bluuebunny/crossref_metadata_2025 huggingface dataset:
Cholinergic and inflammatory phenotypes in transgenic tau mouse models of Alzheimer’s disease and frontotemporal lobar degeneration
Authors: Cranston Anna L , Wysocka Adrianna , Steczkowska Marta , Zadrożny Maciej , Palasz Ewelina , Harrington Charles R , Theuring Franz , Wischik Claude M , Riedel Gernot , Niewiadomska Grazyna
Published: March 2020

An early and sizeable loss of basal forebrain cholinergic neurons is a well-characterized feature associated with measurable deficits in spatial learning and cognitive impairment in patients with Alzheimer’s disease. In addition, pro-inflammatory glial cells such as astrocytes and microglia may play a key role in the neurodegenerative cascade of Alzheimer’s disease and tauopathies. We recently presented two mouse models: Line 1, expressing the truncated tau fragment identified as the core of the Alzheimer’s paired helical filament, and Line 66, expressing full-length human tau carrying a double mutation (P301S and G335D). Line 1 mice have a pathology that is akin to Alzheimer’s, whilst Line 66 resembles frontotemporal lobar degeneration. However, their cholinergic and inflammatory phenotypes remain elusive. We performed histological evaluation of choline acetyltransferase, acetylcholinesterase, p75 neurotrophin receptor, microglial ionized calcium binding adaptor molecule 1 and astrocytic glial fibrillary acidic protein in the basal forebrain, hippocampus and cortex of these models. A significant lowering of choline acetyltransferase-positive neurons and p75-positive neurons in the basal forebrain of Line 1 at 3, 6 and 9 months was observed in two independent studies, alongside a significant decrease in acetylcholinesterase staining in the cortex and hippocampus. The reductions in choline acetyltransferase positivity varied between 30% and 50% at an age when Line 1 mice show spatial learning impairments. Furthermore, an increase in microglial ionized calcium binding adaptor molecule 1 staining was observed in the basal forebrain, hippocampus and entorhinal cortex of Line 1 at 6 months. Line 66 mice displayed an intact cholinergic basal forebrain, and no difference in p75-positive neurons at 3 or 9 months. In addition, Line 66 exhibited significant microglial ionized calcium binding adaptor molecule 1 increase in the basal forebrain and hippocampus, suggesting a prominent neuroinflammatory profile. Increased concentrations of microglial interleukin-1β and astrocytic complement 3 were also seen in the hippocampus of both Line 1 and Line 66. The cholinergic deficit in Line 1 mice confirms the Alzheimer’s disease-like phenotype in Line 1 mice, whilst Line 66 revealed no measurable change in total cholinergic expression, a phenotypic trait of frontotemporal lobar degeneration. These two transgenic lines are therefore suitable for discriminating mechanistic underpinnings between the Alzheimer’s and frontotemporal lobar degeneration-like phenotypes of these mice.
The Subplate Layers: The Superficial and Deep Subplate Can be Discriminated on 3 Tesla Human Fetal Postmortem MRI
Authors: Pogledic Ivana , Schwartz Ernst , Mitter Christian , Baltzer Pascal , Milos Ruxandra-Iulia , Gruber Gerlinde Maria , Brugger Peter C , Hainfellner Johannes , Bettelheim Dieter , Langs Georg , Kasprian Gregor , Prayer Daniela
Published: March 2020

The subplate (SP) is a transient structure of the human fetal brain that becomes the most prominent layer of the developing pallium during the late second trimester. It is important in the formation of thalamocortical and cortico-cortical connections. The SP is vulnerable in perinatal brain injury and may play a role in complex neurodevelopmental disorders, such as schizophrenia and autism. Nine postmortem fetal human brains (19–24 GW) were imaged on a 3 Tesla MR scanner and the T2-w images in the frontal and temporal lobes were compared, in each case, with the histological slices of the same brain. The brains were confirmed to be without any brain pathology. The purpose of this study was to demonstrate that the superficial SP (sSP) and deep SP (dSP) can be discriminated on postmortem MR images. More specifically, we aimed to clarify that the observable, thin, hyperintense layer below the cortical plate in the upper SP portion on T2-weighted MR images has an anatomical correspondence to the histologically established sSP. Therefore, the distinction between the sSP and dSP layers, using clinically available MR imaging methodology, is possible in postmortem MRI and can help in the imaging interpretation of the fetal cerebral layers.
Clinical Features and Short-term Outcomes of 102 Patients with Coronavirus Disease 2019 in Wuhan, China
Authors: Cao Jianlei , Tu Wen-Jun , Cheng Wenlin , Yu Lei , Liu Ya-Kun , Hu Xiaorong , Liu Qiang
Published: March 2020

Background

In December 2019, a series of pneumonia cases of unknown cause emerged in Wuhan, Hubei, China. In this study, we investigate the clinical and laboratory features and short-term outcomes of patients with coronavirus disease 2019 (COVID-19).

Methods

All patients with COVID-19 admitted to Wuhan University Zhongnan Hospital in Wuhan, China, between 3 January and 1 February 2020 were included. All those patients were with laboratory-confirmed infections. Epidemiological, clinical, and radiological characteristics; underlying diseases; laboratory tests; treatments; complications; and outcomes data were collected. Outcomes were followed up at discharge until 15 February 2020.

Results

The study cohort included 102 adult patients. The median age was 54 years (interquartile ranger, 37–67 years), and 48.0% were female. A total of 34 patients (33.3%) were exposed to a source of transmission in the hospital setting (as health-care workers, patients, or visitors) and 10 patients (9.8%) had a familial cluster. There were 18 patients (17.6%) who were admitted to the intensive care unit (ICU), and 17 patients died (mortality, 16.7%; 95% confidence interval, 9.4–23.9%). Those patients who survived were younger, were more likely to be health-care workers, and were less likely to suffer from comorbidities. They were also less likely to suffer from complications. There was no difference in drug treatment rates between the survival and nonsurvival groups. Those patients who survived were less likely to require admission to the ICU (14.1% vs 35.3% of those admitted). Chest imaging examinations showed that patients who died were more likely to have ground-glass opacity (41.2% vs 12.9% in survivors).

Conclusions

The mortality rate was high among the COVID-19 patients described in our cohort who met our criteria for inclusion in this analysis. The patient characteristics seen more frequently in those who died were the development of systemic complications following onset of the illness and a severity of disease requiring admission to the ICU. Our data support those described by others indicating that COVID-19 infection results from human-to-human transmission, including familial clustering of cases, and from nosocomial transmission. There were no differences in mortality among those who did or did not receive antimicrobial or glucocorticoid drug treatments.
Prevalence and Sequelae of Cryptococcal Antigenemia in Antiretroviral Therapy–Experienced Populations: An Evaluation of Reflex Cryptococcal Antigen Screening in Botswana
Authors: Hurt William J , Tenforde Mark W , Molefi Mooketsi , Mitchell Hannah K , Milton Thandi , Azama Martin S , Goercke Irene , Mulenga Fredah , Tlhako Nametso , Tsholo Katlego , Srivastava Tuhina , Leeme Tshepo B , Simoonga Godfrey , Muthoga Charles , Lechiile Kwana , Mine Madisa , Jarvis Joseph N
Published: March 2020

Background

Evidence to inform cryptococcal antigen (CrAg)–screening guidelines among ART-experienced populations is lacking. We performed a study evaluating the utility of reflex CrAg screening in Gaborone, Botswana.

Methods

CD4 count data were collected from the HIV reference laboratory from 2014–2016. CrAg screening was performed on samples with CD4 ≤100 cells/µL beginning January 2015. The proportion of CD4 counts ≤100 cells/µL was determined and the frequency of repeat CrAg testing described. Analyses ascertained the impact of ART status on CrAg prevalence and outcomes, and whether CrAg titers could be used for risk stratification.

Results

Overall, 5.6% (3335/59 300) of individuals tested had CD4 ≤100 cells/μL; 2108 samples with CD4 ≤100 cells/μL from 1645 unique patients were CrAg tested. Over half of samples were from ART-experienced individuals: 40.9% (863) on ART and 12.1% (255) defaulters; 22% (463) of CrAg tests were on repeat samples. CrAg prevalence was 4.8% (72/1494; 95% CI, 3.8–6.0%) among outpatients and 21.9% (32/151; 95% CI, 15.3–28.5%) among inpatients. CrAg prevalence rates did not differ by ART status, but 6-month mortality was significantly lower in CrAg-positive individuals on ART at screening. Ten CrAg positives were identified through repeat testing. A CrAg titer cutoff ≥1:80 provided the best discrimination for 6-month survival.

Conclusions

CrAg-positivity rates in an ART-experienced population were comparable to those seen in ART-naive populations. Repeat screening identified individuals who seroconverted to CrAg positivity and were at risk of cryptococcal disease. CrAg titers ≥1:80 can help identify the individuals at highest risk of death for more intensive management.
Isavuconazole as Primary Antifungal Prophylaxis in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome: An Open-label, Prospective, Phase 2 Study
Authors: Bose Prithviraj , McCue David , Wurster Sebastian , Wiederhold Nathan P , Konopleva Marina , Kadia Tapan M , Borthakur Gautam , Ravandi Farhad , Masarova Lucia , Takahashi Koichi , Estrov Zeev , Yilmaz Musa , Daver Naval , Pemmaraju Naveen , Naqvi Kiran , Rausch Caitlin R , Marx Kayleigh R , Qiao Wei , Huang Xuelin , Bivins Carol A , Pierce Sherry A , Kantarjian Hagop M , Kontoyiannis Dimitrios P
Published: March 2020

Background

Mold-active primary antifungal prophylaxis (PAP) is routinely recommended in neutropenic patients with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing remission-induction chemotherapy (RIC). Isavuconazole (ISAV) is an extended spectrum mold-active triazole and has superior tolerability and fewer significant drug–drug interactions compared with other triazoles.

Methods

In our investigator-initiated, phase 2 trial, treatment-naive adult patients with AML or MDS starting RIC received ISAV per the dosing recommendations in the US label until neutrophil recovery (absolute neutrophil count [ANC] ≥ 0.5 × 109/L) and attainment of complete remission, occurrence of invasive fungal infection (IFI), or for a maximum of 12 weeks. The primary endpoint was the incidence of proven/probable IFI during ISAV PAP and up to 30 days after the last dose.

Results

Sixty-five of 75 enrolled patients received ISAV PAP (median age, 67 years, median ANC at enrollment, 0.72 × 109/L). Thirty-two patients (49%) received oral targeted leukemia treatments (venetoclax, FTL3 inhibitors). Including the 30-day follow-up period, probable/proven and possible IFIs were encountered in 4 (6%) and 8 patients (12%), respectively. ISAV trough serum concentrations were consistently > 1 µg/mL, showed low intraindividual variation, and were not significantly influenced by chemotherapy regimen. Tolerability of ISAV was excellent, with only 3 cases (5%) of mild to moderate elevations of liver function tests and no QTc prolongations.

Conclusions

ISAV is a safe and effective alternative for PAP in patients with newly diagnosed AML/MDS undergoing RIC in the era of recently approved or emerging small-molecule antileukemia therapies.

Clinical Trials Registration

NCT03019939.
Character Recognition Algorithm Based on Fusion Probability Model and Deep Learning
Authors: Liu Zhijun , Pan Xuefeng , Peng Yuan
Published: March 2020

The authors proposed a character recognition algorithm to improve the recognition efficiency and recognition accuracy in character recognition. The algorithm is based on a deep belief network classifier. In the character recognition, a comprehensive feature model is established firstly by combining the histogram Gabor feature, grid level feature and gray level co-occurrence matrix. Subsequently, the deep belief network trains the feature model. Finally, the probability model is used to judge the recognition symbols. The algorithm is tested with 74 k data set and is compared and analyzed from three indexes: false acceptance rate, false rejection rate and accuracy. The data set simulation and comparison with other algorithms indicate that the recognition system based on the probability model and depth learning has higher accuracy and better performance.
Collective memory and Spanish cultural politics: the revival of the Roman theatre of Merida (1910–35)
Authors: Balaskas Vasileios
Published: March 2020

In the twentieth century, ancient theatres acquired symbolic values through their excavation, restoration, and cultural reuse. While elsewhere in the Mediterranean comparable cases show an early and powerful engagement of a populace with their antiquities, in Spain national ideals did not automatically engage with classical culture. In the case of the Roman theatre of Merida, cultural and historical realities dictated a series of cultural events that repeatedly concerned collective memory. In addition to the main sequence of the unique occasions surrounding the 1933 and 1934 performances at the theatre, various other agencies had systematically focused on its exploitation from the 1910s. These initiatives were endorsed by numerous formal visits and cultural events that took place in the theatre, from as early as 1914. Through successive spectacles staged at the theatre, a cultural tradition emerged, while political agendas occasionally exploited its increasing popularity, right up to the Spanish Civil War.
Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signalling
Authors: Alesutan Ioana , Luong Trang T D , Schelski Nadeshda , Masyout Jaber , Hille Susanne , Schneider Markus P , Graham Delyth , Zickler Daniel , Verheyen Nicolas , Estepa Misael , Pasch Andreas , Maerz Winfried , Tomaschitz Andreas , Pilz Stefan , Frey Norbert , Lang Florian , Delles Christian , Müller Oliver J , Pieske Burkert , Eckardt Kai-Uwe , Scherberich Juergen , Voelkl Jakob
Published: March 2020

Aims

Uromodulin is produced exclusively in the kidney and secreted into both urine and blood. Serum levels of uromodulin are correlated with kidney function and reduced in chronic kidney disease (CKD) patients, but physiological functions of serum uromodulin are still elusive. This study investigated the role of uromodulin in medial vascular calcification, a key factor associated with cardiovascular events and mortality in CKD patients.

Methods and results 

Experiments were performed in primary human (HAoSMCs) and mouse (MOVAS) aortic smooth muscle cells, cholecalciferol overload and subtotal nephrectomy mouse models and serum from CKD patients. In three independent cohorts of CKD patients, serum uromodulin concentrations were inversely correlated with serum calcification propensity. Uromodulin supplementation reduced phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. In human serum, pro-inflammatory cytokines tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) co-immunoprecipitated with uromodulin. Uromodulin inhibited TNFα and IL-1β-induced osteo-/chondrogenic signalling and activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated β cells (NF-kB) as well as phosphate-induced NF-kB-dependent transcriptional activity in HAoSMCs. In vivo, adeno-associated virus (AAV)-mediated overexpression of uromodulin ameliorated vascular calcification in mice with cholecalciferol overload. Conversely, cholecalciferol overload-induced vascular calcification was aggravated in uromodulin-deficient mice. In contrast, uromodulin overexpression failed to reduce vascular calcification during renal failure in mice. Carbamylated uromodulin was detected in serum of CKD patients and uromodulin carbamylation inhibited its anti-calcific properties in vitro.

Conclusions 

Uromodulin counteracts vascular osteo-/chondrogenic transdifferentiation and calcification, at least in part, through interference with cytokine-dependent pro-calcific signalling. In CKD, reduction and carbamylation of uromodulin may contribute to vascular pathology.
Successful implantation of leadless pacemakers in children: a case series
Authors: Jędrzejczyk-Patej Ewa , Woźniak Aleksandra , Litwin Linda , Skiba-Zdrzałek Alina , Mazurek Michał , Lenarczyk Radosław , Kalarus Zbigniew , Kowalski Oskar
Published: March 2020

Background

A leadless pacemaker is a new concept in which a miniaturized pacing device is self-contained within the heart. Recently published data show that leadless pacemakers are associated with a decreased risk of major complications when compared with transvenous cardiac pacemakers. This seems to be of particular importance in children and young adults in whom various complications may occur during their lifetime.

Case summary

Herein, we report the successful implantation of Micra™ Transcatheter Pacing System in two children: 12-year-old boy and 13-year-old girl, along with a long-term follow-up. The children had indications for pacemaker implantation, however, with an expected low percentage of pacing due to paroxysmal nature of the third-degree atrioventricular block. The implantation procedures were performed in general anaesthesia. There were no complications. During the 2-year follow-up, there were no adverse events and the electrical parameters of the device remained stable. Pacing percentage was below 0.1%.

Discussion

Transvenous cardiac pacemakers improve quality of life and reduce mortality but may be associated with various short- and long-term complications, mainly related to the presence of transvenous leads and the pulse generator. Compared with adult patients, the implantation of conventional pacemakers in children is still a challenge, not only because of their smaller size but also due to continuing growth, as well as a higher rate of lead and device-related complications. We demonstrate that the implantation of leadless pacemakers in children is feasible and could be worth considering in certain clinical scenarios, especially when ventricular pacing is required rarely.
Battista Carioni da Crema (c.1460–1534) and the ‘Third Life’: Visions of Reform in Early Sixteenth-Century Italy
Authors: Mazzonis Querciolo
Published: March 2020

This essay sheds new light on the spirituality and historical significance of the influential and controversial Dominican friar Battista Carioni da Crema (c.1460–1534). A popular spiritual writer, charismatic founder of devout associations such as the Barnabites, and a spiritual director of several well-known Catholic figures, including Gaetano Thiene, Battista’s significance has not yet been fully acknowledged. The essay considers his spirituality in the framework of reforming movements emerging in Italy in the first half of the sixteenth century. In dialogue with previous interpretations of Battista, the essay provides a novel and systematic analysis of his notion of perfection and concept of the Church. Synthesising ascetic and mystic spiritual influences rooted in the monastic and humanist culture of the fifteenth century, Battista presented a distinctive view of Christian life, which included an ecclesiological perspective and a new geography of the sacred. Defined as the ‘third life’ and conceived in a period of religious fluidity, it neither fitted emerging Lutheran ideas nor the orthodox Catholicism of the Roman Church. In addition, the essay argues that Battista’s proselytism can be seen as an attempt to reform society which preceded proposals for religious reform made by groups such as the Spirituali.
Adherence to and Retention in Medications for Opioid Use Disorder Among Adolescents and Young Adults
Authors: Viera Adam , Bromberg Daniel J , Whittaker Shannon , Refsland Bryan M , Stanojlović Milena , Nyhan Kate , Altice Frederick L
Published: March 2020

The volatile opioid epidemic is associated with higher levels of opioid use disorder (OUD) and negative health outcomes in adolescents and young adults. Medications for opioid use disorder (MOUD) demonstrate the best evidence for treating OUD. Adherence to and retention in MOUD, defined as continuous engagement in treatment, among adolescents and young adults, however, is incompletely understood. We examined the state of the literature regarding the association of age with adherence to and retention in MOUD using methadone, buprenorphine, or naltrexone among persons aged 10–24 years, along with related facilitators and barriers. All studies of MOUD were searched for that examined adherence, retention, or related concepts as an outcome variable and included adolescents or young adults. Search criteria generated 10,229 records; after removing duplicates and screening titles and abstracts, 587 studies were identified for full-text review. Ultimately, 52 articles met inclusion criteria for abstraction and 17 were selected for qualitative coding and analysis. Younger age was consistently associated with shorter retention, although the overall quality of included studies was low. Several factors at the individual, interpersonal, and institutional levels, such as concurrent substance use, MOUD adherence, family conflict, and MOUD dosage and flexibility, appeared to have roles in MOUD retention among adolescents and young adults. Ways MOUD providers can tailor treatment to increase retention of adolescents and young adults are highlighted, as is the need for more research explaining MOUD adherence and retention disparities in this age group.
When genetic burden reaches threshold
Authors: Walsh Roddy , Tadros Rafik , Bezzina Connie R
Published: March 2020

Rare cardiac genetic diseases have generally been considered to be broadly Mendelian in nature, with clinical genetic testing for these conditions predicated on the detection of a primary causative rare pathogenic variant that will enable cascade genetic screening in families. However, substantial variability in penetrance and disease severity among carriers of pathogenic variants, as well as the inability to detect rare Mendelian variants in considerable proportions of patients, indicates that more complex aetiologies are likely to underlie these diseases. Recent findings have suggested genetic variants across a range of population frequencies and effect sizes may combine, along with non-genetic factors, to determine whether the threshold for expression of disease is reached and the severity of the phenotype. The availability of increasingly large genetically characterized cohorts of patients with rare cardiac diseases is enabling the discovery of common genetic variation that may underlie both variable penetrance in Mendelian diseases and the genetic aetiology of apparently non-Mendelian rare cardiac conditions. It is likely that the genetic architecture of rare cardiac diseases will vary considerably between different conditions as well as between patients with similar phenotypes, ranging from near-Mendelian disease to models more akin to common, complex disease. Uncovering the broad range of genetic factors that predispose patients to rare cardiac diseases offers the promise of improved risk prediction and more focused clinical management in patients and their families.
Omics phenotyping in heart failure: the next frontier
Authors: Bayes-Genis Antoni , Liu Peter P , Lanfear David E , de Boer Rudolf A , González Arantxa , Thum Thomas , Emdin Michele , Januzzi James L
Published: March 2020

This state-of-the-art review aims to provide an up-to-date look at breakthrough omic technologies that are helping to unravel heart failure (HF) disease mechanisms and heterogeneity. Genomics, transcriptomics, proteomics, and metabolomics in HF are reviewed in depth. In addition, there is a thorough, expert discussion regarding the value of omics in identifying novel disease pathways, advancing understanding of disease mechanisms, differentiating HF phenotypes, yielding biomarkers for diagnosis or prognosis, or identifying new therapeutic targets in HF. The combination of multiple omics technologies may create a more comprehensive picture of the factors and physiology involved in HF than achieved by either one alone and provides a rich resource for predictive phenotype modelling. However, the successful translation of omics tools as solutions to clinical HF requires that the observations are robust and reproducible and can be validated across multiple independent populations to ensure confidence in clinical decision-making.
New strategies for profiling and characterization of human milk oligosaccharides
Authors: Porfirio Sara , Archer-Hartmann Stephanie , Moreau G Brett , Ramakrishnan Girija , Haque Rashidul , Kirkpatrick Beth D , Petri William A , Azadi Parastoo
Published: March 2020

Human breast milk is an incredibly rich and complex biofluid composed of proteins, lipids and complex carbohydrates, including a diverse repertoire of free human milk oligosaccharides (HMOs). Strikingly, HMOs are not digested by the infant but function as prebiotics for bacterial strains associated with numerous benefits. Considering the broad variety of beneficial effects of HMOs, and the vast number of factors that affect breast milk composition, the analysis of HMO diversity and complexity is of utmost relevance. Using human milk samples from a cohort of Bangladeshi mothers participating in a study on malnutrition and stunting in children, we have characterized breast milk oligosaccharide composition by means of permethylation followed by liquid chromatography coupled with high-resolution tandem mass spectrometry (LC-MS/MS) analysis. This approach identified over 100 different glycoforms and showed a wide diversity of milk composition, with a predominance of fucosylated and sialylated HMOs over nonmodified HMOs. We observed that these samples contain on average 80 HMOs, with the highest permethylated masses detected being >5000 mass units. Here we report an easily implemented method developed for the separation, characterization and relative quantitation of large arrays of HMOs, including higher molecular weight sialylated HMOs. Our ultimate goal is to create a simple, high-throughput method, which can be used for full characterization of sialylated and/or fucosylated HMOs. These results demonstrate how current analytical techniques can be applied to characterize human milk composition, providing new tools to help the scientific community shed new light on the impact of HMOs during infant development.
When soft budget constraints promote innovation: Kornai meets Schumpeter in Japan
Authors: Jerneck Max
Published: March 2020

The article examines János Kornai’s influential argument that “soft budget constraints” impede innovation, and finds that under certain conditions, they may promote it instead. Kornai’s concept is derived from his analysis of socialism. In capitalism, soft budget constraints can promote innovation if competition is enforced and finance is well regulated. This argument is developed using the same Schumpeterian foundation as Kornai, illustrated empirically with the case of innovation in post-war Japan. Implications are relevant for innovation and industrial policy in general.
Systematic review of mutations associated with resistance to the new and repurposedMycobacterium tuberculosisdrugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid
Authors: Kadura Suha , King Nicholas , Nakhoul Maria , Zhu Hongya , Theron Grant , Köser Claudio U , Farhat Maha
Published: March 2020

Background

Improved genetic understanding of Mycobacterium tuberculosis (MTB) resistance to novel and repurposed anti-tubercular agents can aid the development of rapid molecular diagnostics.

Methods

Adhering to PRISMA guidelines, in March 2018, we performed a systematic review of studies implicating mutations in resistance through sequencing and phenotyping before and/or after spontaneous resistance evolution, as well as allelic exchange experiments. We focused on the novel drugs bedaquiline, delamanid, pretomanid and the repurposed drugs clofazimine and linezolid. A database of 1373 diverse control MTB whole genomes, isolated from patients not exposed to these drugs, was used to further assess genotype–phenotype associations.

Results

Of 2112 papers, 54 met the inclusion criteria. These studies characterized 277 mutations in the genes atpE, mmpR, pepQ, Rv1979c, fgd1, fbiABC and ddn and their association with resistance to one or more of the five drugs. The most frequent mutations for bedaquiline, clofazimine, linezolid, delamanid and pretomanid resistance were atpE A63P, mmpR frameshifts at nucleotides 192–198, rplC C154R, ddn W88* and ddn S11*, respectively. Frameshifts in the mmpR homopolymer region nucleotides 192–198 were identified in 52/1373 (4%) of the control isolates without prior exposure to bedaquiline or clofazimine. Of isolates resistant to one or more of the five drugs, 59/519 (11%) lacked a mutation explaining phenotypic resistance.

Conclusions

This systematic review supports the use of molecular methods for linezolid resistance detection. Resistance mechanisms involving non-essential genes show a diversity of mutations that will challenge molecular diagnosis of bedaquiline and nitroimidazole resistance. Combined phenotypic and genotypic surveillance is needed for these drugs in the short term.
Bevacizumab for Newly Diagnosed Ovarian Cancers: Best Candidates Among High-Risk Disease Patients (ICON-7)
Authors: Colomban Olivier , Tod Michel , Peron Julien , Perren Timothy J , Leary Alexandra , Cook Adrian D , Sajous Christophe , Freyer Gilles , You Benoit
Published: March 2020

Bevacizumab is approved as a maintenance treatment in first-line setting in advanced-stage III-IV ovarian cancers, because GOG-0218 and ICON-7 phase III trials demonstrated progression-free survival benefits. However, only the subgroup of patients with high-risk diseases (stage IV, and incompletely resected stage III) derived an overall survival (OS) gain in the ICON-7 trial (4.8 months). The modeled CA-125 elimination rate constant K (KELIM) parameter, based on the longitudinal CA-125 kinetics during the first 100 days of chemotherapy, is a potential indicator of the tumor primary chemo-sensitivity. In the ICON-7 trial dataset, the OS of patients within the low- and high-risk disease groups was assessed according to treatment arms and KELIM. Among the patients with high-risk diseases, those with favorable standardized KELIM of at least 1.0 (n = 214, 46.7%) had no survival benefit from bevacizumab, whereas those with unfavorable KELIM less than 1.0 (n = 244, 53.2%) derived the highest OS benefit (absolute difference = 9.1 months, 2-sided log-rank P = .10; Cox hazard ratio = 0.78, 95% confidence interval = 0.58 to 1.04, 2-sided P = .09).
Initiative and Military Effectiveness: Evidence from the Yom Kippur War
Authors: Grauer Ryan , Quackenbush Stephen L
Published: March 2020

Scholars investigating the sources of military capability have located sources of effectiveness in the structure of the international system, the characteristics of states, and features of the armed forces engaged in battle. They also point toward the likely influence of individual-level variables, but such claims tend to lack theoretical and empirical justification. We advance the literature by investigating whether individual initiative—that is, actions taken by soldiers and junior officers to achieve their commander's intent while in the absence of orders, when existing orders no longer fit the situation, or when unforeseen opportunities or threats arise—systematically conditions armed forces’ performance on the battlefield. We develop a theory connecting individual initiative with military effectiveness, highlighting the role of “problem-solving” in facilitating the use of men and materiel in battle. We then assess the empirical validity of our claim through an examination of a uniquely informative episode in military history: Israel's fight on the Sinai front during the first three days of the 1973 Yom Kippur War. The case allows us to hold constant a wide range of potentially confounding variables and, to the best of our knowledge, conduct the first systematic investigation of the impact of individual initiative on the performance of units engaged in combat actions. Our findings suggest individual initiative does have systematic effects on armed forces’ effectiveness in combat. Implications and directions for future research on the development and use of military capabilities are briefly considered.
Pituicytoma associated with Cushing’s disease: a case report and literature review
Authors: rumeh Assem S A l , Bafaqeeh Mohamed , khairan Syed J Allahu , Al shakweer Wafa
Published: March 2020

Pituicytoma is a rare tumor that has been recently recognized and described, where only few reported cases of pituicytoma associated with Cushing’s disease. We describe a case of a 47 years old female with a history of high cortisol levels and a diagnosis of Cushing’s disease was made. Brain magnetic resonance imaging showed lesion in pituitary gland compatible with microadenoma and tumor resection was carried out. The histopathological findings were of a pituicytoma with positive thyroid transcription factor-1 immunostain.
The Discourse Functions of Overspecified Anaphoric Expressions in Biblical Hebrew Narrative: Genesis 12-24 as a Test Case
Authors: Bergström Ulf
Published: March 2020

In Biblical Hebrew, as in other languages, anaphoric reference is often overspecified; that is, an anaphoric noun (lexical anaphora) is used in a place where the inflection of the verb (inflectional anaphora) would be a sufficient indicator as to who is being referred to. The present study investigates the function of overspecified subject referents in Biblical Hebrew narrative discourse. It is found that overspecification can be associated with three main textual phenomena, namely, events of general relevance, subject referent initiative, and various textual discontinuities. The function of indicating subject referent initiative lies behind many of the occurrences of lexical anaphora at the beginning of episodic units, but it may also occur within episodes. The different functions of overspecification and inflectional anaphora arise as a result of the different mental processes triggered by lexical and deictic anaphora, whereby the former evokes general, contextindependent knowledge about the referent and impedes the access to the information contained in the previous clause, whereas the latter makes it immediately available.
Lexical Root vs. Substantive Root: The Status of the Hebrew Alphabet As A Precursory System for Menaḥem Ben Saruq's Root Concept
Authors: Charlap Luba R
Published: March 2020

Menaḥem ben Saruq (Spain, tenth century) is considered to be the first scholar to write a dictionary of Biblical Hebrew - called the Maḥberet - on Spanish soil. His role in the development of Hebrew grammar, however, has not been given pride of place in the scholarly literature. Renewed interest in his theory arose only in the late twentieth century. As some scholars have noted, Menaḥem was the first to reveal the three-consonantal basis of Hebrew roots. This article will continue to establish the basis for this concept, while further elaborating on several emphases in his teaching, especially in the context of the distinction between the radical and the servile letters and their subdivision, which, in our view, led Menaḥem to formulate his root concept. Following our analysis, we note a difference between the ‘lexical root’ concept, by which he arranged the entries in his Maḥberet, and the ‘substantive root’ concept on which he based his innovation. A parallel idea can be seen in the theory of Yusuf Ibn Nūḥ, who set forth the jawhar concept, which means the basic entity of a word on the abstract level (as opposed to a word-based morphology), as Geoffrey Khan has shown. The article concludes with a clarification of the difference between Menaḥem's theory and that of Judah Ḥayyūj. Despite the enormous development made by Menaḥem, he was not able to offer a coherent morphological system, as Ḥayyūj did.
Near-perihelion activity of comet 67P/Churyumov–Gerasimenko. A first attempt of non-static analysis
Authors: Skorov Yu , Keller H U , Mottola S , Hartogh P
Published: March 2020

The observed rate of water production of comet 67P/Churyumov–Gerasimenko near its perihelion can be approximated by a very steep power function of the heliocentric distance. Widely used thermophysical models based on a static dust layer on top of the icy/refractory matrix are poorly consistent with these observations. We analyse published model results and demonstrate that thermophysical models with a uniform and static ice free layer do not reproduce the observed steep water production rates of 67P near perihelion. Based on transient thermal modeling we conclude that the accelerated gas activity can be explained assuming that the active area fraction near the south pole is increased. The deeper penetration of the heat wave during polar day (no sunset) can activate sublimation through thicker inert dust layers. This can also lead to removal of thicker dust layers and consequently to an expansion of the active area.
Full of Orions: a 200-pc mapping of the interstellar medium in the redshift-3 lensed dusty star-forming galaxy SDP.81
Authors: Rybak Matus , Hodge J A , Vegetti S , van der Werf P , Andreani P , Graziani L , McKean J P
Published: March 2020

We present a sub-kpc resolved study of the interstellar medium properties in SDP.81, a $z$ = 3.042 strongly gravitationally lensed, dusty star-forming galaxy, based on high-resolution, multiband ALMA observations of the far-infrared (FIR) continuum, CO ladder, and the [C ii] line. Using a visibility-plane lens modelling code, we achieve a median source-plane resolution of ∼200 pc. We use photon-dominated region (PDR) models to infer the physical conditions – far-ultraviolet (FUV) field strength, density, and PDR surface temperature – of the star-forming gas on 200-pc scales, finding a FUV field strength of ∼103−104G0, gas density of ∼105 cm−3, and cloud surface temperatures up to 1500 K, similar to those in the Orion Trapezium region. The [C ii] emission is significantly more extended than that FIR continuum: ∼50 per cent of [C ii] emission arises outside the FIR-bright region. The resolved [C ii]/FIR ratio varies by almost 2 dex across the source, down to ∼2 × 10−4 in the star-forming clumps. The observed [C ii]/FIR deficit trend is consistent with thermal saturation of the C+ fine-structure-level occupancy at high gas temperatures. We make the source-plane reconstructions of all emission lines and continuum data publicly available.
Mass calibration of the CODEX cluster sample using SPIDERS spectroscopy – II. The X-ray luminosity–mass relation
Authors: Capasso R , Mohr J J , Saro A , Biviano A , Clerc N , Finoguenov A , Klein M , Grandis S , Collins C , Damsted S , Kirkpatrick C , Kukkola A
Published: March 2020

We perform the calibration of the X-ray luminosity–mass scaling relation on a sample of 344 CODEX clusters with z < 0.66 using the dynamics of their member galaxies. Spectroscopic follow-up measurements have been obtained from the SPIDERS survey, leading to a sample of 6658 red member galaxies. We use the Jeans equation to calculate halo masses, assuming an NFW mass profile and analysing a broad range of anisotropy profiles. With a scaling relation of the form $L_{\rm {X}} \propto \text{A}_{\rm {X}}M_{\text{200c}}^{\text{B}_{\rm {X}}} E(z)^2 (1+z)^{\gamma _{\rm {X}}}$, we find best-fitting parameters $\text{A}_{\rm {X}}=0.62^{+0.05}_{-0.06} (\pm 0.06)\times 10^{44}\, \mathrm{erg\, s^{-1}}$, $\text{B}_{\rm {X}}=2.35^{+0.21}_{-0.18}(\pm 0.09)$, $\gamma _{\rm {X}}=-2.77^{+1.06}_{-1.05}(\pm 0.79)$, where we include systematic uncertainties in parentheses and for a pivot mass and redshift of $3\times 10^{14}\, \mathrm{M}_\odot$ and 0.16, respectively. We compare our constraints with previous results, and we combine our sample with the SPT SZE-selected cluster subsample observed with XMM–Newton  extending the validity of our results to a wider range of redshifts and cluster masses.
Nihil Obstat: Lewis’s Compatibilist Account of Abilities
Authors: Beebee Helen , Svedberg Maria , Whittle Ann
Published: March 2020

In an outline of a paper found amongst his philosophical papers and correspondence after his untimely death in 2001—“Nihil Obstat: An Analysis of Ability,” reproduced in this volume—David Lewis sketched a new compatibilist account of abilities, according to which someone is able to A if and only if there is no obstacle to their A-ing, where an obstacle is a ‘robust preventer’ of their A-ing. In this paper, we provide some background context for Lewis’s outline, a section-by-section commentary, and a general discussion of the account’s main features.
Early specializations for mimicry and defense in a Jurassic stick insect
Authors: Yang Hongru , Shi Chaofan , Engel Michael S , Zhao Zhipeng , Ren Dong , Gao Taiping
Published: March 2020

Mimicry and secondary defense are staples among predator–prey interactions. Among insects, the stick and leaf insects are masters of camouflage. Nonetheless, a meager understanding of their origin and early mimetic evolution persists. Here, we report the earliest mimetic and defensive strategies of a stick insect from the Middle Jurassic of China, Aclistophasma echinulatum gen. et sp. nov., exquisitely preserving abdominal extensions and femoral spines. The distribution of these characteristics mapped onto the phylogeny of Phasmatodea reveals that abdominal extensions and femoral spines developed multiple times during the evolution of stick insects, and indicates that the origin of abdominal extensions predates other modifications, while tergal extensions predate other expansions of the body, such as those of the sterna and pleura, as well as defensive femoral spines. The new fossil provides clues into early antipredator defensive strategies, allows inferences as to the potential environment and predators, and reveals the mimetic and defensive mechanisms of stick insects from 165 million years ago.
Rapidly enlarging malignant abdominal PEComa with hepatic metastasis: a promising initial response to sirolimus following surgical excision of primary tumor
Authors: Uhlenhopp Dustin J , West Jacob , Heckart Jonathan , Campbell Ruth , Elhaddad Abdelaziz
Published: March 2020

Intra-abdominal perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors. Although no effective therapies have been agreed upon, mTOR inhibitors are currently being investigated as a potential therapy for this extremely rare tumor. We present a case of a 64-year-old male found to have a large intra-abdominal PEComa with multiple metastatic lesions in the liver. Patient underwent surgical resection of the primary lesion in the abdomen and sigmoid colon followed by adjuvant therapy with the mTOR inhibitor, sirolimus. Initial response was noted with a decrease in size and number of lesions found in the patient’s liver. After 8 months of therapy, restaging imaging showed disease progression in the liver lesions. Patient subsequently failed treatments with pazopanib, investigational therapy TAK-228 (Sapanisertib) and nivolumab and ipilimumab. Overall the patient died after 22 months of disease. PEComas generally follow a benign course. This case is a much rarer entity given the malignant features/outcome.
The knowledge needs for Canadian paediatric emergency physicians in the diagnosis and management of tropical diseases: A national physician survey
Authors: Wan Melissa Mengyan , Doan Quynh , Kissoon Niranjan
Published: March 2020

Objectives

To assess the knowledge gaps and need for continuing medical education (CME) resources for Canadian paediatric emergency department (PED) physician management of common tropical diseases.

Methods

A cross-sectional survey study of Canadian PED was performed from May to July 2017 using the Pediatric Emergency Research Canada (PERC) database.

Results

The response rate was 56.4% (133/236). The mean performance on the case-based vignettes identifying clinical presentation of tropical illnesses ranged from 59.9% to 76.0%, with only 15.8% (n=21) to 31.1% (n=42) of participants scoring maximum points. Those who ‘always’ asked about fever performed better than those who only ‘sometimes’ asked (40.4% versus 23.8%). For management cases, the majority of the participants (59.4% to 89.5%) were able to interpret investigations; however, many were unsure of subsequent actions relating to initial treatment, discharge instructions, and reporting requirements. Many would consult infectious diseases (87.8% to 99.3%). Fifty-three per cent of the participants reported a low comfort level in diagnosing or managing these patients. They rated the importance of CME materials with a median of 50/100, via various modalities such as case studies (71.9%), emphasizing a need for PED-specific content.

Conclusion

This study identified a knowledge gap in the recognition and management of pediatric tropical diseases by Canadian PED physicians. There is a need for formal CME materials to supplement physician practice.
Public Agency Strategies, Collaborative Contracting, and Medicaid Managed Care
Authors: Saidel Judith R , Searing Elizabeth A M
Published: March 2020

The nature of the interactions between the organizational entities involved in contracting receives less attention than the efficiency of the procurement and distribution of those services. This is particularly true in periods of policy turbulence, where tensions are high and environments unstable. This study builds on earlier theoretical contributions by cataloging almost 100 different strategies in interviews with state agencies and related policy experts, then distilling important traits and modifying earlier analytical constructs to reflect the empirical findings. The result is a new understanding of the range of relationships and extent of collaboration in contracting interactions at different points in the policy process. This study contributes to the literature not only through the elicitation and nature of these contracting strategies but also by contributing to the theoretical underpinnings of both collaboration in contracting and how such relationships provide a means of navigating periods of policy turbulence.