bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional analysis of the ScAG and ScAGL11 MADS-box transcription factors for anthocyanin biosynthesis and bicolour pattern formation inSenecio cruentusray florets
Authors: Qi Fangting , Liu Yuting , Luo Yiliu , Cui Yumeng , Lu Chenfei , Li Hao , Huang He , Dai Silan
Published: March 2022

Cineraria (Senecio cruentus) is an ornamental plant with pure colour and bicolour cultivars, widely used for landscaping. Anthocyanin biosynthesis influences coloration patterns in cineraria. However, how anthocyanins accumulate and distribute in cineraria is poorly understood. This study investigated the molecular mechanisms underlying anthocyanin biosynthesis and bicolour formation in cineraria using pure colour and bicolour cultivars. Transcriptome and gene expression analysis showed that five genes, ScCHS2, ScF3H1, ScDFR3, ScANS, and ScbHLH17, were inhibited in the white cultivar and colourless regions of bicolour cultivars. In contrast, two MADS-box genes, ScAG and ScAGL11, showed significantly higher expression in the colourless regions of bicolour cultivars. ScAG and ScAGL11 were localized in the nucleus and co-expressed with the bicolour trait. Further functional analysis verified that ScAG inhibits anthocyanin accumulation in tobacco (Nicotiana tabacum). However, virus-induced gene silencing (VIGS) experiments showed that silencing of ScAG and ScAGL11 increases anthocyanin content in cineraria leaves. Similar results were observed when ScAG and ScAGL11 were silenced in the cineraria capitulum, accompanied by the smaller size of the colourless region, specifically in the ScAG/ScAGL11-silenced plants. The expression of ScCHS2, ScDFR3, and ScF3H1 increased in silenced cineraria leaves and capitulum. Furthermore, yeast two-hybrid and bimolecular fluorescence complementation experiments demonstrated that ScAG interacts with ScAGL11. Moreover, ScAG directly inhibited the transcription of ScF3H1 while ScAGL11 inhibited ScDFR3 expression by binding to their promoters separately. The findings reported herein indicate that ScAG and ScAGL11 negatively regulate anthocyanin biosynthesis in cineraria ray florets, and their differential expression in ray florets influences the bicolour pattern appearance.
Engineering high levels of saffron apocarotenoids in tomato
Authors: Ahrazem Oussama , Diretto Gianfranco , Rambla José Luis , Rubio-Moraga Ángela , Lobato-Gómez María , Frusciante Sarah , Argandoña Javier , Presa Silvia , Granell Antonio , Gómez-Gómez Lourdes
Published: March 2022

Crocins and picrocrocin are high-value hydrophilic pigments produced in saffron and used commercially in the food and pharmaceutical industries. These apocarotenoids are derived from the oxidative cleavage of zeaxanthin by specific carotenoid cleavage dioxygenases. The pathway for crocins and picrocrocin biosynthesis was introduced into tomato using fruit specific and constitutive promoters and resulted in 14.48 mg/g of crocins and 2.92 mg/g of picrocrocin in the tomato DW, without compromising plant growth. The strategy involved expression of CsCCD2L to produce crocetin dialdehyde and 2,6,6-trimethyl-4-hydroxy-1-carboxaldehyde-1-cyclohexene, and of glycosyltransferases UGT709G1 and CsUGT2 for picrocrocin and crocins production, respectively. Metabolic analyses of the engineered fruits revealed picrocrocin and crocetin-(β-D-gentiobiosyl)-(β-D-glucosyl)-ester, as the predominant crocin molecule, as well as safranal, at the expense of the usual tomato carotenoids. The results showed the highest crocins content ever obtained by metabolic engineering in heterologous systems. In addition, the engineered tomatoes showed higher antioxidant capacity and were able to protect against neurological disorders in a Caenorhabditis elegans model of Alzheimer’s disease. Therefore, these new developed tomatoes could be exploited as a new platform to produce economically competitive saffron apocarotenoids with health-promoting properties.
Positivity-preserving and energy-dissipative finite difference schemes for the Fokker–Planck and Keller–Segel equations
Authors: Hu Jingwei , Zhang Xiangxiong
Published: March 2022

In this work we introduce semi-implicit or implicit finite difference schemes for the continuity equation with a gradient flow structure. Examples of such equations include the linear Fokker–Planck equation and the Keller–Segel equations. The two proposed schemes are first-order accurate in time, explicitly solvable, and second-order and fourth-order accurate in space, which are obtained via finite difference implementation of the classical continuous finite element method. The fully discrete schemes are proved to be positivity preserving and energy dissipative: the second-order scheme can achieve so unconditionally while the fourth-order scheme only requires a mild time step and mesh size constraint. In particular, the fourth-order scheme is the first high order spatial discretization that can achieve both positivity and energy decay properties, which is suitable for long time simulation and to obtain accurate steady state solutions.
Actions of Nilpotent Groups on Complex Algebraic Varieties
Authors: Abboud Marc
Published: March 2022

We study nilpotent groups that act faithfully on complex algebraic varieties. In the finite case, we show that when $\textbf {k}$ is a number field, a finite $p$-subgroup of the group of polynomial automorphisms of $\textbf {k}^d$ is isomorphic to a subgroup of $\textrm {GL}_d(\textbf {k})$. In the case of infinite nilpotent group actions, we show that a finitely generated nilpotent group $H$ acting on a complex quasiprojective variety $X$ of dimension $d$ can be embedded in a $p$-adic Lie group that acts faithfully and analytically on $\textbf {Z}_p^d$. As a consequence, we show that the virtual derived length of $H$ is at most the dimension of $X$.
Bounds on Entries in Bianchi Group Generators
Authors: Martin Daniel E
Published: March 2022

Upper and lower bounds are given for the maximum Euclidean curvature among faces in the Ford domain for $\text {PSL}_2({\mathcal{O}})$ in the upper-half space model of hyperbolic space, where ${\mathcal{O}}$ is an imaginary quadratic ring of integers with discriminant $\Delta $. We prove these bounds are asymptotically within $(\log |\Delta |)^{8.54}$ of one another. This improves on the previous best upper bound, which is roughly off by a factor between $\Delta ^2$ and $|\Delta |^{5/2}$ depending on the smallest prime dividing $\Delta $. The gap between our upper and lower bounds is determined by an analog of Jacobsthal’s function, introduced here for imaginary quadratic fields.
515 Deficiencies of Rule-based Technology generated Antibiograms and Application in Patients with Prolonged Lengths of Stay
Authors: Hill David M , Arif Faisal , Sultan-Ali Ibrahim , Velamuri Sai R
Published: March 2022

Introduction

Antibiograms are unit specific annual reports of cumulative pathogen incidence and antibiotic susceptibilities, used to guide selection of empiric antibiotic therapies. Rule-based technology (RBT) expedites data compilation, but follows “first pathogen, per patient” and limits applicability, especially for prescribing antibiotics in units with higher lengths of stay. The objective was to compare the pathogens and susceptibilities of the current automated RBT antibiogram with one manually collected through chart review with additional rules applied.

Methods

This is a single-center, retrospective cohort study utilizing chart review to assess patients admitted to the Burn Center between January 2018 and December 2019 from whom significant bacterial cultures were obtained. Demographics and burn injury characteristics were collected. Treatment data related to the infection and antibiotic usage was also collected. Specific to the culture, timing, site, pathogen, and sensitivity were collected. All cultures within the first 30 days of admission were included. The current RBT antibiogram served as the control. And new antibiogram versions were created using additional rules and compared to the RBT antibiogram.

Results

During the 2 years, 657 patients were admitted. Two-hundred four patients remained after applicable exclusions. Sixty-one percent were excluded due to lack of cultures. Mean age was 50.6 ± 16.5 years and 66% were male. Forty-nine percent were Caucasian. Seventy-two percent were admitted for an acute burn injury with flame as the primary mechanism and a median percent total body surface area of 10 (3, 21). Fifty-nine percent had at least one hospital acquired risk factor with over one-third having recent illicit drug use and one-third having a recent hospitalization. Of the 410 cultures included, 57% were Gram-negative and half were from wound infections. Sensitivities were significantly different when comparing the RBT to those created from significant cultures within 7 days of admission, cultures within 7 days of admission and without hospital-acquired infection risk factors (Figure 1), and those being treated with an initial or subsequent course of antibiotics. Recommended empiric antibiotic changed from double coverage to a single β-lactam with > 90% susceptibility. The susceptibilities between first and subsequent courses were dramatically different (Figure 2)

Conclusions

The antibiogram was significantly different from the RBT version after including factors, such as days since admission, presence of hospital acquired risk factors, or previous antibiotic courses. Before developing an antibiogram or interpreting the output, it is important to consider which automated criteria are utilized, especially for units with extended lengths of stay.
537 Laser-Assisted Drug Delivery in the Treatment of Hypertrophic and Keloid Scars: A Systematic Review
Authors: Bernabe Rendell , Calero Tiffany , Lin Joshua , Dang Justin , Madigral Paloma , Yenikomshian Haig A , Gillenwater Justin
Published: March 2022

Introduction

Hypertrophic scars (HTS) and keloids (K) cause significant morbidity and disfigurement. Care of HTS and keloids range from less invasive treatments, such as pressure garments and silicone products, to more invasive treatments, such as intralesional injections (ISI) of medication, and surgical excision. Laser-Assisted Drug Delivery (LADD) is becoming a more popular treatment for HTS and K. The ablative fractional laser creates microchannels in the skins which allows the delivery of drugs into deeper skin layers. We have conducted a systematic review of the literature to assess the effectiveness of LADD in the treatment of HTS and K.

Methods

A search was performed on PubMed between January 1998-August 2021 using the following keywords: Laser Assisted Drug Delivery, Laser Combined Drug Delivery, Laser Drug Delivery, Laser Drug, Hypertrophic, Burn, Keloid, Scar. Inclusion criteria was the use of LADD in HTS or K. Exclusion criteria were studies in animal models, case reports, reviews, and non-english articles. One article was excluded due to concerns of plagiarism.

Results

A total of 11 articles were included in the final review. One study found no difference in HTS outcomes between LADD of corticosteroids (CTS) and laser with topical petrolatum used as a control. Two prospective studies found that LADD of CTS led to improved HTS outcomes. Two split-scar studies found no difference in K outcomes between LADD of CTS and ISI of CTS. One prospective study assessed LADD of CTS in K and found statistically significant improvements in scar outcomes. A retrospective study looking at K outcomes found a 50% mean improvement when treated with LADD of CTS. A split-scar study found statistically significant better HTS outcomes with LADD of 5-FU compared to topical 5-FU alone. One study found no difference in HTS outcomes between LADD of CTS and 5-Fluorouracil (5-FU). Two studies assessed both HTS and K. The first study found that both LADD of 5-FU and LADD of CTS led to significantly better scar outcomes when compared to laser monotherapy. The other reported that HTS outcomes were significantly better with LADD of Botulinum toxin A and K outcomes were better with ISI of Botulinum Toxin A.

Conclusions

The use of LADD is effective in the setting of HTS. There is evidence that LADD of scar modulating agents to HTS lesions is more effective than topical delivery or ISI of the same agent. LADD shows promise as an alternative treatment for K as it displays similar efficacy as ISI.
700 Use of Antibiograms and Changes in Bacterial Resistance Patterns
Authors: D'Abbondanza Josephine , Ziolkowski Natalia , Rehou Sarah , Shahrokhi Shahriar
Published: March 2022

Introduction

Infection is a leading cause of death in burn patients. With an increase in resistance patterns, management of these infections has become progressively difficult. Antibiograms, a summary of susceptibilities to bacteria in a given institution or area, are often used to guide empiric treatment of infections. However, inappropriate prescribing and use of empiric antimicrobials may greatly impact the incidence of resistance. Currently, we do not know the patterns of antibiotic use since the introduction of institutional antibiograms or associated changes in antibiotic resistance. The objective of this study is to describe trends in antibiotic susceptibilities in burn patients in Canada pre- (PrA) and post-introduction (PoA) of antibiograms.

Methods

We performed a retrospective review of patients admitted to an ABA-verified Burn Centre 2 years pre- (2013-2014) and post-introduction (2016-2017) of institutional antibiograms and started on broad-spectrum antibiotics (meropenem, piperacillin-tazobactam, and/or vancomycin).

Results

A total of 864 patients were admitted during the study period (n=420 PrA and n=444 PoA). Average age, % total body surface area (%TBSA), and length of stay were similar between cohorts. Administration of empiric meropenem increased (43.2% vs. 56.8%) and piperacillin-tazobactam decreased (60.6% vs. 39.4%), which was significant (p=0.002). The use of vancomycin was unchanged. There was a significant decrease in the overall use of empiric antibiotics (p=0.002) since the inception of antibiograms, with a significant improvement in culture and sensitivity (C&S) testing within 5 days of starting empiric antibiotics (p=0.002). There was no significant difference in use of targeted antibiotics pre- or post-antibiogram introduction.

Conclusions

Our study demonstrates that since the inception of antibiograms, there has been a significant decrease in overall use of empiric antibiotics and improvement in acquiring C&S within 5 days. However, these antibiotics were not always targeted to the appropriate organism and therefore may contribute to multi-drug resistant organisms in a burn population.
745 Evaluating Nurses' Perceptions of Code Cart Competency
Authors: Folliard Sarah A , Grubbs Alicia K , Beyene Robel , Doyle Kelly , Gondek Stephen , Young Miranda
Published: March 2022

Introduction

This study was conducted to evaluate critical care nurses' perceptions of competency when using the code cart during Advance Cardiac Life Support (ACLS) resuscitation. During post-resuscitation debrief, it was noted that nurses reported lack of familiarity with using the code cart and could not quickly locate items when needed.

Methods

Using an email distribution list sent to nurses employed in the Burn Center, a pre-survey was conducted to evaluate baseline competency levels and provide the opportunity to self report level of familiarity with the code cart and the roles needed to conduct effective ACLS resuscitation. Following the pre-survey, various educational opportunities were offered to the nursing staff including written and hands-on activities in a low-stress setting. These activities were offered to day and night shift nurses on several occasions, and there was no limit to how many times a nurse could participate. Following 3 months of targeted educational intervention, a post-survey was conducted to re-evaluate the nurses' perceived comfort level with using the code cart during ACLS resuscitation.

Results

The average years of nursing experience among participants was 3-4, with only two participants reporting 5 or more years of critical care experience. The nurses reported an increase in self-reported confidence level with using the code cart. The most common educational intervention that nurses felt would increase their comfort levels with using the crash cart were more frequent simulation scenarios (ie: mock codes), and hands-on training with open crash carts during in a low stress setting.

Conclusions

Because ACLS resuscitation is a stressful, chaotic event, it is not feasible for nurses to learn "in the moment." Critical care nurses in the Burn Center are trained on resuscitation and are required to maintain ACLS certification, but this is not enough training for them to feel comfortable with their responsibilities during a code. After identifying that nurses were not confident in being able to work the crash cart and could not find necessary items when asked to do so during an emergency, a plan for additional hands-on education in a low-stress setting was developed. Using a pre/post survey, the multi-faceted educational opportunities were evaluated to see if they would impact the nurses' self-reported perceptions of code cart competency. Results indicated that not only were the educational interventions successful, but the nurses would like further opportunities for ongoing participation to maintain their level of comfort with the crash cart.
Sand Flies (Diptera: Psychodidae): Fauna and Ecology in the Northeast of Algeria
Authors: Amira Aicha , Bounamous Azzedine , Kouba Yacine , Kadjoudj Nadia , Zeroual Samir , Boubendir Abdelhafid , Boularouk Yakoub
Published: March 2022

Sand flies (Diptera: Psychodidae) transmit several Leishmania (Kinetoplastida: Trypanosomatidae) species, which cause leishmaniasis, a significant public health concern in Algeria. We compared sand fly species abundance and composition among different biotopes (urban, peri-urban, rural areas), bioclimatic zones (humid, sub-humid, semi-arid), and elevation ranges. We also used the additive partitioning of beta diversity to test whether the variation in sand fly composition among biotopes, bioclimatic zones, and elevation ranges is due to species turnover or community subsetting. In total, 7,478 specimens were captured; of which, 7,162 (51.5% males vs. 48.5% females) belong to eight species: Phlebotomus perniciosus Newstead, 1911 (77.4% of the total captured specimens), Phlebotomus perfiliewi Parrot, 1930 (14.6%), Phlebotomus longicuspis Nitzulescu, 1911 (5.9%), Phlebotomus papatasi Scopoli, 1786 (<1%), Phlebotomus sergenti Parrot, 1917 (<1%) and Phlebotomus chadlii Rioux, Juminer et Gibily 1966 (<1%), Sergentomyia minuta Adler et Theodor, 1927 (1%), and Sergentomyia fallax Parrot, 1921 (<1%). Sand fly total abundance showed negative correlations with altitude and was significantly higher in rural areas. Sandfly community composition was significantly different between rural and urban/peri-urban areas. The additive partitioning of beta diversity showed that 71.4% of the compositional dissimilarity among elevation ranges and bioclimates was due to sand fly species turnover, and 28.6% resulted from nestedness. However, the variation in sand fly composition among different biotopes was mainly due to community nestedness. Findings from this study help define the risk of Leishmania transmission and develop methods for vector control in Mila province and Algeria as a whole.
Students’ Perception of Online Learning During COVID-19: A U.S.-Based Music Therapy Survey
Authors: Kern Petra , Tague Daniel B
Published: March 2022

The Coronavirus disease 2019 (COVID-19) global pandemic affected music therapy education, with many university programs instantly shifting from in-person to remote online teaching. As literature related to various aspects of COVID-19 is emerging, none has yet examined music therapy students’ responses to the sudden modification of teaching modalities. The aim of this study was to understand how the music therapy learning environment changed during the COVID-19 pandemic; students’ experiences with unexpected remote learning, clinical training, and examination; and their perception of barriers and benefits of online learning. American Music Therapy Association students attending courses from Spring 2020 through Spring 2021 were invited to participate in this national survey. In total, 230 music therapy students across seven regions responded to the 26-item questionnaire through Qualtrics®. Seven questions were further explored with a student focus group. Results indicated that courses were mainly altered to synchronous lectures, clinical training changed to varied telepractice experiences, and examination was modified across universities. Students spent about the same time in remote learning and found synchronous lectures mostly engaging. Commonly perceived barriers included screen fatigue, physical isolation from peers, and poor internet connection. Safety during COVID-19, no traveling time, and being more comfortable at home were noted as key benefits. In conclusion, online learning allowed the continuation of music therapy education during the COVID-19 pandemic. Moving forward, the development of effective online courses and research-based guidelines for tele-interventions is desirable to improve the music therapy educational landscape during future crises and to prepare students for competent services in a digital world.
Research on performance optimization of gas–liquid ejector in multiphase mixed transportation device
Authors: Zhao Junyou , Wei Xin , Zou Junyan , Zhang Yaning , Sun Jiafeng , Liu Zhongping
Published: March 2022

In the process of oil and gas extraction, a system that uses a pump and reversing mechanism to achieve high-efficiency export of gas–liquid mixture is devised. A gas–liquid ejector is fitted in the front of the device to boost pressure inside the tank in order to store more gas in the tank under a given volume. To meet the working conditions of gas–liquid high-efficiency transport device and obtain a larger outlet pressure and better ejection performance, this paper investigates the effect of outlet pressure, ratio of throat inlet area to nozzle outlet area and nozzle contraction angle on the ejection performance of gas–liquid ejector, and simulations using the computational fluid dynamics approach. At the same time, an experiment platform is built for testing. The research findings show that the ejection gas flow rate and ejection ratio of gas–liquid ejector decrease with the increase of the outlet pressure; as the ratio of throat inlet area to nozzle outlet area increases, the ejection gas flow rate and the ejection ratio of gas–liquid ejector increase first and then decrease. Different nozzle diameters correspond to different optimal area ratios; under the specified working parameters, with the increase of the nozzle contraction angle, the ejection gas flow rate and injection ratio of the gas–liquid ejector increase first and then decrease, and there is an optimal nozzle contraction angle.
Poor Uptake of MMR Vaccine 1-year Post-Measles Outbreak: New York City and Israel
Authors: Paret Michal , Trillo Rebecca , Lighter Jennifer , Youngster Ilan , Ratner Adam J , Pellett Madan Rebecca
Published: March 2022

Background

In 2018-2019, large outbreaks of measles occurred in Israel and in New York City, driven in part by travel of unimmunized children between the 2 communities.

Methods

A retrospective chart review was conducted for children tested for measles (March 2018-September 2019) at NYU Langone Health in New York, NY, and in Ramla subdistrict, Israel. Vaccination records were reviewed to determine vaccination status for measles, mumps, and rubella (MMR) at the time of measles testing and 1-year post-testing.

Results

A total of 264 children were tested for measles, and 102 (38.6%) had confirmed measles. Only 20 (19.6%) of measles-positive cases received a full 2-dose course of vitamin A. 82.4% of children with measles were ≥1 year at the time of diagnosis and fully eligible for MMR vaccine. Of the 100 measles-positive cases with available vaccine records, 63 were unvaccinated at testing, and 27 remained unimmunized against MMR 1 year later. At testing, measles-negative children were significantly more likely to have received MMR than measles-positive children (65.4% vs 37%, P < .01). One year later, 70.4% of measles-negative cases and only 57.1% of measles-positive cases had received MMR vaccine (P = .18).

Conclusions

The majority of measles cases occurred in unimmunized children eligible for vaccination, and >25% of children in both measles-positive and -negative groups remained unimmunized for MMR 1-year post-outbreak. Our results suggest the need for novel, longitudinal vaccination strategies and increased awareness of the role of vitamin A.
Picturing Music: Doubling Ekphrasis in Six Rossetti Sonnets
Authors: Helsinger Elizabeth
Published: March 2022

What happens when the visual subject of ekphrastic writing is itself a representation of music – music as it is made and heard by the figures in a picture? In the six sonnets considered in this essay, Dante Gabriel Rossetti – himself an artist as well as a poet – doubles the ekphrastic action to summon an elusive music from what is offered to the eye alone. The poems on the page, in these examples, explore both the promise and the limits of poetry’s long association with song. They participate in shared Pre-Raphaelite and Aesthetic efforts to conjure an experience of music from the resistant genres of painting and poetry, desiring (and regretting) a lost time when poetry and music were regarded as one. But Rossetti’s sonnets are less interested in evoking the sounds of music than in exploring in poetic form what music means – how it affects the mind through multiple senses and the emotions, how its harmonic and rhythmic structures shape those responses in time, and what a modern poetry might learn from a kinship with music. Music in these poems appears as a special kind of embodied knowing, one whose meanings can – perhaps – be conveyed by the different representational means and formal structures of a picture or a poem. What Rossetti’s ekphrastic sonnets on music offer, I suggest, is less a music that can be heard than a form of melopoetics: a literary-musical criticism.
Does SCO need its own energy charter treaty? From the perspective of Chinese BITs
Authors: Li Kuangran , Shen Wei
Published: March 2022

Since the reform and opening up, China has developed into a major energy importer and become increasingly dependent on the international energy market. Owing to the impact of shale oil exploration and gas extraction in the USA, the influence of Russia and Organization of the Petroleum Exporting Countries (OPEC) on international oil prices, and the increasing development of clean energy technologies, China’s energy supply and security are facing serious challenges. This international energy landscape highlights the need to strengthen energy investment and cooperation among Shanghai Cooperation Organisation (SCO) Member States. However, energy resources are distributed unevenly among the SCO Member States. Specifically, some Member States are rich in energy resources and highly dependent on energy exports for national economic development, which can form a satisfactory supply and demand relationship with China. Therefore, strengthening energy cooperation in SCO is conducive to not only maintaining energy security in the SCO region but also promoting overall regional development and further deepening the economic interconnectivity. An important prerequisite for strengthening energy cooperation between countries is the legal mechanisms for energy investment protection. However, current legal foundations for energy investment among SCO Member States rely mainly on bilateral investment treaties between Member States, which are largely outdated and inconsistent. Likely, this status quo is not conducive to the stable regional energy cooperation for sustainable operation. The purpose of this article is to examine the need to build a unified legal mechanism for energy investment protection under the SCO framework. Accordingly, China should emphasize this legal mechanism to protect the country’s foreign energy investment in the SCO.
Readers’ reception of translated literary work:Fortress Besiegedin the digital English world
Authors: Zheng Jianwei , Fan Wenjun
Published: March 2022

This article explores English readers’ reception of Fortress Besieged as a translated literary work in the digital space, based on descriptive statistics, sentiment analysis, and content analysis of their comments at categorized dimensions. This study discovers that English readership online tends to devalue the translators’ craftsmanship, especially the interlingual transfer of cultural contents, and the sluggish pace of this novel’s storyline. However, the generally successful preservation of the humor and satire of the source text is appreciated. Through bringing cyberspace readers’ voices to the academic frontier, this study highlights the necessity of a fluent plot, cultural transfer challenges, and the adornment of figurative language when translating novels for English readers.
Time and time again: a multi-scale hierarchical framework for time-consciousness and timing of cognition
Authors: Singhal Ishan , Srinivasan Narayanan
Published: March 2022

Temporality and the feeling of ‘now’ is a fundamental property of consciousness. Different conceptualizations of time-consciousness have argued that both the content of our experiences and the representations of those experiences evolve in time, or neither have temporal extension, or only content does. Accounting for these different positions, we propose a nested hierarchical model of multiple timescales that accounts for findings on timing of cognition and phenomenology of temporal experience. This framework hierarchically combines the three major philosophical positions on time-consciousness (i.e. cinematic, extensional and retentional) and presents a common basis for temporal experience. We detail the properties of these hierarchical levels and speculate how they could coexist mechanistically. We also place several findings on timing and temporal experience at different levels in this hierarchy and show how they can be brought together. Finally, the framework is used to derive novel predictions for both timing of our experiences and time perception. The theoretical framework offers a novel dynamic space that can bring together sub-fields of cognitive science like perception, attention, action and consciousness research in understanding and describing our experiences both in and of time.
Occupational asthma in office workers
Authors: Huntley C C , Burge P S , Moore V C , Robertson A S , Walters G I
Published: March 2022

Background

Office work has a relative perception of safety for the worker. Data from surveillance schemes and population-based epidemiological studies suggest that office work carries a low risk of occupational asthma (OA). Office workers are frequently used as comparators in studies of occupational exposure and respiratory disease.

Aims

We aimed to describe and illustrate our tertiary clinical experience of diagnosing OA in office workers.

Methods

We searched the Birmingham NHS Occupational Lung Disease Service clinical database for cases of occupational respiratory disease diagnosed between 2002 and 2020, caused by office work or in office workers. For patients with OA, we gathered existing data on demographics, diagnostic tests including Occupational Asthma SYStem (OASYS) analysis of serial peak expiratory flow and specific inhalational challenge, and employment outcome. We summarised data and displayed them alongside illustrative cases.

Results

There were 47 cases of OA (5% of all asthma) confirmed using OASYS analysis of PEFs in the majority. Sixty percent of cases occurred in healthcare, education and government sectors. The most frequently implicated causative exposures or agents were: indoor air (9), printing, copying and laminating (7), cleaning chemicals (4), mould and damp (4), and acrylic flooring and adhesives (4). Exposures were grouped into internal office environment, office ventilation-related and adjacent environment.

Conclusions

Clinicians should be vigilant for exposures associated with OA in office workers who present with work-related symptoms, where respiratory sensitizing agents may be present. A structured approach to assessment of the workplace is recommended.
Immune Activation in Primary Human Immunodeficiency Virus: Influence of Duration of Infection, Treatment, and Substance Use
Authors: Gilada Trupti , Schnittman Samuel R , White Edward , Mercader Jacqueline , Wang Yixin , Dasgupta Sayan , Valdez Rogelio , Pinto-Santini Delia , Pasalar Siavash , Sanchez Jorge , Gonzales Pedro , Lama Javier R , Bender Ignacio Rachel , Duerr Ann
Published: March 2022

Background

Primary human immunodeficiency virus (HIV) is characterized by dynamic changes in viral load and innate and adaptive immune responses; it is unclear the extent to which time from acquisition to antiretroviral therapy (ART) initiation and substance use impact these immunologic changes.

Methods

We studied plasma immune activation biomarkers, viral load, and CD4+ and CD8+ cell counts in participants from the Sabes primary infection study in Peru, who had been randomized to begin ART immediately after diagnosis vs 24 weeks later. We modeled influence of substance use and duration of HIV infection on biomarkers at baseline and over 24 weeks.

Results

Compared to participants enrolled >30 days after HIV acquisition, participants enrolled during acute infection (≤30 days) had higher mean interferon (IFN)–γ and IFN-α2a (1.7-fold and 3.8-fold interquartile range [IQR] higher, respectively). Participants enrolled >30 days after HIV acquisition had higher mean baseline CD8+ cell count (2.7 times the IQR). Alcohol use (positive phosphatidylethanol level) was associated with elevated IFN-γ, tumor necrosis factor alpha (TNF-α), and interleukin 12p70 (IL-12p70), and smoking was associated with higher macrophage inflammatory protein 1α, TNF-α, and IL-12p70. Most biomarkers declined more quickly in participants who initiated ART immediately; however, substance use and duration of HIV infection at enrollment had little influence on rate of decline.

Conclusions

IFN-γ and other biomarkers are elevated during early primary infection, when exposure to HIV antigens is high. Immune activation decreased most quickly in those who started ART during acute/early primary infection. Higher CD8+ cell counts and a trend toward higher soluble CD163 levels during the 30 days after acquisition suggest the onset of compensatory responses and immune exhaustion.
Potent Activity of Ertapenem Plus Cefazolin Within Staphylococcal Biofilms: A Contributing Factor in the Treatment of Methicillin-Susceptible Staphylococcus aureus Endocarditis
Authors: Gilbertie Jessica , Ulloa Erlinda R , Daiker Jennifer C , Nguyen Khanh , Smelter Dan , Rose Warren , Geriak Matthew , Schnabel Lauren V , Nizet Victor , Sakoulas George
Published: March 2022

Background

Besides antistaphylococcal beta-lactams and source control, there are limited validated antimicrobial salvage options in patients with prolonged methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, including infective endocarditis (IE).

Methods

MSSA IE cases treated with ertapenem (ETP) plus cefazolin (CZ) were compared with matched IE cases treated with standard beta-lactam monotherapy. The bactericidal activity of ETP plus CZ was also compared with nafcillin (NAF), CZ, and ETP alone using an in vitro MSSA biofilm model.

Results

The median duration of bacteremia experienced by patients (n = 12) while on CZ or NAF was 4 days (range 1–16 days) compared with 1 day (range 1–3 days) for patients (n = 5) treated with ETP + CZ (P = .01, Mann-Whitney U test). Cefazolin and NAF alone or in combination did not achieve biofilm eradication at clinically relevant concentrations. However, the addition of ETP to CZ led to bactericidal eradication within biofilms at standard dosing.

Conclusions

Ertapenem reduces CZ concentrations required to eradicate MSSA biofilms to those achievable in vivo by standard dosing, translating into shorter bacteremia duration in patients with MSSA endocarditis. Larger studies are needed to investigate ETP plus CZ therapy in the treatment of biofilm-related MSSA infections such as endocarditis.
Lenvatinib for the Treatment of Radioiodine-Refractory Differentiated Thyroid Cancer: Treatment Optimization for Maximum Clinical Benefit
Authors: Wirth Lori J , Durante Cosimo , Topliss Duncan J , Winquist Eric , Robenshtok Eyal , Iwasaki Hiroyuki , Luster Markus , Elisei Rossella , Leboulleux Sophie , Tahara Makoto
Published: March 2022

Background

Lenvatinib is a multitargeted tyrosine kinase inhibitor approved for treating patients with locally recurrent or metastatic progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC). In this review, we discuss recent developments in the optimization of RR-DTC treatment with lenvatinib.

Initiation of lenvatinib treatment before a worsening of Eastern Cooperative Oncology Group performance status and elevated neutrophil-to-lymphocyte ratio could benefit patients with progressive RR-DTC. The median duration of response with lenvatinib was inversely correlated with a smaller tumor burden, and prognosis was significantly worse in patients with a high tumor burden. An 18 mg/day starting dose of lenvatinib was not noninferior to 24 mg/day and had a comparable safety profile. Timely management of adverse events is crucial, as patients with shorter dose interruptions benefitted more from lenvatinib treatment. Caution should be exercised when initiating lenvatinib in patients who have tumor infiltration into the trachea or other organs, or certain histological subtypes of DTC, as these are risk factors for fistula formation or organ perforation. The Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT) eligibility criteria should be considered prior to initiating lenvatinib treatment.

Conclusions

Current evidence indicates that patients benefit most from lenvatinib treatment that is initiated earlier in advanced disease when the disease burden is low. A starting dose of lenvatinib 24 mg/day, with dose modifications as required, yields better outcomes as compared to 18 mg/day. Appropriate supportive care, including timely identification of adverse events, is essential to manage toxicities associated with lenvatinib, avoid longer dose interruptions, and maximize efficacy.
Daratumumab Improves Depth of Response and Progression-free Survival in Transplant-ineligible, High-risk, Newly Diagnosed Multiple Myeloma
Authors: Jakubowiak Andrzej J , Kumar Shaji , Medhekar Rohan , Pei Huiling , Lefebvre Patrick , Kaila Shuchita , He Jianming , Lafeuille Marie-Hélène , Cortoos Annelore , Londhe Anil , Mavros Panagiotis , Lin Thomas S , Usmani Saad Z
Published: March 2022

Background

Patients with high-risk, newly diagnosed multiple myeloma (HR-NDMM) who are ineligible for autologous stem cell transplant (ASCT) have limited first-line treatment options. Recent meta-analyses evaluating the impact of incorporating daratumumab in the backbone regimen on progression-free survival (PFS) have found mixed results in these patients.

Materials and Methods

A pooled analysis of patient-level data for ASCT-ineligible patients with HR-NDMM [ie, del(17p), t(4;14), t(14;16)] from the MAIA and ALCYONE trials; stratified by study identifier and adjusting for cytogenetic abnormality subtype, baseline performance status, International Staging System stage, myeloma type, and renal impairment; was conducted. Impact of daratumumab on PFS and rates of complete response or better (≥CR), minimal residual disease (MRD)-negative CR, very good partial response or better (≥VGPR), and overall response (ORR) was compared to control.

Results

Among 101 patients in the daratumumab and 89 patients in the control cohort, median follow-up was 43.7 months. Daratumumab reduced the risk of progression or death by 41% (adjusted hazard ratio for PFS [95% confidence interval (CI)] = 0.59 [0.41-0.85]) versus control. At 36 months, the estimated proportion of patients who did not progress and were still alive was 41.3% in the daratumumab and 19.9% in the control cohort. Rates of ≥CR (41.6% vs. 22.5%), MRD-negative CR (24.8% vs. 5.6%), ≥VGPR (75.2% vs. 46.1%), and ORR (92.1% vs. 74.2%) were higher for daratumumab versus control.

Conclusion

These findings demonstrate that incorporation of daratumumab in frontline treatment regimens reduced the risk of progression or death and improved response rates among ASCT-ineligible HR-NDMM patients.
Systemic Therapies Following Progression on First-line CDK4/6-inhibitor Treatment: Analysis of Real-world Data
Authors: Martin James M , Handorf Elizabeth A , Montero Alberto J , Goldstein Lori J
Published: March 2022

Background

Metastatic hormone receptor positive (HR+)/human epidermal growth factor receptor-2 negative (Her2−) breast cancer remains a significant cause of cancer-related mortality. First-line treatment with endocrine therapy (ET) with a cyclin-dependent kinases 4 and 6 inhibitor (CDK4/6i) has largely become the standard systemic therapy. Following progression, no prospective randomized data exist to help guide second-line treatment.

Materials and Methods

This study used a nationwide electronic health record (EHR)-derived de-identified database, specifically analyzing 1210 patients with HR+/Her2− metastatic breast cancer (MBC) who were treated in the first-line setting with a CDK4/6i from the years 2015-2020. The aim of this study was to assess what therapies were given after first-line progression on CDK4/6i and to observe treatment patterns over time. Determination of second-line treatment efficacy, specifically assessing real-world progression-free survival (rwPFS) and overall survival (OS) was performed.

Results

A total of 839 patients received a documented second-line therapy after progression on first-line CDK4/6i treatment. Chemotherapy was chosen for 29.7% of patients, and the use of chemotherapy decreased over time. Three hundred two (36.0%) of patients continued a CDK4/6i. Data were adjusted for age, race, Eastern Cooperative Oncology Group (ECOG) performance status, stage at breast cancer diagnosis, and insurance payer type. Continuation of the CDK4/6i was associated with improved rwPFS (HR 0.48, 95% CI 0.43-0.53, P < .0001) and OS (HR 0.30, 95% CI 0.26-0.35, P < .0001) compared to chemotherapy. A majority of these patients continued the same CDK4/6i in the second-line setting, as was given in the first-line setting.

Conclusion

While prospective data are needed, analysis of real-world data suggests a survival benefit for continuation of a CDK4/6i beyond frontline progression for patients with HR+/Her2− MBC.
A linear programming-based strategy to save pipette tips in automated DNA assembly
Authors: Sechkar Kirill , Tuza Zoltan A , Stan Guy-Bart
Published: March 2022

Laboratory automation and mathematical optimization are key to improving the efficiency of synthetic biology research. While there are algorithms optimizing the construct designs and synthesis strategies for DNA assembly, the optimization of how DNA assembly reaction mixes are prepared remains largely unexplored. Here, we focus on reducing the pipette tip consumption of a liquid-handling robot as it delivers DNA parts across a multi-well plate where several constructs are being assembled in parallel. We propose a linear programming formulation of this problem based on the capacitated vehicle routing problem, as well as an algorithm which applies a linear programming solver to our formulation, hence providing a strategy to prepare a given set of DNA assembly mixes using fewer pipette tips. The algorithm performed well in randomly generated and real-life scenarios concerning several modular DNA assembly standards, proving to be capable of reducing the pipette tip consumption by up to $59\%$ in large-scale cases. Combining automatic process optimization and robotic liquid handling, our strategy promises to greatly improve the efficiency of DNA assembly, either used alone or combined with other algorithmic DNA assembly optimization methods.

Graphical Abstract
Clinical Features of Multisystem Inflammatory Syndrome in Children Associated with COVID-19 in Indonesia
Authors: Putri Nina Dwi , Prawira Yogi , Tartila Tartila , Jasin Madeleine Ramdhani , Puspitasari Henny Adriani , Puspaningtyas Niken Wahyu , Indawati Wahyuni , Karyanti Mulya Rahma , Setyanto Darmawan Budi , Prayitno Ari , Yuniar Irene , Alatas Fatima Safira , Hidayati Eka Laksmi , Muhaimin Riski , Prawitasari Titis , Soebadi Amanda , Muktiarti Dina , Primacakti Fitri , Rahmadhany Anisa , Octavius Gilbert Sterling , Djer Mulyadi M , Hendarto Aryono , Dewi Rismala , Kaswandani Nastiti , Pudjiadi Antonius Hocky
Published: March 2022

Background

While the number of cases of multisystem inflammatory syndrome in children (MIS-C) is increasing, reported cases in Asian countries are still low, particularly in Indonesia. This study aimed to describe the characteristics of patients with MIS-C in a tertiary referral hospital in Indonesia.

Methods

This is a cross-sectional study with collected data of patients with MIS-C admitted to Dr. Cipto Mangunkusumo from March 2020 to April 2021.

Results

The first case of MIS-C was detected 5 months after the first reported coronavirus disease 2019 case in Indonesia. Thirteen patients out of 158 positive admitted patients for COVID-19 were diagnosed with MIS-C during the study period. Of these 13 patients, 2 patients (15%) had a fatal outcome. Subjects were predominantly male, and the median age was 7.58 years (IQR 12.3) years. Most patients required mechanical ventilation (7 out of 13 patients) and intubation (8 out of 13 patients). Patients who needed intubation usually needed mechanical ventilation. All inflammatory markers, white blood cells, neutrophil counts, and all coagulation factor parameters (except for normal prothrombin time and activated partial prothrombin time) were elevated. The median time to MIS-C diagnosis was 2 days in the survivor group (n = 11) compared to 8.5 days in the non-survivor group (n = 2). Compared to the non-survivor group, those who survived spent more days in the hospital, received vasopressors earlier, and did not require mechanical ventilation as early as the non-survivors.

Conclusions

Our work highlights the differences in MIS-C clinical course, treatment, and clinical outcomes between the two groups.