bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo peripheral nerve activation using sinusoidal low‐frequency alternating currents
Authors: Alhawwash Awadh , Muzquiz M. Ivette , Richardson Lindsay , Vetter Christian , Smolik Macallister , Goodwill Adam , Yoshida Ken 
Published: June 2022

AbstractBackgroundThe sinusoidal low‐frequency alternating current (LFAC) waveform was explored recently as a novel means to evoke nerve conduction block. In the present work, we explored whether increasing the amplitude of the LFAC waveform results in nerve fiber activation in autonomic nerves. In‐silico methods and preliminary work in somatic nerves indicated a potential frequency dependency on the threshold of activation. The Hering‐Breuer (HB) reflex was used as a biomarker to detect cervical vagus nerve activation.MethodsExperiments were conducted in isoflurane‐anesthetized swine (n = 5). Two stimulating bipolar cuff electrodes and a tripolar recording cuff electrode were implanted on the left vagus nerve. To ensure the electrical stimulation affects only the afferent pathways, the nerve was crushed caudal to the electrodes to eliminate cardiac effects. (1) Standard pulse stimulation (Vstim) using a monophasic train of pulses was applied through the caudal electrode to elicit HB reflex and to identify the activated nerve fiber type. (2) Continuous sinusoidal LFAC waveform with a frequency ranging from 5 through 20 Hz was applied to the rostral electrode without Vstim to explore the activation thresholds at each LFAC frequency. In both cases, the activation of nerve fibers was detected by a HB reflex‐induced reduction in the breathing rate.ResultsLFAC was found to be capable of eliciting an HB response. The LFAC activation thresholds were found to be frequency‐dependent. The HB threshold was 1.02 ± 0.3 mAp at 5 Hz, 0.66 ± 0.3 mAp at 10 Hz, and 0.44 ± 0.2 mAp at 20 Hz. In comparison, it was 0.7 ± 0.47 mA for a 100 μs pulse. The LFAC amplitude was within the linear limits of the electrode interface. Damage to the cuff electrodes or the nerve tissues was not observed. Analysis of Vstim‐based compound nerve action potentials (CNAP) indicated that the decrease in breathing rate was found to be correlated with the activation of slower components of the CNAP suggesting that LFAC reached and elicited responses from these slower fibers associated with afferents projecting to the HB response.ConclusionsThese results suggest the feasibility of the LFAC waveform at 5, 10, and 20 Hz to activate autonomic nerve fibers and potentially provide a new modality to the neurorehabilitation field.
β2‐Adrenoceptor agonist profiling reveals biased signalling phenotypes for the β2‐adrenoceptor with possible implications for the treatment of asthma
Authors: De Pascali Francesco , Ippolito Michael , Wolfe Emily , Komolov Konstantin E. , Hopfinger Nathan , Lemenze Douglas , Kim Nicholas , Armen Roger S. , An Steven S. , Scott Charles P. , Benovic Jeffrey L. 
Published: June 2022

Background and Purposeβ‐Adrenoceptor agonists relieve airflow obstruction by activating β2‐adrenoceptors, which are G protein‐coupled receptors (GPCRs) expressed on human airway smooth muscle (HASM) cells. The currently available β‐adrenoceptor agonists are balanced agonists, however, and signal through both the stimulatory G protein (Gs)‐ and β‐arrestin‐mediated pathways. While Gs signalling is beneficial and promotes HASM relaxation, β‐arrestin activation is associated with reduced Gs efficacy. In this context, biased ligands that selectively promote β2‐adrenoceptor coupling to Gs signalling represent a promising strategy to treat asthma. Here, we examined several β‐adrenoceptor agonists to identify Gs‐biased ligands devoid of β‐arrestin‐mediated effects.Experimental ApproachGs‐biased ligands for the β2‐adrenoceptor were identified by high‐throughput screening and then evaluated for Gs interaction, Gi interaction, cAMP production, β‐arrestin interaction, GPCR kinase (GRK) phosphorylation of the receptor, receptor trafficking, ERK activation, and functional desensitization of the β2‐adrenoceptor.Key ResultsWe identified ractopamine, dobutamine, and higenamine as Gs‐biased agonists that activate the Gs/cAMP pathway upon β2‐adrenoceptor stimulation while showing minimal Gi or β‐arrestin interaction. Furthermore, these compounds did not induce any receptor trafficking and had reduced GRK5‐mediated phosphorylation of the β2‐adrenoceptor. Finally, we observed minimal physiological desensitization of the β2‐adrenoceptor in primary HASM cells upon treatment with biased agonists.Conclusion and ImplicationsOur work demonstrates that Gs‐biased signalling through the β2‐adrenoceptor may prove to be an effective strategy to promote HASM relaxation in the treatment of asthma. Such biased compounds may also be useful in identifying the molecular mechanisms that determine biased signalling and in design of safer drugs.
Frugal innovation: Antecedents, mediators, and consequences
Authors: Hossain Mokter , Agarwal Nivedita , Bhatti Yasser , Levänen Jarkko 
Published: June 2022

Frugal innovation (FI) describes a phenomenon whereby solutions are developed to serve low‐income customers, mainly in developing countries, with affordable products and services that help address pressing social and environmental problems. Despite a decade of academic interest in FI, we still lack an overarching understanding of the various facets of this phenomenon. Based on 48 in‐depth interviews for 23 cases, we integrated and validated 10 years of FI scholarship. This study therefore set out to develop a comprehensive framework for FI, one that would identify its antecedents, mediators, and consequences. Such a framework promises a holistic perspective for FI by linking these identified factors to the concept of sustainability. The findings also reinforce the dual contribution that FI makes in terms of both business growth and inclusive growth. Finally, this study discusses the theoretical and practical implications and provides some suggestions for future research on FI.
Sparse labels, no problems: Infant categorization under challenging conditions
Authors: LaTourrette Alexander , Waxman Sandra R. 
Published: June 2022

AbstractLabeling promotes infants' object categorization even when labels are rare. By 2 years, infants engage in “semi‐supervised learning” (SSL), integrating labeled and unlabeled exemplars to learn categories. However, everyday learning contexts pose substantial challenges for infants' SSL. Here, two studies (n = 74, 51% female, 62% non‐Hispanic White, 18% multiracial, 8% Asian, 6% Black, Mage = 27.3 months, collected 2018–2020) implemented a familiarization‐novelty preference paradigm assessing 2‐year‐olds' SSL when (i) exemplars from the target category are interspersed with other objects (Study 1, d = .67) and (ii) multiple categories are learned simultaneously (Study 2, d = .74). The findings indicate 2‐year‐olds' SSL is robust enough to support object categorization despite substantial challenges posed by everyday learning contexts.
Investigation of CYP3A induction by PF‐05251749 in early clinical development: comparison of linear slope physiologically based pharmacokinetic prediction and biomarker response
Authors: Lin Jian , Gaudreault Francois , Johnson Nathaniel , Lin Zhiwu , Nouri Parya , Goosen Theunis C. , Sawant‐Basak Aarti 
Published: June 2022

AbstractPF‐05251749 is a dual inhibitor of casein kinase 1 δ/ε under clinical development to treat disruption of circadian rhythm in Alzheimer's and Parkinson's diseases. In vitro, PF‐05251749 (0.3–100 μM) induced CYP3A in cryopreserved human hepatocytes, demonstrating non‐saturable, dose–dependent CYP3A mRNA increases, with induction slopes in the range 0.036–0.39 μM−1. In a multiple‐dose study (B8001002) in healthy participants, CYP3A activity was explored by measuring changes in 4β‐hydroxycholesterol/cholesterol ratio. Following repeated oral administration of PF‐05251749, up to 400 mg q.d., no significant changes were observed in 4β‐hydroxycholesterol/cholesterol ratio; this ratio increased significantly (~1.5‐fold) following administration of PF‐05251749 at 750 mg q.d., suggesting potential CYP3A induction at this dose. Physiologically based pharmacokinetic (PBPK) models were developed to characterize the observed clinical pharmacokinetics (PK) of PF‐05251749 at 400 and 750 mg q.d.; the PBPK induction model was calibrated using the in vitro linear fit induction slope, with rifampin as reference compound (Indmax = 8, EC50 = 0.32 μM). Clinical trial simulation following co‐administration of PF‐05251749, 400 mg q.d. with oral midazolam 2 mg, predicted no significant drug interaction risk. PBPK model predicted weak drug interaction following co‐administration of PF‐05251749, 750 mg q.d. with midazolam 2 mg. In conclusion, good agreement was obtained between CYP3A drug interaction risk predicted using linear‐slope PBPK model and exploratory biomarker trends. This agreement between two orthogonal approaches enabled assessment of drug interaction risks of PF‐05251749 in early clinical development, in the absence of a clinical drug–drug interaction study.
Out‐of‐hospital versus in‐hospital status epilepticus: The role of etiology and comorbidities
Authors: Brigo Francesco , Turcato Gianni , Lattanzi Simona , Orlandi Niccolò , Turchi Giulia , Zaboli Arian , Giovannini Giada , Meletti Stefano 
Published: June 2022

AbstractBackground and purposeOur objectives were to identify differences in clinical characteristics between patients with out‐of‐hospital and in‐hospital status epilepticus (SE) onset, and to evaluate the influence of SE onset setting on 30‐day mortality and SE cessation.MethodsWe included consecutive patients with SE admitted from 2013–2021 at Modena Academic Hospital. A propensity score was obtained with clinical variables unevenly distributed between the two groups.ResultsSeven hundred eleven patients were included; 55.8% (397/711) with out‐of‐hospital and 44.2% (314/711) with in‐hospital onset. Patients with in‐hospital SE onset were older and had a higher frequency of comorbidities, acute and/or potentially fatal etiologies, impaired consciousness before treatment, and nonconvulsive or myoclonic SE. No difference was found in SE cessation between the groups. Patients with in‐hospital SE had higher 30‐day mortality (127/314, 62.9% vs. 75/397, 37.1%; p < 0.001). In‐hospital onset was an independent risk factor for 30‐day mortality (adjusted odds ratio = 1.720; 95% confidence interval = 1.107–2.674; p = 0.016). In the propensity group (n = 244), no difference was found in 30‐day mortality and SE cessation between out‐of‐hospital and in‐hospital SE onset groups (36/122, 29.5% vs. 34/122, 27.9%; p = 0.888; and 47/122, 38.5% vs. 39/122; 32%; p = 0.347, respectively).ConclusionsIn‐hospital SE is associated with higher 30‐day mortality without difference in SE cessation. The two groups differ considerably for age, acute and possibly fatal etiologies, comorbidities, and SE semiology. The patient location at SE onset is an important prognostic predictor. However, the increased mortality is probably unrelated to the setting of SE onset and reflects intrinsic prognostic predictors.
Don't interfere with my rights! Employee rights violation and the cost of bank loans
Authors: Fard Amirhossein , Siraj Ibrahim , Wang Bin 
Published: June 2022

AbstractWe study the relationship between the cost of bank loans and the charges filed to the National Labor Relations Board (NLRB) due to managerial interference in employee rights. Loans issued after the filing of the allegations are associated with significantly higher loan spreads than loans initiated before the filing of allegations. Strong allegations that result in withdrawal with adjustments or compliance tend to positively affect the loan pricing. Further, interfering firms tend to experience higher default risks in the years following the filing of charges. Our paper is the first in the literature to show the impact of violation of employee rights on the cost of bank loans, which has an implication for environmental, social, and governance (ESG) lending where loan contract terms are contingent on borrower ESG performance.
Environmental change and the rate of phenotypic plasticity
Authors: Burton Tim , Ratikainen Irja Ida , Einum Sigurd 
Published: June 2022

AbstractWith rapid and less predictable environmental change emerging as the ‘new norm’, understanding how individuals tolerate environmental stress via plastic, often reversible changes to the phenotype (i.e., reversible phenotypic plasticity, RPP), remains a key issue in ecology. Here, we examine the potential for better understanding how organisms overcome environmental challenges within their own lifetimes by scrutinizing a somewhat overlooked aspect of RPP, namely the rate at which it can occur. Although recent advances in the field provide indication of the aspects of environmental change where RPP rates may be of particular ecological relevance, we observe that current theoretical models do not consider the evolutionary potential of the rate of RPP. Whilst recent theory underscores the importance of environmental predictability in determining the slope of the evolved reaction norm for a given trait (i.e., how much plasticity can occur), a hitherto neglected possibility is that the rate of plasticity might be a more dynamic component of this relationship than previously assumed. If the rate of plasticity itself can evolve, as empirical evidence foreshadows, rates of plasticity may have the potential to alter the level predictability in the environment as perceived by the organism and thus influence the slope of the evolved reaction norm. However, optimality in the rate of phenotypic plasticity, its evolutionary dynamics in different environments and influence of constraints imposed by associated costs remain unexplored and may represent fruitful avenues of exploration in future theoretical and empirical treatments of the topic. We conclude by reviewing published studies of RPP rates, providing suggestions for improving the measurement of RPP rates, both in terms of experimental design and in the statistical quantification of this component of plasticity.
Dolutegravir in real life: Self‐reported mental and physical health outcomes after transitioning from efavirenz‐ to dolutegravir‐based antiretroviral therapy in a prospective cohort study in Lesotho
Authors: Brown Jennifer A. , Nsakala Bienvenu L. , Mokhele Kuena , Rakuoane Itumeleng , Muhairwe Josephine , Glass Tracy R. , Amstutz Alain , Tschumi Nadine , Belus Jennifer M. , Klimkait Thomas , Labhardt Niklaus D. 
Published: June 2022

AbstractIntroductionHIV programmes across many countries in Africa have recently transitioned people living with HIV from efavirenz (EFV)‐ to dolutegravir (DTG)‐containing antiretroviral therapy (ART). As both drugs are associated with neuropsychiatric adverse effects, this study assessed the mental health and HIV/ART‐associated symptoms of people living with HIV before and after transition to DTG.MethodsThe prospective DO‐REAL cohort enrolled people starting DTG‐based ART in Lesotho from February to December 2020. For this analysis within DO‐REAL, we included adults changing from tenofovir disoproxil fumarate (TDF)/lamivudine (3TC)/EFV to TDF/3TC/DTG within first‐line therapy. At transition and 16 weeks thereafter, participants completed the Patient Health Questionnaire‐9 (PHQ‐9; depression screening), the 12‐item Short‐Form Health Survey (SF‐12; mental and physical health), and a modified HIV Symptom Index (mHSI; HIV/ART‐related symptoms). We also assessed weight change. We used McNemar tests with Bonferroni corrections to assess binary outcomes.ClinicalTrials.gov: NCT04238767.ResultsAmong 1228 participants, 1131 completed follow‐up. Of these, 60.0% were female, the median age was 46 years (interquartile range [IQR] 38–55), and the median time taking ART was 5.7 years (IQR 3.5–8.9). No change was observed for weight or overall PHQ‐9 or SF‐12 outcomes. However, three mHSI items decreased at follow‐up: ‘feeling sad/down/depressed’ (bothered 6.0% vs. 3.3% of participants at least ‘a little’ before vs. after transition; adjustedp = 0.048); ‘feeling nervous/anxious’ (7.4% vs. 3.4%; adjustedp = 0.0009); and ‘nightmares, strange/vivid dreams’ (6.3% vs. 3.5%; adjustedp = 0.027). Individual PHQ‐9 or SF‐12 items also improved. Being symptom free across all measures increased from 5.1% to 11.4% (p < 0.0001).ConclusionsWe observed no negative impacts and potential moderate improvements with DTG, providing further support for the rollout of DTG.
Antimicrobial evaluation of the Cynara cardunculus extract in Helicobacter pylori cells using mid-infrared spectroscopy and chemometric methods
Authors: Sousa Sampaio Pedro N. , Calado Cecília R. C. 
Published: June 2022

Abstract
The treatment effectiveness of gastric diseases caused by the bacteria Helicobacter pylori is failing due to high resistance to some antibiotics. Consequently, it is urgent to develop an accurate methodology to screen new antimicrobial agents.

Methods and Results
A preliminary assay, using both therapeutic-based antibiotics (clarithromycin and metronidazole), was conducted to optimize experimental conditions in terms of the sensibility of the Fourier-transform mid-infrared (MIR-FTIR) spectroscopy associated with chemometric methods. Principal component analysis was applied to understand how the Cynara extract concentration acts differentially against H. pylori bacteria. The partial least squares model, characterized by R2 = 0.98, and root mean square error cross-validation, 0.011, was developed for the spectral regions (3600–2500 cm−1 and 2000–698 cm−1).

Conclusions
MIR-FTIR spectroscopy associated with chemometric methods can be considered a suitable approach to discover and analyse the promissory antimicrobial agents based on the biomolecular changes observed according to the Cynara extract.

Significance and Impact of the Study
MIR-FTIR spectroscopy and chemometric methods allowed to register the biomolecular changes due to the potential antimicrobial drugs at reduced concentrations comparatively to the conventional assay based on an agar-dilution method, being considered a useful approach to develop a platform to discover new bioactive molecules, allowing to reduce time and costs related to the exploratory step.
Potential biological control agents ofZeugodacus cucurbitae(Coquillett): A review
Authors: Diksha  , Mahajan Evani , Singh Sumit , Sohal Satwinder Kaur 
Published: June 2022

AbstractZeugodacus cucurbitae(Coquillett) (Diptera: Tephritidae) is a serious agro‐economic pest of cucurbits around the world. Management of tephritid fruit flies is till date mainly dependent on the use of chemical pesticides. In a rising concern about environment quality and rapid development of resistance in insect pests, biological control of insect pests is being contemplated, and in response, research approaches are constantly evolving. Various naturally occurring control agents of melon fruit fly such as parasitoids, bacteria, fungi and nematodes have potential in the management ofZ. cucurbitae. Many parasitoids includingPsyttalia fletcheri,Fopius arisanus,Dirhinus giffardiiandSpalangia endiusare known to attack various life stages ofZ. cucurbitae. Although parasitoids are being principally exploited for control ofZ. cucurbitae, various other entomopathogens such as fungi (Beauveria bassiana,Paecilomyces fumosoroseus,Metarhizium anisopliae), bacteria (Bacillus thuringiensis), nematodes (Heterorhabditis indica,Steinernema feltiae) and microbial toxins/products (spinosad, avermectin) are being investigated or used for biological control. The development of farming methodologies with greater credence on ecosystem services such as biological control ofZ. cucurbitaewill increase sustainability of agroecosystems. This review provides a concise compilation of these biological control agents along with their effectiveness and will help researchers in designing various integrated pest management strategies againstZ. cucurbitaethat involve biological control agents.
Fully digital workflow for the fabrication of a tooth‐colored space maintainer for a young patient
Authors: Lee Ju‐Hyoung 
Published: June 2022

AbstractObjectivesPreventive orthodontic therapy with a band and loop is recommended to reduce the prevalence and severity of malocclusion on premature loss of a primary molar. However, when young patients are less cooperative and have a severe gag reflex, using traditional impression methods may be challenging. The use of a conventional metal space maintainer (SM) requires manual laboratory procedures and does not provide optimal esthetics. Moreover, gingival submergence of the wire and gingivitis caused by metal structures may occur. This clinical report describes a complete digital workflow for the fabrication of a zirconia SM to overcome these limitations.Clinical ConsiderationsAn 8‐year‐old boy with a band and loop SM for a missing primary mandibular right second molar presented with plaque accumulation around the band, soft tissue impingement by the loop, and loss of cement. A reverse band and loop SM had been proposed for the restoration of the primary mandibular right first molar. After conservative tooth preparation, a digital impression procedure was performed. A customized band and loop SM was designed using a computer‐aided design software and milled out of the zirconia block. After sintering, the SM was luted with adhesive resin cement.ConclusionsUsing an intraoral scanner, computer‐aided design, and computer‐aided manufacturing technology, the limitations of traditional impression procedures were overcome, and a zirconia SM with mechanical, biological, and esthetic advantages was fabricated.Clinical SignificanceAdvancements in dental materials and digital technologies allow for the efficient fabrication of a tooth‐colored SM with an improved patient satisfaction and reduced human error.