bluuebunny/crossref_metadata_2025 huggingface dataset:
The Southern and Western Prehistory of “Liberty of Contract”: Revisiting the Path to Lochner in Light of the New History of American Capitalism
Authors: Clark Gabrielle E
Published: June 2020

This article examines the local legal histories of two “liberty of contract” constitutional disputes prior to Lochner in the South and West: Allgeyer v. Louisiana (1897) and Holden v. Hardy (1898). Drawing inspiration from the new history of American capitalism literature that has recently rethought the genesis of the modern American economy through a Southern and Western lens, this article argues that we have yet to fully grasp the relationship between uneven state development politics and economic rights jurisprudence under American constitutional law. In so doing, I build a new narrative that takes into account development politics, Louisiana lawyers with roots in the Confederacy, and Western Populist constitution-makers to rethink the origins and development of a doctrine that arguably continues to shape the modern world.
Scirpy: a Scanpy extension for analyzing single-cell T-cell receptor-sequencing data
Authors: Sturm Gregor , Szabo Tamas , Fotakis Georgios , Haider Marlene , Rieder Dietmar , Trajanoski Zlatko , Finotello Francesca
Published: June 2020

Advances in single-cell technologies have enabled the investigation of T-cell phenotypes and repertoires at unprecedented resolution and scale. Bioinformatic methods for the efficient analysis of these large-scale datasets are instrumental for advancing our understanding of adaptive immune responses. However, while well-established solutions are accessible for the processing of single-cell transcriptomes, no streamlined pipelines are available for the comprehensive characterization of T-cell receptors. Here, we propose single-cell immune repertoires in Python (Scirpy), a scalable Python toolkit that provides simplified access to the analysis and visualization of immune repertoires from single cells and seamless integration with transcriptomic data.

Availability and implementation

Scirpy source code and documentation are available at https://github.com/icbi-lab/scirpy.

Supplementary information

Supplementary data are available at Bioinformatics online.
Functional Connectivity within and beyond the Face Network Is Related to Reduced Discrimination of Degraded Faces in Young and Older Adults
Authors: Grady Cheryl L , Rieck Jenny R , Nichol Daniel , Garrett Douglas D
Published: June 2020

Degrading face stimuli reduces face discrimination in both young and older adults, but the brain correlates of this decline in performance are not fully understood. We used functional magnetic resonance imaging to examine the effects of degraded face stimuli on face and nonface brain networks and tested whether these changes would predict the linear declines seen in performance. We found decreased activity in the face network (FN) and a decrease in the similarity of functional connectivity (FC) in the FN across conditions as degradation increased but no effect of age. FC in whole-brain networks also changed with increasing degradation, including increasing FC between the visual network and cognitive control networks. Older adults showed reduced modulation of this whole-brain FC pattern. The strongest predictors of within-participant decline in accuracy were changes in whole-brain network FC and FC similarity of the FN. There was no influence of age on these brain-behavior relations. These results suggest that a systems-level approach beyond the FN is required to understand the brain correlates of performance decline when faces are obscured with noise. In addition, the association between brain and behavior changes was maintained into older age, despite the dampened FC response to face degradation seen in older adults.
Increased Protection of Earlier Use of Immunoprophylaxis in Preventing Perinatal Transmission of Hepatitis B Virus
Authors: Huang Hongyu , Xu Chenyu , Liu Lanhua , Chen Liping , Zhu Xiaoqin , Chen Jie , Feng Jing , Chen Tingmei , Xu Biao , Yang Jishi , Xu Biyun , Pan Mingjie , Dai Yimin , Hu Yali , Zhou Yi-Hua
Published: June 2020

Background

Passive-active immunoprophylaxis against mother-to-child transmission (MTCT) of hepatitis B virus (HBV) recommends administering hepatitis B immunoglobulin (HBIG) and birth-dose hepatitis B vaccine in infants within 12 or 24 hours after birth. With this protocol, MTCT of HBV still occurs in 5–10% infants of HBV-infected mothers with positive hepatitis B e antigen (HBeAg). The present study aimed to investigate whether earlier administration of HBIG and hepatitis B vaccine after birth can further increase protection efficacy.

Methods

We conducted a prospective, multi-center observational study in infants born to mothers with HBV infection, in whom neonatal HBIG and birth dose hepatitis B vaccine were administered within one hour after birth. The infants were followed up for HBV markers at 7–14 months of age.

Results

A total of 1140 pregnant women with HBV were enrolled, and 982 infants (9 twins) of 973 mothers were followed up at 9.6 ± 1.9 months of age. HBIG and birth-dose vaccine were administered in newborn infants within a median of 0.17 (0.02–1.0) hours after birth. The overall rate of MTCT was 0.9% (9/982), with none (0%) of the 607 infants of HBeAg-negative mothers and 9 (2.4%) of 375 infants of HBeAg-positive mothers acquiring HBV. All 9 HBV-infected infants were born to mothers with HBV DNA >2.75 × 106 IU/mL. Maternal HBV DNA levels >2 × 106 IU/mL were an independent risk factor (odds ratio, 10.627; 95% confidence interval, 2.135–∞) for immunoprophylaxis failure.

Conclusions

Earlier use (within 1 hour after birth) of HBIG and hepatitis B vaccine can provide better protection efficacy against MTCT of HBV.
Rusty Blackbirds select areas of greater habitat complexity during stopover
Authors: Wright James R , Powell Luke L , Matthews Stephen N , Tonra Christopher M
Published: June 2020

The Rusty Blackbird (Euphagus carolinus) is a widespread, uncommon migrant that has experienced heavy population declines over the last century. This species can spend over a quarter of their annual cycle on migration, so it is important to determine their habitat requirements during stopover events to inform effective conservation planning. We assessed their habitat selection at an important stopover site in northern Ohio during both fall and spring migration. Since stopover habitat selection is scale-dependent, we investigated both patch-scale (between patches) and fine-scale (within a patch) selection using radio telemetry to locate foraging and roosting flocks, and compared habitat variables between used and available points across the study site. At the patch scale, we found that birds preferred dogwood–willow swamp, low-lying forest patches, and areas of greater habitat complexity for foraging in both seasons. At the fine scale, spring migrants foraged closer to habitat edges than random, and preferred areas with more wet leaf litter and shallow water, and less grass cover. Fall migrants also preferred shallow water and leaf litter cover, and avoided areas with dense grass, forbs, and herbaceous shrub cover. By contrast, birds consistently roosted in dense stands of emergent Phragmites or Typha marsh, suggesting that the best stopover or staging sites are those with a matrix of different wetland habitats. Although the migratory range of Rusty Blackbirds is currently dominated by agricultural development, our results suggest that fragmented landscapes can still provide adequate habitat for migrants if the available land is managed for a variety of wet habitat types.
Whole Blood Profiling of T-cell-Derived microRNA Allows the Development of Prognostic models in Inflammatory Bowel Disease
Authors: Kalla R , Adams A T , Ventham N T , Kennedy N A , White R , Clarke C , Ivens A , Bergemalm D , Vatn S , Lopez-Jimena B ,   IBD Character Consortium, Ricanek P , Vatn M H , Söderholm Johan D , Gomollón F , Nowak J K , Jahnsen J , Halfvarson J , McTaggart S , Ho G T , Buck A , Satsangi J
Published: June 2020

Background

MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD.

Methods

In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohn’s disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards.

Results

In stage 1, each leukocyte subset [CD4+ and CD8+ T-cells and CD14+ monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p [p = 0.01], miR-3615 [p = 0.02] and miR-4792 [p = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20–3.27; logrank p = 1.80 × 10–3), in particular CD [HR 2.81; IQR: 1.11–3.53, p = 6.50 × 10–4]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met.

Interpretation

We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated.
Metformin Use Is Associated with a Lower Risk of Inflammatory Bowel Disease in Patients with Type 2 Diabetes Mellitus
Authors: Tseng Chin-Hsiao
Published: June 2020

Aim

Our aim was to compare the risk of developing inflammatory bowel disease [IBD] between ever users and never users of metformin.

Methods

Patients with newly diagnosed type 2 diabetes mellitus from 1999 to 2005 were enrolled from Taiwan’s National Health Insurance. A total of 340 211 ever users and 24 478 never users who were free from IBD on January 1, 2006 were followed up until December 31, 2011. Hazard ratios were estimated by Cox regression incorporating the inverse probability of treatment weighting using a propensity score.

Results

New-onset IBD was diagnosed in 6466 ever users and 750 never users. The respective incidence rates were 412.0 and 741.3 per 100 000 person-years and the hazard ratio for ever vs never users was 0.55 [95% confidence interval: 0.51–0.60]. A dose–response pattern was observed while comparing the tertiles of cumulative duration of metformin therapy to never users. The respective hazard ratios for the first [<26.0 months], second [26.0–58.3 months] and third [>58.3 months] tertiles were 1.00 [0.93–1.09], 0.57 [0.52–0.62] and 0.24 [0.22–0.26]. While patients treated with oral antidiabetic drugs [OADs] without metformin were treated as a reference group, the hazard ratios for patients treated with OADs with metformin, with insulin without metformin [with/without other OADs] and with insulin and metformin [with/without other OADs] were 0.52 [0.42–0.66], 0.95 [0.76–1.20] and 0.50 [0.40–0.62], respectively.

Conclusion

A reduced risk of IBD is consistently observed in patients with type 2 diabetes mellitus who have been treated with metformin.
EMF awareness in the Japanese EFL/EMI context
Authors: Ishikawa Tomokazu
Published: June 2020

The notion of English as a multilingua franca (EMF) positions English within multilingualism, and EMF awareness prepares students to communicate effectively in this multilingual world of mobility. The present paper explores how, if ever, EMF-aware pedagogic intervention influences Japanese students’ perceptions of their communicative practices, particularly for English-major undergraduates in L1-shared classrooms. This intervention was made by providing opportunities for participants to engage in EMF and by examining their first-hand experiences and published EMF communication extracts in the classrooms. Empirical data from an open-ended questionnaire demonstrate that multilingual and transmodal accommodation was a way for them to notice and take advantage of global networks, develop capability and confidence in communication, and foster sensitivity to interactants’ backgrounds. The data also illustrate the invaluable role of individual multilingual experiences as classroom ‘materials’, and suggest that discussing these experiences potentially turns L1-shared classrooms into EMF scenarios through foregrounding students’ multilingual repertoires.
Extracellular and intracellular DNA for bacterial profiling of long-ripened cheeses
Authors: Bardelli Tommaso , Rossetti Lia , Zago Miriam , Carminati Domenico , Giraffa Giorgio , Tidona Flavio
Published: June 2020

A novel approach was developed to extract the extracellular DNA (eDNA), i.e. the free DNA outside the microbial cell, compared to the intracellular DNA (iDNA). The two DNA fractions were investigated in seven long-ripened cheeses. Among different buffer solutions tested, EDTA 0.5 M at pH 8 enabled a mild homogenization of cheese samples and the highest eDNA recovery. The extraction protocol was tested on single strains of lactic acid bacteria characterizing many Italian long-ripened cheeses, such as Streptococcus thermophilus, Lactobacillus helveticus, and Lactobacillus rhamnosus. The method resulted suitable for eDNA extraction because it minimized cell-lysis, avoiding the leakage of iDNA from the cells. The yields of eDNA, ranging from 0.01 to 0.36 µg g−1 cheese, were generally higher than the iDNA, indicating that autolytic phenomena prevailed over intact cells after 8–12 months of ripening. In four of the seven cheeses, the same LAB species were detected in the eDNA and iDNA fractions by length-heterogeneity PCR, while in the remaining three samples, a higher number of species was highlighted in the eDNA compared to the corresponding iDNA. The sequential extraction of eDNA and iDNA can be applied to obtain additional information on the composition of the bacterial community in long-aged cheeses.
Candida albicans Mrv8, is involved in epithelial damage and biofilm formation
Authors: Costa Anna Carolina Borges Pereira , Back-Brito Graziella Nuernberg , Mayer François L , Hube Bernhard , Wilson Duncan
Published: June 2020

Candida albicans is the most common human fungal pathogen that can cause superficial and deep-seated infections in susceptible individuals. Despite its medical importance, the vast majority of C. albicans genes remain of unknown function. Here, we report a role for the lineage-specific gene, MRV8, in host pathogen interactions, mycelial microcolony maturation and biofilm formation. In silico analysis indicated that MRV8 encodes a four-pass transmembrane protein unique to the closely related pathogens C. albicans and Candida dubliniensis. Deletion of MRV8 did not affect C. albicans adherence to, or initial invasion into human oral epithelia, but inhibited mycelial development and strongly reduced epithelial damage. mrv8Δ/Δ cells exhibited a media-dependent defect in biofilm formation and mutant biofilm metabolic activity was enhanced by cyclosporin A. mrv8Δ/Δ biofilms were more tolerant to treatment with caspofungin, but not to fluconazole or amphotericin B. Co-stimulation with calcium chloride and calcofluor white rescued biofilm growth in the presence of caspofungin, and this rescue-effect was Mrv8-dependent. Together, our data demonstrate an important role for a lineage-specific gene (MRV8) in C. albicans biofilm formation, drug tolerance and host–pathogen interactions.
Development of a Novel Mind–Body Activity and Pain Management Program for Older Adults With Cognitive Decline
Authors: Mace Ryan A , Gates Melissa V , Bullard Breanna , Lester Ethan G , Silverman Ilyssa H , Quiroz Yakeel T , Vranceanu Ana-Maria
Published: June 2020

Background and Objectives

Chronic pain (CP) and cognitive decline (CD) often co-occur in older adults, which can reinforce a “disability spiral.” Early interventions teaching pain coping skills and gradual increases in activity (walking) are needed to promote overall well-being and potentially delay further decline of cognition and daily functioning. The goal of this mixed-methods study was to guide the development of two mind–body activity programs for CP and CD which focus on increasing walking using time goals (Active Brains) or step count reinforced by a Fitbit (Active Brains–Fitbit).

Research Design and Methods

Older adults with CP and CD (N = 23) participated in a one-time focus group (four total) and completed measures of physical, emotional, and cognitive functioning. Qualitative analyses identified population-specific needs, preferences, and perceptions of proposed program skills. Quantitative analysis compared clinical characteristics to population norms and explored intercorrelations among treatment targets.

Results

Thematic analyses revealed six main themes: (1) challenges living with CP and (2) CD, (3) current walking, (4) technology (Fitbit) to increase walking, (5) perceptions of proposed program skills (e.g., mind–body, pain, and increased walking), and (6) program barriers and facilitators. Quantitative analyses showed that (a) participants had physical function below reference values and (b) higher self-efficacy correlated with higher cognitive, emotional, and physical functioning.

Discussion and Implications

Focus group participants were enthusiastic about the proposed program skills. Current work includes open pilot testing, qualitative interviews, and a small randomized controlled trial to optimize the programs and methodology in preparation for efficacy testing against an educational control.
From space to lithosphere: inversion of the GOCE gravity gradients. Supply to the Earth’s interior study
Authors: Plasman Matthieu , Tiberi Christel , Cadio Cecilia , Saraswati Anita Thea , Pajot-Métivier Gwendoline , Diament Michel
Published: June 2020

The emergence of high resolution satellite measurements of the gravitational field (GOCE mission) offers promising perspectives for the study of the Earth’s interior. These new data call for the development of innovant analysis and interpretation methods. Here we combine a forward prism computation with a Bayesian resolution approach to invert for these gravity gradient data configuration. We apply and test our new method on satellite data configuration, that is 225 km height with a global and homogeneous geographic distribution. We first quantify the resolution of our method according to both data and parametrization characteristics. It appears that for reasonable density contrast values (0.1 g cm−3) crustal structures have to be wider than ∼28 km to be detectable in the GOCE signal. Deeper bodies are distinguishable for greater size (35 km size at 50 km depth, ∼80 km at 300 km depth). We invert the six tensor components, among which five are independent. By carefully testing each of them and their different combinations, we enlighten a trade off between the recovery of data and the sensitivity to inversion parameters. We particularly discussed this characteristic in terms of geometry of the synthetic model tested (structures orientation, 3-D geometry, etc.). In terms of RMS value, each component is always better explained if inverted solely, but the result is strongly affected by the inversion parametrization (smoothing, variances, etc.). On the contrary, the simultaneous inversion of several components displays a significant improvement for the global tensor recovery, more dependent on data than on density variance or on smoothness control. Comparing gravity and gradient inversions, we highlight the superiority of the GG data to better reproduce the structures especially in terms of vertical location. We successfully test our method on a realistic case of a complex subduction case for both gradient and gravity data. While the imaging of small crustal structures requires terrestrial gravity data set, the longest wavelength of the slab is well recovered with both data sets. The precision and homogeneous coverage of GOCE data however, counterbalance the heterogeneous and often quite non-existence coverage of terrestrial gravity data. This is particularly true in large areas which requires a coherent assemblage of heterogeneous data sets, or in high relief, vegetally covered and offshore zones.
Serum biomarkers associated with baseline clinical severity in young steroid-naïve Duchenne muscular dystrophy boys
Authors: Dang Utkarsh J , Ziemba Michael , Clemens Paula R , Hathout Yetrib , Conklin Laurie S ,   CINRG Vamorolone 002/003 Investigators, Hoffman Eric P
Published: June 2020

Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin in muscle, and while all patients share the primary gene and biochemical defect, there is considerable patient–patient variability in clinical symptoms. We sought to develop multivariate models of serum protein biomarkers that explained observed variation, using functional outcome measures as proxies for severity. Serum samples from 39 steroid-naïve DMD boys 4 to <7 years enrolled into a clinical trial of vamorolone were studied (NCT02760264). Four assessments of gross motor function were carried out for each participant over a 6-week interval, and their mean was used as response for biomarker models. Weighted correlation network analysis was used for unsupervised clustering of 1305 proteins quantified using SOMAscan® aptamer profiling to define highly representative and connected proteins. Multivariate models of biomarkers were obtained for time to stand performance (strength phenotype; 17 proteins) and 6 min walk performance (endurance phenotype; 17 proteins) including some shared proteins. Identified proteins were tested with associations of mRNA expression with histological severity of muscle from dystrophinopathy patients (n = 28) and normal controls (n = 6). Strong associations predictive of both clinical and histological severity were found for ERBB4 (reductions in both blood and muscle with increasing severity), SOD1 (reductions in muscle and increases in blood with increasing severity) and CNTF (decreased levels in blood and muscle with increasing severity). We show that performance of DMD boys was effectively modeled with serum proteins, proximal strength associated with growth and remodeling pathways and muscle endurance centered on TGFβ and fibrosis pathways in muscle.
From the American Epicenter: Coronavirus Disease 2019 in Patients with Inflammatory Bowel Disease in the New York City Metropolitan Area
Authors: Axelrad Jordan E , Malter Lisa , Hong Simon , Chang Shannon , Bosworth Brian , Hudesman David
Published: June 2020

Background

We aimed to characterize patients with inflammatory bowel disease (IBD) and novel coronavirus disease 2019 (COVID-19).

Methods

We performed a case series of patients with IBD and confirmed or highly suspected COVID-19 to assess rates of severe outcomes.

Results

We identified 83 patients with IBD with confirmed (54%) or highly suspected (46%) COVID-19. The overall hospitalization rate was 6%, generally comprising patients with active Crohn’s disease or older men with comorbidities, and 1 patient expired.

Discussion

In this series of patients with IBD, severe outcomes of COVID-19 were rare and comparable to similarly aged individuals in the general population.
Linking Ecology, Morphology, and Behavior to Conservation: Lessons Learned from Studies of Sea Turtles
Authors: Wyneken Jeanette , Salmon Michael
Published: June 2020

Synopsis

Here we describe examples of studies that have contributed both to a basic understanding of the biology of imperiled marine turtles, and to their management and conservation. Key elements include, first and foremost, correctly identifying species that differ strikingly in their morphology at different life stages because with growth, they change size by several orders of magnitude and have accompanying shape changes. We also review comprehensive field studies documenting the need for management actions to correct abnormal shifts in sex ratios caused by climate change. We highlight the need to describe those perturbations in terms that are clear to regulators and personnel responsible for management and conservation policies. Finally, we review several basic studies that enhance our understanding of how selection has shaped morphological, functional, and performance attributes, and describe how that knowledge can be applied to the tasks required for enhancing species recovery.
Effect of childhood rotavirus vaccination on community rotavirus prevalence in rural Ecuador, 2008-13
Authors: Kraay Alicia N M , Ionides Edward L , Lee Gwenyth O , Trujillo William F Cevallos , Eisenberg Joseph N S
Published: June 2020

Background

Although live attenuated monovalent human rotavirus vaccine (Rotarix) efficacy has been characterized through randomized studies, its effectiveness, especially in non-clinical settings, is less clear. In this study, we estimate the impact of childhood Rotarix® vaccination on community rotavirus prevalence.

Methods

We analyse 10 years of serial population-based diarrhoea case-control study, which also included testing for rotavirus infection (n = 3430), and 29 months of all-cause diarrhoea active surveillance from a child cohort (n = 376) from rural Ecuador during a period in which Rotarix vaccination was introduced. We use weighted logistic regression from the case-control data to assess changes in community rotavirus prevalence (both symptomatic and asymptomatic) and all-cause diarrhoea after the vaccine was introduced. We also assess changes in all-cause diarrhoea rates in the child cohort (born 2008–13) using Cox regression, comparing time to first all-cause diarrhoea case by vaccine status.

Results

Overall, vaccine introduction among age-eligible children was associated with a 82.9% reduction [95% confidence interval (CI): 49.4%, 94.2%] in prevalence of rotavirus in participants without diarrhoea symptoms and a 46.0% reduction (95% CI: 6.2%, 68.9%) in prevalence of rotavirus infection among participants experiencing diarrhoea. Whereas all age groups benefited, this reduction was strongest among the youngest age groups. For young children, prevalence of symptomatic diarrhoea also decreased in the post-vaccine period in both the case-control study (reduction in prevalence for children <1 year of age = 69.3%, 95% CI: 8.7%, 89.7%) and the cohort study (reduction in hazard for receipt of two Rotarix doses among children aged 0.5-2 years = 57.1%, 95% CI: 16.6, 77.9%).

Conclusions

Rotarix vaccination may suppress transmission, including asymptomatic transmission, in low- and middle-income settings. It was highly effective among children in a rural community setting and provides population-level benefits through indirect protection among adults.
Cognitive Heuristics, Inter-Institutional Politics, and Public Perceptions of Insulated Institutions: The Case of the U.S. Supreme Court
Authors: Zilis Michael A
Published: June 2020

How do citizens form perceptions about the ideological priorities of insulated institutions? Currently, there is little consensus on how or even whether citizens form such views. Focusing on the Supreme Court, I argue that perceptions of institutional ideology are influenced by an inter-institutional heuristic, or the popular perception that the president directly and indirectly influences the Court’s ideological direction. Using a multiple method approach, I demonstrate that citizens perceive the Court’s preferences to coincide with the president’s, changing predictably in the aggregate and varying substantially at the micro-level. The findings speak to debates about polarization in politics, showing that citizens may perceive insulated institutions as ideologically extreme due to factors beyond their control.
Mycobacterium avium Complex: Addressing Gaps in Diagnosis and Management
Authors: Daley Charles L , Winthrop Kevin L
Published: June 2020

Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and an important cause of disease. The most common species causing pulmonary disease are members of Mycobacterium avium complex (MAC). MAC pulmonary disease (MAC-PD) can be chronic, debilitating, costly, and associated with a high mortality. However, MAC diagnoses are often delayed due to the nonspecific presentation of MAC-PD and radiological findings that overlap with other pulmonary diseases. Patients with risk factors and who meet the diagnostic criteria—which include clinical, radiological, and microbiologic criteria—should be considered for treatment. Diagnosis requires 2 or more positive sputum cultures or 1 bronchoscopic specimen culture. The recommendation for those who are treated is a 3-drug regimen including macrolide, rifamycin, and ethambutol that is continued for 12 months beyond sputum culture conversion to negative. MAC-PD is difficult to treat, with frequent drug-related side effects and suboptimal treatment outcomes. Refractory and recurrent disease is common, leading to lifelong follow-up of patients. There are limited treatment options for patients with macrolide-resistant or refractory disease. Amikacin liposome inhalation suspension is recommended for treatment-refractory patients whose cultures remain positive after 6 months of guideline-based therapy. Among the research priorities to improve patient outcomes and quality of life are developing new, more rapid diagnostic tests, investigating biomarkers associated with disease progression, and identifying new drugs and routes of administration as well as new, shorter, and better-tolerated regimens.
Carprofen elicits pleiotropic mechanisms of bactericidal action with the potential to reverse antimicrobial drug resistance in tuberculosis
Authors: Maitra Arundhati , Evangelopoulos Dimitrios , Chrzastek Alina , Martin Liam T , Hanrath Aidan , Chapman Ellie , Hailes Helen C , Lipman Marc , McHugh Timothy D , Waddell Simon J , Bhakta Sanjib
Published: June 2020

Background

The rise of antimicrobial drug resistance in Mycobacterium tuberculosis coupled with the shortage of new antibiotics has elevated TB to a major global health priority. Repurposing drugs developed or used for other conditions has gained special attention in the current scenario of accelerated drug development for several global infectious diseases. In a similar effort, previous studies revealed that carprofen, a non-steroidal anti-inflammatory drug, selectively inhibited the growth of replicating, non-replicating and MDR clinical isolates of M. tuberculosis.

Objectives

We aimed to reveal the whole-cell phenotypic and transcriptomic effects of carprofen in mycobacteria.

Methods

Integrative molecular and microbiological approaches such as resazurin microtitre plate assay, high-throughput spot-culture growth inhibition assay, whole-cell efflux inhibition, biofilm inhibition and microarray analyses were performed. Analogues of carprofen were also synthesized and assessed for their antimycobacterial activity.

Results

Carprofen was found to be a bactericidal drug that inhibited mycobacterial drug efflux mechanisms. It also restricted mycobacterial biofilm growth. Transcriptome profiling revealed that carprofen likely acts by targeting respiration through the disruption of membrane potential. The pleiotropic nature of carprofen’s anti-TB action may explain why spontaneous drug-resistant mutants could not be isolated in practice.

Conclusions

This immunomodulatory drug and its chemical analogues have the potential to reverse TB antimicrobial drug resistance, offering a swift path to clinical trials of novel TB drug combinations.
Clofazimine pharmacokinetics in patients with TB: dosing implications
Authors: Abdelwahab Mahmoud Tareq , Wasserman Sean , Brust James C M , Gandhi Neel R , Meintjes Graeme , Everitt Daniel , Diacon Andreas , Dawson Rodney , Wiesner Lubbe , Svensson Elin M , Maartens Gary , Denti Paolo
Published: June 2020

Background

Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization.

Objectives

To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients.

Patients and methods

Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L.

Results

We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant.

Conclusions

Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.
Inherent privacy limitations of decentralized contact tracing apps
Authors: Bengio Yoshua , Ippolito Daphne , Janda Richard , Jarvie Max , Prud'homme Benjamin , Rousseau Jean-François , Sharma Abhinav , Yu Yun William
Published: June 2020

Recently, there have been many efforts to use mobile apps as an aid in contact tracing to control the spread of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) (COVID-19 [coronavirus disease 2019]) pandemic. However, although many apps aim to protect individual privacy, the very nature of contact tracing must reveal some otherwise protected personal information. Digital contact tracing has endemic privacy risks that cannot be removed by technological means, and which may require legal or economic solutions. In this brief communication, we discuss a few of these inherent privacy limitations of any decentralized automatic contact tracing system.
Analytical Quality by Design as an Important Tool to Determine the Best Analytical Conditions for Isoniazid and Its Respective Succinylated Prodrug
Authors: Rampini Denise , de Araújo Renan Vinícius , Foitinho Rodrigo Esteves , Lourenço Felipe Rebello , Giarolla Jeanine
Published: June 2020

Background

Tuberculosis is a worldwide health concern and isoniazid is the most used and considered one of the most effective drugs for its treatment. The “quality” concept must be incorporated into the final pharmaceutical product, according to the quality by design (QbD) definition. Therefore, the determination of analytical test conditions is extremely important and the design of experiments (DoE) becomes a very useful tool.

Objective

This paper used the concept of QbD to assist the development of analytical conditions for isoniazid and its respective prodrug, applying HPLC.

Method

HPLC analytical methodologies were developed for isoniazid and its succinylated derivative. The experimental design was carried out using three analytical parameters at three levels. Four chromatographic responses were studied. The impact of analytical parameters on chromatographic responses was assessed using a Pareto chart. Regression models were obtained using multiple regression analysis. DoE analysis was conducted using the Minitab® program and the experiments were performed sequentially, with varying factors.

Results

We identify three main risk parameters: mobile phase (high), flow rate (moderate), and pH of buffer (moderate). The ratio of mobile phase buffer (X2) and mobile phase pH (X3) had a major influence on the peak resolutions (Y3). The capacity factors for iso-suc (Y1) and isoniazid (Y2) peaks should be within 3–9 and 4–10, respectively. The peak resolutions between iso-suc and isoniazid (Y3) should be above two.

Conclusions

We designed 27 experiments, obtaining 1.0 mL/min flow rate, 95% buffer in the mobile phase, and pH 7.0 as the optimal analytical conditions.

Highlights

Analytical Quality by Design was used as an important tool to determine the best analytical test conditions for isoniazid and its respective prodrug - succinylated isoniazid
Development of a Loop-Mediated Isothermal Amplification Assay as an Early-Warning Tool for Detecting Emerald Ash Borer (Coleoptera: Buprestidae) Incursions
Authors: Kyei-Poku George , Gauthier Debbie , Quan Guoxing
Published: June 2020

The emerald ash borer (EAB), Agrilus planipennis (Fairmaire), is the most destructive invasive insect species of ash (Fraxinus spp.) in North America. An accurate method for early detection of this noxious insect pest is indispensable to providing adequate warning of A. planipennis infestation. A loop-mediated isothermal amplification (LAMP) assay (EAB-LAMP) was developed based on mitochondrial cytochrome c oxidase subunit I (COI) gene. The EAB-LAMP required only 30 min at 65°C to amplify A. planipennis DNA from specimens collected from geographically distinct locations. There was no cross-reactivity with other Agrilus and insect species. The developed EAB-LAMP differentially detected traces of A. planipennis genome (COI) within frass from various Fraxinus species. EAB-LAMP was also able to distinguish among A. planipennis DNA and other Agrilus species and nontarget insect species in trap captures. By detecting A. planipennis DNA in two additional trap captures (in situ), the EAB-LAMP was more sensitive and reliable than visual inspection. We tested the quantitative nature of the assay by evaluating pooled trap samples and demonstrated that the EAB-LAMP was capable of functioning optimally using a pool size of at least five individual trap samples. This potentially circumvents the need to perform large-scale individual analysis for processing trap samples. Considering its performance, specificity, sensitivity, and repeatability, the developed EAB-LAMP could be a valuable tool to support strategy and operation of large-scale surveillance for A. planipennis and could profitably be used in routine monitoring programs for effective management of A. planipennis.
Field Edge and Field-to-Field Ecotone-Type Influences on Two Cotton Herbivores: Cotton Fleahopper, Pseudatomoscelis seriatus (Hemiptera: Miridae), and Verde Plant Bug, Creontiades signatus
Authors: Esquivel Isaac L , Brewer Michael J , Coulson Robert N
Published: June 2020

In the United States, the average field size has roughly doubled from the 1980s to the mid-2000s, while average cropland has stayed the same. This will likely influence how semi-natural habitats and edges affect local patterns and processes such as natural pest control or pest densities. We hypothesized that densities of two cotton pests, cotton fleahopper (Pseudatomoscelis seriatus) and verde plant bug (Creontiades signatus) (Hemiptera: Miridae), and corresponding cotton injury in a cotton agroecosystem were affected by field edge, ecotone type (described by the neighboring habitat), and the influence of ecotone type on edge effects. Studies over 2 yr using transect and random point sampling indicated that densities of both insects declined significantly and in a linear fashion from the cotton field boundary (0 m) to field interior (200–300 m from field edge). The decline was influenced by ecotone type for cotton fleahopper. Pest densities in cotton at the interface with semi-natural habitat were higher but declined at a greater rate into the cotton field interior compared to densities seen at the interfaces with sorghum or another cotton field. These effects were also observed for verde plant bug and the cotton boll injury it causes. Regardless of the pest densities near the field edge and the rate of decline into the field interior, densities beyond 100 m into the field were up to 70% less than field edges for both insect species and for boll injury. Potential for land managers to improve sampling efficiency when scouting is apparent. For example, pest species may be at economic threshold in certain parts of the field but not others, leading to different management decisions in larger fields. Therefore, for cotton fleahopper and verde plant bug, edges should be the focus of initial pest detection and sampling, and interior field sampling may only be required when edges are above the economic threshold.
Quantitative Assessment of the Effects ofIL-1ß-511 C>T Variant on Breast Cancer Risk: An Updated Meta-Analysis of 3331 Cases and 3609 Controls
Authors: Harati-Sadegh Mahdiyeh , Mohammadoo-Khorasani Milad , Sargazi Saman , Saravani Ramin , Shahraki Sheida , Eskandari Ebrahim
Published: June 2020

Objective

Growing evidence suggests that IL-1β -511C>T, as a functional variant, affects the risk of developing breast cancer (BC); however, the results have not been conclusive. This meta-analysis was conducted to estimate the link between this variant and BC risk.

Methods

We retrieved available publications on IL-1β -511C>T polymorphism by conducting a comprehensive literature search on the Web of Science, MEDLINE, PubMed, Scopus, and Google scholar databases (last search on February 25, 2020).

Results

The overall analysis indicates that IL-1β -511C>T polymorphism conferred an increased risk of BC under a recessive TT vs CT+CC model by 1.14-fold and showed protection against BC under an overdominant CT vs TT+CC genetic contrast model (odds ratio = 0.84). Stratified analysis based on ethnicity revealed the protective effect of this single-nucleotide polymorphism against BC risk in Caucasian patients.

Conclusion

Our data results provide a proof of concept for the association of IL-1β -511C>T with BC risk. Larger, well-designed population-based studies are needed to confirm these findings.
Light Chain Predominant Intact Immunoglobulin Monoclonal Gammopathy Disorders: Shorter Survival in Light Chain Predominant Multiple Myelomas
Authors: Singh Gurmukh , Xu Hongyan
Published: June 2020

Background

A proportion of intact immunoglobulin (Ig)–producing multiple myelomas (MMs) was observed to secrete much higher amounts of free light chains (LCs) than usual.

Objectives

To determine the change point between usual and LC-predominant intact Ig-secreting MMs and other monoclonal gammopathic manifestations and the biological significance of the observation.

Methods

We conducted retrospective examination of laboratory findings in 386 MM, 27 smoldering MM, and 179 monoclonal gammopathy of undetermined significance (MGUS) cases that secreted intact Igs. We recorded the highest levels of involved serum free LC, highest ratio of involved to uninvolved LC, highest concentration of involved LC per g of monoclonal Ig, and highest value for ratio of involved to uninvolved LCs divided by the monoclonal Ig concentration. Each data set was sorted into kappa- and lambda LC-associated lesions. Length of time, in months, between diagnosis and last contact with the patients having myeloma was recorded.

Results

Change point analysis of data revealed a subgroup of cases with distinctly higher levels of free LCs. In myelomas, including plasma cell leukemias, 16.4% of myelomas with kappa LCs and 22.3% of myelomas with lambda LCs, the LC secretion was distinctly higher than in the remaining cases, by a combination of 4 parameters, listed herein. Corresponding figures for smoldering myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) were 12.5, 27.3, 3.8, and 6.8, respectively. Ten of the 13 (77%) cases of plasma cell leukemia) and all cases of IgD myeloma (n = 4) showed excess secretion of serum free LCs. Among IgG and IgA myelomas, including plasma cell leukemias, the LC-predominant lesions had shorter survival, by an average of 22.5 months.

Conclusions

In total, 18.4% of MMs, including plasma cell leukemias, secrete distinctly higher amounts of serum free LCs than other intact Ig-secreting myelomas and confer significantly lower survival. Quantification of monoclonal serum free LCs may be useful in this subgroup in monitoring progress and potentially in ascertaining minimal residual disease. The findings also stress the need for separate criteria for kappa and lambda LC associated monoclonal gammopathic manifestations. The significantly shorter survival of patients with LC-predominant myelomas warrants consideration in prospective trials of treatments.
Standing Type in Dicey/Marshall Issues of The Berkshire Tragedy
Authors: Atkinson David
Published: June 2020

This article considers six printings of the same ballad, The Berkshire Tragedy, by the same bookseller/printer, the Dicey/Marshall firm, which was the major producer of ballads in London throughout the mid-eighteenth-century. The results are rather startling and demonstrate that the ballad was kept in standing type through five different issues, in spite of a change from four-column to five-column format. These findings add to our knowledge of ballad production in the eighteenth century, and call into question the idea of ballads as ephemera.
Simultaneous multi-telescope observations of FRB 121102
Authors: Caleb M , Stappers B W , Abbott T D , Barr E D , Bezuidenhout M C , Buchner S J , Burgay M , Chen W , Cognard I , Driessen L N , Fender R , Hilmarsson G H , Hoang J , Horn D M , Jankowski F , Kramer M , Lorimer D R , Malenta M , Morello V , Pilia M , Platts E , Possenti A , Rajwade K M , Ridolfi A , Rhodes L , Sanidas S , Serylak M , Spitler L G , Townsend L J , Weltman A , Woudt P A , Wu J
Published: June 2020

We present 11 detections of FRB 121102 in ∼3 h of observations during its ‘active’ period on the 10th of 2019 September. The detections were made using the newly deployed MeerTRAP system and single pulse detection pipeline at the MeerKAT radio telescope in South Africa. Fortuitously, the Nançay radio telescope observations on this day overlapped with the last hour of MeerKAT observations and resulted in four simultaneous detections. The observations with MeerKAT’s wide band receiver, which extends down to relatively low frequencies (900–1670 MHz usable L-band range), have allowed us to get a detailed look at the complex frequency structure, intensity variations, and frequency-dependent sub-pulse drifting. The drift rates we measure for the full-band and sub-banded data are consistent with those published between 600 and 6500 MHz with a slope of −0.147 ± 0.014 ms−1. Two of the detected bursts exhibit fainter ‘precursors’ separated from the brighter main pulse by ∼28 and ∼34 ms. A follow-up multi-telescope campaign on the 6th and 8th of 2019 October to better understand these frequency drifts and structures over a wide and continuous band was undertaken. No detections resulted, indicating that the source was ‘inactive’ over a broad frequency range during this time.