bluuebunny/crossref_metadata_2025 huggingface dataset:
Zymogen‐locked mutant prostasin (Prss8) leads to incomplete proteolytic activation of the epithelial sodium channel (ENaC) and severely compromises triamterene tolerance in mice
Authors: Essigke Daniel , Ilyaskin Alexandr V. , Wörn Matthias , Bohnert Bernhard N. , Xiao Mengyun , Daniel Christoph , Amann Kerstin , Birkenfeld Andreas L. , Szabo Roman , Bugge Thomas H. , Korbmacher Christoph , Artunc Ferruh
Published: March 2021

Aim

The serine protease prostasin (Prss8) is expressed in the distal tubule and stimulates proteolytic activation of the epithelial sodium channel (ENaC) in co‐expression experiments in vitro. The aim of this study was to explore the role of prostasin in proteolytic ENaC activation in the kidney in vivo.

Methods

We used genetically modified knockin mice carrying a Prss8 mutation abolishing proteolytic activity (Prss8‐S238A) or a mutation leading to a zymogen‐locked state (Prss8‐R44Q). Mice were challenged with low sodium diet and diuretics. Regulation of ENaC activity by Prss8‐S238A and Prss8‐R44Q was studied in vitro using the Xenopus laevis oocyte expression system.

Results

Co‐expression of murine ENaC with Prss8‐wt or Prss8‐S238A in oocytes caused maximal proteolytic ENaC activation, whereas ENaC was activated only partially in oocytes co‐expressing Prss8‐R44Q. This was paralleled by a reduced proteolytic activity at the cell surface of Prss8‐R44Q expressing oocytes. Sodium conservation under low sodium diet was preserved in Prss8‐S238A and Prss8‐R44Q mice but with higher plasma aldosterone concentrations in Prss8‐R44Q mice. Treatment with the ENaC inhibitor triamterene over four days was tolerated in Prss8‐wt and Prss8‐S238A mice, whereas Prss8‐R44Q mice developed salt wasting and severe weight loss associated with hyperkalemia and acidosis consistent with impaired ENaC function and renal failure.

Conclusion

Unlike proteolytically inactive Prss8‐S238A, zymogen‐locked Prss8‐R44Q produces incomplete proteolytic ENaC activation in vitro and causes a severe renal phenotype in mice treated with the ENaC inhibitor triamterene. This indicates that Prss8 plays a role in proteolytic ENaC activation and renal function independent of its proteolytic activity.
The Effects of opioids on female fertility, pregnancy and the breastfeeding mother‐infant dyad: A Review
Authors: Corsi Daniel J. , Murphy Malia S. Q.
Published: March 2021

Opioids cover a broad class of natural, synthetic and semi‐synthetic drugs that act on opioid receptors to produce powerful analgesic effects. Rates of opioid use and opioid agonist maintenance treatment have increased substantially in recent years, particularly among women. Trends and outcomes of opioids use on fertility, pregnancy and breastfeeding, and longer‐term child developmental outcomes have not been well‐described. Here, we review the existing literature on the health effects of opioid use on female fertility, pregnancy, breastmilk and the exposed infant. We find that the current literature is primarily concentrated on the impact of opioid use in pregnancy and neonatal outcomes, with little exploration of effects on fertility. Studies are limited in number, some with small sample sizes, and many are hampered by methodological challenges related to confounding and other potential biases. Opioid use is becoming more prevalent due to environmental pressures such as COVID‐19. More research is needed to better elucidate its effects on reproductive health among younger women and support the development of evidence‐based recommendations for safe prescription practices and public health messaging.
Effect of lithium on circadian rhythm in bipolar disorder: A systematic review and meta‐analysis
Authors: Xu Ni , Shinohara Kiyomi , Saunders Kate E. A. , Geddes John R. , Cipriani Andrea
Published: March 2021

Objectives

Circadian rhythm disruption is commonly reported in patients with bipolar disorder. Lithium has been suggested to have effects on the circadian clock, the biological basis of the circadian rhythm. The objective of the current review was to review systematically the existing studies on the effect of lithium on circadian rhythm in patients with bipolar disorder.

Methods

We systematically searched the scientific literature up to September 2020 for experimental or observational studies which measured circadian rhythm in bipolar patients taking lithium (in comparison with placebo or other active treatments) and carried out a meta‐analysis. Circadian rest‐activity was our primary outcome, but we also collected data about sleep quality and chronotype (Morningness‐Eveningness). The protocol was registered in PROSPERO (CRD42018109790).

Results

Four observational studies (n = 668) and one experimental study (n = 29) were included. Results from the meta‐analysis suggest a potential association between lithium and shifts towards morningness (standardized mean difference [SMD]: 0.42, 95% confidence interval [CI]: −0.05 to 0.90). One cohort study with 21 days of follow‐up found that patients treated with lithium had significantly larger amplitude (0.68, 0.01 to 1.36) when compared to anticonvulsants.

Conclusion

This review highlights the insufficient evidence to inform us about the effect of lithium on circadian rhythm. However, we found that chronotype can be a potential target for further exploration of biomarkers or biosignatures of lithium treatment in patients with bipolar disorder. Further studies with prospective and longitudinal study design, adopting actigraphy to monitor daily circadian rest‐activity changes are needed.
Thrombotic microangiopathy in untreated myeloma patients receiving carfilzomib, cyclophosphamide and dexamethasone on the CARDAMON study
Authors: Camilleri Marquita , Cuadrado Maria , Phillips Elizabeth , Wilson William , Jenner Richard , Pang Gavin , Kamora Sumaiya , Streetly Matthew , Popat Rakesh , Bygrave Ceri , Owen Roger , Cavenagh James , Chapman Mike , Sive Jonathan , Eccersley Lydia , Sheaff Michael , Benjamin Reuben , Ramasamy Karthik , Cook Gordon , Virchis Andres , Chavda Selina J. , Clifton‐Hadley Laura , Scully Marie Anne , Yong Kwee
Published: March 2021

Proteasome inhibitors have been associated with thrombotic microangiopathy (TMA) — a group of disorders characterised by occlusive microvascular thrombosis causing microangiopathic haemolytic anaemia, thrombocytopenia and end‐organ damage. To date, carfilzomib‐associated TMA has predominantly been described in relapsed/refractory myeloma patients. We report eight patients with newly diagnosed myeloma who experienced TMA events while receiving carfilzomib on the phase II CARDAMON trial. The first three occurred during maintenance single‐agent carfilzomib, two occurred at induction with carfilzomib given with cyclophosphamide and dexamethasone (KCd) and three occurred during KCd consolidation. At TMA presentation 6/8 were hypertensive; 7/8 had acute kidney injury and in three, renal impairment persisted after resolution of TMA in other respects. The mechanism of carfilzomib‐associated TMA remains unclear, though patients with known hypertension seem particularly susceptible. Given the first three cases occurred during maintenance after a longer than five‐week treatment break, a protocol amendment was instituted with: aggressive hypertension management, carfilzomib step‐up dosing (20 mg/m2 on day 1) at start of maintenance before dose escalation to 56 mg/m2 maximum, and adding 10 mg dexamethasone as premedication to maintenance carfilzomib infusions. No further TMA events occurred during maintenance following this amendment and the TMA incidence reduced from 4·2 to 1·6 per 1 000 patient cycles.
Comparative bioacoustics: a roadmap for quantifying and comparing animal sounds across diverse taxa
Authors: Odom Karan J. , Araya‐Salas Marcelo , Morano Janelle L. , Ligon Russell A. , Leighton Gavin M. , Taff Conor C. , Dalziell Anastasia H. , Billings Alexis C. , Germain Ryan R. , Pardo Michael , de Andrade Luciana Guimarães , Hedwig Daniela , Keen Sara C. , Shiu Yu , Charif Russell A. , Webster Michael S. , Rice Aaron N.
Published: March 2021

Animals produce a wide array of sounds with highly variable acoustic structures. It is possible to understand the causes and consequences of this variation across taxa with phylogenetic comparative analyses. Acoustic and evolutionary analyses are rapidly increasing in sophistication such that choosing appropriate acoustic and evolutionary approaches is increasingly difficult. However, the correct choice of analysis can have profound effects on output and evolutionary inferences. Here, we identify and address some of the challenges for this growing field by providing a roadmap for quantifying and comparing sound in a phylogenetic context for researchers with a broad range of scientific backgrounds. Sound, as a continuous, multidimensional trait can be particularly challenging to measure because it can be hard to identify variables that can be compared across taxa and it is also no small feat to process and analyse the resulting high‐dimensional acoustic data using approaches that are appropriate for subsequent evolutionary analysis. Additionally, terminological inconsistencies and the role of learning in the development of acoustic traits need to be considered. Phylogenetic comparative analyses also have their own sets of caveats to consider. We provide a set of recommendations for delimiting acoustic signals into discrete, comparable acoustic units. We also present a three‐stage workflow for extracting relevant acoustic data, including options for multivariate analyses and dimensionality reduction that is compatible with phylogenetic comparative analysis. We then summarize available phylogenetic comparative approaches and how they have been used in comparative bioacoustics, and address the limitations of comparative analyses with behavioural data. Lastly, we recommend how to apply these methods to acoustic data across a range of study systems. In this way, we provide an integrated framework to aid in quantitative analysis of cross‐taxa variation in animal sounds for comparative phylogenetic analysis. In addition, we advocate the standardization of acoustic terminology across disciplines and taxa, adoption of automated methods for acoustic feature extraction, and establishment of strong data archival practices for acoustic recordings and data analyses. Combining such practices with our proposed workflow will greatly advance the reproducibility, biological interpretation, and longevity of comparative bioacoustic studies.
The impact of the COVID‐19 pandemic on hospitalizations for oral and oropharyngeal cancer in Brazil
Authors: da Cunha Amanda Ramos , Antunes José Leopoldo Ferreira , Martins Manoela Domingues , Petti Stefano , Hugo Fernando Neves
Published: March 2021

Timely diagnosis and treatment of oral and oropharyngeal cancers are central for the patient's survival. Our objective was to document the impact of the COVID‐19 pandemic on the rate of hospitalizations due to these cancers in Brazil's National Health System (SUS). The number of hospitalizations by these cancers during the first periods of the pandemic—and between the same period of 2016 to 2019—was retrieved from the SUS Hospital Information System. We compared hospitalization rates between pre‐ and pandemic periods, by State. The hospitalization rate for oral and oropharyngeal cancer during the pandemic was lower than that of the same period of previous years. The decline between 2019 and 2020 was of 49.3%, reaching 60% in the North. The reduction in hospitalization during an extended period suggests that oral and oropharyngeal cancer care will be postponed, with potentially detrimental impact on survival.
Family treatment court participation and permanency in a rural setting: Outcomes from a rigorous quasi‐experiment
Authors: Lloyd Sieger Margaret H. , Becker Jessica , Brook Jody
Published: March 2021

Substance‐affected families are frequently cited as the most challenging families to serve within the child welfare context, particularly in rural settings where treatment services may be few and far between. Growing evidence suggests that family treatment courts (FTCs) may be more effective than their traditional counterpart at achieving key child welfare goals; however, prior studies have been limited in their methodological rigour. This study used treatment and matched comparison data to test foster care exit patterns of families with children in foster care due to parental substance use. Treatment group data were collected on a sample of 91 children with open dependency cases in an integrated FTC in a rural Midwestern town. Propensity score nearest neighbour one‐to‐two matching was used to identify a comparison group of 146 children. Findings suggest that FTC participation significantly influenced foster care exits. Survival analyses revealed that FTC children were 170% more likely to reunify, and 58% more likely to achieve permanency, than comparison cases. The effect of FTC participation on likelihood of reunification and likelihood of permanency was stronger when models estimated outcomes from FTC start date, rather than child removal date. Implications for social work practice, research, and education are discussed.
A Phase I, Randomized, Double‐Blind, Placebo‐Controlled, Single‐Dose and Multiple‐Rising‐Dose Study of the BTK Inhibitor TAK‐020 in Healthy Subjects
Authors: Esfandiari Ehsanollah , Chen Mary , Smithson Glennda , Blair Derek , Faessel Helene , Wagner John , Mclean Lachy , Fedyk Eric R.
Published: March 2021

Bruton’s tyrosine kinase (BTK) is a target for treatment of hematologic malignancies and autoimmune diseases. TAK‐020 is a highly selective covalent BTK inhibitor that inhibits both B cell receptor and fragment crystallizable receptor signaling. We assessed the safety/tolerability and pharmacokinetics/pharmacodynamics (PDs) of TAK‐020 in healthy subjects. Each cohort of the single‐rising dose (n = 72; 9 cohorts) and the multiple‐rising dose (n = 48; 6 cohorts) portions of the study comprised six TAK‐020‐treated and two placebo‐treated, subjects aged 18–55 years (inclusive). The PD effects were assessed by measuring BTK occupancy and the inhibition of fragment crystallizable epsilon receptor 1 (FcεRI)‐mediated activation of basophils. Overall, treatment‐emergent adverse events (TEAEs) were similar to placebo; there were no serious TEAEs or no TEAEs leading to discontinuation. TAK‐020 was rapidly absorbed (median time to maximum plasma concentration (Tmax) 45–60 minutes) with a half‐life of ~ 3–9 hours at doses ≥ 2.5 mg. TAK‐020 exposure was generally dose proportional for single doses ≤ 70 mg and after multiple doses of ≤ 60 mg once daily. Target occupancy was dose dependent, with doses ≥ 2.5 mg yielding maximum and sustained occupancy > 70% for > 96 hours. Single doses ≥ 4.4 mg reduced FcεRI‐mediated activation of basophils by > 80% and comparable inhibition was observed with daily dosing ≥3.75 mg for 9 days. Inhibition persisted for 24–72 hours postdose and the duration generally increased with dose. TAK‐020 was generally well‐tolerated in healthy subjects after single and multiple doses and demonstrated target engagement and pathway modulation. The PD effects outlasted drug exposures, as expected for covalent inhibition of BTK.
Drugs used for the treatment of cerebral and disseminated infections caused by free‐living amoebae
Authors: Taravaud Alexandre , Fechtali‐Moute Zineb , Loiseau Philippe M. , Pomel Sébastien
Published: March 2021

Free‐living amoebae (FLAs) are protozoa developing autonomously in diverse natural or artificial environments. The FLAs Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri represent a risk for human health as they can become pathogenic and cause severe cerebral infections, named granulomatous amoebic encephalitis (GAE), Balamuthia amoebic encephalitis (BAE), and primary amoebic meningoencephalitis (PAM), respectively. Additionally, Acanthamoeba sp. can also rarely disseminate to diverse organs, such as the skin, sinuses, or bones, and cause extracerebral disseminated acanthamebiasis (EDA). No consensus treatment has been established for cerebral FLA infections or EDA. The therapy of cerebral and disseminated FLA infections often empirically associates a large diversity of drugs, all exhibiting a high toxicity. Nevertheless, these pathologies lead to a high mortality, above 90% of the cases, even in the presence of a treatment. In the present work, a total of 474 clinical cases of FLA infections gathered from the literature allowed to determine the frequency of usage, as well as the efficacy of the main drugs and drug combinations used in the treatment of these pathologies. The efficacy of drug usage was determined based on the survival rate after drug administration. The most efficient drugs, drug combinations, and their mechanism of action were discussed in regard to the present recommendations for the treatment of GAE, EDA, BAE, and PAM. At the end, this review aims to provide a useful tool for physicians in their choice to optimize the treatment of FLA infections.
Impacts of COVID‐19 on Global Value Chains
Authors: Hayakawa Kazunobu , Mukunoki Hiroshi
Published: March 2021

We investigate the impacts of COVID‐19 on global value chains by examining bilateral trade in finished machinery products from January to June in both 2019 and 2020. We use the numbers of COVID‐19 cases and deaths as measures of the impact of the pandemic. Specifically, we investigate how these impacts affect value chains in three scenarios—countries that import finished machinery products, countries that export finished machinery products, and countries that export machinery parts to countries exporting finished machinery products—to assess the impacts on demand, output, and supply chain, respectively. In our analysis, the largest negative impacts were from supply chain effects, followed by output effects. In contrast, we did not find significant impacts from demand effects. We also found that output effects are not so strong in intra‐Asian trade compared with trade in other regions.
MRI measures of hypothalamic injury are associated with glucagon‐like peptide‐1 receptor agonist treatment response in people with hypothalamic obesity
Authors: Perez Francisco A. , Elfers Clinton , Yanovski Jack A. , Shoemaker Ashley H. , Abuzzahab M. Jennifer , Roth Christian L.
Published: March 2021

Aim

To evaluate whether neuroimaging‐delineated regions of hypothalamic injury are associated with a differential treatment response to a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) in patients with hypothalamic obesity (HO).

Materials and Methods

We performed a prespecified secondary analysis of a randomized, multicentre, double‐blind, placebo‐controlled trial of people aged 10–25 years with hypothalamic injury and HO randomized to the GLP‐1RA exenatide once‐weekly (ExQW) or placebo for 36 weeks. Subjects underwent MRI prior to enrolment and the degree of hypothalamic damage was assessed using an integrative hypothalamic lesion score (HLS). Mammillary body (MB) damage was specifically determined. The main clinical endpoints were % change in body mass index (BMI) and change in % body fat. Nested ANCOVA models including a treatment × imaging measure interaction were compared using partial F‐tests to assess whether the effect of ExQW treatment differed by severity of hypothalamic damage.

Results

Complete data were available in 35/42 randomized participants (placebo, n = 15; ExQW, n = 20). ExQW‐treated patients with worse HLS or bilateral MB damage had greater reductions in % body fat at 36 weeks (interaction coefficient estimates for HLS: −0.9%, 95% CI –1.6% to −0.2%, p = .02; for MB damage: −7.4%, 95% CI –10.1% to −4.7%, p < .001, respectively) but not for BMI % change. Similarly, patients with more damaged and smaller MB cross‐sectional areas had greater reductions in % body fat following ExQW (interaction coefficient estimate 0.3%, 95% CI 0.2%–0.4%, p < .001).

Conclusions

In people with HO, greater hypothalamic damage as determined by MRI, in particular MB injury, is associated with greater reductions in adiposity following GLP‐1RA treatment.
A new, highly aggressive race of Austropuccinia psidii infects a widely planted, myrtle rust‐resistant, eucalypt genotype in Brazil
Authors: Almeida Rosiane F. , Machado Patrícia S. , Damacena Michelle B. , Santos Samuel A. , Guimarães Lúcio M.S. , Klopfenstein Ned B. , Alfenas Acelino C.
Published: March 2021

Myrtle rust (MR) caused by Austropuccinia psidii is one of the most important diseases affecting eucalypt (Eucalyptus) plantations in Brazil. Over the years, selection and planting of MR‐resistant clones has been the primary strategy for MR management. In May 2013, young trees of the GG100 hybrid (E. grandis × E. urophylla) clone—widely planted in Brazil and previously classified as resistant to MR—were infected by A. psidii in Minas Gerais, Brazil. In this study, artificial inoculations of a eucalypt clone set with differential reactions to A. psidii races were used to discover a new race of A. psidii (race 5) that was highly aggressive on the majority of eucalypt clones tested. In addition, only this new race successfully infected eucalypt G26 and 847 genotypes, which were formerly classified as resistant to the four previously known races of A. psidii. Since G26 genotype is homozygous for Ppr1 (a major resistance gene against A. psidii), this is the first report of MR resistance breakdown in a eucalypt genotype homozygous for Ppr1. Our findings demonstrate that this new A. psidii race is highly aggressive and capable of infecting a larger number of eucalypt genotypes compared with the previously known A. psidii races 1, 2, 3, and 4.
Plant functional type indirectly affects peatland carbon fluxes and their sensitivity to environmental change
Authors: Whitaker Jeanette , Richardson Harriett R. , Ostle Nicholas J. , Armstrong Alona , Waldron Susan
Published: March 2021

The sensitivity of peatland carbon (C) fluxes to changes in climate and hydrology are uncertain due to the complex interactions between plants and peat properties. In this study we examine how peat cores taken from under three plant functional types (PFT) (bryophyte, graminoid and ericoid) differ in their biotic and abiotic properties and how this indirectly modulates the response of C fluxes to environmental change. Peat cores taken from under three PFTs had their aboveground vegetation removed to exclude direct plant‐mediated effects, and were incubated in a temperature × water table factorial experiment at 12, 14 and 16°C (air temperature) with the water table level −25, −15 or −5 cm below the peat surface. Carbon dioxide (CO2) and methane (CH4) fluxes were measured over 11 months. Emissions of CO2and CH4increased with temperature, with strong positive (CH4) and negative (CO2) interactions with increasing water table level. There were significant effects of removed PFT on the environmental sensitivity of CH4, but not CO2fluxes. CH4emissions were greatest in peat with graminoid PFT removed at the warmest temperature but these indirect effects were not explained by peat abiotic or biotic properties, which did not differ between PFTs. These results show that climate change‐induced expansion of graminoids in northern peatlands will have direct and indirect effects on C fluxes and the stability of peatland C stores. These responses will be determined by the interactive effects of vegetation composition, hydrology and warming on methane‐cycling microbial communities.

Highlights

Peatland carbon flux strength under a changing climate is influenced by PFT.

Peat from under graminoid PFT emits more methane than peat from under bryophyte or ericoid PFT.

Prior PFT cover influenced methane emissions, but did not affect peat abiotic or biotic properties.

Increases in graminoid cover with climate change could indirectly increase peatland methane fluxes.
How pore structure non‐stationarity compromises flow properties representativity (REV) for soil samples: Pore‐scale modelling and stationarity analysis
Authors: Gerke Kirill M. , Karsanina Marina V.
Published: March 2021

Classic soil physics relies heavily on the concept of representative elementary volume (REV), which is necessary to perform upscaling from the studied soil samples and parameterize continuum scale hydrological models (e.g., based on Richards or Darcy equations). In this paper, we explore the boundaries of the classic REV concept and conventional representativity studies that claim REV for any given physical property, and that its values converge to a steady value with increasing sample volume. We chose two undisturbed soil samples of standard size from Ah and B horizons, subcropped two subvolumes within each of them and performed pore‐scale flow simulations using binarized X‐ray microtomography scans as input data. The volume of the simulation domains was 9003 voxels, with a physical volume within two orders of magnitude of the whole soil core. Based on the 3D pore geometry images and the resulting flow velocity and pressure fields, we performed REV analysis for the saturated hydraulic conductivity and porosity. Although in general subvolumes showed classical REV behaviour (convergence of porosity and saturated hydraulic conductance (Ksat)to plateau‐like behaviour), their flow properties converged to different REV values. We also evaluated the stationarity of pore structures by computing the directional correlation functions to explain the observed non‐unique behaviour. We concluded that neither of the studied samples can be considered to be representative due to their structural non‐stationarity. We extensively discussed the implications of these results for the upscaling and parameterization of continuum‐scale flow models. We argued that the plateau in Ksat (or any other physical property) is a necessary, but insufficient, condition for the REV, which requires (at least) pore structure stationarity as an additional criterion. REV as a concept is much broader than previously anticipated and the possibility of establishing REVs in structured soils will require an analysis of tensorial flow properties with correct boundary conditions, multiscale soil structure imaging with stationarity analysis, and pore‐scale simulations on fused multiscale images.

Highlights

Ksat analysis within subvolumes showed classical REV behaviour but resulted in non‐unique REVs for the soil samples studied

Based on the stationarity analysis we argued that the conventional soil core samples studied were not REVs

Plateau‐like behaviour in physical properties is a necessary but insufficient condition for REV

Soil structure information is necessary to properly establish REV or upscale flow properties
Carbon sequestration in artificial silicate soils facilitated by arbuscular mycorrhizal fungi and glomalin‐related soil protein
Authors: Son Yejin , Stott Kevin , Manning David A. C. , Cooper Julia M.
Published: March 2021

In urban areas, pre‐existing concrete‐based demolition wastes and purposely introduced crushed dolerite have been used to create artificial soils, which capture carbon (C) as carbonate minerals and offset greenhouse gas (GHG) emissions. Arbuscular mycorrhizal fungi (AMF) can enhance capture of C in artificial soils through production of glomalin‐related soil protein (GRSP), which facilitates soil organic carbon (SOC) storage and aggregation, and may also enhance precipitation of soil inorganic carbon (SIC). In this paper, we show how different mixtures of dolerite and concrete affect AMF community structure and function, GRSP fractions, and soil organic and inorganic carbon contents. We used nine demonstration plots, 1 m deep, to simulate a constructed urban soil, consisting of different proportions (0, 30, 50, 70 and 100%) of either crushed concrete demolition waste or dolerite quarry fines and sown to a species‐rich meadow mixture, to investigate AMF colonization and community structure (using DNA terminal restriction fragment length polymorphism), contents of easily‐extractable and difficultly‐extractable GRSP, and both organic and inorganic carbon contents. All artificial soils supported functioning AMF communities with different levels of GRSP, SIC and SOC. The 100% dolerite and 100% concrete soils had higher values of difficultly‐to‐extract GRSP andSOC than pure sand, whereas 100% concrete had higher AMF colonization and SOC than sand. AMF community analysis indicated that high GRSP producing species were abundant in 100% dolerite and 100% concrete. These findings demonstrate that there is potential to incorporate demolition waste or dolerite products into the land to support environmental sustainability and enhance soil C sequestration.

Highlights

In constructed soils, crushed concrete and dolerite more effectively enhance GRSP and soil organic and inorganic carbon contents than sand.

Use of crushed concrete and dolerite in plant‐growing substrates is a novel way to combat climate change.
Soil respiration spatial and temporal variability in China between 1961 and 2014
Authors: Jian Jinshi , Yuan Xuefeng , Steele Meredith K. , Du Can , Ogunmayowa Oluwatosin
Published: March 2021

Soil respiration (Rs) plays an important role in terrestrial–atmospheric carbon exchange but remains one of the least studied components of the carbon cycle. How environmental changes influence Rs, and in turn, how Rs influences terrestrial carbon storage in China is unclear. Here, we estimated spatial patterns and temporal trends in Rs from 1961 to 2014 to determine the influence of the recent warming hiatus on the Rs temporal variability in China. We evaluated the relationship between Rs and a set of environmental factors and developed biome‐specific Rs models that were parameterized based on 2,862 Rs records and 18 continuous variables (e.g., air temperature, precipitation and leaf area index). Based on the biome‐specific Rs models and environmental information, we estimated the annual Rs as well as the change trend of Rs in China during the study period. The mean annual Rs from 1961 to 2014 was 3.50 (confidence interval ± 0.87) Pg·C·year−1. Rs in China increased at a rate of 0.008 Pg·C·year−2 between 1982 and 1998 (warming period), but was static between 1999 and 2014 (warming hiatus). This reduction in Rs increase rate may have an important role in enhancing terrestrial carbon sequestration. These findings confirm that temporal heterogeneity in Rs could be influenced by regional environmental changes, and further help in improving the understanding of soil carbon dynamics in China.

Highlights

No study in China has integrated multiple biotic and abiotic factors and analysed how soil respiration correlates with different factors across biomes.

In this study, biome‐specific models, including biotic and abiotic factors, were developed to estimate soil respiration in China.

Annual soil respiration in China was estimated to be 3.50 (confidence interval ± 0.87) Pg·C·year‐1.

Annual soil respiration in China had greater deceleration compared to the global deceleration between 1999 and 2014.
Untreated patients with multiple sclerosis: A study of French expert centers
Authors: Moisset Xavier , Fouchard Audrey‐Anne , Pereira Bruno , Taithe Frédéric , Mathey Guillaume , Edan Gilles , Ciron Jonathan , Brochet Bruno , De Sèze Jérôme , Papeix Caroline , Vermersch Patrick , Labauge Pierre , Defer Gilles , Lebrun‐Frenay Christine , Moreau Thibault , Laplaud David , Berger Eric , Pelletier Jean , Stankoff Bruno , Gout Olivier , Thouvenot Eric , Heinzlef Olivier , Al‐Khedr Abdullatif , Bourre Bertrand , Casez Olivier , Cabre Philippe , Montcuquet Alexis , Créange Alain , Camdessanché Jean‐Philippe , Bakchine Serge , Maurousset Aude , Hankiewicz Karolina , Pottier Corinne , Maubeuge Nicolas , Dimitri Boulos Dalia , Nifle Chantal , Vukusic Sandra , Clavelou Pierre ,   the OFSEP investigators
Published: March 2021

Background and purpose

Disease‐modifying therapies (DMTs) have an impact on relapses and disease progression. Nonetheless, many patients with multiple sclerosis (MS) remain untreated. The objectives of the present study were to determine the proportion of untreated patients with MS followed in expert centers in France and to determine the predictive factors of nontreatment.

Methods

We conducted a retrospective cohort study. Data were extracted from the 38 centers participating in the European Database for Multiple Sclerosis (EDMUS) on December 15, 2018, and patients with MS seen at least once during the study period (from June 15, 2016 to June 14, 2017) were included.

Results

Of the 21,189 patients with MS (age 47.1 ± 13.1 years; Expanded Disability Status Scale (EDSS) score 3.4 ± 2.4), 6,631 (31.3%; 95% confidence interval [CI] 30.7–31.9) were not receiving any DMT. Although patients with a relapsing‐remitting course (n = 11,693) were the most likely to receive DMT, 14.8% (95% CI 14.2–15.4) were still untreated (6.8% never treated). After multivariate analysis among patients with relapsing‐remitting MS, the main factors explaining never having been treated were: not having ≥9 lesions on brain magnetic resonance imaging (odds ratio [OR] 0.52 [95% CI 0.44–0.61]) and lower EDSS score (OR 0.78 [95% CI 0.74–0.82]). Most patients with progressive MS (50.4% for secondary and 64.2% for primary progressive MS) did not receive any DMT during the study period, while 11.6% of patients with secondary and 34.0% of patients with primary progressive MS had never received any DMT.

Conclusion

A significant proportion of patients with MS did not receive any DMT, even though such treatments are reimbursed by the healthcare system for French patients. This result highlights the unmet need for current DMTs for a large subgroup of patients with MS.
Structural biology of the invasion arsenal of Gram‐negative bacterial pathogens
Authors: Grishin Andrey , Voth Kevin , Gagarinova Alla , Cygler Miroslaw
Published: March 2021

In the last several years, there has been a tremendous progress in the understanding of host–pathogen interactions and the mechanisms by which bacterial pathogens modulate behavior of the host cell. Pathogens use secretion systems to inject a set of proteins, called effectors, into the cytosol of the host cell. These effectors are secreted in a highly regulated, temporal manner and interact with host proteins to modify a multitude of cellular processes. The number of effectors varies between pathogens from ~ 30 to as many as ~ 350. The functional redundancy of effectors encoded by each pathogen makes it difficult to determine the cellular effects or function of individual effectors, since their individual knockouts frequently produce no easily detectable phenotypes. Structural biology of effector proteins and their interactions with host proteins, in conjunction with cell biology approaches, has provided invaluable information about the cellular function of effectors and underlying molecular mechanisms of their modes of action. Many bacterial effectors are functionally equivalent to host proteins while being structurally divergent from them. Other effector proteins display new, previously unobserved functionalities. Here, we summarize the contribution of the structural characterization of effectors and effector–host protein complexes to our understanding of host subversion mechanisms used by the most commonly investigated Gram‐negative bacterial pathogens. We describe in some detail the enzymatic activities discovered among effector proteins and how they affect various cellular processes.
Temporal variation in the diet of Yangtze finless porpoise calls for conservation of semi‐migratory fish
Authors: Yang Jiwei , Wang Kang , Mei Zhigang , Xu Jun , Zheng Jinsong , Wan Xiaoling , Hao Yujiang , Wang Kexiong , Wang Ding
Published: March 2021

Identifying the feeding patterns of large‐bodied predators is necessary to predict their potential effects on food‐web dynamics and to inform species conservation. In contrast to diet information from stomach contents, diet estimates obtained using stable isotopes in blood and muscle can reveal temporal variation in diets.

Here, we used an extensive stable isotope dataset and Bayesian stable isotope mixing model to evaluate the trophic role of the Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis), a critically endangered species distributed in the middle and lower catchments of the Yangtze River. We analysed blood samples from 24 individuals captured during March 2017 in Poyang Lake (which adjoins the Yangtze River), and muscle samples from 8 individuals stranded in the lake over a 1‐year period (2012–2013). We additionally genotyped prey from faecal samples taken from 13 individuals captured in March 2017.

We found that as a generalist apex predator, this finless porpoise consumes semi‐migratory and non‐migratory fish prey. However, relative proportions of these two prey resources were different between dietary analyses based on blood samples compared to muscle samples, reflecting recent and longer‐term consumption patterns, respectively.

Non‐migratory fish contributed mainly to the diet of predators in the early and middle of March. In contrast, semi‐migratory fish comprised the majority of the prey composition over a more extended period (e.g. 2–3 months), and the difference may be linked to changes in the fish abundance influenced by seasonal factors.

Our findings provide insights into the trophic role of this critically imperilled but little studied species, demonstrate how stable isotope analyses can elucidate finless porpoise feeding ecology, and emphasise the importance of semi‐migratory fish to conserving this porpoise population.
Factor VIII/IX inhibitor testing practices in the United Kingdom: Results of a UKHCDO and UKNEQAS national survey
Authors: Batty Paul , Riddell Anne , Kitchen Steve , Sardo Infirri Sofia , Walker Isobel , Woods Tim , Jennings Ian , Hart Daniel P.
Published: March 2021

Introduction

Inhibitor formation is the greatest challenge facing persons with haemophilia treated with factor concentrates. The gold standard testing methodologies are the Nijmegen‐Bethesda assay (NBA) for FVIII and Bethesda assay (BA) for FIX inhibitors, which are affected by pre‐analytical and inter‐laboratory variability.

Aims

To evaluate inhibitor testing methodology and assess correlation between self‐reported and actual methodology.

Methods

Methodology was evaluated using a survey distributed alongside a UK National External Quality Assessment Service Blood Coagulation external quality assurance (EQA) exercise for FVIII and FIX inhibitor testing.

Results

Seventy four survey and EQA exercise responses were received (response rate 63.2%), with 50 paired survey/EQA results. 47.1% (33/70) reported using the NBA and 42.9% (30/70) the BA for FVIII inhibitor testing. Review of FVIII inhibitor assay methodology demonstrated discrepancy (self‐reported to actual) in 64.3% (BA reporting) and 27.6% (NBA reporting). Pre‐analytical heat treatment was used by 32.4%, most commonly 56°C for 30 minutes. Assay cut‐offs of 0.1‐1.0 BU/mL were reported. EQA samples (acquired FVIII and congenital FIX) demonstrated titres and coefficients of variation (CV) of 3.1 BU/mL (0.7‐15.4 BU/mL; CV = 43%) and 18.0 BU/mL (0‐117 BU/mL; CV = 33%), respectively. No significant assay or laboratory factors were found to explain this variance, which could have resulted in change in management for 6 patients (5 misclassified high‐titre FVIII inhibitors and 1 false negative for a FIX inhibitor).

Conclusions

Heterogeneity was seen at each stage of assay methodology. No assay‐related factors were found to explain variation in inhibitor titres. Further standardization is required to improve inhibitor quantification to guide patient care.
Effects of a non‐pharmacological approach for chronic pain management in patients with haemophilia: efficacy of cognitive‐behavioural therapy associated with physiotherapy
Authors: García‐Dasí María , Pérez‐Alenda Sofía , Carrasco Juan J. , Marques‐Sule Elena , Aguilar‐Rodríguez Marta , Moreno‐Segura Noemí , Gómez‐Tomás Cinta , Querol Felipe , Bonanad Santiago
Published: March 2021

Introduction

More than half of adult patients with severe haemophilia (PWH) suffer pain daily, with chronic pain (CP) in more than 15% of cases, thereby reducing their quality of life (QoL). However, there are no evidence‐based therapeutic guidelines for pain management.

Aim

To evaluate the effectiveness of a combined protocol based on psychology and physiotherapy in the improvement of CP self‐efficacy in PWH with CP. Secondary outcomes are changes in QoL, emotional status, pain and kinesiophobia.

Methods

In this prospective controlled trial study, recruited patients were allocated either to an experimental group (EG, n = 10) or to a control group (CG, n = 9). EG received interventions over four months: one cognitive‐behavioural therapy (CBT) session per month and three home exercise sessions per week.

Self‐efficacy (Chronic Pain Self‐Efficacy Scale), QoL (A36 Hemophilia‐QoL), emotional status (Hospital Anxiety and Depression Scale and Rosenberg's Self‐esteem Scale), pain (Visual Analogue Scale) and kinesiophobia (Tampa Scale for Kinesiophobia) were assessed at three time points (Week 0, Month 4 and Month 7). The intervention effects were determined with mixed 2‐factor ANOVAs.

Results

The EG showed a significant improvement (p < .05) in the control of symptoms and pain management scores on the Self‐Efficacy Scale, QoL, self‐esteem emotional status, pain and kinesiophobia. The intervention effects remained significant (p < .05) over time for pain management, QoL, pain and kinesiophobia.

Conclusion

The non‐pharmacological treatment applied based on CBT and physiotherapy showed to be effective in improving CP self‐efficacy, QoL and emotional status, while reducing pain and kinesiophobia in PWH with CP.
Clinical Guidelines for Female Lower Urinary Tract Symptoms (second edition)
Authors: Takahashi Satoru , Takei Mineo , Asakura Hirotaka , Gotoh Momokazu , Ishizuka Osamu , Kato Kumiko , Koyama Masayasu , Takeyama Masami , Tomoe Hikaru , Yamanishi Tomonori , Yokoyama Osamu , Yoshida Masaki , Yoshimura Yasukuni , Yoshizawa Tsuyoshi
Published: March 2021

The present article is an abridged English translation of the Japanese Clinical Guidelines for Female Lower Urinary Tract Symptoms (second edition), published in September 2019. These guidelines consist of a total of 212 pages and are unique worldwide in that they cover female lower urinary tract symptoms other than urinary incontinence. They contain two algorithms for “primary treatment” and “specialized treatment,” respectively. These guidelines, consisting of six chapters, address a total of 26 clinical questions including: (i) treatment algorithms; (ii) what are female lower urinary tract symptoms?; (iii) epidemiology and quality of life; (iv) pathology and illness; (v) diagnosis; and (vi) treatment. When the patient’s symptoms mainly involve voiding and post‐micturition symptoms, specialized treatment should be considered. In the event of voiding symptoms concurrent with storage symptoms, residual urine should be measured; if the residual urine volume is <100 mL, then diagnosis and treatment for storage symptoms is prioritized, and if the volume is ≥100 mL, then specialized treatment should be considered. When storage symptoms are the primary condition, then the patient is subject to the primary treatment algorithm. Specialized treatment for refractory overactive bladder includes botulinum toxin injection and sacral nerve stimulation. For stress urinary incontinence, surgical treatment is indicated, such as urethral slings. The two causes of voiding symptoms and post‐micturition symptoms are lower urinary tract obstruction and detrusor underactivity (underactive bladder). Mechanical lower urinary tract obstruction, such as pelvic organ prolapse, is expected to improve with surgery.
Safety and chronic lesion characterization of pulsed field ablation in a Porcine model
Authors: Stewart Mark T. , Haines David E. , Miklavčič Damijan , Kos Bor , Kirchhof Nicole , Barka Noah , Mattison Lars , Martien Matt , Onal Birce , Howard Brian , Verma Atul
Published: March 2021

Background

Pulsed field ablation (PFA) has been identified as an alternative to thermal‐based ablation systems for treatment of atrial fibrillation patients. The objective of this Good Laboratory Practice (GLP) study was to characterize the chronic effects and safety of overlapping lesions created by a PFA system at intracardiac locations in a porcine model.

Methods

A circular catheter with nine gold electrodes was used for overlapping low‐ or high‐dose PFA deliveries in the superior vena cava (SVC), right atrial appendage (RAA), and right superior pulmonary vein (RSPV) in six pigs. Electrical isolation was evaluated acutely and chronic lesions were assessed via necropsy and histopathology after 4‐week survival. Acute and chronic safety data were recorded peri‐ and post‐procedurally.

Results

No animal experienced ventricular arrhythmia during PFA delivery, and there was no evidence of periprocedural PFA‐related adverse events. Lesions created in all anatomies resulted in electrical isolation postprocedure. Lesions were circumferential, contiguous, and transmural, with all converting into consistent lines of chronic replacement fibrosis, regardless of trabeculated or smooth endocardial surface structure. Ablations were non‐thermally generated with only minimal post‐delivery temperature rises recorded at the electrodes. There was no evidence of extracardiac damage, stenosis, aneurysms, endocardial disruption, or thrombus.

Conclusion

PFA deliveries to the SVC, RAA, and RSPV resulted in complete circumferential replacement fibrosis at 4‐week postablation with an excellent chronic myocardial and collateral tissue safety profile. This GLP study evaluated the safety and efficacy of a dosage range in preparation for a clinical trial and characterized the non‐thermal nature of PFA.
Systematic reviews of antihypertensive drugs: A review of publication trends, characteristics, and quality
Authors: Esam Hariprasad , Kanukula Raju , Dhurjati Rupasvi , Aerram Rupa , Chevireddy Sindhujareddy , Bhaumik Soumyadeep , Atkins Emily , Huffman Mark D. , Rodgers Anthony , Salam Abdul
Published: March 2021

This review presents publication trends, characteristics, and quality of systematic reviews (SRs) of randomized controlled trials (RCTs) of antihypertensive drugs (AHTDs). Between 1985 and 2017, 1,173 SRs were published, and in the last 20 years, 10, 35, and 116 were published in the year 1996, 2006, and 2016, respectively. Angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers were the most common class of drugs studied. Fourteen percent of the SRs were prospectively registered/published protocol. Three‐fourth of the SRs did not report a full search strategy, and 45% did not report a PRISMA or similar diagram. Of the 34 SRs published in the five high impact factor journals in the last 10 years, 15%, 21%, and 65% have unclear, low, and high risk of bias, respectively. There has been a steady increase in the publication of SRs of RCTs of AHTDs. However, adherence to standard methods of conduct and reporting continues to be low.