bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial
Authors: Bevers Lisanne A H , Waalewijn Hylke , Szubert Alexander J , Chabala Chishala , Bwakura-Dangarembizi Mutsa , Makumbi Shafic , Nangiya Joan , Mumbiro Vivian , Mulenga Veronica , Musiime Victor , Burger David M , Gibb Diana M , Colbers Angela
Published: June 2023

Background

Dolutegravir (DTG), combined with a backbone of 2 nucleoside reverse transcriptase inhibitors, is currently the preferred first-line treatment for human immunodeficiency virus (HIV) in childhood. CHAPAS4 is an ongoing randomized controlled trial investigating second-line treatment options for children with HIV. We did a nested pharmacokinetic (PK) substudy within CHAPAS4 to evaluate the DTG exposure in children with HIV taking DTG with food as part of their second-line treatment.

Methods

Additional consent was required for children on DTG enrolled in the CHAPAS4 trial to participate in this PK substudy. Children weighing 14–19.9 kg took 25 mg DTG as dispersible tablets and children ≥20 kg took 50 mg film-coated tablets. Steady-state 24-hour DTG plasma concentration-time PK profiling was done at t = 0 and 1, 2, 4, 6, 8, 12, and 24 hours after observed DTG intake with food. Reference adult PK data and pediatric data from the ODYSSEY trial were used primarily for comparison. The individual target trough concentration (Ctrough) was defined as 0.32 mg/L.

Results

Thirty-nine children on DTG were included in this PK substudy. The geometric mean (GM) area under the concentration–time curve over the dosing interval (AUC0-24h) was 57.1 hours × mg/L (coefficient of variation [CV%], 38.4%), which was approximately 8% below the average AUC0-24h in children in the ODYSSEY trial with comparable dosages, but above the adult reference. The GM (CV%) Ctrough was 0.82 mg/L (63.8%), which was comparable to ODYSSEY and adult reference values.

Conclusions

This nested PK substudy shows that the exposure of DTG taken with food in children on second-line treatment is comparable with that of children in the ODYSSEY trial and adult references.

Clinical Trials Registration.ISRCTN22964075.
‘Not Time to Make a Change’? Reviewing the Rhetoric of Law Reform
Authors: Lee James
Published: June 2023

How do we talk about changing the law? This article considers the rhetoric of law reform and what it can tell us about the current relationships between key institutions involved in the relevant processes. A key claim is that the rhetoric deployed in formulating proposals can complicate the fate of law reform projects as they develop. Several examples from private and criminal law are used to support the argument, with assessment of the interaction of time and legal development. The language of ‘modernisation’—a noticeable theme in contemporary proposals from the Law Commission of England and Wales—is scrutinised. The Commission’s statutory functions expressly include ‘the repeal of obsolete and unnecessary enactments… and generally the simplification and modernisation of the law’, but what ‘modernisation’ means in this area has, so far, been under-examined. The author then goes on to identify attitudinal and structural tensions in the current relationship between the Law Commission and Government. Constructive suggestions are offered for reforming our law reform practices. The way in which we talk about law reform can be understood as both a cause and symptom of some of the problems in developing the law today.
How can physiology best contribute to wildlife conservation in a warming world?
Authors: Seebacher Frank , Narayan Edward , Rummer Jodie L , Tomlinson Sean , Cooke Steven J
Published: June 2023

Global warming is now predicted to exceed 1.5°C by 2033 and 2°C by the end of the 21st century. This level of warming and the associated environmental variability are already increasing pressure on natural and human systems. Here we emphasize the role of physiology in the light of the latest assessment of climate warming by the Intergovernmental Panel on Climate Change. We describe how physiology can contribute to contemporary conservation programmes. We focus on thermal responses of animals, but we acknowledge that the impacts of climate change are much broader phylogenetically and environmentally. A physiological contribution would encompass environmental monitoring, coupled with measuring individual sensitivities to temperature change and upscaling these to ecosystem level. The latest version of the widely accepted Conservation Standards designed by the Conservation Measures Partnership includes several explicit climate change considerations. We argue that physiology has a unique role to play in addressing these considerations. Moreover, physiology can be incorporated by institutions and organizations that range from international bodies to national governments and to local communities, and in doing so, it brings a mechanistic approach to conservation and the management of biological resources.
Clinical significance of ST-segment depression during atrial fibrillation rhythm for subsequent heart failure events
Authors: Kawaji Tetsuma , Hamatani Yasuhiro , Kato Masashi , Yokomatsu Takafumi , Miki Shinji , Abe Mitsuru , Akao Masaharu
Published: June 2023

Aims

The clinical significance of ST-segment depression during atrial fibrillation (AF) rhythm has not been fully evaluated. The aim of the present study was to explore the association of ST-segment depression during AF rhythm with subsequent heart failure (HF) events.

Methods and results

The study enrolled 2718 AF patients whose baseline electrocardiography (ECG) was available from a Japanese community-based prospective survey. We assessed the association of ST-segment depression in baseline ECG during AF rhythm with clinical outcomes. The primary ednpoint was a composite HF endpoint: cardiac death or hospitalization due to HF. The prevalence of ST-segment depression was 25.4% (upsloping 6.6%, horizontal 18.8%, downsloping 10.1%). Patients with ST-segment depression were older and had more comorbidities than those without. During the median follow-up of 6.0 years, the incidence rate of the composite HF endpoint was significantly higher in patients with ST-segment depression than those without (5.3% vs. 3.6% per patient-year, log-rank P < 0.01). The higher risk was present in horizontal or downsloping ST-segment depression, but not in upsloping one. By multivariable analysis, ST-segment depression was an independent predictor for the composite HF endpoint (hazard ratio 1.23, 95% confidence interval 1.03–1.49, P = 0.03). In addition, ST-segment depression at anterior leads, unlike inferior or lateral leads, was not associated with higher risk for the composite HF endpoint.

Conclusion

ST-segment depression during AF rhythm was associated with subsequent HF risk; however, the association was affected by type and distribution of ST-segment depression.
Cardiovascular disease risk in women with hyperandrogenism, oligomenorrhea/menstrual irregularity or polycystic ovaries (components of polycystic ovary syndrome): a systematic review and meta-analysis
Authors: Lo Andre C Q , Lo Charmaine Chu Wen , Oliver-Williams Clare
Published: June 2023

Aims

Prior meta-analyses indicate polycystic ovary syndrome (PCOS) is associated with cardiovascular diseases (CVDs), but have high statistical heterogeneity, likely because PCOS is a heterogenous syndrome diagnosed by having any two of the three components: hyperandrogenism, oligomenorrhea/menstrual irregularity or polycystic ovaries. Several studies report higher risk of CVDs from individual PCOS components, but a comprehensive assessment of how each component contributes to CVD risk is lacking. This study aims to assess CVD risk for women with one of the PCOS components.

Methods and results

A systematic review and meta-analysis of observational studies was conducted. PubMed, Scopus, and Web of Science were searched without restrictions in July 2022. Studies meeting inclusion criteria examined the association between PCOS components and risk of a CVD. Two reviewers independently assessed abstracts and full-text articles, and extracted data from eligible studies. Where appropriate, relative risk (RR) and 95% confidence interval (CI) were estimated by random-effects meta-analysis. Statistical heterogeneity was assessed using the I2 statistic. Twenty-three studies, including 346 486 women, were identified. Oligo-amenorrhea/menstrual irregularity was associated with overall CVD (RR = 1.29, 95%CI = 1.09–1.53), coronary heart disease (CHD) (RR = 1.22, 95%CI = 1.06–1.41), and myocardial infarction (MI) (RR = 1.37, 95%CI = 1.01–1.88) but not cerebrovascular disease. These results were broadly consistent even after further adjustment for obesity. There was mixed evidence for the role of hyperandrogenism in CVDs. No studies examined polycystic ovaries as an independent exposure for CVD risk.

Conclusion

Oligo-amenorrhea/menstrual irregularity is associated with greater risk of overall CVD, CHD, and MI. More research is needed to assess the risks associated with hyperandrogenism or polycystic ovaries.
Samuel Kwadwo Boaten Asante and the United Nations Centre on Transnational Corporations (1975–1992)
Authors: Folake Olaoye Kehinde
Published: June 2023

This article uses Samuel Kwadwo Boaten Asante’s career at the United Nations Centre on Transnational Corporations (UNCTC) as a prism for examining the place of Third World Approaches to International Law within mainstream international organizations (IO) law. By focusing on his role as chief legal adviser, director and highest-ranking legal civil servant at the UNCTC during the heydays of the New International Economic Order (NIEO), it uncovers a less-examined international institution and the dilemmas faced by the Third World international legal civil servant. By examining Asante’s intellectual history and publications during the operational years of the UNCTC, it identifies three main under-explored typologies of Third World approaches to IO law. It argues that the low visibility of Third World approaches within mainstream IO law is closely linked to the failures of the NIEO movement, the abolition of the UNCTC, which symbolized the non-realization of aspirations to codify the principles of the NIEO through IOs, and minimal engagement by IO law scholars with Third World problems. This article argues that, even though the UNCTC ceased to exist in 1992, it created a lasting legacy through its advisory services, which forms part of IO law history.
The pandemic as a catalyst for teacher and student well-being
Authors: Ončevska Ager Elena
Published: June 2023

This article reports on a well-being project in which I took part and which was supported by my institution, a university department supporting the development of prospective teachers and translators of English, but also of other foreign languages. The project was designed and run in response to the COVID-19 pandemic and has the potential to inspire other institutions or ELT professionals to consider organizing similar well-being support in their own contexts. I first outline the setting that gave rise to the project and the literature that informed it. I then describe its design and report on the benefits for teacher and student well-being, as evidenced by their engagement in the project. Finally, I reflect on the lessons learnt and the implications for practitioners elsewhere.
Spatial inequality of opportunity in access to secondary education in nineteenth-century Spain
Authors: Insa-Sánchez Pau
Published: June 2023

In this paper, secondary education graduation age is proposed as a way of measuring the obstacles students had to face to acquire education in historical contexts. Using a novel historical source, I find that students from rural areas bore increasingly larger obstacles than those from cities. The size of the municipality of origin exerts a larger negative effect on students who graduated later in life—that is, those who bore larger impediments to study. These results suggest that a phenomenon of spatial isolation from knowledge created a problem of access to secondary education.
State and evolution of the geodynamo from numerical models reaching the physical conditions of Earth’s core
Authors: Aubert Julien
Published: June 2023

Our understanding of the geodynamo has recently progressed thanks to geomagnetic data of improved quality, and analyses resting on numerical simulations of increasing realism. Here, these two advances are combined in order to diagnose the state and present dynamics of Earth’s core in physically realistic conditions. A sequential, ensemble-based framework assimilates the output of geomagnetic field models covering the past 180 yr into a numerical geodynamo simulation, the physical realism of which is also advanced as data is assimilated. The internal dynamical structure estimated for the geodynamo at present reproduces previously widely documented features such as a planetary-scale, eccentric westwards gyre and localization of buoyancy release beneath the Eastern (0°E−180°E) hemisphere. Relating the typical magnetic variation timescale of the assimilated states to the power at which they operate, the present convective power of the geodynamo is estimated at 2.95 ± 0.2 TW, corresponding to an adiabatic heat flow out of the core of 14.8 ± 1 TW if the top of the core is convectively neutrally stratified at present. For the first time, morphologically and dynamically relevant trajectories are obtained by integrating the estimated states forward for a few decades of physical time using a model reaching the physical conditions of Earth’s core. Such simulations accurately account for the spatio-temporal content of high-resolution satellite geomagnetic field models and confirm earlier interpretations in terms of rapid core dynamics. The enforcement of a realistic force balance approaching a Taylor state allows for propagation of weak (velocity perturbation of about 0.6 $\mathrm{km\,yr^{-1}}$) axisymmetric torsional waves with period about 5 yr, supported by a magnetic field of root-mean-squared amplitude of 5.6 mT inside the core. Quasi-geostrophic magneto-Coriolis waves of interannual periods and significantly stronger velocity perturbation (about $7 \mathrm{km\,yr^{-1}}$) are also reproduced, with properties that converge towards those recently retrieved from the analysis of geomagnetic variations before fully achieving Earth’s core conditions. The power spectral density of magnetic variations falls off rapidly at frequencies exceeding the inverse Alfvén time (about $0.6\mathrm{yr^{-1}}$), which indicates that the excitation of hydromagnetic waves occurs preferentially at large spatial scales. The possibility to account for geomagnetic variations from years to centuries in physically realistic models opens the perspective of better constraining properties of the deep Earth through geomagnetic data assimilation.
Housing for vulnerable populations—identifying system cost implications: an analytic literature review
Authors: Kongats Krystyna , Paulden Mike , Pabayo Roman , Campbell Sandra , Nykiforuk Candace I J
Published: June 2023

We explored how investments in housing for vulnerable populations (including those experiencing homelessness) are described as leading to cost containment for the health, justice, and social service systems; the nature of any costs and benefits; and variations by housing type and over time. A structured search of peer-reviewed academic research focused on the core concepts of economic benefit, public housing programs, and vulnerable populations. Findings from 42 articles reporting on cost containment specific to health, justice, and social service systems at the municipal, regional, and/or state/provincial level were synthesized. Most of the studies focused on supportive housing interventions, targeted adults (mainly men) experiencing chronic homelessness in the USA, and reported results over 1–5 years. Approximately half of the articles reported on the costs required to house vulnerable populations. About half reported on funding sources, which is critical information for leadership decisions in cost containment for supportive housing. Most of the studies assessing program cost or cost-effectiveness reported a reduction in service costs and/or greater cost-effectiveness. Studies mostly reported impacts on health services, with hospital/inpatient care and emergency service use typically decreasing across the intervention types. All the studies that assessed cost impacts on the justice system reported a decrease in expenditures. Housing vulnerable populations was also found to decrease shelter service use and engagement with the foster care/welfare systems. Housing interventions may offer cost-savings in the short- and medium-term, with a limited evidence base also demonstrating long term benefit.
Born without a Silver Spoon: A Review of the Causes and Consequences of Adversity during Early Life
Authors: Mainwaring Mark C , Tobalske Bret W , Hartley Ian R
Published: June 2023

Synopsis

A huge amount of research attention has focused on the evolution of life histories, but most research focuses on dominant individuals that acquire a disproportionate level of reproductive success, while the life histories and reproductive tactics of subordinate individuals have received less attention. Here, we review the links between early life adversity and performance during adulthood in birds, and highlight instances in which subordinate individuals outperform dominant conspecifics. Subordinate individuals are those from broods raised under high risk of predation, with low availability of food, and/or with many parasites. Meanwhile, the broods of many species hatch or are born asynchronously and mitigation of the asynchrony is generally lacking from variation in maternal effects such as egg size and hormone deposition or genetic effects such as offspring sex or parentage. Subordinate individuals employ patterns of differential growth to attempt to mitigate the adversity they experience during early life, yet they overwhelmingly fail to overcome their initial handicap. In terms of surviving through to adulthood, subordinate individuals employ other “suboptimal” tactics, such as adaptively timing foraging behaviors to avoid dominant individuals. During adulthood, meanwhile, subordinate individuals rely on “suboptimal” tactics, such as adaptive dispersal behaviors and competing for partners at optimal times, because they represent the best options available to them to acquire copulations whenever possible. We conclude that there is a gap in knowledge for direct links between early life adversity and subordination during adulthood, meaning that further research should test for links. There are instances, however, where subordinate individuals employ “suboptimal” tactics that allow them to outperform dominant conspecifics during adulthood.
Seasonal migration, site fidelity, and population structure of European seabass (Dicentrarchus labrax)
Authors: de Pontual Helene , Heerah Karine , Goossens Jolien , Garren François , Martin Stephane , Le Ru Loic , Le Roy Didier , Woillez Mathieu
Published: June 2023

Large-scale electronic tagging is a very powerful tool to study how fish movements and migrations shape the internal dynamics of populations. This knowledge, crucial for improving fishery management, was still limited for the European seabass, whose stocks in the Northeast Atlantic have declined drastically over the last decade. To better understand the species ecology and the spatio-temporal structure of the population, we tagged seabass in the North Sea, the English Channel, and the Bay of Biscay, from 2014 to 2016. Out of 1220 deployed DSTs, 482 have been recovered by November 2022. Approximately half of them included a period of potential spawning migration. Reconstructed trajectories confirmed seabass to be a partial migratory species, as individuals exhibited either long-distance migrations or residence. Most migrants exhibited fidelity to summer feeding areas and winter spawning areas. Our dataset enriches the knowledge of seabass biological traits (e.g. temperature and depth ranges, vulnerability to predation and fishing). Our results suggest a spatial structure of the Atlantic population that differs from the stock structure currently considered for assessment and management. The consequences should be explored at both the European level and by regional managers involved in conservation outcomes.
Synchronized multidecadal trends and regime shifts in North Atlantic plankton populations
Authors: Bode A
Published: June 2023

Recent changes in oceanic plankton are being reported at unprecedented rates. Most changes are related to environmental factors, and many were identified as driven by climate, either through natural cycles or by anthropogenic effects. However, the separation of both effects is difficult because of the short length of most observational series. Moreover, some changes are related to trends and cycles, while others were perceived as system shifts, often synchronized over large spatial scales. Here, studies on observational series of plankton, with the focus in the North Atlantic, are reviewed. Two main periods of shifts in plankton assemblages were identified: one in the late 1980s and a more recent one at the beginning of the new millennium. While the origin and extent of most shifts varied locally, their synchronization seems to confirm the response of plankton to changes in warming and in large-scale climatic factors. Changes in species abundance and distribution patterns were generally related to hydrographic factors, but also to non-linear effects of warming, the latter particularly affecting species in regions near the limits of their thermal niches. Indeed, most of the changes were attributed to trade-offs between different biological strategies. Taken together, the reviewed case studies indicate a lagged biological response to variations in the local environment driven by large-scale climate forcing. The challenges for interpreting future shifts include considering local changes within a larger geographical area, variations in species life traits, and potential top-down effects of plankton predators.
Transaxillary implantation of a temporary microaxial left ventricular assist device in a patient with a rectangular kinked subclavian artery
Authors: Wert Leonhard , Kempfert Jörg , Falk Volkmar , Potapov Evgenij V
Published: June 2023

Transaxillary implantation of a temporary microaxial left ventricular assist device in patients suffering from cardiogenic shock is an established technique. We present a 77-year-old female patient with severe mitral regurgitation. She underwent minimally invasive surgical mitral valve replacement. After an uneventful postoperative course, the patient developed acute heart failure on the 11th postoperative day. Transthoracic echocardiography revealed new onset of Takotsubo cardiomyopathy with a severely decreased left ventricular ejection fraction. Implantation of a microaxial flow pump for left ventricular decompression was scheduled. Preoperative computed tomography revealed a rectangular course of the right subclavian artery. To advance the Impella, we employed an introducer fitted over the guidewire behind the Impella device as a ‘cue stick’ to move the rigid part of the pump forward to overcome the kinking using a ‘shuffleboard technique’. The haemodynamic situation stabilized immediately after implantation. The Impella 5.5 was successfully weaned after 6 days of support. In the event of (rectangular) kinking of the subclavian artery, the ‘shuffleboard technique’ can be used for the successful positioning of the pump.
BTRX-246040 Acts Through the Ventrolateral Periaqueductal Gray to Exert Antidepressant-Relevant Actions in Mice
Authors: Li Zhenlong , Xu Yuanyuan , Li Rourou , Sheng Zhenyu , Chen Xinya , Liu Xueman , Lee Chau-Shoun , Peng Hsien-Yu , Lin Tzer-Bin , Hsieh Ming-Chun , Lai Cheng-Yuan , Wu Han-Fang , Chou Dylan
Published: June 2023

Background

BTRX-246040, a nociceptin/orphanin FQ peptide receptor antagonist, is being developed for the treatment of depressive patients. However, the underlying mechanism of this potential antidepressant is still largely unclear. Here, we studied the antidepressant-related actions of BTRX-246040 in the ventrolateral periaqueductal gray (vlPAG).

Methods

The tail suspension test, forced swim test, female urine sniffing test, sucrose preference test, and learned helplessness (LH) combined with pharmacological approaches were employed to examine the antidepressant-like effects and drug effects on LH-induced depressive-like behavior in C57BL/6J mice. Electrophysiological recordings in vlPAG neurons were used to study synaptic activity.

Results

Intraperitoneal administration of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Systemic BTRX-246040 (10 mg/kg) resulted in an increased frequency and amplitude of miniature excitatory postsynaptic currents (EPSCs) in the vlPAG. Moreover, slice perfusion of BTRX-246040 directly elevated the frequency and amplitude of miniature EPSCs and enhanced the evoked EPSCs in the vlPAG, which were blocked by pretreatment with the nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198. In addition, intra-vlPAG application of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Moreover, intra-vlPAG pretreatment with 6-cyano-7-nitroquinoxaline-2,3-dione reversed both systemic and local BTRX-246040–mediated antidepressant-like behavioral effects. Furthermore, both systemic and local BTRX-246040 decreased the LH phenotype and reduced LH-induced depressive-like behavior.

Conclusions

The results suggested that BTRX-246040 may act through the vlPAG to exert antidepressant-relevant actions. The present study provides new insight into a vlPAG-dependent mechanism underlying the antidepressant-like actions of BTRX-246040.
Evolving landscape of carbapenem-resistant Pseudomonas aeruginosa at a single centre in the USA
Authors: Sakurai Aki , Dinh An Q , Hanson Blake M , Shropshire William C , Rizvi Samie A , Rydell Kirsten , Tran Truc T , Wanger Audrey , Arias Cesar A , Miller William R
Published: June 2023

Objectives

The increased identification of carbapenem-resistant Pseudomonas aeruginosa (CR-PA) is an ongoing concern. However, information on the evolving antimicrobial resistance profile and molecular epidemiology of CR-PA over time is scarce. Thus, we conducted a cross-sectional analysis to investigate the phenotypic and genotypic characteristics of CR-PA recovered over different time periods, focusing on the isolates exhibiting a ceftolozane/tazobactam resistance phenotype.

Methods

A total of 169 CR-PA isolated from clinical specimens at a single centre in Houston, TX, USA were studied. Among them, 61 isolates collected between 1999 and 2005 were defined as historical strains, and 108 collected between 2017 and 2018 were defined as contemporary strains. Antimicrobial susceptibilities against selected β-lactams was determined. WGS data were used for the identification of antimicrobial resistance determinants and phylogenetic analysis.

Results

Non-susceptibility to ceftolozane/tazobactam and ceftazidime/avibactam increased from 2% (1/59) to 17% (18/108) and from 7% (4/59) to 17% (18/108) from the historical to the contemporary collection, respectively. Carbapenemase genes, which were not identified in the historical collection, were harboured by 4.6% (5/108) of the contemporary strains, and the prevalence of ESBL genes also increased from 3.3% (2/61) to 16% (17/108). Genes encoding acquired β-lactamases were largely confined to the high-risk clones. Among ceftolozane/tazobactam-resistant isolates, non-susceptibility to ceftazidime/avibactam, imipenem/relebactam and cefiderocol was observed in 94% (15/16), 56% (9/16) and 12.5% (2/16), respectively. Resistance to ceftolozane/tazobactam and imipenem/relebactam was primarily associated with the presence of exogenous β-lactamases.

Conclusions

Acquisition of exogenous carbapenemases and ESBLs may be a worrisome trend in P. aeruginosa.
Phenotypic and molecular characterization of ESBL producing Escherichia coli and Klebsiella pneumoniae among Lebanese patients
Authors: El-Hariri Saria A , Saleh Fatima , Moghnieh Wafaa , Sokhn Elie S
Published: June 2023

Introduction

Antimicrobial resistance is a major public health issue worldwide and became one of the principal international healthcare crises of the 21st century. The production of ESBLs is one of the resistance mechanisms in Enterobacteriaceae, and they are increasingly detected in Escherichia coli and Klebsiella pneumoniae globally. Therefore, the aim of this study was to determine the phenotypic and molecular characteristics of ESBL-producing E. coli and K. pneumoniae among Lebanese patients.

Methods

A total of 152 ESBL-producing E. coli and K. pneumoniae were obtained from Geitaoui Hospital in Beirut between September 2019 and October 2020 from various clinical samples. The phenotype of ESBL producers was confirmed by a double-disc synergy test and antibiotic susceptibility was determined using the disc diffusion method. Genotypically, multiplex PCR was used to detect the ESBL genes (blaTEM, blaCTX-M and blaSHV).

Results

All strains were confirmed to be ESBL producers (121 isolates were E. coli and 31 isolates were K. pneumoniae). All isolates showed resistance to cefotaxime, cefuroxime, ampicillin and piperacillin. On the other hand, they showed a low susceptibility rate to trimethoprim/sulfamethoxazole and ciprofloxacin. Almost all the isolates were susceptible to ertapenem, imipenem and amikacin. In our study, ESBL genes were detected among 48 (39.67%) E. coli isolates and 8 (58.06%) K. pneumoniae isolates, and the most prevalent gene was blaTEM (25%), followed by blaCTX-M (19.08%) and blaSHV (16.45%).

Conclusion

Imipenem and ertapenem are the most effective drugs to treat ESBL producers. However, antibiotic stewardship programs must be implemented immediately to combat antibiotic resistance.
Recent progress in CRISPR-based bioengineering of microbial cell factories for important nutraceuticals synthesis
Authors: Hussain Muhammad Iftikhar , Raziq Abdur , Ahmed Aqsa , Iqbal Muhammad Waheed , Tian Rongzhen , Li Jianghua , Liu Long , Liu Yanfeng
Published: June 2023

Nutraceuticals are defined as food or food components with therapeutic capabilities that have few side effects and are regarded as a natural therapy for preventing the onset of several life-threatening illnesses. The use of microbial cell factories to produce nutraceuticals is considered to be sustainable and promising for meeting market demand. Among the diverse strategies for optimizing microbial cell factories, the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) system has emerged as a valuable tool for gene integration, deletion, activation, and downregulation. With the advent of multiplexed and precise CRISPR strategies, optimized microbial cell factories are revolutionizing the yield of nutraceuticals. This review focuses on the development of highly adaptable CRISPR strategies to optimize the production in microbial cell factories of some important nutraceuticals (belonging to the class of carotenoids, flavonoids, stilbenoids, polysaccharides, and nonprotein amino acids). Further, we highlighted current challenges related to the efficiency of CRISPR strategies and addressed potential future directions to fully harness CRISPR strategies to make nutraceutical synthesis in microbial cell factories an industrially favorable method.
Analytical Quality by Design-Driven RP-HPLC Method Conditions to Concomitantly Determine Cinnarizine and Morin Hydrate in Combined Drug Solution and Dual Drug-Loaded Formulations
Authors: Goswami Abhinab , Rahman Syed Nazrin R , Pawde Datta M , Shunmugaperumal Tamilvanan
Published: June 2023

Background

The replacement of traditional oils with a camphor and menthol-based eutectic mixture is done to prepare oil-less emulsion-like dispersions for co-delivery of cinnarizine (CNZ) and morin hydrate (MH) for managing Meniére’s disease (MD). Since two drugs are loaded into the dispersions, the development of a suitable reverse phase–high performance liquid chromatography (RP-HPLC) method for their simultaneous analysis becomes inevitable.

Objective

By applying the analytical quality by design (AQbD) approach, the RP-HPLC method conditions were optimized for the concomitant determination of two drugs.

Methods

The systematic AQbD started with identifying critical method attributes (CMA) through an Ishikawa fishbone diagram, risk estimation matrix, and risk priority number-based failure mode effect analysis followed by screening using fractional factorial design and optimization by face-centered central composite design. The concomitant determination of two drugs by the optimized RP-HPLC method condition was substantiated via specificity checking using combined drug solution, drug entrapment efficiency, and in vitro release of the two drugs from emulsion-like dispersions.

Results

The AQbD optimized RP-HPLC method conditions revealed the retention time for CNZ and MH at 5.017 and 5.323, respectively. The studied validation parameters were found within the ICH-prescribed limits. Exposing the individual drug solutions to acidic and basic hydrolytic conditions yielded extra chromatographic peaks for MH, probably due to the degradation of MH. The DEE % values of 87.40 ± 4.70 and 74.79 ± 2.94, respectively, were noticed for CNZ and MH in emulsion-like dispersions. More than 98% CNZ and MH release was occurred from emulsion-like dispersions within 30 min post-dissolution in artificial perilymph.

Conclusions

Overall, the AQbD approach could be helpful for systematic optimization of RP-HPLC method conditions to estimate concomitantly other therapeutic moieties.

Highlights

The proposed article shows the successful application of AQbD for the optimization of RP-HPLC method conditions to concomitantly estimate CNZ and MH in combined drug solution and dual-drug-loaded emulsion-like dispersions.
Effect of voluntary waiting period on metabolism of dairy cows during different phases of the lactation
Authors: Burgers Eline E A , Goselink Roselinde M A , Bruckmaier Rupert M , Gross Josef J , Jorritsma Ruurd , Kemp Bas , Kok Akke , van Knegsel Ariette TM
Published: June 2023

An extended calving interval (CInt) by extending the voluntary waiting period (VWP) could be associated with altered metabolism in dairy cows. The aim of this study was first to evaluate the effects of VWP on metabolism and body condition during the first 305 d after the first calving in the experiment (calving 1), around the end of the VWP, and during pregnancy (280 d before calving 2). Second, the effects of the VWP on metabolism were determined from 2 wk before until 6 wk after calving 2. Third, individual cow characteristics were used to predict milk production and body condition of cows after different VWP. Holstein-Friesian cows (N = 154, 41 primiparous [PP], 113 multiparous [MP]) were blocked for parity, milk production, and lactation persistency, randomly assigned to a VWP of 50, 125, or 200 d (VWP50, VWP125, or VWP200) and followed from calving 1 until 6 wk after calving 2. In the first 6 wk after calving 1 and from 2 wk before until 6 wk after calving 2, weekly plasma samples were analyzed for nonesterified fatty acids (NEFA), β-hydroxybutyrate, glucose, insulin, and insulin-like growth factor 1 (IGF-1). From wk 7 after calving 1 until 2 wk before calving 2, insulin and IGF-1 were analyzed every 2 wk. Fat- and protein-corrected milk (FPCM) and body weight (BW) gain were measured weekly. Cows were divided in two parity classes based on calving 1 (PP and MP) and remained in these classes after calving 2. During pregnancy, MP cows in VWP200 had greater plasma insulin and IGF-1 concentration and lower FPCM compared with MP cows in VWP125 (insulin: 18.5 vs. 13.9 µU/mL, CI 13.0–19.7, P < 0.01; IGF-1: 198.5 vs. 175.3 ng/mL ± 5.3, P = 0.04; FPCM: 22.6 vs. 30.0 kg/d ± 0.8, P < 0.01) or VWP50 (insulin: 15.8 µU/mL, P < 0.01; IGF-1: 178.2 ng/mL, P < 0.01; FPCM: 26.6 kg/d, P < 0.01) and had a greater daily BW gain compared with cows in VWP50 (3.6 vs. 2.5 kg/d ± 0.2; P < 0.01). After calving 2, MP cows in VWP200 had greater plasma NEFA concentration (0.41 mmol/liter) compared with MP cows in VWP125 (0.30 mmol/liter, P = 0.04) or VWP50 (0.26 mmol/liter, P < 0.01). For PP cows, the VWP did not affect FPCM or body condition during the first lactation in the experiment, or metabolism after calving 2. Independent of the VWP, higher milk production and lower body condition before insemination were associated with higher milk production and lower body condition at the end of the lactation. Variation in these characteristics among cows could call for an individual approach for an extended VWP.
First mitochondrial genomes of Anaspidacea (Malacostraca, Crustacea) and the phylogenetic relationships of mountain shrimps (AnaspidesThomson, 1894) and their relatives within Anaspidesidae
Authors: Höpel Christoph G , Yeo Darren , Ahyong Shane T , Meier Rudolf , Richter Stefan
Published: June 2023

We present the first complete mitochondrial genomes for Anaspidacea by sequencing 24 specimens from 12 different species in four genera (AnaspidesThomson, 1894; ParanaspidesSmith, 1908; AllanaspidesSwain, Wilson, Hickman & Ong, 1970; and MicraspidesNicholls, 1931). We recovered 20 complete (13 protein coding genes, two ribosomal RNA genes, 22 transfer RNAs), and four partial mitogenomes. The full mitogenomes range in length from 15,213 bp to 17,962 bp. We found five different gene orders and reconstruct the ground pattern of Anaspidacea, which differs from the hypothetical pancrustacean ground pattern by the translocation and reversal of tRNA-L1. The same translocation is also found in Euphausiacea and could represent a synapomorphy of these two taxa. Moreover, we reconstruct the phylogenetic relationships of the Anaspidesidae using a data set consisting of the mitochondrial protein coding genes, the two ribosomal RNAs as well as nuclear 18S and 28S rRNA. Our results strongly corroborate the monophyly of all three anaspidesiid genera, with Paranaspides as the sister group to Anaspides, which together, are sister to Allanaspides. Lastly, we resolve the main phylogenetic relationships within Anaspides.
Structural optimization of multistage centrifugal pump via computational fluid dynamics and machine learning method
Authors: Zhao Jiantao , Pei Ji , Yuan Jianping , Wang Wenjie
Published: June 2023

To implement energy savings in multistage centrifugal pumps, a return channel is utilized to replace the origin inter-stage flow channel structure, and then a single-objective optimization work containing high-precision numerical simulation, design variable dimensionality reduction, and machine learning is conducted to obtain the optimal geometric parameters. The variable dimensionality reduction process is based on the Spearman correlation analysis method. The influence of 15 design variables of the impeller and return channel is investigated, and seven of them with high-impact factors are selected as the final optimization variables. Thereafter, a genetic algorithm-backpropagation neural network (GA-BPNN) model is used to create a surrogate model with a high-fitting performance by employing a GA to optimize the initial thresholds and weights of a BPNN. Finally, a multi-island genetic algorithm (MIGA) is employed to maximize hydraulic efficiency under the nominal condition. The findings demonstrate that the optimized model’s efficiency is increased by 4.29% at 1.0Qd, and the deterioration of the pump performance under overload conditions is effectively eliminated (the maximum efficiency increase is 14.72% at 1.3Qd). Furthermore, the internal flow analysis indicates that the optimization scheme can improve the turbulence kinetic energy distribution and reduce unstable flow structures in the multistage centrifugal pump.
Entomology beyond research and education: 2022 student debates
Authors: Sandhi Ramandeep Kaur , Pickens Victoria , Bello Elizabeth , Elzay Sarah , Salgado Sara , Hauri Kayleigh C , Ternest John J , Constancio Natalie , Gula Scott , Gearner Olivia M , Anderson Magdeline , Edeburn Molly , Hall Brandon , Maille Jacqueline , Toth Mollie , Khadka Arjun , Doherty Ethan , Musgrove Tyler , Silva Tiago , Desoto Alexia , Rampone Emily , Jocson Dowen , Luppino Mario , Pautzke Kellen , Wagstaff Camille
Published: June 2023

The 2022 student debates of the Entomological Society of America (ESA) happened during the Joint Annual Meeting of the Entomological Societies of America, Canada, and British Columbia in Vancouver, BC, and addressed entomological aspects beyond research and education. The Student Debates Subcommittee of the ESA Student Affairs Committee and the participating student team members communicated for 8 months and prepared for the debates. The theme of the ESA meeting in 2022 was “Entomology as inspiration: Insects through art, science, and culture”. There were 2 unbiased speakers who introduced the debate topics as well as 4 teams who debated the following 2 topics: (i) Is forensic entomology viable in criminal case investigations and court cases today? and (ii) Are insects being treated ethically in scientific research? The teams prepared for about 8 months, debated their arguments, and shared their thoughts with the audience. The teams were judged by a panel and the winners were recognized at the ESA Student Awards Session during the annual meeting.
Current treatment strategies for EGFR-mutated non-small cell lung cancer: from first line to beyond osimertinib resistance
Authors: Araki Taisuke , Kanda Shintaro , Horinouchi Hidehito , Ohe Yuichiro
Published: June 2023

Osimertinib, a third-generation EGFR TKI, is the standard therapy for previously untreated EGFR-mutated non-small cell lung cancer patients following the landmark FLAURA study. However, resistance inevitably hinders patient prognosis, increasing the need for new therapeutic strategies beyond osimertinib. Frontline osimertinib-based combination strategies (platinum-based chemotherapy and angiogenesis inhibitors) are currently being tested primarily to prevent initial resistance. In the later-line setting after osimertinib, many next-line therapeutic candidates have been actively examined in clinical trials. Notably, several drugs with novel mechanisms of action, such as antibody–drug conjugates and EGFR -MET bispecific antibodies, have shown promising efficacy despite the resistance mechanisms and are close to clinical application. In addition, genotype-based target strategies have been investigated for a better understanding of osimertinib resistance mechanisms based on molecular profiling tests at relapse. The C797S mutation and MET gene alterations are commonly identified following osimertinib resistance, for which targeting strategies are actively tested. This review describes current pharmacotherapeutic strategies for EGFR-mutated non-small cell lung cancer based on the results of clinical trials and the latest published data, broadly grouped into two sections: 1) EGFR TKIs-based combination therapy in the front-line setting and 2) novel therapeutic strategies after osimertinib resistance.
Labor provisions in trade agreements: recasting the protectionist debate
Authors: LeClercq Desirée , Robertson Raymond , Samaan Daniel
Published: June 2023

Labor provisions are integral to regional trade agreements (RTAs). Critics argue that they are a protectionist measure by reducing trade flows. Efforts to test that argument by employing various economic gravity models to trade agreements with labor provisions have failed to apply clear legal criteria and updated estimation methods. Drawing from the law of transnational contracts, we apply clear legal criteria to labor clauses and estimate a Poisson regression by pseudo maximum likelihood with high-dimensional fixed effects and controls for other “deep” agreement provisions associated with trade. We estimate the relationship between labor provisions and bilateral trade by classifying labor clauses found in all World Trade Organization-notified RTAs from the 1990s through February 2016. Contrary to previous efforts, our concise typology, updated estimation methods, and controls for additional trade-agreement variables find no robust evidence that labor provisions impact, much less reduce, trade flows (JEL F1, C5, F14, F66).
Introduction to the special issue of social media: the good, the bad, and the ugly
Authors: Stromer-Galley Jennifer , Wojcieszak Magdalena , John Nicholas , Massanari Adrienne L
Published: June 2023

As social media scholarship pervades the communication discipline, it is time to reflect on the good, bad, and ugly of social media. The theme for this special issue is inspired in part by the 1966 film, “The Good, The Bad, and The Ugly.” Like its portrayal of the American Civil War, we again face deep divisions. The question is what role is social media helping us to heal those divides versus fragmenting us further? The seven articles in this issue reflect the complexity of the answer. Although we aimed for diversity, this issue focuses on the Global North. This reflects the field and the need to decenter Western epistemology. Nevertheless, the articles help us see that social media is not easily reduced to simplistic framings, but instead enables new connections and collective action, while also risking further fragmentation of our information environment and greater polarization—while technology companies profit.
Factors Associated With Viral Suppression and Drug Resistance in Children and Adolescents Living With HIV in Care and Treatment Programs in Southern Tanzania
Authors: Khamadi Samoel A , Bahemana Emmanuel , Dear Nicole , Mavere Caroline , George Fredy , Kapene Razack , Papianus Grace , Willoughby Walidah , Chambers Jillian , Ganesan Kavitha , Mwakabanje Iman , Bacha Jason M , Desai Priyanka , Almas Shaban , Coakley Peter D , Wolfman Vanessa , Lee Elizabeth H , Hickey Patrick W , Livezey Jeffrey , Agaba Patricia A
Published: June 2023

Background

Achieving viral suppression (VS) for persons living with HIV is key to reaching epidemic control. We assessed the prevalence of VS and the frequency of HIV drug resistance mutations (HIVDRM) among children and adolescents living with HIV (CALHIV) in the Southern Highland zone of Tanzania.

Methods

From 2019 to 2021, we enrolled CALHIV aged 1–19 years on ART for >6 months in a cross-sectional study. Participants had viral load (VL) testing; those with VL ≥ 1000 copies/mL underwent HIVDRM testing. VS (<1000 copies/mL) prevalence estimates were calculated and robust Poisson regression was used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for associations with potential predictors of VS.

Results

Of 707 participants, 595 had VS (PR: 0.84, 95% CI: 0.81–0.87). Use of an integrase strand transfer inhibitor-containing regimen (aPR 1.15, 95% CI: 0.99–1.34), age 5–9 years (aPR 1.16, 95% CI: 1.07–1.26), and seeking care at a referral center (aPR 1.12, 95% CI: 1.04–1.21) were associated with VS. Factors inversely associated with VS included having one (aPR 0.82, 95% CI: 0.72–0.92) or two or more (aPR 0.79, 95% CI: 0.66–0.94) referrals for adherence counselling, and self-reporting missing one to two (aPR 0.88, 95% CI: 0.78–0.99) or three or more (aPR 0.77, 95% CI: 0.63–0.92) doses of ART in the past month. Of 74 participants with PRRT and INT sequencing done, 60 (81.1%) had HIVDRMs at the following frequencies: 71.6%, 67.6%, 1.4%, and 4.1% for major NNRTI, NRTI, PI, and INSTI respectively.

Conclusions

Higher rates of VS were observed in this cohort, and HIVDRMs were common in those without VS. This evidence supports ART optimization using dolutegravir-based regimens. However, better strategies to improve adherence are needed.