bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of introducing procalcitonin testing on antibiotic usage in acute NHS hospitals during the first wave of COVID-19 in the UK: a controlled interrupted time series analysis of organization-level data
Authors: Llewelyn Martin J. , Grozeva Detelina , Howard Philip , Euden Joanne , Gerver Sarah M. , Hope Russell , Heginbothom Margaret , Powell Neil , Richman Colin , Shaw Dominick , Thomas-Jones Emma , West Robert M. , Carrol Enitan D. , Pallmann Philip , Sandoe Jonathan A. T.
Published: January 2022

Background

Blood biomarkers have the potential to help identify COVID-19 patients with bacterial coinfection in whom antibiotics are indicated. During the COVID-19 pandemic, procalcitonin testing was widely introduced at hospitals in the UK to guide antibiotic prescribing. We have determined the impact of this on hospital-level antibiotic consumption.

Methods

We conducted a retrospective, controlled interrupted time series analysis of organization-level data describing antibiotic dispensing, hospital activity and procalcitonin testing for acute hospitals/hospital trusts in England and Wales during the first wave of COVID-19 (24 February to 5 July 2020).

Results

In the main analysis of 105 hospitals in England, introduction of procalcitonin testing in emergency departments/acute medical admission units was associated with a statistically significant decrease in total antibiotic use of −1.08 (95% CI: −1.81 to −0.36) DDDs of antibiotic per admission per week per trust. This effect was then lost at a rate of 0.05 (95% CI: 0.02–0.08) DDDs per admission per week. Similar results were found specifically for first-line antibiotics for community-acquired pneumonia and for COVID-19 admissions rather than all admissions. Introduction of procalcitonin in the ICU setting was not associated with any significant change in antibiotic use.

Conclusions

At hospitals where procalcitonin testing was introduced in emergency departments/acute medical units this was associated with an initial, but unsustained, reduction in antibiotic use. Further research should establish the patient-level impact of procalcitonin testing in this population and understand its potential for clinical effectiveness.
PCV-15 and PPSV-23 coverage of invasive and respiratory tract Streptococcus pneumoniae, including MDR and XDR isolates: CANWARD 2007–20
Authors: Golden Alyssa R. , Baxter Melanie , Adam Heather J , Martin Irene , Demczuk Walter , Mulvey Michael R , Karlowsky James A , Zhanel George G
Published: January 2022

Objectives

To compare the proportion of invasive and respiratory tract isolates of Streptococcus pneumoniae, including MDR and XDR strains, that demonstrated PCV-15 and PPSV-23 serotypes in Canada from 2007 to 2020.

Methods

The CANWARD study collected 2984 S. pneumoniae isolates from 2007 to 2020 (1054 invasive, 1930 respiratory). Serotyping was performed using the Quellung reaction. Antimicrobial susceptibility testing was performed using CLSI methods. MDR/XDR was defined as resistance to ≥3/≥5 antimicrobial classes, respectively.

Results

Overall, the proportion of vaccine serotypes demonstrating a PCV-15/PPSV-23 serotype was significantly higher in blood isolates (54.6%/76.2%, respectively) than respiratory isolates (38.9%/55.3%; P < 0.0001). Similarly, PCV-15 and PPSV-23 vaccine coverage was higher for blood isolates for all demographic categories, including both genders, all regions and all age groups (P ≤ 0.0213). PCV-15/PPSV-23 coverage was also significantly higher for blood isolates demonstrating clarithromycin resistance (60.4/75.1% blood, 47.8/57.4% respiratory; P ≤ 0.009) and penicillin resistance (68.9/63.0% blood, 45.2/43.0% respiratory; P < 0.0001) and trimethoprim/sulfamethoxazole-resistant isolates for PPSV-23 only (82.6% blood, 64.3% respiratory; P = 0.0057). Vaccine coverage was numerically higher but not significantly different between specimen source for children <2 years of age, as well as ceftriaxone-, doxycycline- and levofloxacin-resistant isolates. PCV-15/PPSV-23 vaccine coverage for MDR isolates (61.8%/67.3% blood, 52.2%/56.2% respiratory) and XDR isolates (93.3% blood, 89.6% respiratory for both vaccines) was not significantly different between specimen sources.

Conclusions

PCV-15 and PPSV-23 serotype coverage is generally greater for blood versus respiratory isolates but not for MDR and XDR isolates. Continued pneumococcal surveillance is warranted to determine future trends in vaccine coverage, serotype distribution and antimicrobial susceptibilities under the pressure of vaccine use.
Surveillance of Stability Under Different Stress Conditions in Desloratadine and Study of Degradation Kinetics
Authors: Pandey Swati , Pandey Ravindra , Shukla Shiv Shankar
Published: January 2022

Background

A stability-indicating method (SIM) stipulates the testing of the drug product and drug substances under the stressed conditions that will imply a clear notion about the stress conditions that would affect the drug in its finished dosage form. Furthermore, manufactures can clearly define the state at which the drug is unstable and present its storage conditions.

Objective

The present article deals with the stability testing and degradation kinetic studies of desloratadine (DL).

Method

The method of analysis was UV visible spectroscopy, which is a most convenient and reliable method for the analyst. A method was developed and validated according to the ICH Q2 guidelines along with the amendment in 2018 (ICH Q14).

Results

The study denotes that the drug is extremely unstable in the presence of dry heat and then follows the oxidative and basic degradations. The acidic, neutral, and photolysis did not show notable degradations.

Conclusions

The chemical kinetic studies were carried out to more clearly understand the mechanism of degradation and to present the order of reaction, rate of reaction, and reaction half-time.

Highlights

The application of a spectrophotometric method in the development of a SIM and study of degradation kinetics is much handier and cost-effective.
Rapid and Quantitative Analysis of Aflatoxin M1 From Milk Using Atmospheric Pressure—Matrix Assisted Laser Desorption/Ionization (AP-MALDI)-Triple Quadrupole Selected Reaction Monitoring
Authors: Mahale Vishal , Gupta Madhuri , Dhanshetty Manisha , Chawan Subodh , Moskovets Eugene , Banerjee Kaushik , Bhattacharya Nivedita , Panchagnula Venkateswarlu
Published: January 2022

Background

Aflatoxin M1 (AFM1) is a carcinogenic hydroxylated metabolite commonly found in milk. It is relatively stable toward decontamination procedures posing a major health risk, and it requires an international regulatory mandate of detection at trace levels.

Objective

To develop a high-throughput, reliable, and compliant method for the identification of AFM1 in milk samples using atmospheric pressure—matrix assisted laser desorption/ionization (AP-MALDI) selected reaction monitoring (SRM) quantitation.

Method

The milk sample was diluted in water and cleaned with immunoaffinity chromatography (IAC), followed by analysis using AP-MALDI hyphenated with a triple quadrupole mass spectrometer for SRM.

Results

A fast and reliable AP-MALDI SRM quantitative method was developed for the determination of AFM1 with analysis time of 1 min per sample. The diagnostic product ions of AFM1 at 273.1 u and 229.2 u were monitored during the SRM. The calibration curves yielded excellent linearity (R2 = 0.99) with good recoveries for quality control samples (97–106%). The ion ratios of the qualifier to quantifier displayed excellent RSD (1–7.8%) for n = 3.

Conclusions

The developed method provided rapid quantification for AFM1. The fast AP-MALDI SRM method can allow analysis of AFM1 in a large number of milk samples. Given the time required for analysis, cost-effectiveness, and superior analytical performance, this method can be adopted in commercial food testing laboratories.

Highlights

Aflatoxins (AF) are a major health risk. Speedy analysis of large sample sizes from food is a risk mitigation strategy but remains an unmet need. Quantitative, chromatography-free, and internal standard-free AP-MALDI SRM based analysis of AF is a high-throughput and cost-efficient alternative. Satisfactory performance was achieved for quantitative AP-MALDI SRM analysis of AFM1 in milk subsequent to a simple sample clean-up step.
Effectiveness of Steinernema rarum PAM 25 (Rhabditida: Steinernematidae) Against Drosophila suzukii (Diptera: Drosophilidae)
Authors: dos Santos José Junior , de Brida Andressa Lima , Jean-Baptiste Maguintontz Cedney , Bernardi Daniel , Wilcken Silvia Renata Siciliano , Leite Luís Garrigós , Garcia Flavio Roberto Mello
Published: January 2022

Drosophila suzukii (Matsumura 1931) represents one of the main pests of small fruits. The use of biological agents is very promising for insect control. In the present study, the nematode Steinernema rarum PAM 25 was evaluated for the control of D. suzukii pupae, this species has not been evaluated previously. First, we evaluated the pathogenicity of S. rarum PAM 25 at the concentration of 1,000 infective juveniles (IJs) inoculated into D. suzukii pupae. In the second bioassay, we evaluated the influence of 1,500; 2,000; 2,500; 3,000; 4,000 IJs/ml nematode concentration and temperature on D. suzukii mortality. In the third bioassay, we evaluated the influence of the isolate S. rarum PAM 25 on D. suzukii adult lifespan following pupal infection, using the concentrations with the highest mortality rate of pupae at each temperature as determined in the second experiment. The S. rarum PAM 25 isolate is pathogenic to D. suzukii. The most effective temperature for S. rarum PAM 25 activity was 14°C at a concentration of 4,000 IJs/ml. Adults infected with S. rarum PAM 25 showed a significant reduction in longevity. The results confirmed the potential of S. rarum PAM 25 for the control of D. suzukii.
Likelihood of Extreme Early Flight of Myzus persicae (Hemiptera: Aphididae) Across the UK
Authors: Hemming Deborah , Bell James , Collier Rosemary , Dunbar Tyrone , Dunstone Nick , Everatt Matthew , Eyre Dominic , Kaye Neil , Korycinska Anastasia , Pickup Jon , Scaife Adam A
Published: January 2022

Myzus persicae (Sulzer, Hemiptera: Aphididae) is a major global crop pest; it is the primary aphid vector for many damaging viruses and has developed resistance to most insecticides. In temperate regions, the risk of widespread crop infection and yield loss is heightened following warm winters, which encourage rapid population growth and early flight. Estimates of the frequency and magnitude of warm winters are, therefore, helpful for understanding and managing this risk. However, it is difficult to quantify the statistical distribution of climate events, particularly extremes, because climate observations represent just a small sample of the possible climate variations in a region. The purpose of this study was to establish a large-scale relationship between temperature and M. persicae observations across the UK and apply this to a very large ensemble of climate model simulations, which better sample the variability in climate, to quantify the current likelihood of extreme early M. persicae flight across the UK. The timing of M. persicae flight was shown to be significantly related to January-February mean temperature, where a 1°C warmer/cooler temperature relates to about 12 d earlier/later flight. Climate model simulations predict 40% likelihood of experiencing a year with unprecedented early M. persicae flight during the next decade in the UK. Results from this method can help crop managers assess the long-term viability of crops and management practices across the UK and provide early warning information for targeting pest surveillance activities on the locations and timings at highest risk of early M. persicae flight.
Optimizing Spinosyn Insecticide Applications for Allium Leafminer (Diptera: Agromyzidae) Management in Allium Crops
Authors: Nault Brian A , Sandhi Ramandeep K , Harding Riley S , Grundberg Ethan A , Rusinek Teresa
Published: January 2022

Allium leafminer, Phytomyza gymnostoma Loew (Diptera: Agromyzidae), is an invasive pest of allium crops in North America. Spinosyn insecticides, spinetoram and spinosad, have been effective choices for managing P. gymnostoma infestations in allium crops, but their use should be optimized for economical and resistance management purposes. In New York from 2018 through 2020, performance of each spinosyn insecticide was evaluated by making two applications spaced either 1 or 2 wk apart beginning at various intervals after P. gymnostoma was first detected in the field; a weekly spray program also was included. Results indicated that weekly applications of each spinosyn insecticide provided ≥98% reduction of P. gymnostoma densities in scallions and leeks relative to the untreated control. Spinetoram applied twice, regardless of initial timing and duration between sprays, provided an acceptable level of P. gynostoma control (71 to 98% reduction in densities relative to the untreated control). Spinosad also was effective when applied twice (85 to 95% reduction in densities relative to the untreated control), but not when sprays were made consecutively beginning when P. gymnostoma was first detected and not when the P. gymnostoma infestation was extremely high (i.e., 38 insects per plant in the untreated control). Management of P. gymnostoma with spinosyns can be successful with only two applications, but control tended to be best when first applied 2 to 3 wk after initial detection. Optimizing applications of spinetoram and spinosad will save growers time, reduce insecticide costs, and mitigate resistance development without significantly increasing the risk of yield reduction.
A History of Health Economics and Healthcare Delivery Research at the National Cancer Institute
Authors: Doria-Rose V Paul , Breen Nancy , Brown Martin L , Feuer Eric J , Geiger Ann M , Kessler Larry , Lipscomb Joseph , Warren Joan L , Yabroff K Robin
Published: January 2022

With increased attention to the financing and structure of healthcare, dramatic increases in the cost of diagnosing and treating cancer, and corresponding disparities in access, the study of healthcare economics and delivery has become increasingly important. The Healthcare Delivery Research Program (HDRP) in the Division of Cancer Control and Population Sciences at the National Cancer Institute (NCI) was formed in 2015 to provide a hub for cancer-related healthcare delivery and economics research. However, the roots of this program trace back much farther, at least to the formation of the NCI Division of Cancer Prevention and Control in 1983. The creation of a division focused on understanding and explaining trends in cancer morbidity and mortality was instrumental in setting the direction of cancer-related healthcare delivery and health economics research over the subsequent decades. In this commentary, we provide a brief history of health economics and healthcare delivery research at NCI, describing the organizational structure and highlighting key initiatives developed by the division, and also briefly discuss future directions. HDRP and its predecessors have supported the growth and evolution of these fields through the funding of grants and contracts; the development of data, tools, and other research resources; and thought leadership including stimulation of research on previously understudied topics. As the availability of new data, methods, and computing capacity to evaluate cancer-related healthcare delivery and economics expand, HDRP aims to continue to support this growth and evolution.
Nitrogen addition overrides the effects ofStellera chamaejasmelitter on the growth ofLeymus chinensisand its associated mycorrhizal fungi
Authors: Guo Qiang , Zhang Ruo-Hui , Li Xue-Li , Liu Xiao-Wei , Li Ya-Nan , Xing Fu
Published: January 2022

Rapid spread and growth of plants that are poisonous to animals produce large amounts of plant litter in degraded grasslands. Nitrogen (N) input may promote the growth of these poisonous plants and alter the rhizosphere microbes and arbuscular mycorrhizal fungi (AMF) in particular. However, it is unclear how poisonous plant litter affects the growth of palatable plants and their associated AMF in the rhizosphere and whether and how N deposition may mediate these effects. A greenhouse experiment was performed to test the combined effects of litter addition of a poisonous plant, Stellera chamaejasme, and N addition on the growth of a dominant grass, Leymus chinensis, AMF characteristics and soil properties. Litter addition significantly increased the ramet number and aboveground biomass of L. chinensis and soil available phosphorus (AP) concentration and decreased the spore density of AMF. However, the interaction of both treatments had no significant effects on traits of L. chinensis and AMF properties. Stellera chamaejasme litter positively affected L. chinensis by increasing AP and negatively affected AMF by combining balanced changes in soil nutrients and litter-induced allelopathic compositions. High N addition may alleviate soil N limitation and inhibit litter decomposition, thus overriding the litter’s effects on L. chinensis and AMF. These findings imply that it is necessary to objectively and comprehensively evaluate the ecological functions of poisonous plants beyond their harmful effects on livestock. Simultaneously, N deposition should be an indispensable factor in predicting the relationships between poisonous plants and edible plants in degraded grasslands.
Evaluation of general practice pharmacists’ role by key stakeholders in England and Australia
Authors: Akhtar Noshad , Hasan Syed Shahzad , Babar Zaheer-Ud-Din
Published: January 2022

Objectives

This study aims to measure expectations and perceptions about the general practice pharmacists’ (GPPs) roles in England and Australia.

Methods

The study is based on the interviews conducted with key stakeholders from England and Australia, including general practitioners, nurses, GPPs, organizational lead and academics. There were a total of 14 participants, 7 each from England and Australia. The participants were involved in a semi-structured, audio-recorded interview, which was later transcribed verbatim, coded and underwent a thematic analysis to extract the general themes, raised by participants’ views and experiences about GPPs’ role.

Key findings

From the transcribed data, the main themes extracted were initial expectations and reservations by key stakeholders, barriers and facilitators, working collaboration, GPPs’ skillset, views on key performance indicators (KPIs), patients’ feedback and the stakeholders’ views on the future of GPPs in England and Australia. The participants from both England and Australia did acknowledge the growing role of GPPs. Few concerns were raised by some participants about aspects like role description, training pathways, prescribing protocols and funding. Despite these concerns, all participants strongly believed that by taking steps to overcome main barriers like funding in Australia and training pathways in England, GPPs could be an ideal professional to bridge the gaps in the general practice framework.

Conclusions

GPPs could be an ideal professional to bridge the gaps in the general practice framework, but steps need to be taken to overcome barriers. Based on the comparative data, recommendations were made on funding structure, role description, prescribing qualification, training pathways and KPIs. These recommendations can be used as guidance for both England and Australia while implementing relative policies in these countries.
A rare case of advanced sinonasal adenoid cystic carcinoma with intracranial and intradural extension
Authors: Rassam Joseph , Sood Tarun
Published: January 2022

Adenoid cystic carcinoma (ACC) is a rare cancer of the head and neck that primarily occurs in the salivary glands. Sino-nasal ACC (SNACC) is a much rarer entity; this paper presents an exceedingly rare case of SNACC with both intracranial and intradural extension which was ultimately treated with palliative radiotherapy due to its extensive invasion. In addition to this, a review of the literature has been performed to delineate specific learning points for the management of intracranial SNACC.
Iron in leaves: chemical forms, signalling, and in-cell distribution
Authors: Sági-Kazár Máté , Solymosi Katalin , Solti Ádám
Published: January 2022

Iron (Fe) is an essential transition metal. Based on its redox-active nature under biological conditions, various Fe compounds serve as cofactors in redox enzymes. In plants, the photosynthetic machinery has the highest demand for Fe. In consequence, the delivery and incorporation of Fe into cofactors of the photosynthetic apparatus is the focus of Fe metabolism in leaves. Disturbance of foliar Fe homeostasis leads to impaired biosynthesis of chlorophylls and composition of the photosynthetic machinery. Nevertheless, mitochondrial function also has a significant demand for Fe. The proper incorporation of Fe into proteins and cofactors as well as a balanced intracellular Fe status in leaf cells require the ability to sense Fe, but may also rely on indirect signals that report on the physiological processes connected to Fe homeostasis. Although multiple pieces of information have been gained on Fe signalling in roots, the regulation of Fe status in leaves has not yet been clarified in detail. In this review, we give an overview on current knowledge of foliar Fe homeostasis, from the chemical forms to the allocation and sensing of Fe in leaves.
Five young δ Scuti stars in the Pleiades seen with Kepler/K2
Authors: Murphy Simon J , Bedding Timothy R , White Timothy R , Li(李亚光) Yaguang , Hey Daniel , Reese Daniel , Joyce Meridith
Published: January 2022

We perform mode identification for five δ Scuti stars in the Pleiades star cluster, using custom light curves from K2 photometry. By creating échelle diagrams, we identify radial and dipole mode ridges, comprising a total of 28 radial and 16 dipole modes across the five stars. We also suggest possible identities for those modes that lie offset from the radial and dipole ridges. We calculate non-rotating stellar pulsation models to verify our mode identifications, finding good agreement within the age and metallicity constraints of the cluster. We also find that for all stars, the least dense models are preferred, reflecting the lower density of these oblate, rotating stars. Three of the five stars show rotationally split multiplets. We conclude that the sample shows promise for asteroseismic rotation rates, masses, and ages with rotating models in the future. Our preliminary modelling also indicates some sensitivity to the helium abundance.
Starquakes in millisecond pulsars and gravitational waves emission
Authors: Giliberti E , Cambiotti G
Published: January 2022

So far, only transient gravitational waves (GWs) produced by catastrophic events of extra-galactic origin have been detected. However, it is generally believed that there should be also continuous sources of GWs within our Galaxy, such as accreting neutron stars (NSs), that could in principle be detected in the next near future. In fact, in these objects, centrifugal forces can be so strong to break the NS crust (causing a starquake), thus producing a quadrupole moment responsible for the continuous emission of GWs. At equilibrium, the angular momentum gained by accretion and the one lost via GWs emission should balance each other, stopping the stellar spin-up. We hereinafter investigate the above physical picture within the framework of a Newtonian model describing compressible, non-magnetized, and self-gravitating NSs. In particular, we calculate the rotational frequency need to break the stellar crust of an accreting pulsar and we estimate the upper limit for the ellipticity due to this event. We find that the maximum starquake-induced ellipticity ranges from 10−9 to 10−5, depending on the stellar mass and its equation of state. The corresponding equilibrium frequency that we calculate is in good agreement with observations and, for all the scenarios, it is below the higher NS frequency observed of 716.36 Hz. Finally, we also discuss possible observational constraints on the ellipticity upper limit of accreting pulsars.
The present-day globular cluster kinematics of lenticular galaxies from the E-MOSAICS simulations and their relation to the galaxy assembly histories
Authors: Dolfi Arianna , Pfeffer Joel , Forbes Duncan A , Couch Warrick J , Bekki Kenji , Brodie Jean P , Romanowsky Aaron J , Kruijssen J M Diederik
Published: January 2022

We study the present-day rotational velocity (Vrot) and velocity dispersion (σ) profiles of the globular cluster (GC) systems in a sample of 50 lenticular (S0) galaxies from the E-MOSAICS galaxy formation simulations. We find that $82{{\ \rm per\ cent}}$ of the galaxies have GCs that are rotating along the photometric major axis of the galaxy (aligned), while the remaining $18{{\ \rm per\ cent}}$ of the galaxies do not (misaligned). This is generally consistent with the observations from the SLUGGS survey. For the aligned galaxies, classified as peaked and outwardly decreasing ($49{{\ \rm per\ cent}}$), flat ($24{{\ \rm per\ cent}}$), and increasing ($27{{\ \rm per\ cent}}$) based on the Vrot/σ profiles out to large radii, we do not find any clear correlation between these present-day Vrot/σ profiles of the GCs and the past merger histories of the S0 galaxies, unlike in previous simulations of galaxy stars. For just over half of the misaligned galaxies, we find that the GC misalignment is the result of a major merger within the last $10\, \mathrm{Gyr}$ so that the ex-situ GCs are misaligned by an angle between 0° (co-rotation) and 180° (counter-rotation), with respect to the in situ GCs, depending on the orbital configuration of the merging galaxies. For the remaining misaligned galaxies, we suggest that the in situ metal-poor GCs, formed at early times, have undergone more frequent kinematic perturbations than the in situ metal-rich GCs. We also find that the GCs accreted early and the in situ GCs are predominantly located within 0.2 virial radii (R200) from the centre of galaxies in 3D phase-space diagrams.
A2B-COVID: A Tool for Rapidly Evaluating Potential SARS-CoV-2 Transmission Events
Authors: Illingworth Christopher J R , Hamilton William L , Jackson Christopher , Warne Ben , Popay Ashley , Meredith Luke , Hosmillo Myra , Jahun Aminu , Fieldman Tom , Routledge Matthew , Houldcroft Charlotte J , Caller Laura , Caddy Sarah , Yakovleva Anna , Hall Grant , Khokhar Fahad A , Feltwell Theresa , Pinckert Malte L , Georgana Iliana , Chaudhry Yasmin , Curran Martin , Parmar Surendra , Sparkes Dominic , Rivett Lucy , Jones Nick K , Sridhar Sushmita , Forrest Sally , Dymond Tom , Grainger Kayleigh , Workman Chris , Gkrania-Klotsas Effrossyni , Brown Nicholas M , Weekes Michael P , Baker Stephen , Peacock Sharon J , Gouliouris Theodore , Goodfellow Ian , Angelis Daniela De , Török M Estée
Published: January 2022

Identifying linked cases of infection is a critical component of the public health response to viral infectious diseases. In a clinical context, there is a need to make rapid assessments of whether cases of infection have arrived independently onto a ward, or are potentially linked via direct transmission. Viral genome sequence data are of great value in making these assessments, but are often not the only form of data available. Here, we describe A2B-COVID, a method for the rapid identification of potentially linked cases of COVID-19 infection designed for clinical settings. Our method combines knowledge about infection dynamics, data describing the movements of individuals, and evolutionary analysis of genome sequences to assess whether data collected from cases of infection are consistent or inconsistent with linkage via direct transmission. A retrospective analysis of data from two wards at Cambridge University Hospitals NHS Foundation Trust during the first wave of the pandemic showed qualitatively different patterns of linkage between cases on designated COVID-19 and non-COVID-19 wards. The subsequent real-time application of our method to data from the second epidemic wave highlights its value for monitoring cases of infection in a clinical context.
Endogenous retroviruses co-opted as divergently transcribed regulatory elements shape the regulatory landscape of embryonic stem cells
Authors: Bakoulis Stylianos , Krautz Robert , Alcaraz Nicolas , Salvatore Marco , Andersson Robin
Published: January 2022

Transposable elements are an abundant source of transcription factor binding sites, and favorable genomic integration may lead to their recruitment by the host genome for gene regulatory functions. However, it is unclear how frequent co-option of transposable elements as regulatory elements is, to which regulatory programs they contribute and how they compare to regulatory elements devoid of transposable elements. Here, we report a transcription initiation-centric, in-depth characterization of the transposon-derived regulatory landscape of mouse embryonic stem cells. We demonstrate that a substantial number of transposable element insertions, in particular endogenous retroviral elements, are associated with open chromatin regions that are divergently transcribed into unstable RNAs in a cell-type specific manner, and that these elements contribute to a sizable proportion of active enhancers and gene promoters. We further show that transposon subfamilies contribute differently and distinctly to the pluripotency regulatory program through their repertoires of transcription factor binding site sequences, shedding light on the formation of regulatory programs and the origins of regulatory elements.
Off-the-shelf, steroid-resistant, IL13Rα2-specific CAR T cells for treatment of glioblastoma
Authors: Brown Christine E , Rodriguez Analiz , Palmer Joycelynne , Ostberg Julie R , Naranjo Araceli , Wagner Jamie R , Aguilar Brenda , Starr Renate , Weng Lihong , Synold Timothy W , Tran Vivi , Wang Shelley , Reik Andreas , D’Apuzzo Massimo , Ressler Julie A , Zhou Yuanyue , Mendel Matthew , Gregory Philip D , Holmes Michael C , Tang Winson W , Forman Stephen J , Jensen Michael C , Badie Behnam
Published: January 2022

Background

Wide-spread application of chimeric antigen receptor (CAR) T cell therapy for cancer is limited by the current use of autologous CAR T cells necessitating the manufacture of individualized therapeutic products for each patient. To address this challenge, we have generated an off-the-shelf, allogeneic CAR T cell product for the treatment of glioblastoma (GBM), and present here the feasibility, safety, and therapeutic potential of this approach.

Methods

We generated for clinical use a healthy-donor derived IL13Rα2-targeted CAR+ (IL13-zetakine+) cytolytic T-lymphocyte (CTL) product genetically engineered using zinc finger nucleases (ZFNs) to permanently disrupt the glucocorticoid receptor (GR) (GRm13Z40-2) and endow resistance to glucocorticoid treatment. In a phase I safety and feasibility trial we evaluated these allogeneic GRm13Z40-2 T cells in combination with intracranial administration of recombinant human IL-2 (rhIL-2; aldesleukin) in six patients with unresectable recurrent GBM that were maintained on systemic dexamethasone (4-12 mg/day).

Results

The GRm13Z40-2 product displayed dexamethasone-resistant effector activity without evidence for in vitro alloreactivity. Intracranial administration of GRm13Z40-2 in four doses of 108 cells over a two-week period with aldesleukin (9 infusions ranging from 2500–5000 IU) was well tolerated, with indications of transient tumor reduction and/or tumor necrosis at the site of T cell infusion in four of the six treated research subjects. Antibody reactivity against GRm13Z40-2 cells was detected in the serum of only one of the four tested subjects.

Conclusions

This first-in-human experience establishes a foundation for future adoptive therapy studies using off-the-shelf, zinc-finger modified, and/or glucocorticoid resistant CAR T cells.
Safety and Tolerability of Carboplatin and Paclitaxel in Cancer Patients with HIV (AMC-078), an AIDS Malignancy Consortium (AMC) Study
Authors: Haigentz Missak , Moore Page , Bimali Milan , Cooley Timothy , Sparano Joseph , Rudek Michelle , Ratner Lee , Henry David , Ramos Juan , Deeken John , Rubinstein Paul , Chiao Elizabeth
Published: January 2022

Background

Persons living with human immunodeficiency virus are an underserved population for evidence-based cancer treatment. Paclitaxel and carboplatin (PCb) is an active regimen against a variety of solid tumors, including several seen in excess in patients with HIV infection. We performed a pilot trial to evaluate the safety of full-dose PCb in people living with human immunodeficiency virus and cancer.

Methods

Eligible patients, stratified by concurrent antiretroviral therapy (ART) that included CYP3A4 inhibitors or not, received paclitaxel (175 mg/m2) in combination with carboplatin (target AUC 6) intravenously every 3 weeks for up to 6 cycles.

Results

Sixteen evaluable patients received 64 cycles of PCb, including 6 patients treated with CYP3A4 inhibiting ART (ritonavir). The adverse event profile was consistent with the known toxicity profile of PCb, with no differences between the 2 strata. There were 4 partial responses (25%, 95% CI: 7%-52%), and overall, CD4+ lymphocyte count was similar after completion of therapy (median: 310/μL) compared with baseline values (median: 389/μL). Pharmacokinetic studies in 6 patients revealed no significant differences in Cmax or AUCinf for paclitaxel between the 2 cohorts.

Conclusion

Full doses of PCb chemotherapy are tolerable when given concurrently with ART in people living with human immunodeficiency virus with cancer, including patients receiving CYP3A4 inhibitors.

ClinicalTrials.gov Identifier

NCT01249443.
Impact of the COVID-19 Pandemic on Management of Patients with Metastatic Pancreatic Ductal Adenocarcinoma in the United States
Authors: Paluri Ravi , Laursen Ashley , Gaeta Joseph , Wang Shu , Surinach Andy , Cockrum Paul
Published: January 2022

Background

The purpose of this study was to understand how the COVID-19 pandemic has affected health care patterns and outcomes for patients diagnosed with metastatic pancreatic ductal adenocarcinoma (mPDAC) in 2020 compared with those diagnosed with mPDAC in 2019.

Patients and Methods

We used the Flatiron Health database to identify adults diagnosed with mPDAC from March 1 to September 30, 2019 (pre-COVID-19 cohort) and March 1 to September 30, 2020 (post-COVID-19 cohort). Between-cohort comparisons included demographic and clinical characteristics and year-over-year data for diagnosis of mPDAC, newly treated patients, time to and types of first-line therapy, and adverse events (AEs) during first-line therapy. Overall survival (OS) and milestone survival rates were evaluated. Kaplan-Meier methods were used to assess OS.

Results

Pre-COVID-19 (n = 923) and post-COVID-19 (n = 796) cohorts had similar baseline demographic characteristics. A smaller proportion of patients in the pre-COVID-19 cohort were initially diagnosed with stage IV disease versus the post-COVID-19 cohort (62.2% vs 69.7%). Between 2019 and 2020, there was a 13.8% decrease in diagnosis of mPDAC and a 13.0% decrease in newly treated patients. Median (interquartile range) times to first-line treatment were similar (21 [13-40] and 19 [12-32] days). Median OS (months) was significantly longer in the pre-COVID-19 cohort (8·4 [95% CI: 7·5, 9·0]) versus the post-COVID-19 cohort (6·1 [95% CI: 5·4, 6·9]; P < .001). Survival rates were higher in the pre-COVID-19 versus post-COVID-19 cohorts.

Conclusions

During the pandemic, patients were initially diagnosed with PDAC at more advanced stages. While patients in both cohorts appeared to receive similar care, survival outcomes were adversely affected.
Does R&D tax credit impact firm behaviour? Micro evidence for Portugal
Authors: Paredes Alexandre , Mendonça Joana , Bação Fernando , Damásio Bruno
Published: January 2022

In this study, we use panel data to analyse the impact of an R&D tax credit on R&D personnel, particularly the impact on Ph.D. holders allocation, comparing low R&D intensity firms with medium-high and high R&D intensity firms. The results show that, in medium-high and high R&D intensity firms, the R&D tax credit had a significant impact on allocating Ph.D. holders in firms after 3 years of participation in the tax incentive scheme. We use a database covering 7,710 firms that performed R&D at least once in Portugal over the 23-year period 1995 to 2017, provided by the official business R&D survey data and a database of firms that applied for tax credit incentives at least once in the same period. Based on the estimation of impulse-response functions by local projections, we assess the impact of introducing the tax incentive scheme for corporate R&D in firms from different R&D intensity sectors.
Conversion of the MDHAQ to the HAQ score: a simple algorithm developed and validated in a cohort of 13 391 real-world patients
Authors: Ørnbjerg Lykke M , Svensson Elisabeth , Løngaard Katja , Meincke Rikke H , Pedersen Jens Kristian , Dreyer Lene , Krogh Niels Steen , Jensen Dorte V , Hetland Merete L
Published: January 2022

Objectives

To develop and validate in real-world patients a conversion algorithm from the Multidimensionel Health Assessment Questionnaire physical function scale (MDHAQ) to the Stanford Health Assessment Questionnaire disability index physical function scale (HAQ) score.

Methods

From the DANBIO registry, 13 391 patients with RA (n = 8983), PsA (n = 2649) and axial spondyloarthritis (axSpA, n = 1759) with longitudinal data on HAQ and MDHAQ were included, stratified by diagnosis, and randomized 1:1 into development and validation cohorts. Conversion algorithms were developed by linear regression and applied in validation cohorts. From MDHAQ, the HAQ was calculated (cHAQ) and validated against the observed HAQ for criterion, correlational and construct validity.

Results

For RA, we developed the conversion algorithm cHAQ = 0.15+MDHAQ*1.08, and validated it in the RA validation cohort. Criterion validity: HAQ and cHAQ had comparable discriminative power to distinguish between high and low patient global scores (standardized mean difference: HAQ:–1.29, cHAQ:–1.35). Kappa value between HAQ and cHAQ functional states indicated good agreement (0.83). Correlational validity: baseline HAQ and cHAQ, respectively, correlated well with patient global scores (r = 0.65/0.67). Bland–Altman plots showed good agreement across all functional states. Construct validity: HAQ and cHAQ discriminated equally well between patients reporting symptom state as acceptable vs not, and across responses to an external anchor. Aiming for a common algorithm, the RA conversion algorithm was validated for PsA and axSpA with similar results.

Conclusion

This study suggests that in observational datasets with only the MDHAQ available, a simple algorithm allows valid conversion to HAQ on the group level in RA, PsA and axSpA.
Effects of transcranial direct current stimulation over the right dorsolateral prefrontal cortex on fairness-related decision-making
Authors: Hu Xinmu , Zhang Yu , Liu Xiaoqing , Guo Yunfei , Liu Chao , Mai Xiaoqin
Published: January 2022

Neuroimaging studies suggest that the right dorsolateral prefrontal cortex (rDLPFC) is an important brain area involved in fairness-related decision-making. In the present study, we used transcranial direct current stimulation (tDCS) over the rDLPFC to investigate the effects of changed cortical excitability on fairness norm enforcement in social decision-making. Participants received anodal, cathodal or sham stimulation before performing a modified ultimatum game task, in which participants were asked to accept or reject the proposer’s offer and self-rate the intensity of their anger at offers on a 7-point scale. The results showed that the rejection rate of unfair offers and anger level were higher in the anodal compared to the sham and cathodal groups and that the level of anger at unfair offers can predict the rejection rate. Furthermore, the fairness effect of RTs was more prominent in the anodal group than in the sham and cathodal groups. Our findings validate the causal role of the rDLPFC in fairness-related decision-making through tDCS, suggesting that strengthening the rDLPFC increases individuals’ reciprocal fairness in social decision-making, both in subjective rating and behaviors.
Mine or ours? Neural basis of the exploitation of common-pool resources
Authors: Martinez-Saito Mario , Andraszewicz Sandra , Klucharev Vasily , Rieskamp Jörg
Published: January 2022

Why do people often exhaust unregulated common (shared) natural resources but manage to preserve similar private resources? To answer this question, in this study we combine a neurobiological, economic and cognitive modeling approach. Using functional magnetic resonance imaging on 50 participants, we show that a sharp decrease of common and private resources is associated with deactivation of the ventral striatum, a brain region involved in the valuation of outcomes. Across individuals, when facing a common resource, ventral striatal activity is anticorrelated with resource preservation (less harvesting), whereas with private resources the opposite pattern is observed. This indicates that neural value signals distinctly modulate behavior in response to the depletion of common vs private resources. Computational modeling suggested that overharvesting of common resources was facilitated by the modulatory effect of social comparison on value signals. These results provide an explanation of people’s tendency to over-exploit unregulated common natural resources.
Cadmium Suppresses Bone Marrow Thrombopoietin Production and Impairs Megakaryocytopoiesis in Mice
Authors: Zhao Yifan , Zhang Yufan , He Jinyi , Zhai Yue , Yang Guangrui , Xue Peng , Yao Ye , He Miao , Qu Weidong , Zhang Yubin
Published: January 2022

Cadmium (Cd) is a highly toxic heavy metal in our environment. The influence of Cd on the development of platelets, or megakaryocytopoiesis, remains to be defined. The aim of this study was to investigate the impact of Cd on megakaryocytopoiesis. C57BL/6 (B6) mice aged 6–8 weeks were treated with 10 ppm Cd via drinking water or control for 3 months, and megakaryocytopoiesis was evaluated thereafter. Mice treated with Cd had a decreased number of platelets in the blood, which was associated with the reduced number of megakaryocyte progenitors (MkP) and megakaryocytes (MK) in the bone marrow (BM). Functional analyses indicate that Cd treatment impaired the proliferation and differentiation of MkP as well as the maturation of MK in the BM, suggesting that Cd treatment impeded megakaryocytopoiesis. Intriguingly, the impaired megakaryocytopoiesis in the BM of mice treated with Cd was not caused by increased apoptosis of MkP. Moreover, in vitro treatment of MkP with Cd did not impact their proliferation or differentiation, indicating that the impeded megakaryocytopoiesis in the BM of mice was likely not caused by direct action of Cd on MkP. On the other hand, Cd treatment selectively suppressed thrombopoietin (TPO) production in the BM and decreased the cellular myelocytomatosis oncogene signaling in MkP, thus likely leading to the impeded megakaryocytopoiesis in the BM and thrombocytopenia in the blood of mice. This study revealed a previously unrecognized hematopoietic toxicity of Cd, which may extend our current understanding of Cd toxicity.
Late-day measurement of excised branches results in uncertainty in the estimation of two stomatal parameters derived from response curves inPopulus deltoidesBartr. × Populus nigraL.
Authors: Davidson Kenneth J , Lamour Julien , Rogers Alistair , Serbin Shawn P
Published: January 2022

Many terrestrial biosphere models depend on an understanding of the relationship between stomatal conductance and photosynthesis. However, unlike the measurement of photosynthetic parameters, such as the maximum carboxylation capacity, where standard methods (e.g., CO2 response or ACi curves) are widely accepted, a consensus method for empirically measuring parameters representing stomatal response has not yet emerged. Most models of stomatal response to environment represent stomatal conductance as being bounded by a lower intercept parameter (g0), and linearly scaled based on a multivariate term described by the stomatal slope parameter (g1). Here we employ the widely used Unified Stomatal Optimization model, to test whether g1 and g0 parameters are impacted by the choice of measurement method, either on an intact branch or a cut branch segment stored in water. We measured paired stomatal response curves on intact and excised branches of a hybrid poplar clone (Populus deltoides Bartr. × Populus nigra L. OP367), measured twice over a diurnal period. We found that predawn branch excision did not significantly affect measured g0 and g1 when measured within 4 h of excision. Measurement in the afternoon resulted in significantly higher values of g1 and lower values of g0, with values changing by 55% and 56%, respectively. Excision combined with afternoon measurement resulted in a marked effect on parameter estimates, with g1 increasing 89% from morning to afternoon and a 25% lower g1 for cut branches than those measured in situ. We also show that in hybrid poplar the differences in parameter estimates obtained from plants measured under different conditions can directly impact models of canopy function, reducing modeled transpiration by 18% over a simulated 12.5-h period. Although these results are only for a single isohydric woody species, our findings suggest that stomatal optimality parameters may not remain constant throughout the day.
Decisions under the law of European Union: ‘You May Be Six People, But I Love You’
Authors: Cherubini Francesco
Published: January 2022

This article analyses one of the most recurrent and flexible acts in the system of sources of EU law: decisions. After a brief introduction, the second part is devoted to a reconstruction of the general categories of classification of legal acts of the Union. The third part proposes a general classification scheme. The fourth part analyses typical decisions: those of individual application and those of general application. Part Five examines and classifies decisions of atypical nature. The article concludes with a few final considerations.
A Novel Patient-specific Titanium Mesh Implant Design for Reconstruction of Complex Orbital Fracture
Authors: Kittichokechai Pakaporn , Sirichatchai Kanin , Puncreobutr Chedtha , Lohwongwatana Boonrat , Saonanon Preamjit
Published: January 2022

Background:

Complex orbital fractures, including orbital rims and walls, require precise reconstruction. A titanium-based patient-specific implant (PSI) benefits over other implants when challenged with narrow surgical space and designable implant fixation point.

Methods:

This is a prospective noncomparative case series to evaluate the effect of complex orbital reconstruction using the newly designed lateral fixation patient-specific implant. The PSI was individually fabricated by 3D reconstruction using the mirrored nonaffected orbit as a template. The fixation point was at maxillary or zygomatic bone, depending on the bony remnant. Outcomes were obtained from computed tomography scan to compare orbital tissue volume and exophthalmometry value by posterior clinoid method before and after the surgery and also between both orbits in each patient.

Results:

Sixteen patients with complex orbital fracture with inferior orbital rim defect were enrolled. Seven were previously repaired with other implants. Compared with the preoperative measurement, the postoperative mean difference of orbital volume and exophthalmometry value between both eyes was significantly decreased (reduction of the mean difference of 2904.40 mm3; P < 0.001 and 2.89 mm; P < 0.001, respectively). The mean orbital volume and exophthalmometry value between affected and unaffected eyes were not different after surgical correction (P = 0.57 and P = 0.28, respectively). There was one infected wound from retained foreign body and one unresolved vertical diplopia after the reconstruction.

Conclusions:

Reconstruction of complex orbital fractures using the novel designed-PSI had excellent outcomes. Appropriate implant design with caution of orbital anatomy and placement techniques are keys for successful results.