bluuebunny/crossref_metadata_2025 huggingface dataset:
Challenges in evaluating implementation and effectiveness in real-world settings: evaluation proposal for school-based health-promoting intervention
Authors: Hahnraths Marla T H , Willeboordse Maartje , van Schayck Onno C P
Published: January 2023

There are various research designs and approaches to investigate how health-promoting activities are implemented in complex, real-world systems, and to identify potential health effects that might occur following implementation. Although literature describes guidelines to perform and report about implementation research and effect evaluations, no specific guidelines exist on analysing and reporting about the combination of effectiveness data and implementation data collected as part of intervention evaluation in complex and diverse settings. This paper describes the evaluation of primary school-based health-promoting activities in complex systems. Furthermore, an approach for data categorization inspired by Rogers’ Diffusion of Innovations theory is presented that can facilitate structuring the study’s results and relating the degree of implementation to any impact on effectiveness outcomes that might be observed. Researchers interested in using this approach for data categorization have to ensure that the following three conditions are met: (i) data on an intervention’s efficacy in a controlled setting with optimal implementation is available; (ii) key points that define an intervention’s optimal implementation are available and (iii) an evaluation study is performed, collecting both effectiveness data and implementation data in a real-world context. This data categorization approach can be useful to generate more insight into an intervention’s effectiveness under varying circumstances, and optimal support and advice can be provided to stakeholders to achieve maximum impact of population-based health-promoting interventions in complex, real-world systems. However, the proposed approach is a first suggestion and further testing and adaptation is necessary to increase its usefulness. Knowledge and experience sharing among researchers performing comparable research can increase the knowledge base regarding this subject.
Health(care) matters: where do the transgender individuals of Kashmir situate themselves?
Authors: Jahangir Mohmad Saleem , Gadda Zakir Hussain , Ganayee Shameem Ahamad , Kumar Hilal Ahmad , Ahmad Mansoor , Shafi Aneesa
Published: January 2023

While employing a phenomenological perspective, the present study aimed to explore the varied experiences of transgender individuals in Kashmir, concerning their health-seeking behavior, and the constraints they face while accessing healthcare resources on a day-to-day basis in their life world. Participants were recruited through the purposive and snowball sampling strategies and the sufficiency of sample size was determined by data saturation. Data were collected using face-to-face in-depth interviews and analyzed through Colaizzi’s procedure of extracting recurrent themes and their interwoven relationships in qualitative research. Three main themes of awareness and the preferences for healthcare, gender identity and persistent stigmatization in care settings, and intra-community support and the resultant caregiving were prominent. Results of the study revealed that the transgender individuals in Kashmir experience inappropriate health-seeking behaviour primarily due to their unawareness regarding health, diseases and public healthcare programs/schemes, financial constraints, social exclusion, improper support and social stigma. They often prefer treating their health issues, mostly through local pharmacies or patent medicine vendors (PMVs), instead of visiting the medical professionals in the organized sector. Moreover, in many instances, they were also found to delay their decisions to seek care or simply decided to remain far from any medical intervention. As a result, the transgender individuals in Kashmir usually experience underutilization of formal healthcare services, which undermines their right to proper health and well-being.
Therapeutic reduction of GGGGCC repeat RNA levels by hnRNPA3 suppresses neurodegeneration in Drosophila models of C9orf72-linked ALS/FTD
Authors: Taminato Tomoya , Takeuchi Toshihide , Ueyama Morio , Mori Kohji , Ikeda Manabu , Mochizuki Hideki , Nagai Yoshitaka
Published: January 2023

The abnormal expansion of GGGGCC hexanucleotide repeats within the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of GGGGCC repeat-containing RNAs as RNA foci, and the deposition of dipeptide repeat proteins (DPR) produced from these repeat RNAs by unconventional translation are major pathological hallmarks of C9orf72-linked ALS/FTD (C9-ALS/FTD), and are both thought to play a crucial role in the pathogenesis of these diseases. Because GGGGCC repeat RNA is likely to be the most upstream therapeutic target in the pathogenic cascade of C9-ALS/FTD, lowering the cellular level of GGGGCC repeat RNA is expected to mitigate repeat RNA toxicity, and will therefore be a disease-modifying therapeutic strategy for the treatment of C9-ALS/FTD. In this study, we demonstrated using a Drosophila model of C9-ALS/FTD that elevated expression of a subset of human RNA-binding proteins that bind to GGGGCC repeat RNA, including hnRNPA3, IGF2BP1, hnRNPA2B1, hnRNPR and SF3B3, reduces the level of GGGGCC repeat RNA, resulting in the suppression of neurodegeneration. We further showed that hnRNPA3-mediated reduction of GGGGCC repeat RNA suppresses disease pathology, such as RNA foci and DPR accumulation. These results demonstrate that hnRNPA3 and other RNA-binding proteins negatively regulate the level of GGGGCC repeat RNA, and mitigate repeat RNA toxicity in vivo, indicating the therapeutic potential of the repeat RNA-lowering approach mediated by endogenous RNA-binding proteins for the treatment of C9-ALS/FTD.
Epigenetic gestational age and the relationship with developmental milestones in early childhood
Authors: Polinski Kristen J , Robinson Sonia L , Putnick Diane L , Guan Weihua , Gleason Jessica L , Mumford Sunni L , Sundaram Rajeshwari , Mendola Pauline , London Stephanie , Yeung Edwina H
Published: January 2023

Shorter gestational age (GA) is a risk factor of developmental delay. GA is usually estimated clinically from last menstrual period and ultrasound. DNA methylation (DNAm) estimates GA using sets of cytosine-guanine-sites coupled with a clock algorithm. Therefore, DNAm-estimated GA may better reflect biological maturation. A DNAm GA greater than clinical GA, known as gestational age acceleration (GAA), may indicate epigenetic maturity and holds potential as an early biomarker for developmental delay risk. We used data from the Upstate KIDS Study to examine associations of DNAm GA and developmental delay within the first 3 years based on the Ages & Stages Questionnaire® (n = 1010). We estimated DNAm GA using two clocks specific to the Illumina Methylation EPIC 850K, the Haftorn clock and one developed from the Effects of Aspirin in Gestation and Reproduction study, in which women were followed to detect pregnancy at the earliest time possible. Among singletons, each week increase in DNAm GA was protective for overall delay (odds ratio:0.74; 95% confidence interval:0.61–0.90) and delay in all domains except for problem-solving skills. Among twins, we observed similar point estimates but lower precision. Results were similar for clinical GA. GAA was largely not associated with developmental delays. In summary, either DNAm GA or clinical GA at birth, but not epigenetic maturity (i.e. GAA), was associated with decreased odds of developmental delay in early childhood. Our study does not support using DNAm GA or GAA as separate risk factors for future risk of developmental delay within the first 3 years of age.
Direct evaluation of neuroaxonal degeneration with the causative genes of neurodegenerative diseases in Drosophila using the automated axon quantification system, MeDUsA
Authors: Nitta Yohei , Kawai Hiroki , Maki Ryuto , Osaka Jiro , Hakeda-Suzuki Satoko , Nagai Yoshitaka , Doubková Karolína , Uehara Tomoko , Watanabe Kenji , Kosaki Kenjiro , Suzuki Takashi , Tavosanis Gaia , Sugie Atsushi
Published: January 2023

Drosophila is an excellent model organism for studying human neurodegenerative diseases (NDs). However, there is still almost no experimental system that could directly observe the degeneration of neurons and automatically quantify axonal degeneration. In this study, we created MeDUsA (a ‘method for the quantification of degeneration using fly axons’), a standalone executable computer program based on Python that combines a pre-trained deep-learning masking tool with an axon terminal counting tool. This software automatically quantifies the number of retinal R7 axons in Drosophila from a confocal z-stack image series. Using this software, we were able to directly demonstrate that axons were degenerated by the representative causative genes of NDs for the first time in Drosophila. The fly retinal axon is an excellent experimental system that is capable of mimicking the pathology of axonal degeneration in human NDs. MeDUsA rapidly and accurately quantifies axons in Drosophila photoreceptor neurons. It enables large-scale research into axonal degeneration, including screening to identify genes or drugs that mediate axonal toxicity caused by ND proteins and diagnose the pathological significance of novel variants of human genes in axons.
Biochemical characterization of two novel mutations in the human high-affinity choline transporter 1 identified in a patient with congenital myasthenic syndrome
Authors: Rizvi Midhat , Truong Tina K , Zhou Janet , Batta Manav , Moran Ellen S , Pappas John , Chu Mary Lynn , Caluseriu Oana , Evrony Gilad D , Leslie Elaine M , Cordat Emmanuelle
Published: January 2023

Congenital myasthenic syndrome (CMS) is a heterogeneous condition associated with 34 different genes, including SLC5A7, which encodes the high-affinity choline transporter 1 (CHT1). CHT1 is expressed in presynaptic neurons of the neuromuscular junction where it uses the inward sodium gradient to reuptake choline. Biallelic CHT1 mutations often lead to neonatal lethality, and less commonly to non-lethal motor weakness and developmental delays. Here, we report detailed biochemical characterization of two novel mutations in CHT1, p.I294T and p.D349N, which we identified in an 11-year-old patient with a history of neonatal respiratory distress, and subsequent hypotonia and global developmental delay. Heterologous expression of each CHT1 mutant in human embryonic kidney cells showed two different mechanisms of reduced protein function. The p.I294T CHT1 mutant transporter function was detectable, but its abundance and half-life were significantly reduced. In contrast, the p.D349N CHT1 mutant was abundantly expressed at the cell membrane, but transporter function was absent. The residual function of the p.I294T CHT1 mutant may explain the non-lethal form of CMS in this patient, and the divergent mechanisms of reduced CHT1 function that we identified may guide future functional studies of the CHT1 myasthenic syndrome. Based on these in vitro studies that provided a diagnosis, treatment with cholinesterase inhibitor together with physical and occupational therapy significantly improved the patient’s strength and quality of life.
Nuclear modifier YARS2 allele correction restored retinal ganglion cells-specific deficiencies in Leber’s hereditary optic neuropathy
Authors: Chen Jia-Rong , Chen Chao , Chen Jie , Ji Yanchun , Lian Yanna , Zhang Juanjuan , Yu Jialing , Li Xiang-Yao , Qu Jia , Guan Min-Xin
Published: January 2023

Leber’s hereditary optic neuropathy (LHON) is a maternally transmitted eye disease due to the degeneration of retinal ganglion cells (RGCs). Mitochondrial 11778G > A mutation is the most common LHON-associated mitochondrial DNA (mtDNA) mutation. Our recent studies demonstrated some LHON families manifested by synergic interaction between m.11778G > A mutation and YARS2 allele (c.572G > T, p.Gly191Val) encoding mitochondrial tyrosyl-tRNA synthetase. However, the RGC-specific effects of LHON-associated mtDNA mutations remain elusive and there is no highly effective therapy for LHON. Here, we generated patients-derived induced pluripotent stem cells (iPSCs) from fibroblasts derived from a Chinese LHON family (both m.11778G > A and c.572G > T mutations, only m.11778G > A mutation, and control subject). The c.572G > T mutation in iPSC lines from a syndromic individual was corrected by CRISPR/Cas9. Those iPSCs were differentiated into neural progenitor cells and subsequently induced RGC-like cells using a stepwise differentiation procedure. Those RGC-like cells derived from symptomatic individual harboring both m.11778G > A and c.572G > T mutations exhibited greater defects in neuronal differentiation, morphology including reduced area of soma, numbers of neurites and shortened length of axons, electrophysiological properties than those in cells bearing only m.11778G > A mutation. Furthermore, these RGC-like cells revealed more drastic reductions in oxygen consumption rates, levels of mitochondrial ATP and increasing productions of reactive oxygen species than those in other cell models. These mitochondrial dysfunctions promoted the apoptotic process for RGC degenerations. Correction of YARS2 c.572G > T mutation rescued deficiencies of patient-derived RGC-like cells. These findings provide new insights into pathophysiology of LHON arising from RGC-specific mitochondrial dysfunctions and step toward therapeutic intervention for this disease.
Loss of TMCC2 activates endoplasm reticulum stress and causes auditory hair cell death
Authors: Ren Rui , Xing Haiyue , Wang Xiaoying , Du Haibo , Wang Yanfei , Xu Zhigang
Published: January 2023

As the auditory and balance receptor cells in the inner ear, hair cells are responsible for converting mechanical stimuli into electrical signals, a process referred to as mechano-electrical transduction. Hair cell development and function are tightly regulated, and hair cell deficits are the main reasons for hearing loss and balance disorders. TMCC2 is an endoplasmic reticulum (ER)-residing transmembrane protein whose physiological function largely remains unknown. In the present work, we show that Tmcc2 is specifically expressed in the auditory hair cells of mouse inner ear. Tmcc2 knockout mice were then established to investigate its physiological role in hearing. Auditory brainstem responses measurements show that Tmcc2 knockout mice suffer from congenital hearing loss. Further investigations reveal progressive auditory hair cell loss in the Tmcc2 knockout mice. The general morphology and function of ER are unaffected in Tmcc2 knockout hair cells. However, increased ER stress was observed in Tmcc2 knockout mice and knockdown cells, suggesting that loss of TMCC2 leads to auditory hair cell death through elevated ER stress.
The class B heat shock factor HSFB1 regulates heat tolerance in grapevine
Authors: Chen Haiyang , Liu Xinna , Li Shenchang , Yuan Ling , Mu Huayuan , Wang Yi , Li Yang , Duan Wei , Fan Peige , Liang Zhenchang , Wang Lijun
Published: January 2023

Grape is a widely cultivated crop with high economic value. Most cultivars derived from mild or cooler climates may not withstand increasing heat stress. Therefore, dissecting the mechanisms of heat tolerance in grapes is of particular significance. Here, we performed comparative transcriptome analysis of Vitis davidii ‘Tangwei’ (heat tolerant) and Vitis vinifera ‘Jingxiu’ (heat sensitive) grapevines after exposure to 25°C, 40°C, or 45°C for 2 h. More differentially expressed genes (DEGs) were detected in ‘Tangwei’ than in ‘Jingxiu’ in response to heat stress, and the number of DEGs increased with increasing treatment temperatures. We identified a class B Heat Shock Factor, HSFB1, which was significantly upregulated in ‘Tangwei’, but not in ‘Jingxiu’, at high temperature. VdHSFB1 from ‘Tangwei’ and VvHSFB1 from ‘Jingxiu’ differ in only one amino acid, and both showed similar transcriptional repression activities. Overexpression and RNA interference of HSFB1 in grape indicated that HSFB1 positively regulates the heat tolerance. Moreover, the heat tolerance of HSFB1-overexpressing plants was positively correlated to HSFB1 expression level. The activity of the VdHSFB1 promoter is higher than that of VvHSFB1 under both normal and high temperatures. Promoter analysis showed that more TATA-box and AT~TATA-box cis-elements are present in the VdHSFB1 promoter than the VvHSFB1 promoter. The promoter sequence variations between VdHSFB1 and VvHSFB1 likely determine the HSFB1 expression levels that influence heat tolerance of the two grape germplasms with contrasting thermotolerance. Collectively, we validated the role of HSFB1 in heat tolerance, and the knowledge gained will advance our ability to breed heat-tolerant grape cultivars.
Single-cell Transcriptomics Reveal the Importance of Distinct Epithelial Cell Populations in Ileal-specific, Treatment-naïve, and Treated Crohn’s Disease Patients
Authors: Corridoni Daniele , Pizarro Theresa T
Published: January 2023

Lay Summary

The advent of single-cell technologies has revolutionized analyses of IBD-specific processes by identifying important, often novel, mucosal cells subpopulations and their associated functions. We discuss recent findings reporting transcriptomic and cellular diversity of treatment-naïve and treated patients with ileal-specific CD.
The power of modularity today: 20 years of “Design Rules”
Authors: Brusoni Stefano , Henkel Joachim , Jacobides Michael G , Karim Samina , MacCormack Alan , Puranam Phanish , Schilling Melissa
Published: January 2023

In 2000, Carliss Baldwin and Kim Clark published “Design Rules: The Power of Modularity,” a book that introduced new ways of understanding and explaining the architecture of complex systems This Special Issue of Industrial and Corporate Change celebrates this seminal work, the research it has inspired, and the insights that these collective efforts have generated. In this introductory essay, we review the impact of “Design Rules” across numerous fields, including organization theory, competitive strategy, industry structure, and innovation management. We offer perspectives on key themes that emerge from contributions in this issue, including the alignment between organizational and technical designs (“mirroring”), the dynamics of industry evolution, and the role that individuals play in shaping and responding to system designs. We close by highlighting opportunities to apply the theory in Design Rules to new phenomena and puzzles that have emerged in the past 20 years.
Influence of maternal age on birth and infant outcomes at 6 months: a cohort study with quantitative bias analysis
Authors: Gebreegziabher Elisabeth , Bountogo Mamadou , Sié Ali , Zakane Alphonse , Compaoré Guillaume , Ouedraogo Thierry , Lebas Elodie , Nyatigo Fanice , Glymour Maria , Arnold Benjamin F , Lietman Thomas M , Oldenburg Catherine E
Published: January 2023

Background

Maternal age is increasingly recognized as a predictor of birth outcomes. Given the importance of birth and growth outcomes for children’s development, wellbeing and survival, this study examined the effect of maternal age on infant birth and growth outcomes at 6 months and mortality. Additionally, we conducted quantitative bias analysis (QBA) to estimate the role of selection bias and unmeasured confounding on the effect of maternal age on infant mortality.

Methods

We used data from randomized–controlled trials (RCTs) of 21 555 neonates in Burkina Faso conducted in 2019–2020. Newborns of mothers aged 13–19 years (adolescents) and 20–40 years (adults) were enrolled in the study 8–27 days after birth and followed for 6 months. Measurements of child’s anthropometric measures were collected at baseline and 6 months. We used multivariable linear regression to compare child anthropometric measures at birth and 6 months, and logistic regression models to obtain the odds ratio (OR) of all-cause mortality. Using multidimensional deterministic analysis, we assessed scenarios in which the difference in selection probability of adolescent and adult mothers with infant mortality at 6 months increased from 0% to 5%, 10%, 15% and 20% if babies born to adolescent mothers more often died during the first week or were of lower weight and hence were not eligible to be included in the original RCT. Using probabilistic bias analysis, we assessed the role of unmeasured confounding by socio-economic status (SES).

Results

Babies born to adolescent mothers on average had lower weight at birth, lower anthropometric measures at baseline, similar growth outcomes from enrolment to 6 months and higher odds of all-cause mortality by 6 months (adjusted OR = 2.17, 95% CI 1.35 to 3.47) compared with those born to adult mothers. In QBA, we found that differential selection of adolescent and adult mothers could bias the observed effect (OR = 2.24, 95% CI 1.41 to 3.57) towards the null [bias-corrected OR range: 2.37 (95% CI 1.49 to 3.77) to 2.84 (95% CI 1.79 to 4.52)], whereas unmeasured confounding by SES could bias the observed effect away from the null (bias-corrected OR: 2.06, 95% CI 1.31 to 2.64).

Conclusions

Our findings suggest that delaying the first birth from adolescence to adulthood may improve birth outcomes and reduce mortality of neonates. Babies born to younger mothers, who are smaller at birth, may experience catch-up growth, reducing some of the anthropometric disparities by 6 months of age.
How Can Pro-regime Online Comments Influence Chinese Netizens’ Attitudes and Opinion Expressions? Normative or Informational Social Influence?
Authors: Pan Yating , Shu Zhan
Published: January 2023

China, as an authoritarian regime that has tight control over social media, has always sought to manipulate public opinion. In addition to censorship, the state mobilizes undercover paid posters to manufacture a pro-regime opinion environment. In this study, we examine the effectiveness of this adaptation by conducting an online survey experiment. We explore whether pro-regime comments accompanying a news post can effectively affect viewers’ private and expressed thoughts, as well as whether these are driven by normative or informational social influence. The results indicate that pro-regime comments cannot significantly influence individuals’ attitudes in favor of the authorities. Moreover, uniform pro-regime comments can even produce counterproductive effects. However, pro-regime comments do have an impact on individuals’ opinion expressions. Respondents who take dissenting viewpoints tend to avoid expressing themselves when facing a climate of pro-regime opinion. Additionally, the persuasive effects of high-quality pro-regime arguments were found to be better compared to low-quality arguments.
Fast splitting algorithms for sparsity-constrained and noisy group testing
Authors: Price Eric , Scarlett Jonathan , Tan Nelvin
Published: January 2023

In group testing, the goal is to identify a subset of defective items within a larger set of items based on tests whose outcomes indicate whether at least one defective item is present. This problem is relevant in areas such as medical testing, DNA sequencing, communication protocols and many more. In this paper, we study (i) a sparsity-constrained version of the problem, in which the testing procedure is subjected to one of the following two constraints: items are finitely divisible and thus may participate in at most $\gamma $ tests; or tests are size-constrained to pool no more than $\rho $ items per test; and (ii) a noisy version of the problem, where each test outcome is independently flipped with some constant probability. Under each of these settings, considering the for-each recovery guarantee with asymptotically vanishing error probability, we introduce a fast splitting algorithm and establish its near-optimality not only in terms of the number of tests, but also in terms of the decoding time. While the most basic formulations of our algorithms require $\varOmega (n)$ storage for each algorithm, we also provide low-storage variants based on hashing, with similar recovery guarantees.
Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood
Authors: Edner Natalie M , Ntavli Elisavet , Petersone Lina , Wang Chun Jing , Fabri Astrid , Kogimtzis Alexandros , Ovcinnikovs Vitalijs , Ross Ellen M , Heuts Frank , Elfaki Yassin , Houghton Luke P , Talbot Toby , Sheri Amna , Pender Alexandra , Chao David , Walker Lucy S K
Published: January 2023

Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg. Remarkably, unsupervised clustering analysis of pre-treatment T cell subsets revealed differences in individuals that went on to respond to PD-1 blockade compared to individuals that did not. These differences mapped to expression of the proliferation marker Ki67 and the costimulatory receptor CD28 as well as the inhibitory molecules 2B4 and KLRG1. While these results require validation in larger patient cohorts, they suggest that flow cytometric analysis of a relatively small number of T cell markers in peripheral blood could potentially allow stratification of PD-1 blockade treatment response prior to therapy initiation.
Dimension-Free Estimates for the Discrete Spherical Maximal Functions
Authors: Mirek Mariusz , Szarek Tomasz Z , Wróbel Błażej
Published: January 2023

We prove that the discrete spherical maximal functions (in the spirit of Magyar, Stein, and Wainger) corresponding to the Euclidean spheres in $\mathbb {Z}^{d}$ with dyadic radii have $\ell ^{p}(\mathbb {Z}^{d})$ bounds for all $p\in [2, \infty ]$ independent of the dimensions $d\ge 5$. An important part of our argument is the asymptotic formula in the Waring problem for the squares with a dimension-free multiplicative error term. By considering new approximating multipliers, we will show how to absorb an exponential in dimension (like $C^{d}$ for some $C>1$) growth in norms arising from the sampling principle of Magyar, Stein, and Wainger and ultimately deduce dimension-free estimates for the discrete spherical maximal functions.
Development of a Bispecific Antibody Targeting Clinical Isolates of Acinetobacter baumannii
Authors: Nielsen Travis B , Yan Jun , Slarve Matthew , Li Rachel , Junge Jason A , Luna Brian M , Wilkinson Ian , Yerramalla Udaya , Spellberg Brad
Published: January 2023

Background

We previously reported developing 2 anticapsular monoclonal antibodies (mAbs) as a novel therapy for Acinetobacter baumannii infections. We sought to determine whether a bispecific mAb (bsAb) could improve avidity and efficacy while maximizing strain coverage in one molecule.

Methods

Humanized mAb 65 was cloned into a single-chain variable fragment and attached to humanized mAb C8, combining their paratopes into a single bsAb (C73). We tested bsAb C73’s strain coverage, binding affinity, ex vivo opsonic activity, and in vivo efficacy compared to each mAb alone and combined.

Results

The bsAb demonstrated strain coverage, binding affinity, opsonization, and in vivo efficacy superior to either original mAb alone or combined.

Conclusions

A humanized bsAb targeting distinct A. baumannii capsule moieties enabled potent and effective coverage of disparate A. baumannii clinical isolates. The bsAb enhances feasibility of development by minimizing the number of components of a promising novel therapeutic for these difficult-to-treat infections.
Transversal Politics of Big Tech
Authors: Monsees Linda , Liebetrau Tobias , Austin Jonathan Luke , Leander Anna , Srivastava Swati
Published: January 2023

Our everyday life is entangled with products and services of so-called Big Tech companies, such as Amazon, Google, and Facebook. International relations (IR) scholars increasingly seek to reflect on the relationships between Big Tech, capitalism, and institutionalized politics, and they engage with the practices of algorithmic governance and platformization that shape and are shaped by Big Tech. This collective discussion advances these emerging debates by approaching Big Tech transversally, meaning that we problematize Big Tech as an object of study and raise a range of fundamental questions about its politics. The contributions demonstrate how a transversal perspective that cuts across sociomaterial, institutional, and disciplinary boundaries and framings opens up the study of the politics of Big Tech. The discussion brings to the fore perspectives on the ontologies of Big Tech, the politics of the aesthetics and credibility of Big Tech and rethinks the concepts of legitimacy and responsibility. The article thereby provides several inroads for how IR and international political sociology can leverage their analytical engagement with Big Tech and nurture imaginaries of alternative and subversive technopolitical futures.
Emerging resistance inStaphylococcus epidermidisduring dalbavancin exposure: a case report andin vitroanalysis of isolates from prosthetic joint infections
Authors: Al Janabi Jasmina , Tevell Staffan , Sieber Raphael Niklaus , Stegger Marc , Söderquist Bo
Published: January 2023

Background

Dalbavancin, a semisynthetic lipoglycopeptide with exceptionally long half-life and Gram-positive spectrum, is an attractive option for infections requiring prolonged therapy, including prosthetic joint infections (PJIs).

Objectives

To investigate the prevalence of reduced susceptibility to dalbavancin in a strain collection of Staphylococcus epidermidis from PJIs, and to investigate genomic variation in isolates with reduced susceptibility selected during growth under dalbavancin exposure.

Methods

MIC determination was performed on S. epidermidis isolates from a strain collection (n = 64) and from one patient with emerging resistance during treatment (n = 4). These isolates were subsequently cultured on dalbavancin-containing agar and evaluated at 48 h; MIC determination was repeated if phenotypical heterogeneity was detected during growth. Population analysis profile (PAP-AUC) was performed in isolates where a  ≥ 2-fold increase in MIC was detected, together with corresponding parental isolates (n = 21). Finally, WGS was performed.

Results

All strains grew at 48 h on agar containing 0.125 mg/L dalbavancin. PAP-AUC demonstrated significant differences between parental and derived strains in four of the eight analysed groups. An amino acid change in the walK gene coinciding with emergence of phenotypic resistance was detected in the patient isolates, whereas no alterations were found in this region in the in vitro derived strains.

Conclusions

Exposure to dalbavancin may lead to reduced susceptibility to dalbavancin through either selection of pre-existing subpopulations, epigenetic changes or spontaneous mutations during antibiotic exposure. Source control combined with adequate antibiotic concentrations may be important to prevent emerging reduced susceptibility during dalbavancin treatment.
QMAC-dRAST for the direct testing of antibiotic susceptibility for Enterobacterales in positive blood-culture broth: a comparison of the performances with the MicroScan system and direct disc diffusion testing methods
Authors: Gallois E , Fihman V , Danjean M , Gomart C , Kimseng H , Le Guen R , Royer G , Woerther P L
Published: January 2023

Objectives

To evaluate the performances of the QMAC-dRAST GN (Gram-negative) kit for rapid antimicrobial sensitivity testing (AST) and two other methods, directly on positive blood-culture broth (PBCB), by comparison with a reference method: the MicroScan method based on broth microdilution on colonies isolated on PBCB subculture.

Methods

In total, 156 samples were collected prospectively from blood cultures positive for a Gram-negative rod. Each sample was tested with four AST techniques: (i) the QMAC dRAST GN kit, (ii) the disc diffusion (DD) method, (iii) the MicroScan method applied directly to PBCB; and (iv) MicroScan with isolates from PBCB subculture, as a reference.

Results

For 124 PBCB containing Enterobacterales, overall essential agreement (EA) and categorical agreement (CA) between the QMAC-dRAST on PBCB and the reference reached 95.7% and 93.5%, respectively. There were 3.0% very major errors (VME), 4.0% major errors (ME) and 2.8% minor errors (mE). A comparison of MicroScan on PBCB and the reference yielded 98.8% EA, 98.5% CA, and rates of 0.6% VME, 0.9% ME and 0.7% mE. The DD method on PBCB gave a CA of 95.8% and rates of 1.7% for VME, 2.0% for ME and 1.9% for mE. Results were obtained more rapidly for QMAC-dRAST (median of 6 h 37 min versus 18 h for the MicroScan and DD methods on PBCB).

Conclusions

The QMAC-dRAST system provided rapid results well correlated with the reference method on PBCB containing Enterobacterales. Given the shorter time-to-results, the QMAC-dRAST system constitutes a fast and reliable alternative to conventional AST methods.
Antibiotic treatment of respiratory tract infections in adults in Norwegian general practice
Authors: Skow Marius , Fossum Guro H , Høye Sigurd , Straand Jørund , Emilsson Louise , Brænd Anja Maria
Published: January 2023

Objectives

To analyse the prevalence of respiratory tract infection (RTI) episodes with and without antibiotic prescriptions in adult patients in Norwegian general practice during the period 2012–2019.

Methods

Observational study linking data from the Norwegian Control and Payment for Health Reimbursements Database and the Norwegian Prescription Database. Episodes of acute RTIs in patients aged 18 years or older were identified and linked to antibiotic prescriptions dispensed within 7 days after diagnosis. We analysed annual infection rates and antibiotic prescription rates and antibiotics prescribed for the different RTI conditions.

Results

RTI episode rate per 1000 inhabitants was 312 in 2012 and 277 in 2019, but showed no linear trend of change during the study period (P = 0.205). Antibiotic prescription rate decreased from 37% of RTI episodes in 2012 to 23% in 2019 (P < 0.001). The reduction in prescribing was most pronounced for episodes coded with ICPC-2 symptom diagnoses, as well as upper RTIs, influenza, acute bronchitis and sinusitis. Prescriptions for phenoxymethylpenicillin decreased from 178 746 in 2012 to 143 095 in 2019, but increased as proportion of total antibiotic prescriptions from 40% in 2012 to 53% in 2019 (P < 0.001).

Conclusions

This study demonstrates stable RTI episode rates and reduced antibiotic prescription rates for RTIs for adults in Norwegian general practice 2012–2019. We also observed a shift towards relatively more use of phenoxymethylpenicillin and less broad-spectrum antibiotics. These changes are in line with the aims of the Norwegian strategy against antibiotic resistance.
Fidaxomicin to prevent recurrent Clostridioides difficile: what will it cost in the USA and Canada?
Authors: Patel Devangi , Senecal Julien , Spellberg Brad , Morris Andrew M , Saxinger Lynora , Footer Brent W , McDonald Emily G , Lee Todd C
Published: January 2023

Importance

Recent changes in guidelines for managing Clostridioides difficile infections (CDI) have placed fidaxomicin as a first-line treatment.

Objective

To estimate the net cost of first-line fidaxomicin compared to vancomycin in the American and Canadian healthcare systems and to estimate the price points at which fidaxomicin would become cost saving for the prevention of recurrence.

Data sources and study selection

We identified randomized, placebo-controlled trials directly comparing fidaxomicin with vancomycin that reported on recurrence. Medication costs were obtained from the Veterans Affairs Federal Supply Schedule (US) and the Quebec drug formulary (Canada). The average cost of a CDI recurrence was established through a systematic review for each country.

Data extraction, synthesis and outcome measures

For efficacy, data on CDI recurrence at day 40 were pooled using a restricted maximal likelihood random effects model. For the cost review, the mean cost across identified studies was adjusted to reflect May 2022 dollars. These were used to estimate the net cost per recurrence prevented with fidaxomicin and the price point below which fidaxomicin would be cost saving.

Results

The estimated mean system costs of a CDI recurrence were $15 147USD and $8806CAD, respectively. Preventing one recurrence by using first-line fidaxomicin over vancomycin would cost $38 222USD (95%CI $30 577–$57 332) and $13 760CAD (95%CI $11 008–$20 640), respectively. The probability that fidaxomicin was cost saving exceeded 95% if priced below $1140USD or $860CAD, respectively.

Conclusions and Relevance

An increased drug expenditure on fidaxomicin may not be offset through recurrence prevention unless the fidaxomicin price is negotiated.
A call to action—stopping antimicrobial resistance
Authors: Eisinger Robert W , Williams Mark P , Choe Sung Hee , Krofah Esther
Published: January 2023

Antimicrobial resistance is a public health emergency and represents an impending pandemic. Implementing the lessons learned from responding to the COVID-19 pandemic is essential in accelerating the development of new antimicrobials and therapeutic strategies, rapid diagnostics and improved vaccines. A rededicated, coordinated and collaborative global effort of all stakeholders in academia, healthcare, government agencies, industry, finance and philanthropy is essential to halt the continued spread of antimicrobial resistance and to prevent further morbidity and mortality from drug-resistant pathogens.
Methylorubrum rhodesianumM520 as a biocontrol agent againstMeloidogyne incognita(Tylenchida: Heteroderidae) J2s infecting cucumber roots
Authors: Zhao Zhengyang , Wang Lin , Khan Raja Asad Ali , Song Xiaojun , Najeeb Saba , Zhao Jianlong , Yang Yuhong , Ling Jian , Mao Zhenchuan , Jiang Xianzhi , Xie Bingyan , Li Yan
Published: January 2023

Aims

Root-knot nematodes (RKNs) are plant pathogens that cause huge economic losses worldwide. The biological management of RKNs may be a sustainable alternative to chemical control methods. Here, the biocontrol potential of Methylorubrum rhodesianum M520 against the RKN Meloidogyne incognita was investigated to theoretically support its application as a biocontrol agent in field production.

Methods and results

In-vitro assays showed 91.9% mortality of M. incognita second-stage juveniles in the presence of strain M520 and that the hatching rate of M. incognita eggs was 21.7% lower than that of eggs treated with sterile water. In pot experiments, the M520 treatment caused 70.8% reduction in root-knots and increased plant shoot length and stem and root fresh weights, compared to control plant values. In split-root experiments, cucumber roots treated with M520 showed 25.6% decrease in root gall number, compared to that in control roots.

Conclusion

M520 has multiple mechanisms against RKNs and might be used as a biocontrol agent against M. incognita in cucumber, laying a foundation for further studying M520 biocontrol against RKNs.
StoryboardR: an R package and Shiny application designed to visualize real-world data from clinical patient registries
Authors: Miller David M , Shalhout Sophia Z
Published: January 2023

Objectives

Tumor registries are a rich source of real-world data which can be used to test important hypotheses that inform clinical care. Exploratory data analysis at the level of individual subjects, when enhanced by interactive data visualizations, has the potential to provide novel insights and generate new hypothesis.

Materials and Methods

We created StoryboardR: an R package and Shiny application designed to visualize real-word data from tumor registries.

Results

StoryboardR facilitates the data visualization of real-word data from tumor registries captured in REDCap®. The output is an interactive timeline that allows for a visual interpretation of the relationship between potential prognostic and/or predictive biomarkers and outcomes.

Conclusions

StoryboardR is freely available under the Massachusetts Institute of Technology license and can be obtained from GitHub. StoryboardR is executed in R and deployed as a Shiny application for non-R users. It produces data visualizations of patient journeys from tumor registries.
Evaluation of Heating Times for Loss on Drying at 105°C for Estimation of Laboratory Dry Matter in Animal Feeds
Authors: Quirino Daiana F , Lima Nicole S A , Palma Malber N N , Franco Marcia O , Detmann Edenio
Published: January 2023

Background

Dry matter (DM) is a routine test for all animal feeds, facilitating feed comparisons and diet formulation. It is the most frequent test, yet the most challenging with respect to precision and accuracy.

Objective

Our objective was to evaluate the accuracy, repeatability, and physicochemical impacts of oven-drying times on LDM test results in animal feeds obtained by loss on drying (LoD) at 105°C.

Methods

Eighteen primary samples collected from different feed sources were grouped into high-moisture (HM) and low-moisture (LM) content materials. The tested methods were based on LoD at 105°C and Karl Fischer titration was adopted as the reference method. Test portions were oven dried at 105°C for 3, 6, 12, 16, and 24 h, and test results were compared to the reference method. Test portions were also subjected to a color evaluation using a colorimetric technique.

Results

The method based on 3 h of drying provided the closest estimates to those obtained by Karl Fischer titration. Extending heating time (i.e., above 3 h) increased the bias, especially for HM feeds, which was attributed to a higher occurrence of non-enzymatic reactions. This was corroborated by the color of the residues, which became darker with increased heating time. The repeatability of LoD methods was considered adequate, ranging from 0.32 to 0.73%.

Conclusion

The LoD method based on the binomial 105°C × 3 h minimizes the bias in the water recovery and causes less non-enzymatic browning in the test portions.

Highlights

The loss-on-drying method recommended for laboratory DM in animal feeds is drying the test portions at 105°C for 3 h.
3-Nitrooxypropanol supplementation of a forage diet decreased enteric methane emissions from beef cattle without affecting feed intake and apparent total-tract digestibility
Authors: Alemu Aklilu W , Gruninger Robert J , Zhang Xiu Min , O’Hara Eóin , Kindermann Maik , Beauchemin Karen A
Published: January 2023

Supplementation of ruminant diets with the methane (CH4) inhibitor 3-nitrooxypropanol (3-NOP; DSM Nutritional Products, Switzerland) is a promising greenhouse gas mitigation strategy. However, most studies have used high grain or mixed forage-concentrate diets. The objective of this study was to evaluate the effects of supplementing a high-forage diet (90% forage DM basis) with 3-NOP on dry matter (DM) intake, rumen fermentation and microbial community, salivary secretion, enteric gas emissions, and apparent total-tract nutrient digestibility. Eight ruminally cannulated beef heifers (average initial body weight (BW) ± SD, 515 ± 40.5 kg) were randomly allocated to two treatments in a crossover design with 49-d periods. Dietary treatments were: 1) control (no 3-NOP supplementation); and 2) 3-NOP (control + 150 mg 3-NOP/kg DM). After a 16-d diet adaption, DM intake was recorded daily. Rumen contents were collected on days 17 and 28 for volatile fatty acid (VFA) analysis, whereas ruminal pH was continuously monitored from days 20 to 28. Eating and resting saliva production were measured on days 20 and 31, respectively. Diet digestibility was measured on days 38–42 by the total collection of feces, while enteric gas emissions were measured in chambers on days 46–49. Data were analyzed using the mixed procedure of SAS. Dry matter intake and apparent total-tract digestibility of nutrients (DM, neutral and acid detergent fiber, starch, and crude protein) were similar between treatments (P ≥ 0.15). No effect was observed on eating and resting saliva production. Relative abundance of the predominant bacterial taxa and rumen methanogen community was not affected by 3-NOP supplementation but rather by rumen digesta phase and sampling hour (P ≤ 0.01). Total VFA concentration was lower (P = 0.004) following 3-NOP supplementation. Furthermore, the reduction in acetate and increase in propionate molar proportions for 3-NOP lowered (P < 0.001) the acetate to propionate ratio by 18.9% as compared with control (4.1). Mean pH was 0.21 units lower (P < 0.001) for control than 3-NOP (6.43). Furthermore, CH4 emission (g/d) and yield (g/kg DMI) were 22.4 and 22.0% smaller (P < 0.001), respectively, for 3-NOP relative to control. Overall, the results indicate that enteric CH4 emissions were decreased by more than 20% with 3-NOP supplementation of a forage diet without affecting DM intake, predominant rumen microbial community, and apparent total-tract nutrients digestibility.
Clustering climate and management practices to define environmental challenges affecting gastrointestinal parasitism in Katahdin sheep
Authors: Arisman Brian C , Burke Joan M , Morgan James L M , Lewis Ronald M
Published: January 2023

Gastrointestinal nematodes (GIN) negatively affect the performance and well-being of sheep. Due to anthelmintic resistance, GIN are difficult to control leading producers to choose breeds that can exhibit resistance to parasitism. An example is Katahdin sheep. Katahdins are raised in various climates and management systems in the United States. These environmental factors can be combined to form eco-management groupings or clusters. We hypothesized that GIN challenge varies predictably based on the characteristics of these environmental clusters. Forty Katahdin producers from across the United States were surveyed for management information, with body weights (BW), fecal egg counts (FEC), and FAMACHA scores (FAM) available from 17 of the 40 flocks. The performance data included 3,426 lambs evaluated around 90 d of age. Management and climate data were combined into clusters using multiple correspondence and principal component (PC) analysis. Performance data were aligned with their corresponding cluster. Depending on the trait, eco-management cluster, birth-rearing type, sex, and, as a covariate, dam age, were fitted as systematic effects with ANOVA. Clusters also were formed based on climate or management data alone. When compared with fitting the eco-management clusters, they defined less variation in each of the traits based on Akaike and Bayesian information criterion, and adjusted r2 values. To further examine variation defined by eco-management clusters, residuals from an ANOVA model excluding eco-management cluster were retained, and their correlation with PC loadings calculated. All PC loadings were included as potential independent variables and tested for significance using backward stepwise regression. The PC loadings with a correlation |≥0.49| explained significant variation in each trait and were included in the final models chosen; adjusted r2 values for BW, FEC, and FAM were 0.90, 0.81, and 0.97, respectively. When analyzing GIN challenge, eco-management clusters corresponding with hotter temperatures and greater rainfall, and with pasture-born lambs, suffered greater parasitism. Conversely, the eco-management clusters with lambs turned out to pasture at older ages benefited from reduced parasitism. Through the formation of eco-management clusters, an environmental variable can be defined to study interactions of genotypes to their environment, providing a potentially useful tool for identifying parasite-resistant sheep.