bluuebunny/crossref_metadata_2025 huggingface dataset:
Local soil legacy effects in a multispecies grassland community are underlain by root foraging and soil nutrient availability
Authors: in ‘t Zandt Dina , Hoekstra Nyncke J. , Wagemaker Cornelis A. M. , de Caluwe Hannie , Smit‐Tiekstra Annemiek E. , Visser Eric J. W. , de Kroon Hans
Published: June 2020

Plant‐soil legacies consisting of species‐specific microbial communities are hypothesized to play a critical, structuring role in plant species coexistence processes. Plant species are thought to perform worse on soil conditioned by the same species compared to soil of other species, which serves as a self‐limitation mechanism and averts monodominance of strong competitors. Here, we test in a multispecies community setting, whether root colonization and resource utilization of soil patches with distinct soil legacies are consistent with this hypothesis.

We grew eight grassland species together in an outdoor mesocosm set‐up in unconditioned soil and created soil patches in these communities conditioned by one of four plant species, or a soil mixture of all four. During two subsequent growing seasons, we tested the effect of these conditioned soil patches on below‐ground root colonization into the patches of each surrounding plant species using a novel sequencing‐based approach. In addition, we tested the effect of soil conditioning on local root functioning by injecting tracers into the soil patches and measuring the recovery in above‐ground biomass.

Against expectations, plant species did not place less roots in own soil patches compared to foreign soil patches, nor did species take up less tracer from own compared to foreign soil patches. Using structural equation modelling, we found that tracer uptake of the plant species was to a varying degree explained by root densities in the various soil patches and by differing soil nutrient availability of the soil patches. We conclude that soil legacy effects are inextricably connected to soil nutrient availability, which needs to be taken into account in plant‐soil feedback research to understand the processes that shape plant communities.

Synthesis. We found that soil legacy effects in complex, multispecies semi‐field conditions did not match expectations based on theory and experiments in controlled conditions. Among the many complicating factors that may modify or even overrule soil legacy effects in semi‐field settings, we identified soil nutrient availability as a critical force that may, together with soil biota, shape plant species coexistence processes.
A regime shift from erosion to carbon accumulation in a temperate northern peatland
Authors: Milner Alice M. , Baird Andy J. , Green Sophie M. , Swindles Graeme T. , Young Dylan M. , Sanderson Nicole K. , Timmins Madeleine S. I. , Gałka Mariusz
Published: June 2020

Peatlands are globally important ecosystems but many are degraded and some are eroding. However, some degraded peatlands are undergoing apparently spontaneous recovery, with switches from erosion to renewed carbon accumulation—a type of ecological regime shift.

We used a palaeoecological approach to investigate and help understand such a switch in a blanket peatland in North Wales, UK.

Our data show: (a) a rapid accumulation of new peat after the switch from the eroding state, with between 5.2 and 10.6 kg/m2 carbon accumulating since the beginning of the recovery which occurred between the late 1800s and early to mid‐1900s CE, with an average carbon accumulation rate in the new peat between 46 and 121 g C m−2 year−1; (b) three main successional pathways in peat‐forming vegetation and (c) hydrological changes with an increase to moderately high water‐tables after the switch that promoted new carbon accumulation as well as protecting vulnerable old carbon. External factors, including changes in climate and industrial activity, can only partially explain our results. Following previous studies, we suggest that internal ecosystem processes offer a substantial part of the explanation and interpret the switch to renewed carbon accumulation as a bifurcation‐type tipping point involving changes in the physical form of the eroded landscape.

Synthesis. Our long‐term ecological data reveal a switch from a degraded peatland with active erosion and loss of carbon to a revegetated, wetter peatland accumulating carbon. The switch can be interpreted as a bifurcation tipping point. We suggest that external factors such as climate and pollution levels are important for setting suitable boundary conditions for peatland recovery, but internal mechanisms can explain the change in peatland state. Our study is the first of its kind to apply tipping point theory to the internal mechanisms linked to peat erosion and recovery and may help improve understanding of the trajectories of other peatlands in a changing climate.
SuPAR, a potential inflammatory mediator in psoriasis pathogenesis
Authors: Hamie Lamiaa , Eid Edward , Abbas Ossama , Safi Remi , Nammour Tarak , Tamim Hani , Makki Maha , Stephan Carla , Hasbani Divina , Wehbe Hisham , Ghaoui Nohra , Hawa Mariana , Nasser Nourhan , Eid Assaad , Kibbi Abdul‐Ghani , Kurban Mazen
Published: June 2020

Psoriasis is an inflammatory skin disorder that is strongly associated with the metabolic syndrome. The sole reliance on clinical examination to guide prognostication and treatment is insufficient at best; accurate diagnostic and prognostic psoriatic molecular biomarkers are needed. Soluble urokinase plasminogen activator receptor (suPAR) has been implicated in inflammation. The aim of this study is to determine whether suPAR plays a role in the pathogenesis of psoriasis and whether an association exists between suPAR levels, disease severity, and other variables like insulin, erythrocyte sedimentation rate (ESR) and C‐reactive protein (CRP). This study also compares the pattern of uPAR staining in healthy vs psoriatic skin: 39 psoriatic and 30 control subjects were included. Two biopsies (affected and unaffected skin) and one biopsy were taken from psoriasis patients and healthy controls, respectively, with uPAR staining of all skin biopsies. Blood samples from all subjects were obtained to determine suPAR, ESR, CRP, and fasting insulin levels. uPAR staining was prominent in unaffected skin from psoriasis patients and healthy individuals vs weak/absent uPAR staining in psoriatic skin. CRP, ESR and suPAR levels were not significantly elevated in the mild psoriasis group compared to healthy controls. The loss of epidermal uPAR is suggestive of its tentative role in the pathogenesis of psoriasis. Patients with mild–moderate psoriasis possibly lack the powerful association attributed to metabolic syndrome in psoriatic patients. Further studies on larger cohorts are needed to ascertain the validity of the mentioned conclusions.
Anaerobic guilds responsible for mercury methylation in boreal wetlands of varied trophic status serving as either a methylmercury source or sink
Authors: Schaefer Jeffra K , Kronberg Rose‐Marie , Björn Erik , Skyllberg Ulf
Published: June 2020

Wetlands are common sites of active Hg methylation by anaerobic microbes; however, the amount of methylmercury produced varies greatly, as Hg methylation is dependent upon both the availability of Hg and the composition and activity of the microbial community involved. In this study, we identified the major microbial guilds responsible for Hg methylation along a trophic gradient composed of two sites and three different types of wetlands: a bog–fen peatland gradient and a black alder swamp, serving as net sources and a sink for methylmercury respectively. Iron‐reducing bacteria in the Geobacteraceae were important Hg methylators across all wetlands and seasons examined, as evidenced by abundant 16S rRNA and hgcA transcripts clustering with this family. Molybdate inhibited Hg methylation more efficiently in the peatlands than in the swamp, suggesting an increasing role of sulfate‐reducing bacteria and/or related syntrophs in the methylation of Hg with decreasing trophic status. Sulfate addition failed to increase Hg methylation rates in the peatlands, suggesting that SRBs/syntrophs were instead likely metabolizing alternative substrates such as syntrophic fermentation of organic compounds with methanogens. These results highlight the interconnectivity of anaerobic metabolism and importance of community dynamics on the methylation of Hg in wetlands with different trophic status.
Death in the town square: body performance and community healing in a Catalan traditional sport
Authors: Vaczi Mariann
Published: June 2020

Human tower building (castells) is a two‐hundred‐year‐old traditional sport in Catalonia (Spain), which has boomed since the democratic Transition (1975) as a national symbol and low‐cost intergenerational pastime activity. In 2006, however, a child performer died as a result of a collapse. Catalonia responded with profound grief, and the human tower community embarked on a process of ‘overcoming’ (superació), whose success was made contingent on the iconic outcome of towers ritually performed throughout a year and a half. Performers produced and deployed cultural meanings of verticality, and operationalized them for bereavement and meaning making. The case inserts the iconicity of body practice in anthropological debates about death in three ways. First, the verticality and body experience of tower building allowed the bereaved community to imagine life, death, transcendence, and ‘resurrection’, thus establishing continuing bonds and a social afterlife. Second, the structural completion of towers lent itself to stage‐ and task‐oriented interpretations of bereavement, whereby each tower level was a task the community had to execute to proceed to the next stage of bereavement. However, and third, mourning through sport performance also acknowledged the uncertainties of those cultural scripts of bereavement through the performative contingencies of the outcome of tower building.
Whole‐genome sequencing to detect mutations associated with resistance to insecticides and Bt proteins in Spodoptera frugiperda
Authors: Guan Fang , Zhang Jianpeng , Shen Huiwen , Wang Xingliang , Padovan Amanda , Walsh Tom K. , Tay Wee Tek , Gordon Karl H. J. , James William , Czepak Cecilia , Otim Michael Hilary , Kachigamba Donald , Wu Yidong
Published: June 2020

The fall armyworm (FAW), Spodoptera frugiperda, is a major pest native to the Americas that has recently invaded the Old World. Point mutations in the target‐site proteins acetylcholinesterase‐1 (ace‐1), voltage‐gated sodium channel (VGSC) and ryanodine receptor (RyR) have been identified in S. frugiperda as major resistance mechanisms to organophosphate, pyrethroid and diamide insecticides respectively. Mutations in the adenosine triphosphate‐binding cassette transporter C2 gene (ABCC2) have also been identified to confer resistance to Cry1F protein. In this study, we applied a whole‐genome sequencing (WGS) approach to identify point mutations in the target‐site genes in 150 FAW individuals collected from China, Malawi, Uganda and Brazil. This approach revealed three amino acid substitutions (A201S, G227A and F290V) of S. frugiperda ace‐1, which are known to be associated with organophosphate resistance. The Brazilian population had all three ace‐1 point mutations and the 227A allele (mean frequency = 0.54) was the most common. Populations from China, Malawi and Uganda harbored two of the three ace‐1 point mutations (A201S and F290V) with the 290V allele (0.47–0.58) as the dominant allele. Point mutations in VGSC (T929I, L932F and L1014F) and RyR (I4790M and G4946E) were not detected in any of the 150 individuals. A novel 12‐bp insertion mutation in exon 15 of the ABCC2 gene was identified in some of the Brazilian individuals but absent in the invasive populations. Our results not only demonstrate robustness of the WGS‐based genomic approach for detection of resistance mutations, but also provide insights for improvement of resistance management tactics in S. frugiperda.
Clearance of chloroquine and hydroxychloroquine by the Seraph® 100 Microbinda Affinity Blood Filter ‐a device approved for the treatment of COVID‐19 patients
Authors: Seffer Malin‐Theres , Martens‐Lobenhoffer Jens , Schmidt Julius J. , Eden Gabriele , Bode‐Böger Stefanie M. , Kielstein Jan T.
Published: June 2020

On April 17 2020, the United States Food and Drug Administration granted Coronavirus Disease 2019 (COVID‐19) emergency use authorizations for the Seraph 100 Microbind Affinity Blood Filter. The medical device is aimed to treat critically ill COVID‐19 patients with confirmed or imminent respiratory failure. The aim of this life size in vitro pharmacokinetic study was to investigate the in vitro adsorption of chloroquine and hydroxychloroquine from human plasma using equipment that is also used at the bedside. After start of the hemoperfusion, Pre (Cpre) Seraph plasma levels were obtained at 5 (C5), 10 (C10), 15 (C15), 30 (C30), 60 (C60), and 120 (C120) minutes into the procedure. At two timepoints (5 and 120 minutes) post (Cpost) Seraph plasma levels were determined that were used to calculate the plasma clearance of the Seraph. Both drugs were determined using a validated HPLC method. Median [IQR] plasma clearance of the Seraph for chloroquine/hydroxychloroquine was 1.71 [0.51‐4.38] mL/min/1.79 [0.21‐3.68] mL/min respectively. The lack of elimination was also confirmed by the fact that plasma levels did not change over the 120 minutes treatment. As neither chloroquine nor hydroxychloroquine were removed by the treatment with the Seraph dose adjustments in COVID‐19 patients undergoing this treatment are not necessary.
Incidence and factors associated with discontinuation of opioid agonist therapy among people who inject drugs in Australia
Authors: Geddes Louise , Iversen Jenny , Wand Handan , Maher Lisa
Published: June 2020

Aims

To estimate incidence and predictors of opioid agonist therapy (OAT) discontinuation in a national cohort of people who inject drugs (PWID).

Design and Setting

Annually repeated cross‐sectional serosurveillance among PWID attending ~50 needle–syringe programmes across Australia.

Participants

Between 1995 and 2018, 2651 PWID who reported current OAT and had subsequent survey participation completed 6739 surveys. Respondents were followed over 11 984 person‐years of observation (PYO). Respondents were predominantly male (60%), and the median age was 34 years. Heroin was the most commonly reported drug last injected (46%), and methadone was the most commonly prescribed OAT (77%).

Measurements

The primary outcome was discontinuation of OAT (methadone, buprenorphine or buprenorphine–naloxone). Among respondents who reported current OAT, those who did not report current OAT in all subsequent records were defined as discontinued, and those with current OAT at all subsequent records were defined as retained. Predictors of discontinuation included self‐reported demographic (sex, location, Indigenous status) and drug use characteristics (drug last injected, frequency of injection).

Findings

Just fewer than one‐third of respondents (29%) reported an OAT discontinuation event. The crude discontinuation rate was 6.3 [95% confidence intervals (CI) = 5.9–6.8] per 100 PYO. Discontinuation was significantly higher among respondents who reported last injecting pharmaceutical opioids [adjusted hazard ratio (aHR) = 1.75, 95% CI = 1.41–2.17,P < 0.001], being prescribed buprenorphine (aHR = 1.44, 95% CI = 1.18–1.76,P = 0.001) or buprenorphine–naloxone (aHR = 1.68, 95% CI = 1.20–2.34,P = 0.002), daily or more frequent injection (aHR = 1.51, 95% CI = 1.23–1.85,P < 0.001), recent public injecting (aHR = 1.37, 95% CI = 1.17–1.60,P < 0.001), incarceration in the previous 12 months (aHR = 1.31, 95% CI = 1.05–1.64,P = 0.017), recent receptive syringe or injection equipment sharing (aHR = 1.28, 95% CI = 1.10–1.48,P = 0.001) and male sex (aHR = 1.27, 95% CI = 1.09–1.47,P = 0.002).

Conclusion

People who inject drugs attending needle–syringe programmes in Australia appear to be significantly more likely to discontinue opioid agonist treatment if they were prescribed buprenorphine or buprenorphine–naloxone compared with methadone, are male or report injection risk behaviours and recent incarceration.
Natural killer cells and reproductive success
Authors: Sacks Gavin , Finkelstein Emma
Published: June 2020

Natural killer (NK) cell assessment has been attempted since the 1990s and, apart from antibody testing, is probably the commonest immune test available to clinicians. It is clear that simple enumeration of uterine NK cells by immunohistochemistry is inadequate, although better methodology such as flow cytometry may prove to be more beneficial in the future. Blood testing is an appealing noninvasive test that may be a marker for immune dysfunction, rather than a guide to uterine numbers per se. It is currently performed in women with repeated reproductive failure and should be done using tests of activation. Patients value investigation and clinicians should prefer it to blind empirical immune therapy in repeated reproductive failure cases. But, in addition to blood NK testing, a fundamental new NK genetic test (the KIR/HLA‐C interaction) is likely to provide an even more effective diagnostic tool. Insights from KIR/HLA‐C analysis imply that new immune therapy trials will need to take KIR/HLA‐C results into account.
EAACI Guidelines on the effective transition of adolescents and young adults with allergy and asthma
Authors: Roberts Graham , Vazquez‐Ortiz Marta , Knibb Rebecca , Khaleva Ekaterina , Alviani Cherry , Angier Elizabeth , Blumchen Katharina , Comberiati Pasquale , Duca Bettina , DunnGalvin Audrey , Garriga‐Baraut Teresa , Gore Claudia , Gowland M. Hazel , Hox Valérie , Jensen Britt , Mortz Charlotte G. , Pfaar Oliver , Pite Helena , Santos Alexandra F. , Sanchez‐Garcia Silvia , Timmermans Frans
Published: June 2020

Adolescent and young adult (AYA) patients need additional support, while they experience the challenges associated with their age. They need specific training to learn the knowledge and skills required to confidently self‐manage their allergies and/or asthma. Transitional care is a complex process, which should address the psychological, medical, educational and vocational needs of AYA in the developmentally appropriate way. The European Academy of Allergy and Clinical Immunology has developed a clinical practice guideline to provide evidence‐based recommendations for healthcare professionals to support the transitional care of AYA with allergy and/or asthma. This guideline was developed by a multidisciplinary working panel of experts and patient representatives based on two recent systematic reviews. It sets out a series of general recommendations on operating a clinical service for AYA, which include the following: (a) starting transition early (11‐13 years), (b) using a structured, multidisciplinary approach, (c) ensuring AYA fully understand their condition and have resources they can access, (d) active monitoring of adherence and (e) discussing any implications for further education and work. Specific allergy and asthma transition recommendations include (a) simplifying medication regimes and using reminders; (b) focusing on areas where AYA are not confident and involving peers in training AYA patients; (c) identifying and managing psychological and socio‐economic issues impacting disease control and quality of life; (d) enrolling the family in assisting AYA to undertake self‐management; and (e) encouraging AYA to let their friends know about their allergies and asthma. These recommendations may need to be adapted to fit into national healthcare systems.
Family history and risk of miscarriage: A systematic review and meta‐analysis of observational studies
Authors: Woolner Andrea M. F. , Nagdeve Priti , Raja Edwin‐Amalraj , Bhattacharya Siladitya , Bhattacharya Sohinee
Published: June 2020

Introduction

Miscarriage, a spontaneous pregnancy loss at <24 weeks’ gestation, is a common complication of pregnancy but the etiologies of miscarriage and recurrent miscarriage are not fully understood. Other obstetric conditions such as preeclampsia and preterm birth, which may share similar pathophysiology to miscarriage, exhibit familial patterns, suggesting inherited predisposition to these conditions. Parental genetic polymorphisms have been associated with unexplained miscarriage, suggesting there could be a genetically inherited predisposition to miscarriage. This systematic review and meta‐analysis of observational studies aimed to assess the association between family history of miscarriage and the risk of miscarriage in women.

Material and methods

A systematic review and meta‐analysis of observational studies was carried out in accordance with Meta‐analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Electronic searches using databases (MEDLINE, EMBASE and CINAHL) were carried out to identify eligible studies from 1946 until 2019. Observational studies (cohort or case‐control) were included. Human studies only were included. Participants were women of reproductive age. Exposure was a family history of one or more miscarriage(s). The primary outcome was miscarriage in women. Abstracts were screened and data were extracted by two independent reviewers. Study quality was assessed using Critical Appraisal Skills Program (CASP) tools. Data were pooled from individual studies using the Mantel‐Haenszel method to produce pooled odds ratios (ORs) with 95% confidence intervals (95% CI). Systematic review registration number (PROSPERO): CRD42019127950.

Results

Thirteen studies were identified in the systematic review; 10 were eligible for inclusion in the meta‐analysis. Twelve studies reported an association between family history of miscarriage and miscarriage in women. In all, 41 287 women were included in the meta‐analysis. Women who miscarried were more likely to report a family history of miscarriage (pooled unadjusted OR 1.90, 95% CI 1.37‐2.63). Overall study quality and size varied, with few adjusting for confounding factors. Results should be interpreted with caution as the associations presented are based on unadjusted analyses only.

Conclusions

Women who miscarry may be more likely to have a family history of miscarriage. Further research is required to confirm or refute the findings.
Optimal cannula positioning of HeartMate 3 left ventricular assist device
Authors: Imamura Teruhiko , Narang Nikhil , Nitta Daisuke , Fujino Takeo , Nguyen Ann , Kim Gene , Raikhelkar Jayant , Rodgers Daniel , Ota Takeyoshi , Jeevanandam Valluvan , Sayer Gabriel , Uriel Nir
Published: June 2020

Cannula position in HeartMate II and HeartWare left ventricular assist devices (LVADs) is associated with clinical outcome. This study aimed to investigate the clinical implication of the device positioning in HeartMate 3 LVAD cohort. Consecutive patients who underwent HeartMate 3 LVAD implantation were followed for one year from index discharge. At index discharge, chest X‐ray parameters were measured: (a) cannula coronal angle, (b) height of pump bottom, (c) cannula sagittal angle, and (d) cannula lumen area. The association of each measurement of cannula position with one‐year clinical outcomes was investigated. Sixty‐four HeartMate 3 LVAD patients (58 years old, 64% male) were enrolled. In the multivariable Cox regression model, the cannula coronal angle was a significant predictor of death or heart failure readmission (hazard ratio 1.27 [1.01‐1.60], P = .045). Patients with a cannula coronal angle ≤28° had lower central venous pressure (P = .030), lower pulmonary capillary wedge pressure (P = .027), and smaller left ventricular size (P = .019) compared to those with the angle >28°. Right ventricular size and parameters of right ventricular function were also better in the narrow angle group, as was one‐year cumulative incidence of death or heart failure readmission (10% vs. 50%, P = .008). Narrow cannula coronal angle in patients with HeartMate 3 LVADs was associated with improved cardiac unloading and lower incidence of death or heart failure readmission. Larger studies to confirm the implication of optimal device positioning are warranted.
Choriocapillaris thickness and density in axially elongated eyes
Authors: Panda‐Jonas Songhomitra , Holbach Leonard , Jonas Jost B.
Published: June 2020

Purpose

Axial myopia is characterized by a thinning of the choroid. We examined whether the myopic choroidal thinning also includes a thinning of the choriocapillaris.

Methods

Using light microscopy, we measured thickness and density of the choriocapillaris at the posterior pole, posterior pole–equator midpoint (PPEMP), equator and close to the ora serrata on histological sections of 58 enucleated human globes (mean age: 62.4 ± 17.8 years; range: 24–88 years; mean axial length: 27.8 ± 4.0 mm; range: 22.0–37.0 mm).

Results

Choriocapillaris thickness decreased (p < 0.001) from the posterior pole (median: 3.9 µm; interquartile range (IQR): 3.3–6.0) to the equator (median: 2.7 µm; IQR: 1.5, 4.2). It was not significantly associated with axial length, neither at the posterior pole (p = 0.25), the PPEMP (p = 0.81), equator (p = 0.80) or ora serrata (p = 0.50). Mean choriocapillaris density decreased from the posterior pole to the equator (198 µm/300 µm; IQR: 152/300, 246/300 versus 156 µm/300 µm; IQR: 72/300, 216/300; p < 0.001). Choriocapillaris density was not significantly associated with axial length (posterior pole: p = 0.07; PPEMP: p = 0.33; equator: p = 0.22; ora serrata: p = 0.36).

Conclusions

The choriocapillaris thickness and density, decreasing from the posterior pole to the fundus periphery, were not significantly associated with axial length. These findings may be of interest for the understanding of high myopia and pathologic myopia.
Prescription patterns of outpatients and the potential of multiplexed pharmacogenomic testing
Authors: Chan Sze Ling , Liew Hariz Zhen Wei , Nguyen Francis , Thumboo Julian , Chow Wan Cheng , Sung Cynthia
Published: June 2020

Background

Pre‐emptive pharmacogenomic (PGx) testing is potentially an efficient approach to improve drug safety and efficacy but the target population to test is unclear.

Objectives

We aim to describe the prescription pattern of PGx drugs among adult medical outpatients.

Methods

We estimated the 5‐year cumulative incidence (CI) for receiving three groups of PGx drugs using competing risks analysis: (i) all PGx drugs, (ii) PGx drugs with guidelines and (iii) PGx drugs with serious clinical effects. Comparisons of CIs were also done by patient characteristics using Gray's test.

Results

The 5‐year CIs of receiving any new PGx drug, PGx drug with guidelines and serious clinical effects were 42.6%, 37.3% and 13.7%, respectively. The 5‐year CI of receiving any new PGx drug was higher for patients >40 years old (43.6% vs ≤40 years old 36.0%, P < 2.2 × 10−22), Malays and Indians (50.3% and 49.8% vs Chinese 31.1%, P < 2.2 × 10−22), those who attended one of the following four specialties at the index visit compared to other specialties (infectious diseases [46.2% vs 42.6%, P = 2.9 × 10−4], psychiatry [48.3% vs 42.3%, P = 7.4 × 10−13], renal [49.8% vs 40.9%, P < 2.2 × 10−22], and rheumatology and immunology [54.8% vs 41.7%, P < 2.2 × 10−22]) and those prescribed ≥5 drugs at index visit (51.7% vs 0‐4 drugs 41.7%, P < 2.2 × 10−22).

Conclusions

Medical outpatients have a substantial probability of benefiting from pre‐emptive PGx testing and this is higher in certain subgroups of patients.
Evaluation of ABC gene polymorphisms on the pharmacokinetics and pharmacodynamics of capecitabine in colorectal patients: Implications for dosing recommendations
Authors: Sáez‐Belló Marina , Mangas‐Sanjuán Víctor , Martínez‐Gómez Mª. Amparo , López‐Montenegro Soria Mª. Ángeles , Climente‐Martí Mónica , Merino‐Sanjuán Matilde
Published: June 2020

Aims

The aims are to develop a population pharmacokinetic model of capecitabine (CAP) and its main metabolites after the oral administration of CAP in colorectal cancer patients with different polymorphisms of the ATP‐binding cassette (ABC) gene and a population pharmacokinetic/pharmacodynamic model capable of accounting for the neutropenic effects, and to optimize the dosing strategy based on the polymorphisms of the ABC gene and/or the administration regimen as a single agent or in combination.

Methods

Forty‐eight patients diagnosed with colorectal cancer were included, with 432 plasma levels of CAP, 5′‐desoxi‐5‐fluorouridine (5′‐DFUR) and 5‐fluorouracil (5‐FU), and 370 neutrophil observations. Capecitabine doses ranged from 1250 to 2500 mg/m2/24 h. Plasma measurements of CAP, 5′‐DFUR and 5‐FU were obtained at 1, 2 and 3 hours post administration. Neutrophil levels were measured between day 15 and day 24 post administration.

Results

The pharmacokinetic model incorporates oxaliplatin as a covariate on absorption lag time, rs6720173 (ABCG5 gene) on clearance of 5′‐DFUR (182% increase for mutated rs6720173) and rs2271862 (ABCA2 gene) on clearance of 5‐FU (184% increase for mutated rs2271862). System‐ (Circ0 = 3.54 × 109 cells/mL, MTT = 204 hours and γ = 6.0 × 10−2) and drug‐related (slope [SLP] = 3.1 × 10−2mL/mg). Co‐administration of oxaliplatin resulted in a 2.84‐fold increase in SLP. The predicted exposure thresholds to G3/4 neutropenia in combination and monotherapy were 26 and 70 mg·h/L, respectively.

Conclusions

The population pharmacokinetic/pharmacodynamic model characterized the time course of capecitabine and its metabolites in plasma. Dose recommendations of capecitabine in patients with mutated and wild allele for single nucleotide polymorphisms rs2271862 of ≤3000 and ≤2400 mg/m2/24 h in monotherapy and ≤1750 and ≤600 mg/m2/24 h in combination with oxaliplatin, respectively, have been proposed.
Developing and evaluating risk prediction models with panel current status data
Authors: Chan Stephanie , Wang Xuan , Jazić Ina , Peskoe Sarah , Zheng Yingye , Cai Tianxi
Published: June 2020

Panel current status data arise frequently in biomedical studies when the occurrence of a particular clinical condition is only examined at several prescheduled visit times. Existing methods for analyzing current status data have largely focused on regression modeling based on commonly used survival models such as the proportional hazards model and the accelerated failure time model. However, these procedures have the limitations of being difficult to implement and performing sub‐optimally in relatively small sample sizes. The performance of these procedures is also unclear under model misspecification. In addition, no methods currently exist to evaluate the prediction performance of estimated risk models with panel current status data. In this paper, we propose a simple estimator under a general class of nonparametric transformation (NPT) models by fitting a logistic regression working model and demonstrate that our proposed estimator is consistent for the NPT model parameter up to a scale multiplier. Furthermore, we propose nonparametric estimators for evaluating the prediction performance of the risk score derived from model fitting, which is valid regardless of the adequacy of the fitted model. Extensive simulation results suggest that our proposed estimators perform well in finite samples and the regression parameter estimators outperform existing estimators under various scenarios. We illustrate the proposed procedures using data from the Framingham Offspring Study.
Lenalidomide and pomalidomide potently interfere with induction of myeloid‐derived suppressor cells in multiple myeloma
Authors: Kuwahara‐Ota Saeko , Shimura Yuji , Steinebach Christian , Isa Reiko , Yamaguchi Junko , Nishiyama Daichi , Fujibayashi Yuto , Takimoto‐Shimomura Tomoko , Mizuno Yoshimi , Matsumura‐Kimoto Yayoi , Tsukamoto Taku , Chinen Yoshiaki , Kobayashi Tsutomu , Horiike Shigeo , Taniwaki Masafumi , Gütschow Michael , Kuroda Junya
Published: June 2020

An increase in immunosuppressive myeloid‐derived suppressor cells (MDSCs) is associated with disease progression and treatment resistance in multiple myeloma (MM). We investigated the mechanisms underlying MDSC induction, and sought to discover a strategy for prevention of MDSC induction in MM. Using a transwell co‐culture system, four of nine examined human myeloma‐derived cell lines (HMCLs) were potent in inducing monocytic (M)‐MDSCs from normal peripheral blood mononuclear cells (PBMCs). As the results, we identified that secretion of C‐C motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF) by myeloma cells is a prerequisite for induction of MDSCs in MM. The immunomodulatory drug (IMiD) compounds, such as lenalidomide (LEN) and pomalidomide (POM), were identified as potent inhibitors of MDSC induction through bidirectional molecular effects of cereblon (CRBN)‐dependent and ‐independent downregulation of CCL5 and MIF in myeloma cells; and downregulation of C‐C motif chemokine receptor 5, a receptor for CCL5, and induction of interferon regulatory factor 8, a critical transcription factor for monocytic differentiation, in PBMCs. In the present study of the molecular mechanisms underlying MDSC induction, we identified a novel effect of LEN and POM of inhibiting MDSC induction via overlapping regulatory effects in myeloma cells and normal PBMCs.
Robot‐assisted laparoscopic artificial urinary sphincter insertion in women with stress urinary incontinence: a pilot single‐centre study
Authors: Chartier‐Kastler Emmanuel , Vaessen Christophe , Rouprêt Morgan , Bassi Silvia , Cancrini Fabiana , Phé Veronique
Published: June 2020

Objective

To report the functional outcomes of robot‐assisted laparoscopic artificial urinary sphincter (AUS; AMS 800™, American Medical Systems, Minnetonka, MN, USA) implantation and revision in women with stress urinary incontinence (SUI).

Patients and Methods

A pilot prospective monocentric study included all consecutive female patients with SUI and undergoing an AUS surgery (implantation or revision) using a robotic approach between 2012 and 2018. The AUS was implanted through a transperitoneal robotic approach. The dissection of the bladder neck was initiated using a posterior approach with a permanent visual control. Intraoperative and early postoperative complications were reported (Clavien–Dindo classification). Continence was defined as no pad usage.

Results

A total of 41 patients, median (interquartile range [IQR]) age 67.5 (57–74.7) years were included. In the group of 27 patients undergoing an AUS implantation, one conversion to laparotomy, one bladder neck and one ureteric injury occurred. The AUS was not implanted in the two latest cases. Twelve minor (Clavien–Dindo Grade I–II) early postoperative complications occurring in 10 patients were reported. The median (IQR) follow‐up was 19 (11–27) months. The continence rate was 84% (21/25 patients). In the group of 14 patients undergoing an AUS revision, no vaginal or bladder injury was reported. One patient had a bowel injury with conversion to laparotomy without AUS insertion. Two major (Clavien–Dindo Grade III–V) early postoperative complications occurred in two patients: one intraoperative bowel injury, which ultimately resulted in the death of the patient and one device infection requiring an explantation of the AUS. The median (IQR) follow‐up was 18 (13.5–24.2) months. The continence rate was 83.3% (10/12 patients).

Conclusion

The results obtained after robot‐assisted laparoscopic AUS implantation among women are promising despite the significant morbidity due to previous pelvic surgeries. Longer follow‐up studies are needed.
CB1 receptor‐dependent desensitisation of TRPV1 channels contributes to the analgesic effect of dipyrone in sensitised primary sensory neurons
Authors: Goncalves dos Santos Gilson , Li Ruihui , Ng Melissa Pui Een , Lemes Julia Borges Paes , Vieira Willians Fernando , Nagy Istvan , Tambeli Cláudia Herrera , Parada Carlos Amilcar
Published: June 2020

Background and Purpose

While dipyrone is a widely used analgesic, its mechanism of action is not completely understood. Recently, we have reported that the dipyrone metabolite 4‐aminoantipyrine (4‐AA) reduces PGE2‐induced pain‐related behaviour through cannabinoid CB1 receptors. Here, we ascertained, in naive and PGE2‐induced “inflamed” conditions, both in vivo and in vitro, the molecular mechanisms involved in the 4‐AA‐induced analgesic effects.

Experimental Approach

The effect of local administration of 4‐AA (160 μg per paw) on capsaicin (0.12 μg per paw) injection‐induced pain‐related behaviour and 4‐AA's effect on 500‐nM capsaicin‐induced changes in intracellular calcium concentration ([Ca2+]i) in cultured primary sensory neurons were assessed in vivo and in vitro, respectively.

Key Results

4‐AA reduced capsaicin‐induced nociceptive behaviour in naive and inflamed conditions through CB1 receptors. 4‐AA (100 μM) reduced capsaicin‐induced increase in [Ca2+]i in a CB1 receptor‐dependent manner, when PGE2 was not present. Following PGE2 application, 4‐AA (1–50 μM) increased the [Ca2+]i. Although 4‐AA activated both TRPV1 and TRPA1 channels, increased [Ca2+]i was mediated through TRPV1 channels. Activation of TRPV1 channels resulted in their desensitisation. Blocking CB1 receptors reduced both the excitatory and desensitising effects of 4‐AA.

Conclusion and Implications

CB1 receptor‐mediated inhibition of TRPV1 channels and TRPV1‐mediated Ca2+‐influx‐ and CB1 receptor‐dependent desensitisation of TRPV1 channels contribute to the anti‐nociceptive effect of 4‐AA in naive and inflamed conditions respectively. Agonists active at both CB1 receptors and TRPV1 channels might be useful as analgesics, particularly in inflammatory conditions.
Skeletal resorption in bryozoans: occurrence, function and recognition
Authors: Batson Peter B. , Tamberg Yuta , Taylor Paul D. , Gordon Dennis P. , Smith Abigail M.
Published: June 2020

Skeletal resorption – the physiological removal of mineralised parts by an organism – is an important morphogenetic process in bryozoans. Reports of its occurrence and function across the phylum are patchy, however, and have not previously been synthesised. Here we show that resorption occurs routinely across a wide range of bryozoan clades, colony sizes, growth forms, ontogenetic stages, body wall types, skeletal ultrastructures and mineralogies. Beginning in the early Paleozoic, different modes and functions of resorption have evolved convergently among disparate groups, highlighting its utility as a morphogenetic mode in this phylum. Its functions include branch renovation, formation of branch articulations, excavation of reproductive chambers, part‐shedding, and creation of access portals for budding beyond previously formed skeletal walls. Bryozoan skeletons can be altered by resorption at microscopic, zooidal and colony‐wide scales, typically with a fine degree of control and coordination. We classified resorption patterns in bryozoans according to the morphology and function of the resorption zone (window formation, abscission or excavation), timing within the life of the skeletal element resorbed (primary or secondary), and scale of operation (zooidal or multizooidal). Skeletal resorption is probably greatly underestimated in terms of its utility and role in bryozoan life history, and its prevalence across taxa, especially in fossil forms. It is reported proportionally more frequently in stenolaemates than in gymnolaemates. Some modes of resorption potentially alter or remove the spatial–temporal record of calcification preserved within a skeleton. Consequently, knowledge that resorption has occurred can be relevant for some common applications of skeletal analysis, such as palaeoenvironmental interpretation, or growth and ageing studies. To aid recognition we provide scanning electron microscopy, backscattered electron scanning electron microscopy and transmission electron microscopy examples of skeletal ultrastuctures modified by resorption.
Multimeric TAT peptides are effective in vitro inhibitors of Staphylococcus saprophyticus
Authors: Chiongson Justin Brian V. , Sabido Edna M. , Lin Kuo‐Ging , Alea Glenn V. , Dalisay Doralyn S. , Wu Shih‐Hsiung , Saludes Jonel P.
Published: June 2020

TAT (48–60) is a tridecapeptide from the envelope protein of HIV that was previously shown to possess cell‐penetrating properties and antibacterial activity, making it a potential drug delivery agent for anticancer drugs and as antibacterial compound. Previous reports indicated that dimerization enhances the desired bioactivity of TAT; hence, we sought to synthesize multimeric TAT peptides. Herein, we describe the effects of multimerization on the antibacterial activity and secondary structure of the peptide. Terminal modifications such as N‐acetylation and C‐amidation were employed in the design. TATp monomer, dimer, and tetramer were synthesized using solid‐phase peptide synthesis, purified by reversed‐phase HPLC, and then characterized by mass spectrometry. Multimerization of the peptide did not change the secondary structure conformation. The CD analysis revealed a polyproline‐II conformation for all peptide designs. Thus, this study provides a method of increasing the biological activity of the peptide by multimerization while retaining the secondary conformation of its monomeric unit. Furthermore, the bacteria Staphylococcus saprophyticus was found to be susceptible to the dimer and tetramer, with MIC50 of 12.50 μm and <1.56 μm, respectively. This suggests a structure–activity relationship whereby the antibacterial activity increases with increase in valency.
Eukaryotic phosphatase inhibitors enhance colistin efficacy in gram‐negative bacteria
Authors: Barker William T. , Jania Leigh A. , Melander Roberta J. , Koller Beverly H. , Melander Christian
Published: June 2020

The mounting threat of multi‐drug‐resistant (MDR) bacteria places a tremendous strain on the antimicrobial clinical arsenal, forcing physicians to revert to near‐obsolete antibiotics to treat otherwise intractable infections. Antibiotic adjuvant therapy has emerged as a viable alternative to the development of novel antimicrobial agents. This method uses combinations of an existing antibiotic and a non‐antimicrobial small molecule, where the combination either breaks drug resistance or further potentiates antibiotic activity. Through a high‐content screen of eukaryotic kinase inhibitors, our group previously identified two highly potent adjuvants that synergize with colistin, a cyclic, polycationic antimicrobial peptide that serves as a drug of last resort for the treatment of MDR Gram‐negative bacterial infections. Cell signaling proteins implicated in colistin resistance mechanisms display both kinase and phosphatase activities. Herein, we explore the potential for eukaryotic phosphatase inhibitors to be repurposed as colistin adjuvants. From a panel of 48 unique structures, we discovered that the natural product kuwanon G breaks colistin resistance, while the non‐antimicrobial macrolide ascomycin potentiates colistin in polymyxin‐susceptible bacteria.
Vitamin A deficiency exacerbates extrinsic atopic dermatitis development by potentiating type 2 helper T cell‐type inflammation and mast cell activation
Authors: Yang Huan , Chen Jing‐si , Zou Wen‐jing , Tan Qi , Xiao Yi‐zhu , Luo Xiao‐yan , Gao Peisong , Fu Zhou , Wang Hua
Published: June 2020

Background

Vitamin A deficiency (VAD) has been hypothesized to play a role in the pathophysiology of atopic dermatitis (AD).

Objective

We sought to verify whether VAD can exacerbate AD development, and explore the possible pathophysiologic mechanism.

Methods

We detected serum vitamin A (VA) concentration in different phenotypes of AD infants (intrinsic AD, iAD and extrinsic AD, eAD), and established ovalbumin (OVA) percutaneous sensitized AD model and passive cutaneous anaphylaxis (PCA) model on VAD and vitamin A supplementation (VAS) model in wild‐type mice (C57BL/6) and established AD model on both normal VA (VAN) and VAD feeding mast cell deficiency mice (ckitw‐sh/w‐sh).

Results

The average serum VA concentration of eAD was significantly lower than that of iAD, as well as healthy controls. In OVA‐induced C57BL/6 mouse AD model, compared with VAN group, VAD mice manifested significantly more mast cells accumulation in the skin lesions, more severe Th2‐mediated inflammation, including higher serum IgG1 and IgE levels, more IL‐4, IL‐13 mRNA expression in OVA‐sensitized skin, and lower Th1 immune response, including lower serum IgG2a and IFN‐γ mRNA expression in the skin. But there was no significant difference in the expression of IL‐17 mRNA between OVA‐treated skin of VAN and VAD mice. However, in OVA‐induced ckitw‐sh/w‐sh mouse AD model, we did not find any significant differences in the above measurements between VAD and VAN group. In PCA model, VAD mice showed remarkable more blue dye leakage than that in VAN mice. Compared with VAD group, the above‐mentioned inflammatory measurements in VAS group and VAN group were similar in OVA‐induced AD model mice.

Conclusions and Clinical Relevance

VAD can exacerbate extrinsic AD by augmenting Th2‐mediated inflammation and mast cell activation. Therapeutic VAS can rescue VAD‐aggravated eAD. It may provide a new strategy for future prevention or treatment of atopic dermatitis.
Implant survival after surgical treatment of peri‐implantitis lesions by means of deproteinized bovine bone mineral with 10% collagen: 10‐year results from a prospective study
Authors: Roccuzzo Mario , Fierravanti Ludovica , Pittoni Dario , Dalmasso Paola , Roccuzzo Andrea
Published: June 2020

Objectives

To evaluate the 10‐year outcomes of a regenerative surgical treatment of single peri‐implantitis intrabony defects, by means of deproteinized bovine bone mineral with 10% collagen (DBBMC).

Material and Methods

The original population consisted of 26 patients with one crater‐like defect, around either SLA or TPS dental implants, with a probing depth ≥6 mm and no implant mobility. After debridement and surface decontamination, the defects were filled with DBBMC. Subsequently, patients were placed in an individualized supportive peri‐implant/periodontal therapy (SPT) program.

Results

Fourteen patients (eight SLA and six TPS) reached the 10‐year examination. The overall implant survival rate was 67%, 80% for the SLA, and 55% for the TPS implants. During SPT, five patients were lost to follow‐up, eight patients needed additional antibiotic and/or surgical therapy, and seven patients had the implant removed. PD was reduced from 6.6 ± 1.3 to 3.2 ± 0.7 mm in SLA and from 7.2 ± 1.5 to 3.4 ± 0.6 mm in TPS. BOP decreased from 75.0 ± 31.2% to 7.5 ± 12.1% (SLA) and from 90.0 ± 12.9% to 30.0 ± 19.7% (TPS). Treatment success was found in 5 of the 12 SLA (42%) and in 4 of the 14 TPS (29%).

Conclusions

The proposed reconstructive treatment, followed by SPT, was able to maintain in function the majority of SLA implants, although the overall treatment success was limited and many of TPS implants were removed. Therefore, the decision to treat implants affected by peri‐implantitis should be based on several factors, including surface characteristics.