bluuebunny/crossref_metadata_2025 huggingface dataset:
MeCP2 regulates Gdf11, a dosage-sensitive gene critical for neurological function
Authors: Bajikar Sameer S. , Anderson Ashley G. , Zhou Jian , Durham Mark A. , Trostle Alexander J. , Wan Ying-Wooi , Liu Zhandong , Zoghbi Huda Y.
Published: October 2022

Loss- and gain-of-function of MeCP2 causes Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. MeCP2 binds methyl-cytosines to finely tune gene expression in the brain, though identifying genes robustly regulated by MeCP2 has been difficult. By integrating multiple transcriptomics datasets, we identified that MeCP2 finely regulates Growth differentiation factor 11 (Gdf11). Gdf11 is down-regulated in RTT mouse models and is inversely up-regulated in MDS mouse models. Strikingly, genetically normalizing Gdf11 dosage levels improved several behavioral deficits in a mouse model of MDS. Next, we discovered that losing one copy of Gdf11 alone was sufficient to cause multiple neurobehavioral deficits in mice, most notably hyperactivity and decreased learning and memory. This decrease in learning and memory was not due to changes in proliferation or numbers of progenitor cells in the hippocampus. Lastly, loss of one copy of Gdf11 decreased longevity and survival in mice, corroborating its putative role in aging. Our data demonstrate that Gdf11 dosage is important for brain function.
A novel taurine-respiring murine gut bacterium contributes to colonization resistance against enteropathogens
Authors: Ye Huimin , Borusak Sabrina , Eberl Claudia , Hanson Buck T. , Zwirzitz Benjamin , Herbold Craig W. , Pjevac Petra , Hausmann Bela , Stecher Bärbel , Schleheck David , Loy Alexander
Published: October 2022

Taurine-respiring gut bacteria produce H2S with ambivalent impact on host health. We report the isolation and genomic-ecophysiological characterization of the first taurine-respiring mouse gut bacterium.Taurinivorans murisrepresents a new widespread species with protective capacity against pathogens and differs from the human gut sulfidogenBilophila wadsworthiain its sulfur metabolism and host distribution. Despite alternative physiologies, taurine respiration was the mainin vivolifestyle ofT. murisindependent of mouse diet and genotype. In gnotobiotic mice,T. murisselectively enhanced the activity of a sulfur metabolism gene-encoding prophage and provided slightly increased colonization resistance againstSalmonellaTyphimurium, which showed reduced expression of galactonate catabolism genes. We identifiedT. murisas the dominant sulfidogen of a mouse microbiota that conferred H2S-mediated protection againstKlebsiella pneumoniaein a previous study. Together, we revealed the realized physiological niche of a key murine gut sulfidogen and its impact on pathogen and phage gene expression.

One sentence summary

Our work identified and characterized a new core member of the murine gut microbiota, revealed sulfidogenic taurine respiration as its predominantin vivolifestyle, and emphasizes its protective function in pathogen colonization.
Disentangling positive vs. relaxed selection in animal mitochondrial genomes
Authors: Zwonitzer Kendra D. , Iverson Erik N. K. , Sterling James J. , Weaver Ryan J. , Maclaine Bradley A. , Havird Justin C.
Published: October 2022

Disentangling different types of selection is a common goal in molecular evolution. Elevated dN/dS ratios (the ratio of nonsynonymous to synonymous substitution rates) in focal lineages are often interpreted as signs of positive selection. Paradoxically, relaxed purifying selection can also result in elevated dN/dS ratios, but tests to distinguish these two causes are seldomly implemented. Here, we reevaluated seven case studies describing elevated dN/dS ratios in animal mtDNA and their accompanying hypotheses regarding selection. They included flightless vs. flighted lineages in birds, bats, and insects, and physiological adaptations in snakes, two groups of electric fishes, and primates. We found that elevated dN/dS ratios were often not caused by the predicted mechanism, and we sometimes found strong support for the opposite mechanism. We discuss reasons why energetic hypotheses may be confounded by other selective forces acting on mtDNA and caution against overinterpreting molecular “spandrels”, including elevated dN/dS ratios.
Gastric administration of Cis-9, trans-11 and trans-10, cis-12 conjugated linoleic during the pregestational and gestational periods does not influence the follicular endowment of the progeny
Authors: de Freitas Danielle Storino , de Gouvêa Lopes Guilherme Antonio , Nascimento Barbara Rodrigues , Madureira Ana Paula , Campos-Junior Paulo Henrique Almeida
Published: October 2022

Fetal programming suggests that maternal stimulation and nutrition during the period of fetal development can program the progeny. Conjugated linoleic acid (CLA), an isomer of linoleic acid, has been characterized in several aspects, but few studies have been performed on its involvement in reproduction and fetal programming. The aim of this study was to evaluate the F1, F2 and F3 progeny of female mice supplemented with CLA during the pregestational and gestational periods with respect to biometric and reproductive parameters, as well as ovarian morphophysiology. The F1 progeny of mothers supplemented with CLA exhibited stable weight gain, while the F2 progeny showed no effects (P=0.0187 and P=0.0245, respectively). A reduction in Lee’s Index was observed in both generations at the second post-weaning evaluation week in the animals treated with CLA (P=0.0100 and P=0.0078, respectively). The F2 generation showed an increase in the anogenital index in both sexes of the animals treated with CLA (P= 0.0114 and P<0.0001, female and male respectively). CLA administration to mothers did not affect any of the following in their progeny: ovarian follicle mobilization (P>0.05), follicle number (P>0.05) and the integrated density of the lipid content of oocytes included in antral follicles (P>0.05). This study evaluated the use of CLA in mothers and found that it did not affect the progeny regarding murine reproductive performance, suggesting that this supplement can be used safely.
An estimation of bio-methane and energy project potentials of municipal solid waste using landfill gas emission and cost models
Authors: Usman Abdullahi Mohammed
Published: October 2022

Purpose

The purpose of the study is to analyse municipal solid waste (MSW) disposed of in Jimeta-Yola metropolis for landfill gas (LFG), methane and project viability potential.

Design/methodology/approach

The data was collected daily from landfills for four weeks. About 7,329.55 Mg/year of waste was analysed. These waste were separated into bio-degradable components i.e. paper and textile (263.66 Mg), non-food organic (681.45 Mg), wood and straw (189.50 Mg) and food and kitchen waste (1797.20 Mg). Non-degradable components include plastics, polythene bags, metals, sand, stones, cans etc. (4397.73 Mg). The component's characteristics such as a number of samples, weight, volume, landfill age etc. were measured. The waste, methane (CH4) and energy potential were also analysed using LFG energy cost model.

Findings

The landfills received 15 Gg/year of MSW and emit 0.31 Gg/year of LFG having CH4 content of 82.95 Mg in 2016. These can produce 33.78 GWh of heat energy equivalent to 10.14 GWh of electricity analytically. Therefore, between 2016 and 2022, about 2.24 Gg CH4 and 5201.32 MWh of electricity were wasted. Henceforth, proper management of these waste substances can produce 186.4 Gg CH4 which will generate 432.52 GWh of electricity. The most economically viable project is an electricity project generating 418 kW/year at a sale price of $1.14/kWh (58.38/kWh) and a payback period of 11 years.

Practical implications

Raw LFG collected can be used in heating brick kilns, boilers, furnaces and greenhouses. When treated, the LFG can produce renewable natural gas (RNG), which is used in energy generation and various domestic, vehicle and industrial applications.

Social implications

The analytical energy generation can provide gross revenue of ₦19.46bn at an average of ₦192.71million/year. Using Landfill Gas Emissions Model (LandGEM) model, the gross and net revenue will be $0.42m and $0.28m yearly, respectively. The project can provide jobs and economic boost to the immediate community through associated ripple effect.

Originality/value

The research is a pre-feasibility study for LFG to gas or electricity projects in Jimeta-Yola. The study contributed to the body of knowledge as a source of literature for further studies locally and globally.
Tangible and intangible hotel in-room amenities in shaping customer experience and the consequences in the with-corona era
Authors: Kim Jinkyung Jenny , Lee Jin-Soo , Han Heesup
Published: October 2022

Purpose

This study aims to draw on customer experience theory to shed light on how hotel in-room amenities foster customer experience, which continues to form brand attitude and loyalty before and during the pandemic. Also, this study assesses the impact of the pandemic in the relationships among proposed constructs on the basis of risk perception theory.

Design/methodology/approach

A quantitative approach was deployed using a total of 379 responses, for evaluating the measurement model through confirmatory factor analysis and testing proposed hypotheses through structural equation modeling.

Findings

The findings provide initial support for the predictions, except for the influence of brand attitude on brand loyalty before the pandemic. Particularly, the analysis results observe that the effect of tangible amenities on customer experience was stronger before the COVID-19, whereas the impact of intangible amenities on customer experience is greater during the pandemic. Furthermore, the results validate the significant moderating influence of the COVID-19 pandemic in the path between customer experience and brand loyalty.

Practical implications

This present study guides hotel professionals to be more effective in the management of appropriate in-room amenity to create a satisfactory customer experience, which contributes to brand loyalty in the with-corona era.

Originality/value

The study differs from earlier studies in that it investigates how the pandemic changes the role of hotel in-room amenities on customer experience, which, in turn, increases brand attitude and brand loyalty for the first time.
Stigma, discrimination and HIV or AIDS: an empirical investigation of Asian immigrants and refugees in Canada
Authors: Ullah Akm Ahsan , Huque Ahmed Shafiqul
Published: October 2022

Purpose

HIV or AIDS remains invisible and dismissed by most South Asians living in Canada as HIV or AIDS issues are perceived as an offshoot of Western lifestyle linked with drug use and promiscuity. This paper aims to look into how people living with HIV or AIDS (PLWHA) cope with prejudice and stigma.

Design/methodology/approach

To guide this research, a constructivist grounded theory approach was adopted as the theoretical and methodological framework. The authors reached the participants through a Toronto-based group that works with PLWHA. The authors chose their respondents in a snowball method and interviewed them both in person and online.

Findings

This paper identifies how South Asian immigrants and refugees/refugees with HIV or AIDS claimants are vulnerable to discrimination in Canada due to the following factors, which include but are not limited to: a lack of information about HIV and AIDS incidence in the community; and the Canadian health system's inability to respond appropriately to the lack of information.

Practical implications

HIV service engagements should take place within the context of a constellation of local traditions, or standardized expectations of patient engagement with HIV services can be counterproductive.

Originality/value

It is critical that governmental action prioritizes increasing public understanding of stigma. To minimize the consequences of HIV-related discrimination and stigma, misconceptions about HIV transmission must be debunked.
Tracing the lean thinking in supply chain management: a comprehensive main path analysis
Authors: Yu Dejian , Ye Tong
Published: October 2022

Purpose

The purpose of this paper is to contribute to the existing knowledge system of lean supply chain management (LSCM), i.e. by using main path analysis, and the authors extract the main development track of LSCM. It is advantageous for relevant scholars to deepen their understanding of this academic field from a bibliometrics view to grasp the future directions better.

Design/methodology/approach

Structuring a citation network with the processed data set containing 866 papers and relevant information collected from Web of Science (WoS). Conducting review analyses aiming at the main paths that are extracted from the above citation network.

Findings

There are two different evolution paths in LSCM field, i.e. improving corporate sustainability performance through combining lean and green practices, and seeking the balance between lean and agility to structure leagile supply chain for specific industries. LSCM research studies mainly focus on five aspects: (1) establishment and development of LSCM theory; (2) structuration of lean supply chain; (3) research studies of the relationship between LSCM and corporate performance; (4) supply chain evaluation system; and (5) review and vista of LSCM field. The intersection of two knowledge evolute routes would be Industry 4.0, which is an integrated theory system combining lean, agility, green and other supply chain thinking.

Research limitations/implications

The data set collected from WoS cannot contain all the research studies about LSCM is the main research limitation. Sustainability, as represented by environmental performance, will continue to be a major pursuit of this field. Integrating LSCM in Industry 4.0 will be the next hotspot in LSCM field.

Practical implications

Providing the main research contents and common methods of LSCM field. It is conducive to deepening the understanding of relevant practitioners and scholars to LSCM field from a dynamic perspective.

Originality/value

To the best of the authors’ knowledge, it is the first time to reveal the knowledge diffuse trajectories of LSCM under different view with main path analysis. This study is unique that it provides a new view to understand the field of LSCM.
Taxonomy of candidate’s selection for prioritized predictive maintenance in maintenance, repairs and overhaul organizations
Authors: Fedorov Roman , Pavlyuk Dmitry
Published: October 2022

Purpose

Research questions: Is there a systemic relationship between different methods of screening candidates for predictive maintenance? How do the goals of a predictive project influence the choice of a dropout method? How do the company’s characteristics implementing the predictive project influence the selection of the dropout method?

Design/methodology/approach

The authors described and compiled a taxonomy of currently known methods of screening candidate aircraft components for predictive maintenance for maintenance, repairs and overhaul organizations; identified the boundaries of each way; analyzed the advantages and disadvantages of existing methods; and formulated directions for further development of methods of screening for maintenance, repairs and overhaul organizations.

Findings

The authors identified the relationship between various screening methods by developing the approach proposed by Tiddens WW and supplementing it with economic methods. The authors built them into a single hierarchical structure and linked them with the parameters of the predictive project. The principal advantage of the proposed taxonomy is a clear relationship between the structure of the screening methods and the goals of the predictive project and the characteristics of the company that implements the project.

Originality/value

The authors of the article proposed groups of screening methods for predictive maintenance based on economic indicators to improve the effectiveness and efficiency of the screening process.
Comparing the VITEK 2 ANC card, species‐specific PCR, and MALDI‐TOF mass spectrometry methods for identification of lactic acid bacteria
Authors: Kim Sung‐Youn , Park Sol Yi , Jin Ji‐Eun , Hong Kyong‐Suk , Kim Dae‐Jung , Kim Yong‐Kyoung , Shin Hee‐Chang , Cho Soon‐Kil , Kang Dong‐Hyun
Published: October 2022

Lactic acid bacteria (LAB) are not only the most common probiotics in the food and feed industry but are also used as plant probiotics. Therefore, precise identification of LAB at the species level is required. In this study, we compared three different methods, the VITEK 2 ANC card, species‐specific PCR, and MALDI‐TOF MS, to identify six LAB (Lacticaseibacillus casei, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactiplantibacillus plantarum, Lentilactobacillus buchneri, and Limosilactobacillus fermentum) species previously assigned to the genus Lactobacillus that are used as biofertilizers. Twenty‐two strains of six LAB species were analyzed using the VITEK 2 ANC card, species‐specific PCR, and MALDI‐TOF MS, and identification rates at the species level were 45.5%, 95.5%, and 95.5%, respectively. There were cross‐reactions between L. casei and L. parpacasei, and one strain of L. casei could not be identified by these three methods. PCR assays and MALDI‐TOF MS were applicable for LAB identification.

Practical Application

LAB are the most common probiotics in the food and feed industry, so precise identification and classification of LAB at the species level are required. This study aimed at comparing three different methods for the effective identification of six LAB species: biochemical testing using VITEK 2 ANC card, species‐specific PCR, and MALDI‐TOF MS analysis.
Chemical characterization and solvent fractionation of tilapia oil for its potential application as human milk fat substitute
Authors: Cheng Xinyi , Huang Zhuoneng , Jin Qingzhe , Wang Xiaosan
Published: October 2022

The natural source of human milk fat substitute (HMFS) is a field worth exploring. In this study, tilapia oil was extracted and analyzed. In the triacylglycerol fraction, the contents of sn‐2 palmitic acid and total sn‐1,3 oleic acid and linoleic acid were 48.01% and 66.62%, respectively. The optimal solvent fractionation conditions were determined to be a tilapia oil‐to‐acetone ratio of 1:8 (w/v), crystallization temperature of −30°C, and crystallization duration of 16 h, giving a solid fraction yield of 64.20%. In fractionated tilapia oil, the total content of 1‐oleoyl‐2‐palmitoyl‐3‐linoleoylglycerol (OPL) and 1,3‐dioleoyl‐2‐palmitoylglycerol (OPO) increased by 20.38%, as determined by reversed‐phase liquid chromatography. Ultra‐high‐performance combined‐phase chromatography combined with quadrupole time‐of‐flight mass spectrometry analysis showed that OPL (17.45%) was the most abundant triacylglycerol in fractionated tilapia oil, followed by OPO (13.90%). Fractionated tilapia oil is thus an excellent source of OPL and has great potential for incorporation in HMFS.

Practical Application

Human milk fat substitutes are an important component of infant formulas. This work provides an excellent natural source of oil rich in OPL, which has great potential in the field of preparing human milk fat substitutes highly similar to human milk fat.
Inter‐rater reliability of the Clinical Frailty Scale by staff members in a Swedish emergency department setting
Authors: Hörlin Erika , Munir Ehrlington Samia , Henricson Joakim , John Rani Toll , Wilhelms Daniel
Published: October 2022

Introduction

As frailty among the elderly is receiving increasing attention in emergency departments (EDs) around the world, the use of frailty assessment tools is growing. An often used such tool is the Clinical Frailty Scale (CFS), whose inter‐rater reliability has been sparingly investigated in ED settings. No inter‐rater reliability study regarding CFS has previously been performed within the Scandinavian ED context. The primary aim of this study was to evaluate the inter‐rater reliability of the CFS in a Swedish ED setting.

Methods

This was a prospective observational study conducted at three Swedish EDs. Patients ≥65 years were independently assessed with CFS by their responsible physician, registered nurse, and assistant nurse. Demographic information for each assessor was collected, along with frailty status (frail/not frail) on the basis of clinical judgment. Inter‐rater reliability was calculated using intraclass correlation coefficient (ICC), whereas agreement of frailty assessed by CFS (dichotomized between frail/not frail, cutoff at ≥5 points) versus solely by clinical judgment was calculated by using cross‐tabulation.

Results

One‐hundred patients were included. We found inter‐rater reliability to be moderate to good (ICC 0.78, 95% confidence interval [CI] 0.72–0.84), regardless of whether the care team included an emergency physician (ICC 0.74, 95% CI 0.62–0.83) or an intern/resident from another specialty (ICC 0.83, 95% CI 0.74–0.89). The agreement of clinically judged frailty compared to frailty according to CFS was 84%. In the opposing cases, staff tended to assess patients as frail to a higher extent using clinical judgment than by applying CFS on the same patient.

Conclusions

The CFS appears to have a moderate to good inter‐rater reliability when used in a clinical ED setting. When guiding clinical decisions, we advise that the CFS score should be discussed within the team. Further research needs to be performed on the accuracy of clinical judgment to identify frailty in ED patients.
The utility of ctDNA in colorectal cancer with peritoneal metastases
Authors: Xue Jessica , Prabhakaran Swetha , Prabhakaran Sowmya , Lim Wei Mou , Guerra Glen , Heriot Alexander , Kong Joseph Cherng
Published: October 2022

Background

The development of peritoneal metastases (PM) in patients with colorectal cancer (CRC) connotates a poor prognosis. Circulating tumour (ctDNA) is a promising tumour biomarker in the management CRC. This systematic review aimed to summarize the role of ctDNA in patients with CRC and PM.

Methods

Following the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines, a systematic review of the literature until June 2022 was performed. Studies reporting on the utility of ctDNA in colorectal PM were included. A total of eight eligible studies were identified including a total of 167 patients.

Results

The findings from this review suggest an evolving role for ctDNA in CRC with PM. ctDNA can be isolated from both plasma and peritoneal fluid, with peritoneal fluid preferred as the liquid biopsy of choice with higher mutation detection rates. Concordance rates between tissue and plasma/peritoneal ctDNA mutation detection can vary, but is generally high. ctDNA has a potential role in monitoring anti‐EGFR treatment response and resistance, as well as in predicting future prognosis and recurrence. The detection of ctDNA in plasma of patients with isolated PM is also possibly suggestive of occult systemic disease, and patients exhibiting such ctDNA positivity may benefit from systemic treatment. Limitations to ctDNA mutation detection may include the size of peritoneal lesions, as well as the fact that PM poorly shed ctDNA.

Conclusion

While these findings are promising, further large‐scale studies are needed to better evaluate the utility of ctDNA in this subset of patients.
Perioperative outcomes of emergency and elective colorectal surgery: a bi‐institutional study
Authors: Seeto Alexander H. , Nabi Hajir , Burstow Matthew J. , Lancashire Raymond P. , Grundy Joshua , Gillespie Christopher , Nguyen Khuong , Naidu Sanjeev , Chua Terence C.
Published: October 2022

Background

Emergency colorectal surgery tends to be associated with poorer outcomes compared to elective colorectal surgery. This study assessed the morbidity and mortality in patients undergoing emergency and elective colorectal resection in two metropolitan hospitals.

Methods

Patients were identified retrospectively from two institutions between April 2018 and July 2020. Baseline, operative and postoperative parameters were collected for comparative analysis between emergency and elective surgery groups. A binary logistic regression was performed to identify independent predictors of postoperative complications.

Results

During the study period, 454 patients underwent colorectal resection, 135 were emergency cases (29.74%) and 319 were elective cases (70.26%). Compared with elective resections, patients undergoing emergency resections were observed to have a higher American Society of Anesthesiologists (ASA) score of III to IV (53.33% vs. 38.56%) (P = 0.004). The mortality rate was similar between the emergency and elective group (1.48% vs. 0.63%, P = 0.369). The overall complication rate was higher in patients undergoing emergency resections (64.44% vs. 36.68%, P < 0.001), but the major complication rate was similar between groups (12.59% vs. 10.34%, P = 0.484). Independent predictors for postoperative complications included emergency surgery (Odds Ratio (OR) 2.77, 95% Confidence Interval (CI): 1.66 to 4.61) and an ASA Score of III to IV (OR 2.87, 95% CI: 1.84 to 4.47).

Conclusion

The overall complication rate was higher in patients undergoing emergency colorectal resection, however, rates of major complications and mortality were similar between groups. Higher complication rates reflect advanced disease pathology in patients who are more comorbid.
Disentangling the effects of phosphorus, nitrogen and species identity on the vegetation reflectance spectrum
Authors: Moeneclaey Iris , Baeten Lander , Verheyen Kris , Van Coillie Frieke
Published: October 2022

Questions

Effective and successful restoration of species‐rich semi‐natural grasslands requires knowledge of the soil nutrient status, including soil phosphorus availability. Plants are solid indicators of soil nutrient status, because their growth reflects nutrient availability integrated over a certain period. The use of reflectance spectroscopy to estimate vegetation nutrient content has the potential to offer a fast and efficient approach to provide information about soil nutrient availability for plants. Here, we investigated the effect and relative importance of vegetation phosphorus content compared with vegetation nitrogen content and species identity in explaining variation in vegetation reflectance.

Location

Pot experiment mimicking Western European grassland communities on a restoration trajectory.

Methods

We combined a pot experiment with a broad range of mesotrophic grassland species growing along a soil phosphorus gradient with a multivariate modelling approach. We measured vegetation spectra and vegetation phosphorus and nitrogen content in monocultures and mixtures.

Results

Although vegetation biochemistry explained a considerable part of the variation in vegetation reflectance, we found no pronounced absorption features for vegetation nitrogen and phosphorus content across the reflectance spectrum. The relatively large effect of species and community identity suggest that other drivers, for example vegetation architecture, overruled the effect of vegetation biochemistry on the reflectance spectrum. Our findings indicate that species detection and indirect case‐specific estimation of nutrients is possible, especially in structurally less‐complex canopies such as monospecific grass swards.

Conclusions

Disentangling the specific drivers of variation in spectral reflectance is challenging. Many studies confound the effect of species identity on the vegetation reflectance spectrum with the effect of vegetation biochemistry. Here, we showed the importance of explicitly taking species identity into account. Gaining insight into light–vegetation interactions and the in‐depth integration of ecological theory in remote sensing are the way forward.
A pharmacometrics approach to assess the feasibility of capillary microsampling to replace venous sampling in clinical studies: Tafenoquine case study
Authors: Bachhav Sagar S. , Taylor Maxine , Martin Ana , Green Justin A. , Duparc Stephan , Rolfe Katie , Sharma Hema , Tan Lionel K. , Goyal Navin
Published: October 2022

Aim

Microsampling has the advantage of smaller blood sampling volume and suitability in vulnerable populations compared to venous sampling in clinical pharmacokinetics studies. Current regulatory guidance requires correlative studies to enable microsampling as a technique. A post hoc population pharmacokinetic (POPPK) approach was utilized to investigate blood capillary microsampling as an alternative to venous sampling.

Methods

Pharmacokinetic data from microsampling and venous sampling techniques during a paediatric study evaluating tafenoquine, a single‐dose antimalarial for P. vivax, were used. Separate POPPK models were developed and validated based on goodness of fit and visual predictive checks, with pharmacokinetic data obtained via each sampling technique.

Results

Each POPPK model adequately described tafenoquine pharmacokinetics using a two‐compartment model with body weight based on allometric scaling of clearance and volume of distribution. Tafenoquine pharmacokinetic parameter estimates including clearance (3.4 vs 3.7 L/h) were comparable across models with slightly higher interindividual variability (38.3% vs 27%) in capillary microsampling‐based data. A bioavailability/bioequivalence comparison demonstrated that the point estimate (90% CI) of capillary microsample versus venous sample model‐based individual post hoc estimates for area under the concentration‐time curve from time zero to infinity (AUC0‐inf) (100.7%, 98.0‐103.5%) and Cmax (79.7%, 76.9‐82.5%) met the 80‐125% and 70‐143% criteria, respectively. Overall, both POPPK models led to the same dose regimen recommendations across weight bins based on achieving target AUC.

Conclusions

This analysis demonstrated that a POPPK approach can be employed to assess the performance of alternative pharmacokinetic sampling techniques. This approach provides a robust solution in scenarios where variability in pharmacokinetic data collected via venous sampling and microsampling may not result in a strong linear relationship. The findings also established that microsampling techniques may replace conventional venous sampling methods.
Transcriptomic analysis identifies regulators of the Wnt signalling and hypoxia-inducible factor pathways as possible mediators of androgenetic alopecia
Authors: Philpott Michael
Published: October 2022

Linked Article:  Liu et al. Br J Dermatol 2022; 187:936–947.
TinyAD: Automatic Differentiation in Geometry Processing Made Simple
Authors: Schmidt P. , Born J. , Bommes D. , Campen M. , Kobbelt L.
Published: October 2022

Non‐linear optimization is essential to many areas of geometry processing research. However, when experimenting with different problem formulations or when prototyping new algorithms, a major practical obstacle is the need to figure out derivatives of objective functions, especially when second‐order derivatives are required. Deriving and manually implementing gradients and Hessians is both time‐consuming and error‐prone. Automatic differentiation techniques address this problem, but can introduce a diverse set of obstacles themselves, e.g. limiting the set of supported language features, imposing restrictions on a program's control flow, incurring a significant run time overhead, or making it hard to exploit sparsity patterns common in geometry processing. We show that for many geometric problems, in particular on meshes, the simplest form of forward‐mode automatic differentiation is not only the most flexible, but also actually the most efficient choice. We introduce TinyAD: a lightweight C++ library that automatically computes gradients and Hessians, in particular of sparse problems, by differentiating small (tiny) sub‐problems. Its simplicity enables easy integration; no restrictions on, e.g., looping and branching are imposed. TinyAD provides the basic ingredients to quickly implement first and second order Newton‐style solvers, allowing for flexible adjustment of both problem formulations and solver details. By showcasing compact implementations of methods from parametrization, deformation, and direction field design, we demonstrate how TinyAD lowers the barrier to exploring non‐linear optimization techniques. This enables not only fast prototyping of new research ideas, but also improves replicability of existing algorithms in geometry processing. TinyAD is available to the community as an open source library.
Comparative effectiveness and safety of extended anticoagulant therapy among Medicare beneficiaries with venous thromboembolism
Authors: Park Haesuk , Kang Hye‐Rim , Huang Pei‐Lin , Lo‐Ciganic Wei‐Hsuan , DeRemer Christina E. , Wilson Debbie , Dietrich Eric A.
Published: October 2022

Guidelines recommend an extended course of anticoagulation therapy for patients who experienced venous thromboembolism (VTE) without transient provocation, however, optimal duration remains uncertain. We assessed effectiveness and safety of extended use of apixaban and warfarin greater than 6 months of initial treatment in patients with VTE. We conducted a retrospective cohort study of Medicare beneficiaries aged greater than or equal to 18 years with deep vein thrombosis or pulmonary embolism. Patients were required to have initiated anticoagulants within 30 days of their first VTE diagnosis, completed 6 months of initial anticoagulant treatment, and received extended phase treatment with apixaban (the apixaban group) or warfarin (the warfarin group) or no extended therapy. Multivariable Cox proportional hazards modeling with inverse probability treatment weighting was used to compare recurrent VTE, mortality, and major bleeding risks among the three groups. Mean extended‐treatment duration was up to 10 months and 14 months in apixaban and warfarin groups, respectively. Compared with no extended treatment, apixaban use was associated with decreased risks of recurrent VTE (hazard ratio [HR] = 0.08, [95% confidence interval [CI]: 0.01–0.41]) and mortality (HR = 0.37, [95% CI: 0.27–0.51]) without increased major bleeding risk (HR = 1.29, [95% CI: 0.68–2.45]); warfarin use was associated not with recurrent VTE risk change but with increased major bleeding risk (HR = 2.14, [95% CI: 1.26–3.65]) and decreased mortality risk (HR = 0.39, [95% CI: 0.29–0.51]). Compared with warfarin, apixaban use was associated with decreased recurrent VTE (HR = 0.13, [95% CI: 0.03–0.63]) and major bleeding (HR = 0.56, [95% CI: 0.32–0.98]) risks. Subgroup and sensitivity analyses (e.g., intention‐to‐treat) findings remained consistent. Compared with warfarin or no extended therapy, extended‐apixaban use was associated with reduced risk of recurrent VTE without increased major bleeding risk. Continuing anticoagulant therapy with apixaban greater than 6 months may be effective and safe.
Local complement synthesis—A process with near and far consequences for ischemia reperfusion injury and transplantation
Authors: Nauser Christopher L. , Sacks Steven H.
Published: October 2022

The model of the solid organ as a target for circulating complement deposited at the site of injury, for many years concealed the broader influence of complement in organ transplantation. The study of locally synthesized complement especially in transplantation cast new light on complement's wider participation in ischaemia‐reperfusion injury, the presentation of donor antigen and finally rejection. The lack of clarity, however, has persisted as to which complement activation pathways are involved and how they are triggered, and above all whether the distinction is relevant. In transplantation, the need for clarity is heightened by the quest for precision therapies in patients who are already receiving potent immunosuppressives, and because of the opportunity for well‐timed intervention. This review will present new evidence for the emerging role of the lectin pathway, weighed alongside the longer established role of the alternative pathway as an amplifier of the complement system, and against contributions from the classical pathway. It is hoped this understanding will contribute to the debate on precisely targeted versus broadly acting therapeutic innovation within the aim to achieve safe long term graft acceptance.
Adlayer formation on C‐plane (0001) and R‐plane (11¯${\rm{\bar{1}}}$02) Al2O3 surfaces
Authors: Johnston‐Peck Aaron C. , Maier Russell A.
Published: October 2022

Adlayers on C‐plane (0001) and R‐plane (102) terminated surfaces of corundum phase aluminum oxide were synthesized by annealing mixtures of two oxide powders, aluminum oxide with an additive. Using high‐angle annular dark field scanning transmission electron microscopy, the adsorbed layers were characterized, and image simulations aided interpretation of the results. The adlayers were pseudomorphic, one atomic layer thick, and with a fractional site occupancy. Atomic positions of the adlayer atoms relaxed and changed relative to the bulk structure, where there is evidence that the magnitude of the relaxation is sensitive to the ionic radius of the adsorbate. The pseudomorphic adlayer structure is formed for different elements including, but not limited to, the lanthanides (i.e., Ge, Ba, and Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Dy, Ho, Er, Tm).
Echinacoside inhibited cardiomyocyte pyroptosis and improved heart function of HF rats induced by isoproterenol via suppressing NADPH/ROS/ER stress
Authors: Ni YaJuan , Zhang Jing , Zhu Wenjing , Duan Yixuan , Bai HongYuan , Luan Chunhong
Published: October 2022

Prevalence of heart failure (HF) continues to rise over time and is a global difficult problem; new drug targets are urgently needed. In recent years, pyroptosis is confirmed to promote cardiac remodelling and HF. Echinacoside (ECH) is a natural phenylethanoid glycoside and is the major active component of traditional Chinese medicine Cistanches Herba, which is reported to possess powerful anti‐oxidation and anti‐inflammatory effects. In addition, we previously reported that ECH reversed cardiac remodelling and improved heart function, but the effect of ECH on pyroptosis has not been studied. So, we investigated the effects of ECH on cardiomyocyte pyroptosis and the underlying mechanisms. In vivo, we established HF rat models induced by isoproterenol (ISO) and pre‐treated with ECH. Indexes of heart function, pyroptotic marker proteins, ROS levels, and the expressions of NOX2, NOX4 and ER stress were measured. In vitro, primary cardiomyocytes of neonatal rats were treated with ISO and ECH; ASC speckles and caspase‐1 mediated pyroptosis in cardiomyocytes were detected. Hoechst/PI staining was also used to evaluate pyroptosis. ROS levels, pyroptotic marker proteins, NOX2, NOX4 and ER stress levels were all tested. In vivo, we found that ECH effectively inhibited pyroptosis, down‐regulated NOX2 and NOX4, decreased ROS levels, suppressed ER stress and improved heart function. In vitro, ECH reduced cardiomyocyte pyroptosis and suppressed NADPH/ROS/ER stress. We concluded that ECH inhibited cardiomyocyte pyroptosis and improved heart function via suppressing NADPH/ROS/ER stress.
Methadone‐induced hypoglycemia: A case report
Authors: Malboosbaf Ramin , Hatami Neda , Maghsoomi Zohreh
Published: October 2022

Hypoglycemia is rare in patients without diabetes mellitus. Methadone is a synthetic μ‐opioid receptor agonist used for cancer or non‐cancer pain and the treatment of opioid dependence. Here, we report a case of a 31‐year‐old man who presented with recurrent hypoglycemic events that resolved on discontinuation of methadone. Thus, if hypoglycemia occurs while a patient takes methadone, the amount should be reduced or replaced with another opioid before a full investigation for inappropriate hyperinsulinism is initiated.
On the role of cell surface associated, mucin‐like glycoproteins in the pennate diatom Craspedostauros australis (Bacillariophyceae)
Authors: Poulsen Nicole , Hennig Helene , Geyer Veikko F. , Diez Stefan , Wetherbee Richard , Fitz‐Gibbon Sorel , Pellegrini Matteo , Kröger Nils
Published: October 2022

Diatoms are single‐celled microalgae with silica‐based cell walls (frustules) that are abundantly present in aquatic habitats, and form the basis of the food chain in many ecosystems. Many benthic diatoms have the remarkable ability to glide on all natural or man‐made underwater surfaces using a carbohydrate‐ and protein‐based adhesive to generate traction. Previously, three glycoproteins, termed FACs (Frustule Associated Components), have been identified from the common fouling diatom Craspedostauros australis and were implicated in surface adhesion through inhibition studies with a glycan‐specific antibody. The polypeptide sequences of FACs remained unknown, and it was unresolved whether the FAC glycoproteins are indeed involved in adhesion, or whether this is achieved by different components sharing the same glycan epitope with FACs. Here we have determined the polypeptide sequences of FACs using peptide mapping by LC–MS/MS. Unexpectedly, FACs share the same polypeptide backbone (termed CaFAP1), which has a domain structure of alternating Cys‐rich and Pro‐Thr/Ser‐rich regions reminiscent of the gel‐forming mucins. By developing a genetic transformation system for C. australis, we were able to directly investigate the function of CaFAP1‐based glycoproteins in vivo. GFP‐tagging of CaFAP1 revealed that it constitutes a coat around all parts of the frustule and is not an integral component of the adhesive. CaFAP1‐GFP producing transformants exhibited the same properties as wild type cells regarding surface adhesion and motility speed. Our results demonstrate that FAC glycoproteins are not involved in adhesion and motility, but might rather act as a lubricant to prevent fouling of the diatom surface.
Evaluating the cost‐effectiveness of hepatitis B vaccination strategies in high‐impact settings for adults
Authors: Hall Eric W. , Gounder Prabhu , Angles John , Nelson Noele P. , Rosenberg Eli S. , Weng Mark K.
Published: October 2022

Adults at increased risk for hepatitis B virus (HBV) infection are recommended to receive vaccination. We conducted a cost utility analysis to evaluate approaches for implementing that recommendation in selected high‐risk settings: community outreach events with a large proportion of immigrants, syringe service programs, substance use treatment centres, sexually transmitted infection (STI) clinics, tuberculosis (TB) clinics and jails. We utilized a decision tree framework with a Markov disease progression model to compare quality adjusted life‐years and cost in 2021 United States dollars from four strategies: a 3‐dose vaccination regimen with prevaccination screening and testing (PVST; baseline comparison); PVST at the initial encounter followed by a 2‐dose series (Intervention 1); PVST with the first dose of a 2‐dose vaccination series at the initial encounter (Intervention 2); and a 2‐dose vaccination series without PVST (Intervention 3). In all settings, Intervention 1 resulted in worse health outcomes compared with the baseline strategy. Intervention 2 averted incident chronic HBV infections in all settings (range −9.4% in TB clinics, −14.8% in syringe service programs) and was a cost‐saving approach in settings with higher risk of infection (i.e. jails, −$266 per person; syringe service programs, −$597; substance use treatment centres, −$130). Providing a 2‐dose vaccination series without any screening (Intervention 3) averted incident HBV infections and was cost‐saving in all settings but resulted in more HBV‐related deaths in settings with higher HBV prevalence. These results demonstrate a 2‐dose vaccine series is a cost‐effective approach in these high‐impact settings, even if prevaccination testing is not possible.
Whole genome population structure of North Atlantic kelp confirms high‐latitude glacial refugia
Authors: Bringloe Trevor T. , Fort Antoine , Inaba Masami , Sulpice Ronan , Ghriofa Cliodhna Ní , Mols‐Mortensen Agnes , Filbee‐Dexter Karen , Vieira Christophe , Kawai Hiroshi , Hanyuda Takeaki , Krause‐Jensen Dorte , Olesen Birgit , Starko Samuel , Verbruggen Heroen
Published: October 2022

Coastal refugia during the Last Glacial Maximum (~21,000 years ago) have been hypothesized at high latitudes in the North Atlantic, suggesting marine populations persisted through cycles of glaciation and are potentially adapted to local environments. Here, whole‐genome sequencing was used to test whether North Atlantic marine coastal populations of the kelp Alaria esculenta survived in the area of southwestern Greenland during the Last Glacial Maximum. We present the first annotated genome for A. esculenta and call variant positions in 54 individuals from populations in Atlantic Canada, Greenland, Faroe Islands, Norway and Ireland. Differentiation across populations was reflected in ~1.9 million single nucleotide polymorphisms, which further revealed mixed ancestry in the Faroe Islands individuals between putative Greenlandic and European lineages. Time‐calibrated organellar phylogenies suggested Greenlandic populations were established during the last interglacial period more than 100,000 years ago, and that the Faroe Islands population was probably established following the Last Glacial Maximum. Patterns in population statistics, including nucleotide diversity, minor allele frequencies, heterozygosity and linkage disequilibrium decay, nonetheless suggested glaciation reduced Canadian Atlantic and Greenlandic populations to small effective sizes during the most recent glaciation. Functional differentiation was further reflected in exon read coverage, which revealed expansions unique to Greenland in 337 exons representing 162 genes, and a modest degree of exon loss (103 exons from 56 genes). Altogether, our genomic results provide strong evidence that A. esculenta populations were resilient to past climatic fluctuations related to glaciations and that high‐latitude populations are potentially already adapted to local conditions as a result.
Enzyme 1 of the phosphoenolpyruvate:sugar phosphotransferase system is involved in resistance to MreB disruption in wild‐type and ∆envC cells
Authors: Sloan Ryan , Surber Jacob , Roy Emma J. , Hartig Ethan , Morgenstein Randy M.
Published: October 2022

Cell wall synthesis in bacteria is determined by two protein complexes: the elongasome and divisome. The elongasome is coordinated by the actin homolog MreB while the divisome is organized by the tubulin homolog FtsZ. While these two systems must coordinate with each other to ensure that elongation and division are coregulated, this cross talk has been understudied. Using the MreB depolymerizing agent, A22, we found that multiple gene deletions result in cells exhibiting increased sensitivity to MreB depolymerization. One of those genes encodes for EnvC, a part of the divisome that is responsible for splitting daughter cells after the completion of cytokinesis through the activation of specific amidases. Here we show this increased sensitivity to A22 works through two known amidase targets of EnvC: AmiA and AmiB. In addition, suppressor analysis revealed that mutations in enzyme 1 of the phosphoenolpyruvate:sugar phosphotransferase system (PTS) can suppress the effects of A22 in both wild‐type and envC deletion cells. Together this work helps to link elongation, division, and metabolism.