bluuebunny/crossref_metadata_2025 huggingface dataset:
Target recognition algorithm for compound scanning imaging based on fuzzy theory
Authors: Guo Jiachong , Liu Xing , Cui Silin
Published: November 2020

In order to solve the problem of low recognition rate and poor anti-interference ability of single-mode lidar, a multi-element linear array laser/infrared composite detection device is used to realize scanning images. A target recognition model based on associated information is proposed. The proposed method performs feature extraction and fusion on the top three-dimensional contour of the target and the top infrared radiation information, and comparing with the standard model parameter library. A target recognition algorithm based on fuzzy comprehensive evaluation method is proposed, and three sets of recognition probabilities are obtained. The three types of sub-recognition results use fuzzy theory for decision fusion to obtain the final recognition results. The simulation results show that the recognition probability of the composite detection target is greatly improved compared with the single mode recognition method.
Clinical Utility of Targeted Next-Generation Sequencing in the Evaluation of Low-Grade Lymphoproliferative Disorders
Authors: Jajosky Audrey N , Havens Nathaniel P , Sadri Navid , Oduro Kwadwo A , Moore Erika M , Beck Rose C , Meyerson Howard J
Published: November 2020

Objectives

We investigated the usefulness of a custom-designed 31-gene next-generation sequencing (NGS) panel implemented on a routine basis for the evaluation of low-grade lymphoproliferative disorders (LPDs).

Methods

In total, 147 blood, bone marrow, and tissue specimens were sequenced, including 81% B-cell, 15% T-cell, and 3% natural killer (NK)–cell neoplasms.

Results

Of the cases, 92 (63%) of 147 displayed at least one pathogenic variant while 41 (28%) of 147 had two or more. Low mutation rates were noted in monoclonal B-cell lymphocytoses and samples with small T- and NK-cell clones of uncertain significance. Pathogenic molecular variants were described in specific disorders and classified according to their diagnostic, prognostic, and potential therapeutic value. Diagnostically, in addition to confirming the diagnosis of 15 of 15 lymphoplasmacytic lymphomas, 10 of 12 T large granular lymphocytic leukemias, and 2 of 2 hairy cell leukemias (HCLs), the panel helped resolve the diagnosis of 10 (62.5%) of 16 challenging cases lacking a specified diagnosis based on standard morphology, phenotype, and genetic analysis.

Conclusions

Overall, implementation of this targeted lymphoid NGS panel as part of regular hematopathology practice was found to be a beneficial adjunct in the evaluation of low-grade LPDs.
Resting Heart Rate as a Cardiovascular Risk Factor in Hypertensive Patients: An Update
Authors: Palatini Paolo
Published: November 2020

A large body of evidence has shown that resting heart rate (RHR) holds important prognostic information in several clinical conditions. In the majority of the general population studies, a graded association between RHR and mortality from all causes, cardiovascular (CV) disease, ischemic heart disease, and stroke has been observed. These associations appeared even stronger and more consistent in hypertensive patients. Studies performed with 24-hour ambulatory recording have shown that an elevated nighttime heart rate may confer an additional risk on top of office RHR. The mechanisms by which tachycardia alone or in association with sympathetic overactivity induces CV damage are well understood. Fast RHR is a strong predictor of future hypertension, metabolic disturbances, obesity, and diabetes. Several experimental lines of research point to high RHR as a main risk factor for the development of atherosclerosis, large artery stiffness, and CV disease. Elevated RHR is a common feature in patients with hypertension. Thus, there is a large segment of the hypertensive population that would benefit from a treatment able to decrease RHR. Improvement of unhealthy lifestyle should be the first goal in the management of the hypertensive patient with elevated RHR. Most clinical guidelines now recommend the use of combination therapies even in the initial treatment of hypertension. Although no results of clinical trials specifically designed to investigate the effect of RHR lowering in human beings without CV diseases are available, in hypertensive patients with high RHR a combination therapy including a cardiac slowing drug at optimized dose seems a sensible strategy.

Tachycardia can be considered both as a marker of sympathetic overactivity and as a risk factor for cardiovascular events. In this sketch, the main cardiovascular and metabolic effects of increased sympathetic tone underlying high heart rate are shown. The link between tachycardia and cardiovascular events can be explained also by the direct hemodynamic action of heart rate on the arteries and the left ventricular (LV) wall.
Seed germination in Narcissus yepesii (Amaryllidaceae): clinal variation in the morphophysiological dormancy levels
Authors: Copete Elena , Copete Miguel A , Ferrandis Pablo , Herranz José M
Published: November 2020

Seed dormancy classes determine both population and species-level processes which can be crucial in the life cycle of many plants. However, there are no studies of a dormancy cline between levels of morphophysiological dormancy (MPD). We aimed to determine the class of seed dormancy of Narcissus yepesii exhibits in order to explore links between different dormancy levels, previously characterized in two closely related phylogenetic congeners, N. alcaracensis and N. longispathus. Experiments were carried out under both near-natural temperature and controlled laboratory conditions. The parameters calculated were mean embryo length, radicle and shoot emergence percentages. The effects of different periods of storage; and different periods with or without GA3 of warm, cold or warm plus cold were analysed. The Narcissus populations from the Baetic System of mountain ranges in south-eastern Spain show clinal variation in a northeast–southwest gradient from intermediate to non-deep complex MPD, through the coexistence of intermediate and non-deep complex MPD in N. yepesii (21 % and 74 %, respectively). In addition, 54 % of stored seeds were able to show both levels of MPD. Narcissus yepesii occupies an intermediate position between N. alcaracensis and N. longispathus in the geographical distribution and in the clinal germination ranges. It strongly suggests an evolutionary gradient, which connects the intermediate complex MPD with the non-deep complex MPD in southern Iberian daffodils. This is the first study showing a gradient in the evolution between levels of MPD. Our results demonstrate a cline in these levels in response to both an environmental gradient and genetic differences.
Granzyme B Is a Biomarker for Suspicion of Malignant Seromas Around Breast Implants
Authors: Kadin Marshall E , Morgan John , Xu Haiying , Glicksman Caroline , Sieber David , Adams William P , McGuire Pat , Clemens Mark W , Thakur Archana , Lum Lawrence G
Published: November 2020

Background

Granzyme B (GrB) is a serine protease secreted, along with pore-forming perforin, by cytotoxic lymphocytes to mediate apoptosis in target cells. GrB has been detected in tumor cells associated with systemic and breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) but its potential use for detection of early BIA-ALCL has not been fully investigated.

Objectives

Prompted by the increased incidence of BIA-ALCL, the aim of this study was to assess GrB as a new biomarker to detect early disease in malignant seromas and to better understand the nature of the neoplastic cell.

Methods

A Human XL Cytokine Discovery Magnetic Luminex 45-plex Fixed Panel Performance Assay was used to compare cytokine levels in cell culture supernatants of BIA-ALCL and other T-cell lymphomas, as well as malignant and benign seromas surrounding breast implants. Immunohistochemistry was employed to localize GrB to cells in seromas and capsular infiltrates.

Results

Differences in GrB concentrations between malignant and benign seromas were significant (P < 0.001). GrB was found in and around apoptotic tumor cells, suggesting that the protease may be involved in tumor cell death.

Conclusions

GrB is a useful marker for early detection of malignant seromas and to identify tumor cells in seromas and capsular infiltrates. Because there is an overlap between the lowest concentrations of soluble GrB in malignant seromas and the highest concentrations of GrB in benign seromas, it is recommended that GrB be used only as part of a panel of biomarkers for the screening and early detection of BIA-ALCL.

Level of Evidence: 5
Transcriptomic profiling of fetal membranes of mice deficient in biglycan and decorin as a model of preterm birth†
Authors: Pantham Priyadarshini , Armstrong Don L , Bodnariuc Jonathan , Haupt Owen , Johnson Amy Wagoner , Underhill Lori , Iozzo Renato V , Lechner Beatrice E , Wildman Derek E
Published: November 2020

Approximately, 25% of all preterm births are due to preterm premature rupture of membranes. Mice deficient in proteoglycans biglycan (Bgn) and decorin (Dcn) display abnormal fetal membranes and increased incidence of preterm birth. We conducted RNA-Seq to profile fetal membranes and identify molecular pathways that may lead to preterm birth in double knockout (DKO) mice (Bgn−/−; Dcn−/−) compared to wild-type (WT) at two different gestational stages, E12 and E18 (n = 3 in each group). 3264 transcripts were differentially regulated in E18 DKO vs. WT fetal membranes, and 96 transcripts differentially regulated in E12 DKO vs. WT fetal membranes (FDR < 0.05, log 2 FC ≥ 1). Differentially regulated transcripts in E18 DKO fetal membranes were significantly enriched for genes involved in cell cycle regulation, extracellular matrix–receptor interaction, and the complement cascade. Fifty transcripts involved in the cell cycle were altered in E18 DKO fetal membranes (40↓, 10↑, FDR < 0.05), including p21 and p57 (↑), and Tgfb2, Smad3, CycA, Cdk1, and Cdk2(↓). Thirty-one transcripts involved in the complement cascade were altered (11↓, 20↑, FDR < 0.05) in E18 DKO fetal membranes, including C1q, C2, and C3 (↑). Differentially expressed genes in the top three molecular pathways (1) showed evidence of negative or purifying selection, and (2) were significantly enriched (Z-score > 10) for transcription factor binding sites for Nr2f1 at E18. We propose that in DKO mice, cell cycle arrest results in lack of cell proliferation in fetal membranes, inability to contain the growing fetus, and preterm birth.
A Nationwide Outbreak of Invasive Pneumococcal Disease in Israel Caused by Streptococcus pneumoniae Serotype 2
Authors: Dagan Ron , Ben-Shimol Shalom , Benisty Rachel , Regev-Yochay Gili , Lo Stephanie W , Bentley Stephen D , Hawkins Paulina A , McGee Lesley , Ron Merav , Givon-Lavi Noga , Valinsky Lea , Rokney Assaf
Published: November 2020

Background

Invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae serotype 2 (Sp2) is infrequent. Large-scale outbreaks were not been reported following pneumococcal conjugate vaccine (PCV) implementation. We describe a Sp2 IPD outbreak in Israel, in the PCV13 era, with focus on Sp2 population structure and evolutionary dynamics.

Methods

The data were derived from a population-based, nationwide active surveillance of IPD since 2009. PCV7/PCV13 vaccines were introduced in July 2009 and November 2010, respectively. Sp2 isolates were tested for antimicrobial susceptibility, multilocus sequence typing, and whole-genome sequencing (WGS) analysis.

Results

Overall, 170 Sp2 IPD cases were identified during 2009–2019; Sp2 increased in 2015 and caused 6% of IPD during 2015–2019, a 7-fold increase compared with 2009–2014. The outbreak was caused by a previously unreported molecular type (ST-13578), initially observed in Israel in 2014. This clone caused 88% of Sp2 during 2015–2019. ST-13578 is a single-locus variant of ST-1504, previously reported globally including in Israel. WGS analysis confirmed clonality among the ST-13578 population. Single-nucleotide polymorphism–dense regions support a hypothesis that the ST-13578 outbreak clone evolved from ST-1504 by recombination. All tested strains were penicillin-susceptible (minimum inhibitory concentration <0.06 μg/mL). The ST-13578 clone was identified almost exclusively (99%) in the Jewish population and was mainly distributed in 3 of 7 Israeli districts. The outbreak is still ongoing, although it began declining in 2017.

Conclusions

To the best of our knowledge, this is the first widespread Sp2 outbreak since PCV13 introduction worldwide, caused by the emerging ST-13578 clone.
Evaluation of the effect of T regulatory cell depletion and donor BCG vaccination on Mycobacterium tuberculosis H37Ra infection using an in vitro model of human PBMC infection
Authors: Bhavanam Sudha , Rayat Gina R , Keelan Monika , Kunimoto Dennis , Drews Steven J
Published: November 2020

This study evaluated the effect of T regulatory cells (Treg cells) and the impact of BCG vaccination history of donors using an in vitro model of Mycobacterium tuberculosis H37Ra infection of peripheral blood mononuclear cells (PBMCs). PBMCs from donors with or without prior BCG vaccination were depleted of Treg cells (PBMCs-Tregs) or not depleted with Treg cells (PBMCs + Tregs) were infected up to 8 days with Mtb H37Ra. Cell aggregates were smaller in PBMCs-Tregs compared to PBMCs + Tregs at day 8 post-infection. Mtb CFUs were higher in the PBMCs-Tregs compared to PBMCs + Tregs at days 3, 5 and 8. The levels of IL-17, IFN-γ (at days 3 and 5), and TNF-α and IL-6 (at day 3) were lower in PBMCs-Tregs compared to PBMCs + Tregs. In contrast, the levels of IL-10 and IL-4 cytokines were higher at day 3 in PBMCs-Tregs compared to PBMCs + Tregs. BCG vaccination status of donors had no impact on the mycobacterial culture, level of cytokines and immune cell populations. This study shows that depletion of Tregs in human PBMCs infected with Mtb H37Ra in vitro leads to a shift from a Th1 to a Th2 cytokine rich environment that supports the survival of Mtb in this model.
Improvements in the school environment—results of a Swedish school project 2005–2011
Authors: Persson Louise , Hagquist Curt
Published: November 2020

To examine whether a public health project to reduce problem behavior in schools and improve the classroom climate, undertaken among eight secondary schools in a municipality in Sweden, was accompanied by favorable changes in the school environment over time. Data were collected from ninth grade students (aged 15–16 years) at three different time points: the year before the project began (2005), during the project (2008) and when the project finished (2011). Changes in the school environment, measured as damage, littering, noise and classroom disorder, were compared between the project municipality and a comparison group of other municipalities in the same county, using multinomial logistic regression analysis. Descriptive comparisons were made between the schools within the project municipality. The school environment improved significantly from 2005 to 2011 in the project municipality compared with the other municipalities. The school environment was improved in all schools within the project municipality. The biggest improvements took place in two schools which systematically worked with one program incorporated into the school schedule. This study demonstrates that it may be possible to improve the school environment by implementing health programs. Further studies based on experimental designs are required in order to confirm the potential and efficiency of school health programs.
Chance of live birth: a nationwide, registry-based cohort study
Authors: Kolte Astrid M , Westergaard David , Lidegaard Øjvind , Brunak Søren , Nielsen Henriette Svarre
Published: November 2020

STUDY QUESTION

Does the sequence of prior pregnancy events (pregnancy losses, live births, ectopic pregnancies, molar pregnancy and still birth), obstetric complications and maternal age affect chance of live birth in the next pregnancy and are prior events predictive for the outcome?

SUMMARY ANSWER

The sequence of pregnancy outcomes is significantly associated with chance of live birth; however, pregnancy history and age are insufficient to predict the outcome of an individual woman’s next pregnancy.

WHAT IS KNOWN ALREADY

Adverse pregnancy outcomes decrease the chance of live birth in the next pregnancy, whereas the impact of prior live births is less clear.

STUDY DESIGN, SIZE, DURATION

Nationwide, registry-based cohort study of 1 285 230 women with a total of 2 722 441 pregnancies from 1977 to 2017.

PARTICIPANTS/MATERIALS, SETTING, METHODS

All women living in Denmark in the study period with at least one pregnancy in either the Danish Medical Birth Registry or the Danish National Patient Registry. Data were analysed using logistic regression with a robust covariance model to account for women with more than one pregnancy. Model discrimination and calibration were ascertained using 20% of the women in the cohort randomly selected as an internal validation set.

MAIN RESULTS AND THE ROLE OF CHANCE

Obstetric complications, still birth, ectopic pregnancies and pregnancy losses had a negative effect on the chance of live birth in the next pregnancy. Consecutive, identical pregnancy outcomes (pregnancy losses, live births or ectopic pregnancies) immediately preceding the next pregnancy had a larger impact than the total number of any outcome. Model discrimination was modest (C-index = 0.60, positive predictive value = 0.45), but the models were well calibrated.

LIMITATIONS, REASONS FOR CAUTION

While prior pregnancy outcomes and their sequence significantly influenced the chance of live birth, the discriminative abilities of the predictive models demonstrate clearly that pregnancy history and maternal age are insufficient to reliably predict the outcome of a given pregnancy.

WIDER IMPLICATIONS OF THE FINDINGS

Prior pregnancy history has a significant impact on the chance of live birth in the next pregnancy. However, the results emphasize that only taking age and number of losses into account does not predict if a pregnancy will end as a live birth or not. A better understanding of biological determinants for pregnancy outcomes is urgently needed.

STUDY FUNDING/COMPETING INTEREST(S)

The work was supported by the Novo Nordisk Foundation, Ole Kirk Foundation and Rigshospitalet’s Research Foundation. The authors have no financial relationships that could appear to have influenced the work.

TRIAL REGISTRATION NUMBER

N/A.
Mexican apex judiciary and its multiple interpretations: Challenges for the constitutional right to health
Authors: Cobo Fernanda , Charvel Sofía
Published: November 2020

The judicialization of social rights is a reality in Latin America; however, little has been said about this phenomenon in Mexico or about the role of the Mexican Supreme Court (Suprema Corte de Justicia de la Nación, SCJN) in advancing an effective guarantee of the right to health. In several countries, courts have adopted either an active role in defining health policy and protecting the right to health or a passive one. Studying the ways in which health-related cases are resolved in Mexico enables us to evaluate the role of the SCJN when ruling for or against this right. This article aims to determine whether the SCJN, through the analysis of its rulings, is or could be a catalyst for change in the healthcare system. This article reports on the results of a systematic content analysis of twenty-two SCJN rulings, examining the claimants, their claims as understood by the SCJN, and the elements considered by the justices in their decision-making process. The analysis of the way in which the SCJN ruled in these cases demonstrates that the SCJN must be uniform and consistent in applying constitutional and conventional principles to improve predictability of its decisions and to be innovative in responding to the new requirements posed by economic, social, and cultural rights. The SCJN should increase its possibilities of promoting structural reforms where laws or policies are inconsistent with constitutional or conventional standards by maintaining a middle ground with respect of the executive and legislative branches.
Open 𝑟-Spin Theory I: Foundations
Authors: Buryak Alexandr , Clader Emily , Tessler Ran J
Published: November 2020

We lay the foundation for a version of $r$-spin theory in genus zero for Riemann surfaces with boundary. In particular, we define the notion of $r$-spin disks, their moduli space, and the Witten bundle; we show that the moduli space is a compact smooth orientable orbifold with corners, and we prove that the Witten bundle is canonically relatively oriented relative to the moduli space. In the sequel to this paper, we use these constructions to define open $r$-spin intersection theory and relate it to the Gelfand–Dickey hierarchy, thus providing an analog of Witten’s $r$-spin conjecture in the open setting.
Effects of warming and fertilization interacting with intraspecific competition on fine root traits of Picea asperata
Authors: Li Dan-Dan , Nan Hong-Wei , Zhao Chun-Zhang , Yin Chun-Ying , Liu Qing
Published: November 2020

Aims

Competition, temperature and nutrient are the most important determinants of tree growth in the cold climate on the eastern Tibetan Plateau. Although many studies have reported their individual effects on tree growth, little is known about how the interactions of competition with fertilization and temperature affect root growth. We aim to test whether climate warming and fertilization promote competition and to explore the functional strategies of Picea asperata in response to the interactions of these factors.

Methods

We conducted a paired experiment including competition and non-competition treatments under elevated temperature (ET) and fertilization. We measured root traits, including the root tip number over the root surface (RTRS), the root branching events over the root surface (RBRS), the specific root length (SRL), the specific root area (SRA), the total fine root length and area (RL and RA), the root tips (RTs) and root branching (RB) events. These root traits are considered to be indicators of plant resource uptake capacity and root growth. The root biomass and the nutrient concentrations in the roots were also determined.

Important Findings

The results indicated that ET, fertilization and competition individually enhanced the nitrogen (N) and potassium (K) concentrations in fine roots, but they did not affect fine root biomass or root traits, including RL, RT, RA and RB. However, both temperature and fertilization, as well as their interaction, interacting with competition increased RL, RA, RT, RB and nutrient uptake. In addition, the SRL, SRA, RTRS and RBRS decreased under fertilization, the interaction between temperature and competition decreased SRL and SRA, while the other parameters were not affected by temperature or competition. These results indicate that P. asperata maintains a conservative nutrient strategy in response to competition, climate warming, fertilization and their interactions. Our results improve our understanding of the physiological and ecological adaptability of trees to global change.
“Chronic Disseminated Aspergillosis,” a Novel Fungal Immune Reconstitution Inflammatory Syndrome
Authors: Pourbaix Annabelle , Guery Romain , Bruneau Julie , Blanc Estelle , Jouvion Gregory , Weinandt Marthe , Rouzaud Claire , Lourenço Jérémy , Boutboul David , Mira Jean-Paul , Rouquette Alexandre , Molina Thierry Jo , Lecuit Marc , Lortholary Olivier
Published: November 2020

We report a case of chronic hepatosplenic aspergillosis following immune reconstitution complicating colic aspergillosis in an AIDS patient with multicentric Castleman disease. Symptoms mimicked the clinical presentation of chronic disseminated candidiasis and responded to corticosteroid. This emerging entity enlarges the spectrum of fungal immune reconstitution inflammatory syndrome in the HIV setting.
‘Ndrangheta Dynasties: A Conceptual and Operational Framework for the Cross-Border Policing of the Calabrian Mafia
Authors: Sergi Anna
Published: November 2020

Attention to the Calabrian mafia, the ‘ndrangheta, has been increasing across law enforcement authorities around the world. This paper aims at bringing forward a theoretical and operational conversation on how to best approach, from a policing perspective, what is a complex clan-based criminality able to operate simultaneously in different states. The paper will therefore formulate a preliminary framework for strategies focusing on the policing of mafia dynasties. It will do so by identifying how ‘ndrangheta clans can be studied as family dynasties, including in their assessment also the factors of family life (familiness) that can facilitate or obstruct the dynasty’s success. By looking at ‘ndrangheta clans as family dynasties, we can inform a framework that cuts through the most common policing aims and strategies against organized crime, as shared by states involved in current anti-mafia efforts.
Quantitative towers in finite difference calculus approximating the continuum
Authors: Lawrence R , Ranade N , Sullivan D
Published: November 2020

Multivector fields and differential forms at the continuum level have respectively two commutative associative products, a third composition product between them and various operators like $\partial$, d and ‘*’ which are used to describe many nonlinear problems. The point of this paper is to construct consistent direct and inverse systems of finite dimensional approximations to these structures and to calculate combinatorially how these finite dimensional models differ from their continuum idealizations. In a Euclidean background, there is an explicit answer which is natural statistically.
Serum IgG2 antibody multicomposition in systemic lupus erythematosus and lupus nephritis (Part 1): cross-sectional analysis
Authors: Bruschi Maurizio , Moroni Gabriella , Sinico Renato Alberto , Franceschini Franco , Fredi Micaela  , Vaglio Augusto , Cavagna Lorenzo , Petretto Andrea , Pratesi Federico , Migliorini Paola , Locatelli Francesco , Pazzola Giulia , Pesce Giampaola , Bagnasco Marcello  , Manfredi Angelo , Ramirez Giuseppe A , Esposito Pasquale , Murdaca Giuseppe , Negrini Simone , Cipriani Leda , Trezzi Barbara , Emmi Giacomo , Cavazzana Ilaria , Binda Valentina , Fenaroli Paride , Pisani Isabella , Garibotto Giacomo , Montecucco Carlomaurizio , Santoro Domenico , Scolari Francesco , Mosca Marta , Tincani Angela  , Candiano Giovanni , Prunotto Marco , Volpi Stefano , Verrina Enrico , Angeletti Andrea , Ravelli Angelo , Ghiggeri Gian Marco
Published: November 2020

Objectives

Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis.

Methods

A total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non-commercial techniques.

Results

The presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLE patients at low–medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0–12 months), and high levels at T0–1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLE patients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions.

Conclusion

Nephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLE patients limited to the renal complication and other SLE patients.

Trial registration

The Zeus study was registered at https://clinicaltrials.gov, NCT02403115.
Association between comorbidities and disease activity in axial spondyloarthritis: results from the BSRBR-AS
Authors: Zhao Sizheng Steven , Jones Gareth T , Macfarlane Gary J , Hughes David M , Moots Robert J , Goodson Nicola J
Published: November 2020

Objective

Whether comorbidities influence disease activity assessment in axial SpA (axSpA) is unclear. Comorbidities inflate DAS28 in rheumatoid arthritis through the patient global score. We examined whether axSpA disease activity measures are differentially affected, and whether comorbidities inflate the AS disease activity score (ASDAS) through the patient global component.

Methods

We used baseline data from the British Society for Rheumatology Biologics Register for AS, including 14 physician diagnosed comorbidities. Linear models were used to compare disease activity (BASDAI, spinal pain, ASDAS) and ESR/CRP according to comorbidity count, adjusted for age, gender, BMI, smoking, socioeconomic status, and education. The same models were used to examine whether the patient global score was associated with comorbidities, additionally adjusting for other ASDAS components.

Results

The number of participants eligible for analysis was 2043 (67% male, mean age 49 years); 44% had at least one comorbidity. Each additional comorbidity was associated with higher BASDAI by 0.40 units (95% CI: 0.27, 0.52) and spinal pain by 0.53 (95% CI: 0.37, 0.68). Effect size for ASDAS (0.09 units; 95% CI: 0.03, 0.15) was not clinically significant. ESR and CRP were not associated with comorbidity count. Depression, heart failure and peptic ulcer were consistently associated with higher disease activity measures, but not CRP/ESR. Patient global was associated with comorbidity count, but not independently of other ASDAS components (P = 0.75).

Conclusion

Comorbidities were associated with higher patient reported disease activity in axSpA. Clinicians should be mindful of the potential impact of comorbidities on patient reported outcome measures and consider additionally collecting ASDAS when comorbidities are present.
Detection of circulating highly expanded T-cell clones in at-risk individuals for rheumatoid arthritis before the clinical onset of the disease
Authors: Lamacchia Céline , Calderin Sollet Zuleika , Courvoisier Delphine , Mongin Denis , Palmer Gaby , Studer Oliva , Gabay Cem , Villard Jean , Buhler Stéphane , Finckh Axel
Published: November 2020

Objectives

To quantitatively profile the T-cell repertoire in the peripheral blood of individuals genetically at risk for RA, namely first-degree relatives of RA patients (RA-FDR) at different phases of disease development.

Methods

Next-generation sequencing of the TCR CDR3β repertoire was performed on genomic DNA isolated from whole blood samples of RA-FDR selected at three different pre-clinical stages and of matched RA patients (n = 20/group). T-cell clones were identified by their unique sequence and their degree of expansion (frequency) within each sample was characterized. Clones with a frequency over 0.5% were considered highly expanded clones (HEC).

Results

The absolute number of HEC was significantly higher in established RA patients (mean 4.65) and tended to be higher in symptomatic RA-FDR (mean 3.4) compared with asymptomatic RA-FDR (mean 1.55, P =0.003 and P =0.07, respectively). Asymptomatic individuals with high levels of ACPA did not differ from asymptomatic RA-FDR in terms of absolute number and frequency of clones. The number of HEC tended to be slightly higher at the time of RA onset (P =0.055). Neither clones shared by several patients, nor clones previously associated with RA, were preferentially present within or between the different groups. Finally, a longitudinal analysis did not allow to uncover a kinetic expansion of RA-specific clones closely correlated with disease development.

Conclusions

HEC were detected in the peripheral blood before the clinical onset of RA, in particular in the later pre-clinical phase of RA development, and their presence increased over time.
Kraepelin’s Final Views on Dementia Praecox
Authors: Kendler Kenneth S
Published: November 2020

In 1921, at the age of 65, 6 years after completing the final edition of his textbook, 22 years after first proposing the concept of dementia praecox (DP), and 1 year before retiring from clinical work, Emil Kraepelin completed the last edition of his “Introduction to Clinical Psychiatry,” which contained a mini-textbook for students, 10 pages of which were devoted to DP. This work also included a series of new detailed case histories, 3 of which examined DP. This neglected text represents a distillation of what Kraepelin judged, near the end of his long career, to be the essential features of DP. The relevant text and case histories are translated into English for the first time. Kraepelin did not define DP solely by its chronic course and poor prognosis, acknowledging that remissions and even full recovery might be possible. His clinical description emphasized the frequency of bizarre delusions and passivity symptoms. He recognized the heterogeneity of the clinical presentations, outlining 6 subtypes of DP, including dementia simplex, depressive and stuporous dementia, and an agitated and circular DP. Kraepelin’s original concept of DP was not impervious to change and expanded somewhat, especially with the inclusion of Diem’s concept of simple DP. He also reviews several contributions of Bleuler, including his concept “latent schizophrenia.” He writes poignantly of the psychological consequences of DP. His 3 DP cases, for advanced students, included simple DP, “periodic catatonic,” and “speech confusion.”
Clinical, haematological and biochemical profiling of podoconiosis lymphoedema patients prior to their involvement in a clinical trial in the Northwest Region of Cameroon
Authors: Ndzeshang Bertrand Lontum , Mbiakop Randy Tchachoua , Nchanji Gordon Takop , Kien Chi Anizette , Amambo Glory Ngongeh , Abong Raphael Awah , Yuyun Timothy , Beng Amuam Andrew , Bonekeh John , Ritter Manuel , Esum Mathias Eyong , Cho Jerome Fru , Njouendou Abdel Jelil , Ndifor Ignatius Nde , Deribe Kebede , Fombad Fanny Fri , Enyong Peter , Klarmann-Schulz Ute , Hoerauf Achim , Wanji Samuel
Published: November 2020

Background

Prior to carrying out clinical trials, it is important to assess the health status of the study participants to be able to interpret subsequent changes that may be related to the effects of the treatments during the follow-up of patients. This study presents the clinical, haematological and biochemical profiles of podoconiosis patients prior to their involvement in the PodoLEDoxy clinical trial.

Methods

All lower limb lymphoedema patients visiting the centre were screened and a podoconiosis diagnosis was based on clinical manifestation and detailed medical history. Patients who satisfied the eligibility criteria were enrolled in the study and their demographic data, vital signs and medical history were collected followed by biochemical and haematological examinations.

Results

Of the 222 participants enrolled in the study, 55.4% and 41.4% had either stage 3 or 2 podoconiosis as their highest stages, respectively. On physical examination, gastritis (46%) and poor vision (2.7%) were the most prevalent health issues identified. The majority of haematological and biochemical values were within the normal range except for mean platelet volume (47.7%), plateletcrit (58.1%), platelet distribution width (66.2%), mean corpuscular volume (67.6%) and red cell distribution width-standard deviation (79.3%), where >40% of the study participants had values out of the normal.

Conclusion

The clinical, haematological and biochemical profiles of the study participants were largely within the normal range except for certain haematological parameters that might be worth investigating.
Efficacy Assessment of a New Fungicide, Miravis Ace, for Control of Fusarium Head Blight in Wheat
Authors: Singh Lovepreet , Wight Jason P. , Crank Joseph , Thorne Louis , Dong Yanhong , Rawat Nidhi
Published: November 2020

Fusarium head blight (FHB) is a serious disease of wheat and barley that leads to significant economic losses and deteriorated grain quality because of the associated mycotoxins. Genetic resistance and use of fungicides are the methods used to control FHB. However, in weather conditions conducive for FHB epidemics, higher levels of genetic resistance as well as greater efficacy of fungicides are required to adequately control this disease. Due to the extensive use of a single mode of action for management of FHB, there is a need to diversify fungicides used to lower the risk of resistance development in pathogen populations. In this 2-year study, we evaluated the performance of a new fungicide, Miravis Ace (a proprietary mix of pydiflumetofen and propiconazole active ingredients produced by Syngenta) for controlling FHB. It is a mix of succinate dehydrogenase inhibitor and demethylation inhibitor fungicides and can add diversity to the fungicide toolkit for FHB management. The level of control of FHB and deoxynivalenol (DON) achieved by spraying Miravis Ace at anthesis (Feekes growth stage 10.5.1) was found to be equivalent to that provided by the currently recommended products for managing FHB and reducing DON in wheat and barley.
Current status and hurdles for CAR-T cell immune therapy
Authors: Zhao Ruocong , Cui Yuanbin , Li Shanglin , Qin Le , Li Peng
Published: November 2020

Chimeric antigen receptor T (CAR-T) cells have emerged as novel and promising immune therapies for the treatment of multiple types of cancer in patients with hematological malignancies. There are several key components critical for development and application of CAR-T therapy. First, the design of CAR vectors can considerably affect several aspects of the physiological functions of these T cells. Moreover, despite the wide use of γ-retrovirus and lentivirus in mediating gene transfer into T cells, optimal CAR delivery systems are also being developed and evaluated. In addition, several classes of mouse models have been used to evaluate the efficacies of CAR-T cells; however, each model has its own limitations. Clinically, although surprising complete remission (CR) rates were observed in acute lymphoblastic leukemia (ALL), lymphoma, and multiple myeloma (MM), there is still a lack of specific targets for acute myeloid leukemia (AML). Leukemia relapse remains a major challenge, and its mechanism is presently under investigation. Cytokine release syndrome (CRS) and neurotoxicity are life-threatening adverse effects that need to be carefully treated. Several factors that compromise the activities of anti-solid cancer CAR-T cells have been recognized, and further improvements targeting these factors are the focus of the development of novel CAR-T cells. Overcoming the current hurdles will lead to optimal responses of CAR-T cells, thus paving the way for their wide clinical application.
Novel chimeric antigen receptor T cells based on T-cell receptor-like antibodies
Authors: Zhao Qi
Published: November 2020

The need for novel therapeutics against human cancers such as leukemias and solid tumors is well recognized. Human T cells are poised to make a fundamental change in the therapeutic approach. T-cell interaction with a tumor cell is a critical event and primarily driven by T-cell receptor (TCR) recognition of peptide in the pocket HLA. However, among TCR-based T-cell therapies, either TCR mismatching or the low density of major histocompatibility complex causes tumor cells to escape from the immune response. TCR molecules have low binding affinities, preventing their recognitions. Undoubtedly, antibody therapeutics is an effective treatment for cancer. As the new generation of monoclonal antibodies, TCR-like antibodies can mimic TCR recognition but are not susceptible for mechanisms of tumor evasion from the immune response. As chimeric antigen receptor (CAR) structure expressed on the surface of T cells, TCR-like antibodies can confer antigen specificity to T cells. The new TCR-like CAR may be important to drive new technologies of adoptive cell therapy, in particular, T-cell therapy, and open possibilities to target endogenous tumor-specific antigens.
Astragalin Retards Atherosclerosis by Promoting Cholesterol Efflux and Inhibiting the Inflammatory Response via Upregulating ABCA1 and ABCG1 Expression in Macrophages
Authors: Zhao Zhen-Wang , Zhang Min , Wang Gang , Zou Jin , Gao Jia-Hui , Zhou Li , Wan Xiang-Jun , Zhang Da-Wei , Yu Xiao-Hua , Tang Chao-Ke
Published: November 2020

Lipid metabolism disorder and inflammatory response are considered to be the major causes of atherosclerogenesis. Astragalin, the most important functional component of flavonoid obtained from persimmon leaves, has the hypolipidemic effects. However, it is unknown, how astragalin protects against atherosclerosis. The aim of this study was to observe the effects of astragalin on cholesterol efflux and inflammatory response and to explore the underlying mechanisms. Our results showed that astragalin upregulated the expression of ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1), promoted cholesterol efflux, and suppressed foam cell formation. Inhibition of the PPARγ/LXRα pathway abrogated the promotive effects of astragalin on both transporter expression and cholesterol efflux. In addition, treatment of astragalin markedly decreased the secretion of inflammatory factors, including interleukin 6, monocyte chemotactic protein 1, tumor necrosis factor α, and interleukin 1β. Mechanistically, astragalin upregulated ABCA1 and ABCG1 expression, which in turn reduced TLR4 surface levels and inhibited NF-κB nuclear translocation. Consistently, astragalin reduced atherosclerotic plaque area in apoE−/− mice. Taken together, these findings suggest that astragalin protects against atherosclerosis by promoting ABCA1- and ABCG1-mediated cholesterol efflux and inhibiting proinflammatory mediator release.
Effectiveness of Pharmacokinetic/Pharmacodynamic-Guided Meropenem Treatment in Critically Ill Patients: A Comparative Cohort Study
Authors: Aldaz Azucena , Idoate Grijalba Ana Isabel , Ortega Ana , Aquerreta Irene , Monedero Pablo
Published: November 2020

Background:

The proper dosage of antibiotics is a key element in the effective treatment of infection, especially in critically ill patients. This study aimed to evaluate the efficacy of optimized meropenem regimens based on pharmacokinetic/pharmacodynamic criteria in patients admitted to the intensive care unit.

Methods:

This observational, naturalistic, retrospective, unicentric cohort study was performed between May 2011 and December 2017. The clinical and bacteriologic responses of 77 control intensive care unit patients receiving meropenem were compared with those of 77 propensity score–balanced patients who received meropenem dose adjusted by therapeutic drug monitoring. The primary end point of clinical response was a reduction at the end of treatment of at least 80% of the maximum procalcitonin (PCT) value recorded during the meropenem treatment.

Results:

The primary end point was met by 55 patients (71.4%) in the adjusted group compared with 41 (53.3%) patients in the control group (mean difference 18.1%, P = 0.02). Fifty-one patients (66.2%) in the adjusted group required a meropenem dose adjustment, being necessary in 46 of them (90.2%) to decrease the dose. The reduction of PCT was the greatest in the adjusted group compared with the unadjusted group (93% versus 85%, P = 0.004); a greater percentage of patients reached a PCT level < 0.5 ng/mL (63.6% versus 41.6%, P = 0.006), and there was a trend toward an improved bacteriologic response (relative risk = 1.27; 95% confidence interval: 0.92–1.56). There were no differences in early mortality or safety between groups.

Conclusions:

Adjustment of meropenem therapy by monitoring is a useful strategy for improving meropenem effectiveness in the treatment of infection in critically ill patients, with no impact on safety.
Relationship Between Amphetamine Concentrations in Saliva and Serum in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder
Authors: Wohkittel Christopher , Högger Petra , Fekete Stefanie , Romanos Marcel , Gerlach Manfred
Published: November 2020

Background:

Therapeutic drug monitoring (TDM) is a valid tool for the optimization of psychopharmacotherapy; however, in child and adolescent psychiatry, uncomfortable intravenous sample collection is the main challenge and restricts the use of TDM. Therefore, it is important to evaluate alternate specimens to facilitate TDM. The aim of this study was to evaluate the feasibility of using saliva for the TDM of amphetamine in children and adolescents with attention-deficit/hyperactivity disorder.

Methods:

In this study, 28 patient samples (mean age, 11.3 years; boys, 23; and girls, 5) treated with lisdexamfetamine were included. The active compound amphetamine was extracted and derivatized before quantification by high-performance liquid chromatography with fluorescence detection. Nonparametric Spearman rank correlations were used for correlation analyses; for clinical validation, Bland–Altman analysis was applied.

Results:

The median amphetamine concentrations in saliva were 2.7 times higher (range 0.7–23.6) than those in serum (257.8 ng/mL versus 77.2 ng/mL; z = −4.51, P < 0.001). A strong positive linear correlation was observed between saliva and serum concentrations (ρ = 0.628, P < 0.001). The ratio of saliva-to-serum concentration was strongly pH dependent (ρ = −0.712, P < 0.001). Therefore, a transformation formula, factoring in salivary pH, to calculate serum concentrations from the measured saliva concentrations was applied. Theoretical and measured serum amphetamine concentrations were subjected to Bland–Altman analysis. Using an acceptance limit of 20%, only 21% (n = 6) of samples fulfilled this criterion.

Conclusions:

Amphetamine paired saliva-to-serum concentrations were highly variable and strongly affected by salivary pH, indicating that saliva is an inappropriate sampling matrix for TDM of amphetamine. Furthermore, Bland–Altman analysis did not support saliva as a suitable matrix for TDM.