations between warmer–cooler and wetter–drier periods since the late Pleistocene and an increasing input of freshwater and nutrients from the catchment in recent years. Based on the reviewed literature, we outline perspectives to further understand the effects of global warming on geodiversity and biodiversity and their interplay at Nam Co, which acts as a case study for potentially TP-level or even worldwide processes that are currently shaping high mountain areas.

Aiming at the observation data of CORS multi-mode data quality and inspection in CORS station, based on the observation data of a CORS station in Guilin, Guangxi, the paper used TEQC and Anubis software to check the data quality from data utilization, cycle slip ratio and multipath. The results show that the three quality inspection indicators of Anubis software are better than TEQC software, which proves that Anubis' data quality inspection results are effective and reliable. On this basis, using Anubis drawing tools to perform quality inspection and visual analysis from satellite constellation, signal band and observation data itself, it shows that Anubis' visual content is more elaborate than TEQC, and users can more intuitively understand and control the data quality of CORS station.

With the advent of the era of big data, traditional measurement techniques have been difficult to meet the information extraction required by contemporary measurement products, and light UAV （Unmanned Aerial Vehicles）was used to mapping is one of the development trends of aerial photogrammetry in China. When data is processed on aerial photography, the control points in the measurement area directly affect the accuracy of the later mapping results as the basis of mathematical calculation. However, the traditional aerial photogrammetry lays out the number of image control points according to a wide range of industry specifications, For example, lay Leveling control point at four corners + a row of elevation control points is lay at both ends of the area and lay Leveling control point at four corners + two vertical framed air routes at both ends of the zone (Zhang, J. Q., 2009),there are no specific method for the number of image control points to achieve a certain scale accuracy. As a result, there are too many or too few image control points in different topography and different scales. Measured by the error, image point density and reasonable layout of the data acquisition of the Trimble UX5 UAV, The causes of the errors are analyzed, and the precise data are obtained by comparing the experiments. Based on this, the relationship between changing the density of image control points and reasonable location is analyzed through the typical plain survey area of 0.718 km2. Designing four layout schemes of Image control points, taking the national standard as the standard, four groups of data are studied by comparing and analyzing GPS acquisition data with photogrammetry mapping data of Wuhan VISIONEK INC MapMatrix software. Through experimental analysis, the results show that the experimental data show that the light UAV can satisfy the production of 1:1000 B level digital elevation model in plain area when the image resolution is 350 dpi, the line height is controlled at 180 ± 10 m and the density of image control point is more than 9/km2. At the same time, this image control point layout method is used reasonably can reduce the workload of the field, improve work efficiency, and also help to speed up the calculation of huge amount of aerial survey data so as to produce high-precision digital products.

Aiming at the high demand of close-range photogrammetry for the object control points and the inconvenient carrying of digital camera to take photogrammetry in the field, a method of detail survey based on PhotoModeler Scanner software is proposed. USB camera combines with the centering rod, USB camera captures image data, Total station obtains the coordinates of the centering rod, the coordinate of projective center is calculated by using the coordinate of the centering rod, PhotoModeler Scanner software processes image data and coordinate data. Ultimately, image stereo measurement of the no object control point was realized. The experimental results showed that the error of the plane position of the solved target point was less than 10cm at a shooting distance of about 10m, and it met the accuracy requirements of detail survey. Therefore, the method can reduce the workload of field detail survey, reduce the cost and volume of the photographic equipment, and has certain application value.

Cavitation occurred in hydraulic machines can generate severe pressure fluctuations and induce high-pitched noise. Ventilated cavitation (inject air into the cavitating flow) is one of the most effective ways to control cavitation and then alleviate the noise and fluctuations. Thus, the evolution of ventilation cavitation around a NACA0015 hydrofoil was numerically investigated with a modified model. The results indicated that the ventilated cavitation consists of two parts: the attached cavity which attached to the leading edge of the hydrofoil and the detached cavity which detached from the hydrofoil surface. With the air injection increased, the detached cavity becomes larger. Besides, the ventilated cavity evolves periodically along with two opposite vortexes which fall off in turn near the tailing edge of the hydrofoil. Among three ventilation volumes, an air injection of 250 L/min presents the best alleviation on pressure fluctuation induced by cloud cavitation. The acoustic analysis indicated that air injection is an effective way to alleviate the cavitation induced noise. With air injected into the flow, two new types noises induced by the ventilated cavitation has been detected by monitoring points along the upper side and behind of the hydrofoil: the lower frequency noise induced by the waving of attached cavity and the higher frequency noise induced by the shedding of the detached cavity. While with the air injection increased, both of the two types noises increased. The acoustic and dynamic patterns under different air injection conditions are able to provide guidance in engineering application.

This paper presents a high-resolution, high-gain, wide-input-output-swing open-loop charge steering amplifier for pipelined successive-approximation-register (SAR) analog-to-digital converter (ADC). Compared to prior charge-steering amplifiers where every transistor is in the saturation region, the proposed amplifier uses cascode input transistors operating in the linear region, which improves its linearity and input swing. To increase the gain, the amplification time is extended by charging the load capacitance through PMOS transistors. Besides, the gain-boost structure is used to adjust the drain voltage of input transistors operating in the linear region, so that nearly the same gain at different process corners is realized. We designed two versions of the proposed amplifier. Both are in a 40-nm CMOS technology, and both achieve 7.6-bit ENOB accuracy. Compared to prior charge-steering amplifiers, ENOB is increased by 1.6-bits; gain is increased by 3.2 times (or even larger); and output swing is increased by 3.6 times.

Multiple endocrine neoplasia type 1 (MEN1) is a genetic syndrome in which patients develop neuroendocrine tumors (NETs), including pancreatic neuroendocrine tumors (PanNETs). The prolonged latency of tumor development in MEN1 patients suggests a likelihood that other mutations cooperate with Men1 to induce PanNETs. We propose that Pten loss combined with Men1 loss accelerates tumorigenesis. To test this, we developed two genetically engineered mouse models (GEMMs)—MPR (Men1flox/flox Ptenflox/flox RIP-Cre) and MPM (Men1flox/flox Ptenflox/flox MIP-Cre) using the Cre-LoxP system with insulin-specific biallelic inactivation of Men1 and Pten. Cre in the MPR mouse model was driven by the transgenic rat insulin 2 promoter while in the MPM mouse model was driven by the knock-in mouse insulin 1 promoter. Both mouse models developed well-differentiated (WD) G1/G2 PanNETs at a much shorter latency than Men1 or Pten single deletion alone and exhibited histopathology of human MEN1-like tumor. The MPR model, additionally, developed pituitary neuroendocrine tumors (PitNETs) in the same mouse at a much shorter latency than Men1 or Pten single deletion alone as well. Our data also demonstrate that Pten plays a role in NE tumorigenesis in pancreas and pituitary. Treatment with the mTOR inhibitor rapamycin delayed the growth of PanNETs in both MPR and MPM mice, as well as the growth of PitNETs, resulting in prolonged survival in MPR mice. Our MPR and MPM mouse models are the first to underscore the cooperative roles of Men1 and Pten in cancer, particularly neuroendocrine cancer. The early onset of WD PanNETs mimicking the human counterpart in MPR and MPM mice at 7 weeks provides an effective platform for evaluating therapeutic opportunities for NETs through targeting the MENIN-mediated and PI3K/AKT/mTOR signaling pathways.

Background The purpose of this study is to evaluate the content validity of the National Comprehensive Cancer Network – Functional Assessment of Cancer Therapy – Breast Cancer Symptom Index (NFBSI-16) and the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10b among patients with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. Methods Cognitive debriefing interviews sought to evaluate patients’ ability to read, understand, and meaningfully respond to the questionnaires, as well as to evaluate the questionnaires’ relevance in the target patient population. Interviews were conducted by telephone and lasted approximately 90 min. Audio recordings were transcribed, anonymized, and analyzed using qualitative data analysis software. Results Fifteen cognitive debriefing interviews were conducted with women (mean age 66.0 years [standard deviation = 12.4]). Patients reported metastases in the bone (86.7%), liver (20.0%), lung (13.3%), skin (6.7%), and lymph node (6.7%) (not mutually exclusive). All patients for whom data were available demonstrated understanding of the instructions and the recall period of the NFBSI-16 (n = 14/14, 100.0%) and the PROMIS (n = 14/14, 100.0%). Greater than 90% of patients demonstrated understanding of each of the items in the NFBSI-16 and the PROMIS. Greater than 70% of patients demonstrated understanding of the response options of the NFBSI-16, > 90% understood response options of PROMIS Items 1–6, and ≥ 50% understood response options of PROMIS Items 7–10. Conceptual relevance was supported for most items in both questionnaires based on patients’ reports of experiencing the concepts as part of their breast cancer experience. Conclusions The results of the cognitive debriefing interviews provide evidence that the NFBSI-16 and PROMIS Physical Function Short Form 10b have content validity in the HR+/HER2- advanced breast cancer patient population. Patients may benefit from additional instructions at the point the response options reverse direction in the PROMIS.

IntroductionCervical cancer is the leading cause of cancer deaths among women in Malawi, but preventable through screening. Malawi primarily uses visual inspection with acetic acid (VIA) for screening, however, a follow-up for positive screening results remains a major barrier, in rural areas. We interviewed women who underwent a community-based screen-and-treat campaign that offered same-day treatment with thermocoagulation, a heat-based ablative procedure for VIA-positive lesions, to understand the barriers in accessing post-treatment follow-up and the role of male partners in contributing to, or overcoming these barriers.MethodsWe conducted in-depths interviews with 17 women recruited in a pilot study that evaluated the safety and acceptability of community-based screen-and-treat programme using VIA and thermocoagulation for cervical cancer prevention in rural Lilongwe, Malawi. Ten of the women interviewed presented for post-treatment follow-up at the healthcare facility and seven did not. The interviews were analysed for thematic content surrounding barriers for attending for follow-up and role of male partners in screening.ResultsTransportation was identified as a major barrier to post-thermocoagulation follow-up appointment, given long distances to the healthcare facility. Male partners were perceived as both a barrier for some, that is, not supportive of 6-week post-thermocoagulation abstinence recommendation, and as an important source of support for others, that is, encouraging follow-up attendance, providing emotional support to maintaining post-treatment abstinence and as a resource in overcoming transportation barriers. Regardless, the majority of women desired more male partner involvement in cervical cancer screening.ConclusionDespite access to same-day treatment, long travel distances to health facilities for post-treatment follow-up visits remained a major barrier for women in rural Lilongwe. Male partners were identified both as a barrier to, and an important source of support for accessing and completing the screen-and-treat programme. To successfully eliminate cervical cancer in Malawi, it is imperative to understand the day-to-day barriers women face in accessing preventative care.

BackgroundHeparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death.MethodsWe randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat.ResultsAt 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85).ConclusionsIn moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days.Trial registration numbers: NCT04362085; NCT04444700

Background Malawi has the world’s highest cervical cancer incidence and mortality due to high rate of HIV coupled with inadequate screening and treatment services. The country’s cervical cancer control program uses visual inspection with acetic acid (VIA) and cryotherapy, but screening is largely limited by poor access to facilities, high cost of cryotherapy gas, and high loss-to-follow-up. To overcome these limitations, we implemented a community-based screen-and-treat pilot program with VIA and thermocoagulation. Through a qualitative study, we explore the experiences of women who underwent this community-based pilot screening program. Methods We implemented our pilot program in rural Malawi and conducted an exploratory qualitative sub-study. We conducted in-depth interviews with women who were treated with thermocoagulation during the program. We used semi-structured interviews to explore screen-and-treat experience, acceptability of the program and attitudes towards self-sampling for HPV testing as an alternative screening method. Content analysis was conducted using NVIVO v12. Results Between July – August 2017, 408 participants eligible for screening underwent VIA screening. Thirty participants had VIA positive results, of whom 28 underwent same day thermocoagulation. We interviewed 17 of the 28 women who received thermocoagulation. Thematic saturation was reached at 17 interviews. All participants reported an overall positive experience with the community-based screen-and-treat program. Common themes were appreciation for bringing screening directly to their villages, surprise at the lack of discomfort, and the benefits of access to same day treatment immediately following abnormal screening. Negative experiences were rare and included discomfort during speculum exam, long duration of screening and challenges with complying with postprocedural abstinence. Most participants felt that utilizing self-collected HPV testing could be acceptable for screening in their community. Conclusions Our exploratory qualitative sub-study demonstrated that the community-based screen-and-treat with VIA and thermocoagulation was widely accepted. Participants valued the accessible, timely, and painless thermocoagulation treatment and reported minimal side effects. Future considerations for reaching rural women can include community-based follow-up, cervical cancer education for male partners and self-sampling for HPV testing.

Malawi has the highest invasive cervical cancer (ICC) mortality rate worldwide, and ICC is the leading cause of cancer death among women. In 2004, Malawi adopted visual inspection with acetic acid (VIA) and ablative treatment with cryotherapy. However, screening coverage has remained low (

Hereditary Diffuse Gastric Cancer (HDGC) syndrome is associated with CDH1 germline likely pathogenic/pathogenic variants. Carriers of CDH1 germline likely pathogenic/pathogenic variants are predisposed to diffuse gastric cancer and lobular breast cancer. This study aims to classify the CDH1 c.[715G>A] missense variant identified in a diffuse gastric cancer prone family by performing splicing studies. RT-PCR and subsequent cloning experiments were performed to investigate whether this variant completely disrupts normal splicing. This variant preferentially abolishes normal splicing through activation of a cryptic 3' acceptor splice site within exon 6 of CDH1, presumably leading to a premature protein truncation within first extracellular domain repeat of E-cadherin protein. Our results contributed to evidence necessary to resolve pathogenicity classification of this variant, indicating that this variant is to be classified as pathogenic.

Background In stable coronary artery disease, medications are used for 2 purposes: cardiovascular risk reduction and symptom improvement. In clinical trials and clinical practice, medication use is often not optimal. The ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) trial was the first placebo‐controlled trial of percutaneous coronary intervention. A key component of the ORBITA trial design was the inclusion of a medical optimization phase, aimed at ensuring that all patients were treated with guideline‐directed truly optimal medical therapy. In this study, we report the medical therapy that was achieved. Methods and Results After enrollment into the ORBITA trial, all 200 patients entered a 6‐week period of intensive medical therapy optimization, with initiation and uptitration of risk reduction and antianginal therapy. At the prerandomization stage, the median number of antianginals established was 3 (interquartile range, 2–4). A total of 195 patients (97.5%) reached the prespecified target of ≥2 antianginals; 136 (68.0%) did not stop any antianginals because of adverse effects, and the median number of antianginals stopped for adverse effects per patient was 0 (interquartile range, 0–1). Amlodipine and bisoprolol were well tolerated (stopped for adverse effects in 4/175 [2.3%] and 9/167 [5.4%], respectively). Ranolazine and ivabradine were also well tolerated (stopped for adverse effects in 1/20 [5.0%] and 1/18 [5.6%], respectively). Isosorbide mononitrate and nicorandil were stopped for adverse effects in 36 of 172 (20.9%) and 32 of 141 (22.7%) of patients, respectively. Statins were well tolerated and taken by 191 of 200 (95.5%) patients. Conclusions In the 12‐week ORBITA trial period, medical therapy was successfully optimized and well tolerated, with few drug adverse effects leading to therapy cessation. Truly optimal medical therapy can be achieved in clinical trials, and translating this into longer‐term clinical practice should be a focus of future study. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02062593.

Background: Fractional flow reserve (FFR) uses pressure-based measurements to assess the severity of a coronary stenosis. Distal pressure (Pd) is often at a different vertical height to that of the proximal aortic pressure (Pa). The difference in pressure between Pd and Pa due to hydrostatic pressure, may impact FFR calculation. Methods: One hundred computed tomography coronary angiographies were used to measure height differences between the coronary ostia and points in the coronary tree. Mean heights were used to calculate the hydrostatic pressure effect in each artery, using a correction factor of 0.8 mmHg/cm. This was tested in a simulation of intermediate coronary stenosis to give the “corrected FFR” (cFFR) and percentage of values, which crossed a threshold of 0.8. Results: The mean height from coronary ostium to distal left anterior descending (LAD) was +5.26 cm, distal circumflex (Cx) –3.35 cm, distal right coronary artery-posterior left ventricular artery (RCA-PLV) –5.74 cm and distal RCA-posterior descending artery (PDA) +1.83 cm. For LAD, correction resulted in a mean change in FFR of +0.042, –0.027 in the Cx, –0.046 in the PLV and +0.015 in the PDA. Using 200 random FFR values between 0.75 and 0.85, the resulting cFFR crossed the clinical treatment threshold of 0.8 in 43% of LAD, 27% of Cx, 47% of PLV and 15% of PDA cases. Conclusions: There are significant vertical height differences between the distal artery (Pd) and its point of normalization (Pa). This is likely to have a modest effect on FFR, and correcting for this results in a proportion of values crossing treatment thresholds. Operators should be mindful of this phenomenon when interpreting FFR values.

The ability of Australian native metallophytes to tolerate extreme metal concentrations in the soil and other difficult edaphic conditions is still not well understood. Copper is an essential micronutrient for plants to survive, but at high concentrations (> 20 µg g−1) in plant tissues, it can cause foliar chlorosis, stunted growth, and ultimately plant death. The Roseby Corridor in Central Queensland (near Cloncurry) is host to copper metallophytes (Polycarpaea spirostylis, Bulbostylis barbata, Tephrosia virens, Eriachne mucronata) which are able to tolerate soils with total copper concentrations up to 12,700 µg g−1. Even with these high levels of copper in the rhizosphere, the maximum copper in all species is relatively low when compared to Cu concentrations in the soil (leaf/stem: Bulbostylis barbata: 40.9 µg g−1, Eriachne mucronata: 12.3 µg g−1, Polycarpaea spirostylis: 10.9 µg g−1, Tephrosia virens: 128 µg g−1). Therefore, all of these species can be classified as copper Excluder-type metallophytes. Their affinity to copper makes these metallophytes useful indicators of copper surface mineralisation within the Roseby Corridor.

The prevalence of food allergy (FA) is increasing in some areas of the globe, highlighting the need for better strategies for prevention, diagnosis, and therapy. In the last few decades, we have made great strides in understanding the causes and mechanisms underlying FAs, prompting guideline updates. Earlier guidelines recommended avoidance of common food allergens during pregnancy and lactation and delaying the introduction of allergenic foods in children aged between 1 and 3 years. Recent guidelines for allergy prevention recommend consumption of a healthy and diverse diet without eliminating or increasing the consumption of allergenic foods during pregnancy or breast-feeding. Early introduction of allergenic foods is recommended by most guidelines for allergy prevention after a period of exclusive breast-feedng (6 months [World Health Organization] or 4 months [European Academy of Allergy and Clinical Immunology]). New diagnostics for FA have been developed with varied availability of these tests in different countries. Finally, the first oral immunotherapy drug for FA was approved by the US Food and Drug Administration and European Medicines Agency in 2020. In this review, we will address the global prevalence of FA, our current understanding of the causes of FA, and the latest guidelines for preventing, diagnosing, and treating FA. We will also discuss similarities and differences between FA guidelines. © 2021 American Academy of Allergy, Asthma & Immunology