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Primary nephrotic syndrome is characterized by high urinary excretion of protein, low protein in the blood, high cholesterol, and swelling in the arms and legs.

A new analysis highlights the high risk of kidney failure and different cardiovascular complications in patients with primary nephrotic syndrome.

Washington, DC (June 18, 2021) -- A form of kidney disease called primary nephrotic syndrome is characterized by high urinary excretion of protein, low protein in the blood, high cholesterol, and swelling in the arms and legs. Patients may face a range of negative health outcomes, but the extent of these effects are unknown. In a study appearing in an upcoming issue of JASN, investigators evaluated kidney, cardiovascular, and mortality outcomes in adults with primary nephrotic syndrome.

Alan S. Go, MD (Kaiser Permanente Northern California Division of Research) and his colleagues examined data from a large, integrated healthcare delivery system to identify adults with primary nephrotic syndrome over a 16-year period. The researchers compared 907 patients' long-term kidney and cardiovascular outcomes with those from 89,593 adults without kidney disease.

Over a median follow-up of 4.5 years, adults with primary nephrotic syndrome had a 19.63-times higher risk of developing kidney failure, a 2.58-times higher risk of acute coronary syndrome, a 3.01-times higher risk of heart failure, a 1.80-times higher risk of ischemic stroke, a 2.56-times higher risk of venous thromboembolism, and a 1.34-times higher risk of death compared with controls.

Primary nephrotic syndrome can result from diseases called minimal change disease, focal segmental glomerulosclerosis, or membranous nephropathy. In this study, focal segmental glomerulosclerosis was associated with the highest risk of kidney failure, followed by membranous nephropathy and minimal change disease, but there were no significant differences in the risks of cardiovascular complications or death by cause of primary nephrotic syndrome.

"Our study highlights the high risk of kidney failure and the underappreciated excess risks of different arterial and venous cardiovascular complications linked to primary nephrotic syndrome due to focal segmental glomerulosclerosis, membranous nephropathy, or minimal change disease. Additional information is needed on the most effective ways to lower the risks of both kidney and cardiovascular complications in patients," said Dr. Go. "Our study also points to the need for patients with primary nephrotic syndrome to be identified as early as possible so that they can begin to implement lifestyle changes--such as moving toward a healthy diet, stopping smoking, getting more exercise--and to be evaluated for preventive therapies that can reduce their risk for both cardiovascular disease and kidney failure."

Tokyo, Japan - In Japan, thousands of homes and businesses and hundreds of lives have been lost to typhoons. But now, researchers have revealed that a new flood forecasting system could provide earlier flood warnings, giving people more time to prepare or evacuate, and potentially saving lives.

In a study published this month in Scientific Reports, researchers from The University of Tokyo Institute of Industrial Science have shown that a recently developed flood forecasting system provides much earlier advance warnings of extreme flooding events than current systems. Floods are one of the most common natural disasters and are increasing in frequency. In 2019, Typhoon Hagibis swept across parts of Japan causing severe flooding that resulted in 86 deaths and approximately 400 billion dollars' worth of damage. Most urban areas in Japan lie within a floodplain and typhoons can result in rapid and dangerous flooding. Early warning systems can help people to prepare for imminent flooding, but people need sufficient time to do so.

"Current warning systems can provide accurate flooding predictions, but with only a few hours' notice" says lead author of the study Wenchao Ma. "Because people need more time to respond effectively to flood warnings, we investigated whether a newly developed flood forecasting system could accurately predict flooding locations with a longer lead time."

Flooding predictions in Japan are currently based on gauged upstream water levels. The new system is based on models of the land surface and river routes that used together can simulate the movement of water in floodplains. These models are combined with meteorological data like rainfall, temperature, and wind speed, and statistical analysis; the result is flood predictions for all rivers in Japan.

One of the main challenges with forecasting floods is a lack of data to validate the techniques used. During a disaster, collecting information about floods is challenging and can be dangerous. To overcome this issue, the team looked at the location and timing of dike breaks during Typhoon Hagibis. Dike breaks are a good indicator of which areas flooded during the typhoon and allowed the researchers to test the ability of the forecasting system to predict flood locations.

"The system was very effective," explains Kei Yoshimura, senior author. "In fact, we found that the model accurately predicted flooding at 91% of broken dike locations." Importantly, the system also predicted floods with a 32-hour lead time - a notable improvement on the current system. This extra time could be helpful for disaster preparation and making decisions about evacuation.

As the frequency of flooding is likely to increase in the future, forecasting systems that produce accurate and timely flood warnings are urgently needed in Japan, and the rest of the world.

Germany is a hotspot for dragonflies and damselflies (Odonata) species in Europe, owing to the range of habitats and climates that it provides. While many recent and mostly small-scale studies suggest long-term declines of insect populations in different parts of Europe, studies of freshwater insects - including dragonflies and damselflies - suggest that some species have increased in occurrence. Researchers of iDiv, FSU and UFZ have now provided a nationwide analysis of the occurrence and distribution of dragonflies and damselflies in Germany between 1980 and 2016. For this, they analysed over 1 million occurrence records on 77 species from different regional databases, most of which were collected by citizen scientists and collated by the natural history society of German-speaking odonatologists (GdO).

Habitat loss threatens species of standing waterbodies

The researchers found both losses and gains, but are concerned about the decline of species using standing water habitats. Decreases were observed in 29% of species, mainly in cold-adapted species that prefer standing water habitats such as bogs and fens. Many of these species are already threatened with extinction. These species rely on small or shallow water bodies, which have been vulnerable to droughts and lower groundwater levels. "These species are suffering a lot from habitat loss and degradation. Here, we are still facing serious conservation challenges," said first author Dr Diana Bowler from iDiv, FSU and UFZ.

Overall, the analysis suggests that cold-adapted habitat specialists of standing water habitats are likely to be most vulnerable to further environmental change, including climate change.

By contrast, the study results show increases in the occurrence of 45% of all species, in general, warm-adapted species. "Formerly rare species such as Crocothemis erythraea and Erythromma viridulum have become much more common across Germany," said Diana Bowler. "These species prefer warmer temperatures and so their increase in Germany is most probably an outcome of long-term climate change."

Among the winners were also running-water species, which signals the conservation success that can be achieved by better environmental management. "The increase of these species reflects a recovery from the impacts of past water pollution and the almost complete destruction of natural floodplains," said Klaus-Jürgen Conze, chair GdO. In Germany, projects to improve freshwater quality and river restoration were initiated in the 1990s and the EU Water Framework Directive was adopted in 2000.

A large share of the data was collected by citizen scientists and natural history societies, such as the GdO. "Our study highlights the great value of these monitoring efforts for assessing changes in species' occurrences. We found some signs of accelerating declines in the last decade, which highlights the need to support the efforts of these societies in the future," said senior author Prof Aletta Bonn from UFZ, FSU and iDiv.

This study was financed inter alia by the Deutsche Forschungsgemeinschaft (DFG; FZT-118) as part of "sMon - Biodiversity Trends in Germany". sMon is an iDiv synthesis project to bring together exemplary data sets on a variety of taxa and habitats to explore the possibilities for, and limitations of the analysis of changes in biodiversity. Based on this, prospects for future monitoring programmes in Germany are to be determined. sMon brings together government representatives from all federal states, scientists and members of various professional associations.

TheMUC5Bgene codes for mucin - a protein that is normally found in mucus secretions, and which is part of the body'snaturaldefence against infection. The promoter variantcalledrs35705950is a common variantin theMUC5Bgene, with anallele frequency of 0.1 in the Finnish population.Overexpression ofMUC5Bin lungs influences the development of pulmonary fibrosis.The promoter variant rs35705950 inMUC5Bis the strongest known genetic risk factor for rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, there are no large-scale data on the impact oftheMUC5Bpromoter varianton the long-term incidence of RA-ILD.

AnttiPalomäkiand colleagues usedFinnGen- a collection of epidemiological cohorts and hospital biobank samples - to describe the long-term risk of RA-ILD in people with RA carrying theMUC5Bpromotervariant compared to those without the variant.FinnGenis able tolink people's genetic information with up to 46 years of follow-up data within nationwide registries.

Of 248,400people, 5534 had been diagnosed with RA, and 178 of these (3.2%)haddeveloped ILD.TheMUC5Bpromoterwas a strong predictor ofdevelopingILD inpeople with RA, conferring a lifetime risk of ILD of 14.5%by age 80, compared to 5.2% inpeoplewith RAwho did not carry the promoter variant. In the general populationof people without RA,MUC5Bpromotercarriers and non-carriers had lifetime risks ofdeveloping ILD of3.9% and 1.3%, respectively.

Theauthors found that therisk difference started to emerge attheageof65. The risk was highest in men with RA who areMUC5Bcarriers. In this group,18.5%of carriersdeveloped ILD, compared to 8.5% of non-carriers.

These findings have clinical implications for improving identification of people with RAwho areat high risk for developing ILD.

Massive heavy-lift crane vessels, capable of hauling thousands of tons, navigate the rough waves and strong winds offshore to construct wind turbines and oil fields in the ocean. An international team of researchers has developed a new modeling system to help improve the control, and ultimately the safety, of such vessels. They published their approach in the April issue in IEEE/CAA Journal of Automatica Sinica.

"Dynamic positioning allows the ship to stay fixed in a certain location, by acting on the thruster," said paper author Simone Baldi, professor in the School of Mathematics and School of Cyber Science and Engineering, Southeast University in China, and guest with the Delft Center for System and Control, Delft University of Technology in the Netherlands.

This positioning operation acts as a counterbalance. The thruster applies equal force in the opposite direction of the wind or wave that attempts to dislodge the ship.

"However, it sometimes happens that the dynamic positioning does not cope with such changes, leading the ship to oscillate instead of remaining fixed in one spot," Baldi said. "Our approach allows the dynamic positioning to be robust in challenging sea conditions with large waves."

To help the vessels safely work in rough conditions, Baldi and his team augmented the dynamic positioning model system with a digital observer that can translate wind or wave disturbances into specific measurements that reflect position and velocity.

Baldi noted that other proposed models also include observers, but, he said, those observer designs typically depend on vessels responding quickly to measured disturbances -- which is often impossible due to the sheer size of the thrusters and propellers.

To address this challenge, the researchers incorporated known variables, such as the strength of the lines and thrust holding the ship to the construction site, and worst-case scenario ranges for unknown variables, such as wind and waves. The researchers then applied an observer-controller composite that converts motion into measurements to inform operation directions while also allowing the vessel to respond in a reasonable timeframe. The design is guided by key performance indicators while considering the worst-case uncertainty scenarios.

"Currently, we have tested our method in a realistic simulation, which is only a first step," Baldi said.

Next, Baldi said, the researchers hope to test the proposed solution on a small-scale ship under controlled conditions before moving on to tests on heavy-lift crane vessels in the sea.

Sweet sorghum can be used to produce biogas, biofuels, and novel polymers. In addition, it can help replace phosphate fertilizers. A new sweet sorghum variety developed at Karlsruhe Institute of Technology (KIT) accumulates particularly high amounts of sugar and thrives under local conditions. As the scientists reported in the Industrial Crops & Products journal, sugar transport and sugar accumulation are related to the structure of the plants' vessels. This was the result of a comparison between sweet and grain sorghums. (DOI: 10.1016/j.indcrop.2021.113550)

As the world's population grows, the demand for food, raw materials, and energy is also on the rise. This increases the burden on the environment and the climate. One strategy to reduce greenhouse gas emissions is to grow so-called C4 crops. These carry out photosynthesis particularly efficiently, are therefore more effective in fixing carbon dioxide (CO2), and build up more biomass than other plants. Usually, they are native to sunny and warm places. One of the C4 plants is sorghum, also known as great millet, a species of the sorghum genus in the sweet grass family. The varieties that are particularly rich in sugar are called sweet sorghum (Sorghum bicolor L. Moench). Other varieties include grain sorghum used as animal feed. Sorghum can be grown on so-called marginal land, which is difficult to cultivate, so it does not compete with other food or forage crops.

A new sweet sorghum variety called KIT1 has been developed by Dr. Adnan Kanbar in the Molecular Cell Biology Division research group headed by Professor Peter Nick at the Botanical Institute of KIT. KIT1 accumulates particularly high amounts of sugar and thrives especially well under temperate climate conditions. It can be used both energetically, i.e. for the production of biogas and biofuels, and as a base material for the production of novel polymers. The estimated sugar yield per hectare is over 4.4 tons, which would correspond to almost 3,000 liters of bioethanol. In addition, the digestate produced during biogas production can be used for fertilizers to replace phosphate fertilizer, which will soon be in short supply.

The Plant Stem Anatomy is What Matters

Researchers at Nick's laboratory, which is part of the Institute for Applied Biosciences, and their colleagues at the Institute for Technical Chemistry at KIT and at ARCUS Greencycling Technology in Ludwigsburg compared the KIT1 sweet sorghum and Razinieh grain sorghum varieties in order to investigate the different sugar accumulation behaviors in the plant stem. For the study, published in the Industrial Crops & Products journal, the team looked at the stem anatomy. This includes the thickened areas (nodes) and the narrow areas or spaces between nodes (internodes), but also transcripts of important sucrose transporter genes as well as stress responses of plants to high salt concentrations in the soil. Sugar accumulation was highest in the central internodes in both genotypes. However, a relationship was found between sugar accumulation and the structure of the vessels that serve to transport water, solutes, and organic substances. The vessels are grouped into vascular bundles. These consist of the phloem (bast part) and the xylem (wood part). The phloem mainly transports sugars and amino acids, while the xylem's primary function is to transport water and inorganic salts; in addition, the xylem has a supporting function. The study revealed that in KIT1 and five other sweet sorghum varieties, the phloem cross-sectional area in the stem is much larger than the xylem cross-sectional area - the difference is much more pronounced than in the Razinieh grain sorghum variety. "Our study is the first one to look at the relationship between the structure of the vascular bundles and sugar accumulation in the stem," Nick says.

Sweet Sorghum Copes Better with Salinity Stress

As the study further revealed, salinity stress led to higher sugar accumulation in KIT1 than in Razinieh. The expression of sucrose transporter genes was higher in KIT1 leaves under normal conditions, and increased significantly under salinity stress. "Besides anatomical factors, there also some molecular factors that might contribute to regulating sugar accumulation in the stem," Kanbar explains. "In any case, KIT1 responds better to salinity stress." (or)

Various automobile companies are preparing to shift from internal combustion (IC) engine vehicles to electric vehicles (EVs). However, due to higher cost, EVs are not as easily accessible to consumers; hence, several governments are subsidizing EVs to promote sales. For EV costs to compete with those of IC engine vehicles, their batteries, which account for about 30% of their cost, must be more economical than that of IC-based vehicles.

The Korea Institute of Science and Technology (KIST) has announced that Dr. Sang-Ok Kim's team at the Center for Energy Storage Research had developed a novel, high-performance, economical anode material for use in sodium-ion secondary batteries, which are more cost-effective than lithium-ion batteries. This novel material can store 1.5 times more electricity than the graphite anode used in commercial lithium-ion batteries and its performance does not degrade even after 200 cycles at very fast charging/discharging rates of 10 A/g.

Sodium is over 500 times more abundant in the Earth's crust than lithium; hence, sodium-ion batteries have drawn considerable attention as the next-generation secondary battery because it is 40% cheaper than lithium-ion batteries. However, compared to lithium ions, sodium ions are larger and, thus, cannot be stored as stably in graphite and silicon, which are widely used as anodes in such batteries. Hence, the development of a novel, high-capacity anode material is necessitated.

The KIST research team used molybdenum disulfide (MoS2), a metal sulfide that has garnered interest as a candidate for large-capacity anode materials. MoS2 can store a large amount of electricity, but cannot be used because of its high electrical resistance and structural instability that occur during battery operation. However, Dr. Sang-Ok Kim's team overcame this problem by creating a ceramic nano-coating layer using silicone oil, which is a low-cost, eco-friendly material. Through the simple process of mixing the MoS2 *precursor with silicone oil and heat-treating the mixture, they could produce a stable heterostructure with low resistance and enhanced stability.

*precursor : A material in a stage before becoming a specific material in a metabolism or reaction.

**Heterostructure: A structure created by combining two or more materials

Furthermore, the evaluation of electrochemical properties indicated that this material could stably store at least twice as much electricity (?600 mAh/g) as the MoS2 material without coating and could maintain this capacity even after 200 rapid charge/discharge cycles. This excellent performance was achieved by the formation of the ceramic nano-coating layer with high electric storage capacity, which imparts high conductivity and rigidity to the MoS2 surface, resulting in low electrical resistance of the material and high structural stability.

Dr. Sang-Ok Kim, stated "We could successfully solve the high resistance and structural instability problems of MoS2 through the nano-coating surface stabilization technology. As a result, we could develop a sodium-ion battery that can stably store a large amount of electricity. Our method uses cost-effective, eco-friendly materials and, if adapted for the large-scale manufacturing of anode materials, can lower production costs and, hence, boost the commercialization of sodium-ion batteries for large-capacity power storage devices."

Karin Hellgren and colleagues examined pregnancy outcomes in relation to disease activity and antirheumatic treatment strategies in women with RA. This matched cohort study from Sweden and Denmark explored the associations between maternal RA and pre-term birth (PTB), or delivering babies small for gestational age (SGA)in relation to the mother's disease activity and use of antirheumatic treatment before and during pregnancy. Using national medical birth registers and rheumatology registers, the authors looked at1739pregnancies in women with RA, and 17,390 control pregnancies in the general population.

Overall, women with RA had an increased likelihood of having pre-term and small babies. High maternal disease activity during pregnancy strengthened the associations with both PTB and SGA. Stratifying the results by the type of antirheumatic treatment did not substantially change the outcomes; however, combination therapy with biologics together with oral steroids and/or csDMARDs in the 9months before pregnancy was associated with an increased risk of PTB and SGA. During pregnancy, disease activity appears to be the most important risk factor for PTB and SGA in women with RA. The findings highlight the importance of monitoring RA during pregnancy, especially in women receiving extensive treatment, or those with residual disease activity.

But it is not only maternal underlying disease that can have an impact on pregnancy outcomes.

Paternal older age, sperm DNA integrity and certain genetic defects have been associated with worse pregnancy outcomes, yet the pregnant partners of men with inflammatory arthritis are very scarce. In another abstract presented at EULAR 2021,Luis Fernando Perez-Garcia and colleagues performed a multi-centre cross-sectional retrospective study in 8 Dutch hospitals to look at this question.

In total, 628 men with RA, juvenile idiopathic arthritis and spondyloarthritis over the age of 40 years and who had completed their family were invited to take part in a digital questionnaire that included pregnancy-related, demographic and clinical questions. Pregnancies were classified into two groups: occurring either before or after the diagnosis of the father's inflammatory arthritis.408 men reported 897 singleton pregnancies that resulted in 794 live births. Pregnancies conceived after diagnosis of the father's inflammatory arthritis had a higher mean paternal and maternal age at conception, and lower rate of spontaneous pregnancies. Pregnancies conceived after receiving the inflammatory arthritis diagnosis had a lower rate of live births (86.36% and 89.22%), and a significant higher rate of miscarriages (12.27% versus 7.53%).There were no statistically significant differences between the two groups for the rates of abortions, pre-term births, and pregnancy complications. This is the largest study to describe the pregnancy characteristics and outcomes of partners of men diagnosed with inflammatory arthritis, and the first to demonstrate that paternal disease is associated with a higher risk of miscarriage. Prospective studies are needed to corroborate these findings.

RA is an inflammatory autoimmune disease that causes pain, swelling and stiffness in the joints. It can also cause fatigue, and the underlying inflammation may affect other body systems. It is more common in women than in men. To date, active smoking has been the most reproducibly reported risk factor for a type of RA called anti-citrullinated protein antibody (ACPA) positive RA-particularly in people who carry the HLA-DRB1-shared epitope alleles.

Nguyen and colleagues set out to investigate the relationship between passive smoking and the risk of developing RA in a large prospective cohort of healthy French women.

The E3N-EPIC (Etude Epidémiologique au prèsdes femmes de la Mutuelle générale de l'Education Nationale) has collected data on healthy French women since 1990. RA cases have been identified with specific questionnaires and via the medication reimbursement database. Women were considered to have been exposed to passive smoking in childhood if they self-declared staying in a smoky room several hours a day during childhood, and to passive smoking as an adult if they self-declared being exposed for at least 1 hour a day.

79,806 women were included in the study. Among them, 698 cases of RA were identified. In the whole cohort, 10,810 (13.5%) were exposed to passive smoking as children, and 42,807 (53.6%) to passive smoking as adults.6,581 (8.25%) were exposed to both, and 47,036 (58.9%) were exposed to either.

In the whole population, passive smoking in childhood was positively associated with the risk of RA. When analysed by each person's own smoking status, passive smoking in childhood was associated with RA among women who had never smoked themselves, but not among those who had ever smoked themselves.

When the authors looked at passive smoking in adulthood, there was also a positive risk association in the whole population. But when analysed again by individual smoking status, the association with increased RA risk was only among never-smoking women, not those who had ever themselves been a smoker.

These results suggest that smoking by-products - whether actively or passively inhaled - could generate autoimmunity, at least towards antigens involved in RA pathogenesis.

In a poster examining another link between the lungs and inflammatory arthritis, Adami and colleagues looked at the association between concentration of air pollutants and biologic drug retention rates in people with chronic inflammatory arthritis (CIA) living in the Verona area of Italy.

This was a case-crossover study to compare the exposure to pollutants in the 30?day and 60-day periods preceding a drug switch or swap due to disease progression.

1,286 patients with CIA (888 with RA, 260 with psoriatic arthritis and 138 with ankylosing spondylitis) were included, and 13,636 daily air pollution records were retrieved. The authors found an exposure-dependent relationship between exposure to air pollutants and markers of inflammation in people with CIA. Exposures of greater than 50μg/m3 and greater than 40μg/m3 had a 150% and 65% higher risk of having C-reactive protein (CRP) levels above 5 mg/L, respectively.

If the pollution threshold was set at 30μg/m3(below the European Union health protection limit) there was still a 38% higher risk of having altered CRP (OR 1.383, 95% CI 1.206-1.588).

Air pollutants concentrations were higher before a switch or swap due to drug inefficacy. The authors concluded that environmental air pollution was a determinant of poor response to biologic treatment. Interventions to decrease fossil fuel combustion emissions might have beneficial effects on the persistence rate of biologic treatments in people with inflammatory arthritis.

At the 2021 EULAR congress, Brkic and colleagues presented data from people with rheumatoid arthritis (RA)treated at Norwegian rheumatology outpatient clinics between 2010 and 2019.

The project BioRheuma (BIOlogic treatment of patients suffering from inflammatory RHEUMAtic disorders in Norway) aimed to monitor people receiving b/tsDMARDs. Anonymized data files from10 participating centres were merged and analyzed over a 10-year period to show the annual total b/tsDMARD cost, as well as the mean cost per patient for all current users, for all those who started treatment, and for initiating patients naïve to b/tsDMARDs. The cost was calculated based on price offers given at the annual tender process for the different years.

The number of registered RA patients in the databases increased from 4909 in 2010 to 9335 in 2019, and the number of patients receiving b/tsDMARDs increased from 1959 (39.9%) in 2010 to 4209 (45.1%) in 2019. The total treatment expenditure of these b/tsDMARD-treated patients was lowest in 2010(226 million Norwegian Kroner[NOK]), highest in 2014 (350 million NOK), and second lowest in 2019 (255 million NOK).

For current users of b/tsDMARDs, when the number of treated patients during follow-up doubled, the mean cost to treat one patient was reduced by approximately 50%.The number of patients starting on b/tsDMARDs roughly doubled, while keeping a steady small increase for naïve patients. These data show that the average annual costs of treating a Norwegian RA patient on a current b/tsDMARDs were reduced by approximately 50% over the ten years 2010-2019by the national tender system. For patients starting on a b/tsDMARD, the average annual cost was reduced by approximately 75%. The consequence for payers is that treatment can be offered at a lower price, and thus costly drugs may become more available for patients. The authors believe that tender mechanisms applied to the commercial pharmaceutical market improve competition, and increase availability and use of costly drugs.

Murat Torgutalp and colleagues investigated the longitudinal association between radiographic sacroiliitis progression and treatment with TNFi in patients with early axSpA in a long-term inception cohort. The results were shared in an oral session at the 2021 EULAR congress.

Based on the availability of at least two sets of sacroiliac joint (SIJ radiographs), 166 people with non-radiographic axialspondyloarthritis (nr-axSpA), and135 with radiographic (r-axSpA), from the German Spondyloarthritis Inception Cohort (GESPIC) were included in the analysis. Two trained and calibrated central readers scored the radiographs, and if both scored an image as definite radiographic sacroiliitis, the patient was classified as having r-axSpA. The association between previous and current TNFiuse, and change in the sacroiliitis sum score over 2 years was analysed.

At baseline, 9 (3.0%) patients were treated with a TNFi, and 87 (28.9%) patients received at least one TNFiduring the entire follow-up period. While receiving 12or more months of TNFi in the previous interval was associated with lower progression of the sacroiliitis sum score compared to not receiving TNFi in the previous interval, this was not the case in patients who received TNFi for longer than12 months in the current 2-year interval. The significant association between TNFi use for longer than12 months in the previous interval and progression in the sacroiliitis sum score were confirmed in the adjusted analysis. In addition, a similar trend for the beneficial effects was observed in different models, which included other treatment definitions with TNFi in the previous 2-year interval.

The authors concluded that TNFi treatment was associated with slowing radiographic sacroiliitis progression in people with axSpA. This effect became evident 2-4 years after treatment initiation.

Arani Vivekanantham and colleagues investigated the association between RA and the risk of COVID-19 diagnosis, hospitalization with COVID-19,and COVID-19-related death. This population-based cohort study including all individuals registered in the Information System for Research in Primary Care (SIDIAP)- which covers over80% of the population of Catalonia, Spain. This information was linked to region-wide SARS-CoV-2 testing, hospital and mortality records. Outpatient diagnoses of COVID-19, hospitalizations and deaths with COVID-19 were identified between 1st March and 6th May 2020.

A total of 5,586,565 people were identified, of which 16,344 had RA. Having RA was positively associated with being diagnosed with COVID-19, and being hospitalized with COVID-19. However, the authors did not find an association between RA and the risk of worsening from outpatient diagnosis to hospitalization or death, or from hospitalization to death.

The authors believe this is the largest study performed to date looking at COVID-19 outcomes in people with RA. Further research is needed to address factors linking RA and COVID-19 outcomes, including the presence of other comorbidities, underlying RA disease activity, and the use of immunosuppressive medications.

A second poster from Bower and colleagues looked at all-cause mortality, absolute and relative risks for severe COVID-19 in people with chronic inflammatory joint diseases, compared both over time and to the general population. Using data from ARTIS - a Swedish national database -data on hospitalizations, admission to intensive care, and deaths due to COVID-19 were analysed in 110,567 people with inflammatory joint disease, including RA, psoriatic arthritis, ankylosing spondylitis, spondyloarthritis, or juvenile idiopathic arthritis. These were compared to outcomes for 484,277 people in the general population.

In all groups, the absolute risk of death from any cause in 2020 was higher than 2015-2019, with a peak in mid-April, but the relative risks of death versus the general population remained similar.

Among people with inflammatory joint disease in 2020, the risk of hospitalization, admission to intensive care, and death due to COVID-19 was 0.5%, 0.04% and 0.1%, respectively.

Following the original abstract submission, Dr. Bower adds an update that among people with inflammatory joint disease in 2020, the risk of hospitalization, admission to intensive care, and death due to COVID-19 was 0.3%, 0.03% and 0.07%, respectively.

An international team led by researchers at Princeton University has uncovered a new pattern of ordering of electric charge in a novel superconducting material.

The researchers discovered the new type of ordering in a material containing atoms arranged in a peculiar structure known as a kagome lattice. While researchers already understand how the electron's spin can produce magnetism, these new results provide insights into the fundamental understanding of another type of quantum order, namely, orbital magnetism, which addresses whether the charge can spontaneously flow in a loop and produce magnetism dominated by extended orbital motion of electrons in a lattice of atoms. Such orbital currents can produce unusual quantum effects such as anomalous Hall effects and be a precursor to unconventional superconductivity at relatively high temperatures. The study was published in the journal Nature Materials.

"The discovery of a novel charge order in a kagome superconductor with topological band-structure which is also tuneable via a magnetic field is a major step forward that could unlock new horizons in controlling and harnessing quantum topology and superconductivity for future fundamental physics and next-generation device research," said M. Zahid Hasan, the Eugene Higgins Professor of Physics at Princeton University, who led the research team.

The discovery's roots lie in the workings of two fundamental discoveries in the 1980's. One is the quantum Hall effect - a topological effect which has been the subject of decades-long research. The Hall effect was the first example of how a branch of theoretical mathematics, called topology, could fundamentally change how to describe and classify the matter that makes up the world. Important theoretical concepts on the quantized Hall effect were put forward in 1988 by F. Duncan Haldane, the Thomas D. Jones Professor of Mathematical Physics and the Sherman Fairchild University Professor of Physics, who in 2016 was awarded the Nobel Prize.

The second precedent was the discovery of the unconventional high-temperature superconductor which was the subject of the Nobel Prize in 1987. The unusual state of these superconductors has puzzled scientists. Important theoretical concepts on loop currents as a precursor of unconventional superconductivity were put forward in late 1990s by several theorists. In both cases, the key proposal is that the charge can flow in a special lattice to produce effects like orbital magnetism. However, direct experimental realization of such a highly speculative type of electronic quantum charge order is extremely challenging.

"The realization of orbital current type charge order would require the materials to have both strong interactions and special lattice geometries that were realized only the last few years," said Hasan.

Through several years of intense research on several geometrical lattice systems (Nature 562, 91 (2018); Nature Phys 15, 443 (2019), Phys. Rev. Lett. 123, 196604 (2019), Nature Commun. 11, 559 (2020), Phys. Rev. Lett. 125, 046401 (2020), Nature 583, 533 (2020), Nature Reviews Physics 3, 249 (2021), the team gradually realized that kagome superconductors can host such topological-type charge order. Dozens of superconductors with kagome lattices have been discovered over the last 40 years but none showed the desired pattern. One notable kagome superconductor is AV3Sb5 (A=K,Rb,Cs), which early experiments have shown to contain hints of a hidden order around 80 degrees Kelvin, making it a plausible platform for looking for the topological-type charge order.

"Superconductivity often suggests instabilities for the charge of the system, and the kagome lattice is known to be a frustrated lattice system," Hasan said. "The kagome superconductors can form various exotic charge orders, including the topological-type charge order related to their global band-structure. That led us to our search in this family, although it was not clear whether this superconductivity was unconventional when we started to work on this material."

The Princeton team of researchers used an advanced technique known as sub-atomic-resolution scanning tunneling microscopy, which is capable of probing the electronic and spin wavefunctions of material at the sub-atomic scale with sub-millivolt energy resolution at sub-Kelvin temperatures. Under these fine-tuned conditions, the researchers discovered a novel type of charge order that exhibits chirality - that is, orientation in a particular direction - in AV3Sb5.

"The first surprise was that the atoms of the material rearrange themselves into a higher-order (superlattice) lattice structure that was not expected to be there in our data," said Yuxiao Jiang, a graduate student at Princeton and one of the first co-authors of the paper. "Such a superlattice has never been seen in any other kagome system known to us."

The superlattice was the first hint to the researchers that there could be something unconventional in this material. The researchers further increased the temperature of the material to find that the superlattice disappeared above the critical temperature of the hidden phase estimated from the electrical transport behavior of the bulk of the material.

"This consistency gives us the confidence that what we observed is more likely to be a bulk ordering phenomenon rather than a surface effect," said Jia-Xin Yin, an associate research scholar and another co-first author of the study.

Hasan added, "For a bulk charge order, we need to examine further whether there is an energy gap and whether the charge distribution in the real space shows any reversal across the energy gap."

The researchers soon checked both points to confirm again that the unexpected charge order shows a striking charge reversal across the energy gap, which also disappears at the same critical temperature. The accumulated experimental evidence established that the researchers observed a charge order in a kagome material, which has never been reported in any other kagome system.

"Now we are in a position to ask the bigger question: whether it can be a topological charge order?" said Hasan.

Yin added, "Luckily, through our systematic research of geometrical lattice systems over recent years, we have developed a vector magnetic field-based scanning tunneling microscopy methodology to explore any potential topological feature of the material."

Fundamentally, the magnetic field applied on an electronic system leads to a nontrivial topology: the magnetic flux quantum (h/e) and quantum Hall conductance (Ne2/h, related to Chern number N, a topological invariant) are governed by the same set of fundamental constants, including the Planck's constant h and elemental charge e; the vector nature of the field can differentially interact with the chirality of topological matter to provide access to effects related to the topological invariant.

The researchers performed experiments on the charge order at zero magnetic field, a positive magnetic field, and a negative magnetic field. "Before the data was taken, we really didn't know what would happen," Hasan said.

Once the experiments were complete, Jiang said, the answer to the question of topological-like charge order was "yes."

"We found that the charge order actually exhibits a detectable chirality, which can be switched by the magnetic field," Jiang said.

The researchers are excited about their initial discovery. "Before the claim could be made, we still needed to reproduce this result multiple times, to rule out effects from the scanning probe, which may be extrinsic in nature," said Yin.

The researchers further spent several months to find that this magnetic field-switchable chiral charge order is ubiquitous in KV3Sb5, RbV3Sb5 and CsV3Sb5. "Now we are convinced that it is an intrinsic property of this class of material," Hasan added, "And that's very exciting!"

The magnetic field explicitly breaks time-reversal symmetry. Therefore, their observation shows that the chiral charge order in the kagome lattice breaks time-reversal symmetry. This is somewhat analogous with the Haldane model in the honeycomb lattice or the Chandra Varma model in the CuO2 lattice.

Researchers further identified the direct topological consequence of such chiral charge order. With the help of first-principle calculations of the band structure, the team found that this chiral charge order will produce a large anomalous Hall effect with orbital magnetism, which is consistent with the existing transport result which was interpreted differently in a previous work.

Now the theoretical and experimental focus of the group is shifting to the dozens of compounds with kagome lattice flatband properties and also superconductivity. "This is like discovering water in an exoplanet - it opens up a new frontier of topological quantum matter research our laboratory at Princeton has been optimized for," Hasan said.

Cancer cells have an uncanny ability to evolve and adapt to overcome the treatments used against them.

While patient survival has been extended by modern drugs that block the production or action of male hormones that fuel prostate cancer -- androgen receptor inhibitors such as enzalutamide, apalutamide, darolutamide, and abiraterone -- eventually these drugs stop working. At that point, a patient's disease is considered incurable, or what doctors call metastatic, castration-resistant prostate cancer.

In a new study, a team of researchers led by Joshi Alumkal, M.D., who leads the prostate and genitourinary medical oncology section at the University of Michigan Rogel Cancer Center, uncovered new mechanisms underlying an important type of resistance called lineage plasticity. That's when castration-resistant prostate cancers undergo a deadly identity switch -- shifting from resembling glandular cells to neuroendocrine cells, which can behave more like small cell lung cancer.

The findings using human and mouse cell models and tissue biopsies from patients appear in Clinical Cancer Research and outline a promising path to overcoming this form of resistance: BET bromodomain inhibitors. These compounds work against bromodomain and extra-terminal (BET) proteins, which are involved in regulating gene activation.

"We know that treatment-emergent neuroendocrine prostate cancer is becoming more frequent as we use more newer and more potent androgen receptor inhibitors," Alumkal said. "Our prior work examining patients progressing on these newer androgen receptor inhibitors demonstrated that neuroendocrine prostate cancer was found in 17% of cases. By comparison, we find it in less than 1% of patients who have not undergone any form of androgen receptor inhibition. This strongly suggests that interference with androgen receptor function contributes to the increased numbers of treatment-emergent neuroendocrine prostate cancers we now see clinically."

Patients diagnosed with treatment-emergent neuroendocrine prostate cancer fare much worse than patients whose tumors remain adenocarcinomas -- glandular tumors -- surviving for only about one-third as long. Furthermore, there are very limited treatment options for patients with treatment-emergent neuroendocrine prostate cancer.

"We set out to understand how tumors shift their program to become neuroendocrine, the influence of androgen receptor inhibition on this process, and ways to block the switch to neuroendocrine prostate cancer," said Alumkal, who also co-leads of the translational and clinical research program at the U-M Rogel Cancer Center.

This line of investigation began when Alumkal was at the Knight Cancer Institute at Oregon Health & Science University and continued after his move to the U-M in 2019. The effort included a host of collaborators at other institutions, including scientists from the Dana-Farber Cancer Institute at Harvard University, the University of Washington, the Fred Hutchison Cancer Research Center, the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco and the Memorial Sloan Kettering Cancer Center.

A promising countermeasure

The major question the researchers sought to answer was whether modern prostate cancer drugs -- the new and more potent androgen receptor inhibitors -- might be so effective in shutting down the androgen receptor in some tumors that these drugs could actually promote the tumors' switch to become neuroendocrine tumors.

And the answer appears to be yes.

Through a series of experiments using laboratory cell models that were either sensitive to newer androgen receptor inhibitors or their counterpart cell models with acquired resistance, the research team found that androgen receptor inhibition was accentuating a neuroendocrine prostate cancer lineage plasticity program in the resistant cells -- an effect not achievable in the sensitive cells.

"Ultimately, we found that a critical difference that may allow the resistant cells to react differently and become more neuroendocrine is due to the way their DNA is organized and packaged," Alumkal said. "In the treatment-resistant cells, the chromatin is organized in a way that's more conducive to turning on that neuroendocrine program when the androgen receptor is blocked. It is as though the resistant cells have evolved to develop a rabbit hole through which they can change their identity and escape androgen receptor inhibition. We also found that high levels of a transcription factor called E2F1, which is involved in stemness and cell differentiation, is important for the resistant cells' ability to switch identities."

And it was this work to uncover the mechanisms giving rise to treatment-emergent neuroendocrine cancer that also pointed toward a potential solution: BET inhibitors.

Though E2F1 is not targetable directly, Alumkal's team determined that E2F1 cooperates with BET bromodomain proteins to turn on a neuroendocrine prostate cancer lineage plasticity program. Blocking BET bromodomain proteins in cell models stopped the activation of this program that drives the development of neuroendocrine prostate tumors, the research team found.

"When we treated a variety of treatment-emergent neuroendocrine prostate cancer cell lines with BET inhibitors, we greatly reduced the viability of these tumors, including tumors derived from patients," Alumkal said.

The study builds on a previous clinical trial by Alumkal and colleagues, which found a BET bromodomain inhibitor compound developed by Zenith Epigenetics, ZEN-3694, looked most active in castration-resistant prostate tumors from patients who had the lowest androgen receptor activity. Additionally, patients in the trial whose tumors didn't respond well to androgen receptor inhibitors prior to study enrollment appeared to have the most durable control with ZEN-3694, suggesting the most aggressive tumors may be particularly susceptible to BET bromodomain inhibition.

"We went back and determined that several patients from that ZEN-3694 clinical trial had treatment-emergent neuroendocrine prostate cancer," Alumkal said. "When we looked at the subset of those patients who did the best, they had the highest expression of E2F1 and the BET bromodomain protein BRD4, and the lowest expression of the androgen receptor."

"When we examined the neuroendocrine prostate cancer lineage plasticity program we identified in our cellular models, we found these same genes were highly turned on in the tumors from patients with treatment-emergent neuroendocrine prostate cancer who responded best to treatment with ZEN-3694," he added.

Ultimately, Alumkal said, the research points toward BET bromodomain inhibitors as potentially most beneficial for patients whose prostate cancer is no longer as dependent on the androgen receptor, and those with subsets of treatment-emergent neuroendocrine prostate cancer, particularly tumors in which transcription factor E2F1 may be playing an important role.

Building on the findings in the current study, a larger, international, randomized clinical trial is being planned to evaluate the effectiveness of ZEN-3694 with a particular focus on men whose tumors responded poorly to androgen receptor inhibitors -- tumors that may be less dependent on the androgen receptor.

June 18, 2021 - An experimental artificial heart includes an autoregulation control mechanism, or Auto-Mode, that can adjust to the changing needs of patients treated for end-stage heart failure. Outcomes in the first series of patients managed with the new heart replacement pump in Auto-Mode are presented in the ASAIO Journal, official journal of the American Society for Artificial Internal Organs. The journal is published in the Lippincott portfolio by Wolters Kluwer.

The study reports on the response to "pressure sensor-based autoregulation of blood flow" in ten patients for up to two years after implantation of the Carmat Total Artificial Heart (C TAH). "The C TAH Auto-Mode with built-in pressure sensors effectively produces appropriate physiological responses reflective of changing patients' daily needs and thus provides almost physiological heart replacement therapy," according to the new research. The lead author is Ivan Netuka, MD, of the Institute for Clinical and Experimental Medicine, Prague.

Auto-Mode may increase independence and quality of life in severe heart failure

Heart replacement pumps can restore cardiac output in patients with end-stage, biventricular heart failure (affecting both sides of the heart) whose only other option is heart transplantation. However, to enable patients to go home from the hospital and return to their usual activities, the pump should emulate normal heart function, with minimal need for adjustment.

To meet that goal, the C TAH incorporates an Auto-Mode that automatically adapts the pumping action of the right and left ventricles in response to pressure sensors located inside the device, based on parameters set by the physician. The goal is to mimic normal physiological responses to changing needs - particularly physical activity.

Dr. Netuka and colleagues analyzed the Auto-Mode's performance in the first 10 patients undergoing C TAH implantation in early European clinical experience. The patients were all men, average age 60 years. The C TAH was used as a bridge to heart transplantation in six patients and as a permanently implanted device in four.

In all patients, the artificial heart was successfully switched from manual control to Auto-Mode in the operating room. Auto-Mode led to "an immediate appropriate cardiac output response" to the targeted settings. Hemodynamic data recorded by the C TAH showed expected variations in pumping output of the left and right ventricles, in response to changes in pressures and heart rate. Heart rate averaged 78 to 128 beats per minute; blood pressure was normal as well.

Over almost five years of aggregate follow-up, medical teams made changes in the Auto-Mode settings just 20 times. Most adjustments were performed during the first 30 days after device placement. Only four were done after the patient went home from the hospital: a rate of about 1 change per 11 months.

"The reduced need for device management changes may contribute to greater autonomy for patients outside of the hospital environment and improvement in their quality of life," Dr. Netuka and coauthors write. They acknowledge that their study is an initial experience in a relatively small number of patients.

"Nevertheless," they add, "it represents a significant leap towards the next stage more physiological heart replacement therapy. The overall experience of more than four years of device performance represents a positive and promising outcome for the patients while requiring only minimal intervention from the clinicians." The researchers plan further refinements based on the preliminary results; future studies will provide data on response to exercise and hospital readmission rates. A US clinical trial of the C TAH is scheduled to begin soon.