bluuebunny/crossref_metadata_2025 huggingface dataset:
Generative whole-brain dynamics models from healthy subjects predict functional alterations in stroke at the level of individual patients
Authors: Idesis Sebastian , Allegra Michele , Vohryzek Jakub , Perl Yonatan Sanz , Metcalf Nicholas V , Griffis Joseph C , Corbetta Maurizio , Shulman Gordon L , Deco Gustavo
Published: July 2024

Computational whole-brain models describe the resting activity of each brain region based on a local model, inter-regional functional interactions, and a structural connectome that specifies the strength of inter-regional connections. Strokes damage the healthy structural connectome that forms the backbone of these models and produce large alterations in inter-regional functional interactions. These interactions are typically measured by correlating the time series of the activity between two brain regions in a process, called resting functional connectivity. We show that adding information about the structural disconnections produced by a patient’s lesion to a whole-brain model previously trained on structural and functional data from a large cohort of healthy subjects enables the prediction of the resting functional connectivity of the patient and fits the model directly to the patient’s data (Pearson correlation = 0.37; mean square error = 0.005). Furthermore, the model dynamics reproduce functional connectivity-based measures that are typically abnormal in stroke patients and measures that specifically isolate these abnormalities. Therefore, although whole-brain models typically involve a large number of free parameters, the results show that, even after fixing those parameters, the model reproduces results from a population very different than that on which the model was trained. In addition to validating the model, these results show that the model mechanistically captures the relationships between the anatomical structure and the functional activity of the human brain.
CorrespondenceComment on ‘Gaining exposure on perceptions of sunscreen: a national survey of patients with melanoma’
Authors: Grant William B
Published: July 2024

A recent article stated that sunscreen is a vital tool in protecting against and reducing the risk of developing skin cancer. However, that is only for squamous cell carcinoma and perhaps basal cell carcinoma.
Comment on ‘Skin cancer decision-making in people with dementia’
Authors: Hussain Khawar , Bogucki Pawel , Patel Neil P
Published: July 2024

We write a response letter to the ethical dilemma ‘Skin cancer decision-making in people with dementia’ by Page et al. Clin Exp Dermatol 2024; XX:000–000.
Genetic deletion or pharmacologic inhibition of histone deacetylase 6 protects the heart against ischaemia/reperfusion injury by limiting tumour necrosis factor alpha–induced mitochondrial injury in experimental diabetes
Authors: Baumgardt Shelley L , Fang Juan , Fu Xuebin , Liu Yanan , Xia Zhengyuan , Zhao Ming , Chen Ling , Mishra Rachana , Gunasekaran Muthukumar , Saha Progyaparamita , Forbess Joseph M , Bosnjak Zeljko J , Camara Amadou K S , Kersten Judy R , Thorp Edward B , Kaushal Sunjay , Ge Zhi-Dong
Published: July 2024

Aims

The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A (TubA), reduces myocardial ischaemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments the activity of HDAC6 and the generation of tumour necrosis factor alpha (TNF-α) and impairs mitochondrial complex I (mCI). Here, we examined how HDAC6 regulates TNF-α production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI.

Methods and results

HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNF-α, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of adenosine triphosphate. Importantly, genetic disruption of HDAC6 or TubA decreased TNF-α levels, mitochondrial fission, and myocardial mitochondrial nicotinamide adenine dinucleotide levels in ischaemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or TubA treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNF-α levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown.

Conclusion

HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNF-α–induced mitochondrial injury in experimental diabetes.
HOFE: an interactive forensic entomological database
Authors: Liu Mandie , Qu Yihong , Luo Yifei , Jallow Binta J J , Ma Yuting , Luciano Afito , Huang Jingjing , Cai Jifeng , Meng Fanming
Published: July 2024

The significance of entomological evidence in inferring the time, location and cause of death has been demonstrated both theoretically and practically. With the advancement of sequencing technologies, reports have emerged on necrophagous insects’ nuclear genomes, transcriptomes, proteomes and mitochondrial genomes. However, within the field of forensic entomology, there is currently no available database that can integrate, store and share the resources of necrophagous insects. The absence of a database poses an inconvenience to the application of entomological evidence in judicial practice and hampers the development of the forensic entomology discipline. Given this, we have developed the Home Of Forensic Entomology database, encompassing 10 core functional modules: Home, Browse, Mitochondria, Proteome, JBrowse, Search, BLAST, Tools, Case base and Maps. Notably, the ‘Tools’ module enables multiple sequence alignment analysis (Muscle), homologous protein prediction (Genewise), primer design (Primer), large-scale genomic analysis (Lastz), Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, as well as expression profiling (PCA Analysis, Hcluster and Correlation Heatmap). In addition, the present database also works as an interactive platform for researchers by sharing forensic entomological case reports and uploading data and material. This database provides potential visitors with a comprehensive function for multi-omics data analysis, offers substantial references to researchers and criminal scene investigators and facilitates the utilization of entomological evidence in court.

Database URL: http://ihofe.com/
MSCs-exosomes Can Promote Macrophage M2 Polarisation via Exosomal miR-21-5p through Mesenteric Injection: A Promising Way to Attenuate Murine Colitis
Authors: Qian Wenwei , Wu Enhao , Chen Hong , Yao Jun , Wang Jin , Zhou Yudi , Bai Yanjin , Wang Sheng , Shen Chen , Li Yi , Zhang Yi
Published: July 2024

Background and Aims

Exosome-based therapies are gaining increasing attention, with growing evidence suggesting a link between alterations in mesentery adipose tissue [MAT] and intestinal disease in Crohn’s disease [CD]. However, the specific mechanism by which mesenchymal stem cells [MSCs]-Exos may alleviate colitis through targeting MAT remains not fully understood.

Methods

Human umbilical cord MSCs [HucMSCs] were cultured to isolate the corresponding exosomes [HucMSCs-Exos], which were confirmed by their morphology, size distribution, and expression of markers. In vivo, 2,4,6-trinitrobenzenesulphonic acid [TNBS]- and dextran sodium sulphate [DSS]-induced mouse colitis models were used to detect the therapeutic effects of HucMSCs-Exos. Enzyme-linked immunosorbent assay [ELISA], quantitative reverse transcription-polymerase chain reaction [qRT-PCR], western blotting, and immunofluorescence determined the expression of key molecules. Luciferase reporter assay was used to confirm the relationship between miR-21-5p and SPRY2.

Results

Exosomes treatment through mesenteric injection demonstrated therapeutic effects on mesenteric inflammation and colitis. These therapeutic benefits were contingent on macrophages, significantly facilitating the M2 polarisation of mesenteric macrophages. The expression data from GSE159814 and GSE211008 revealed that exosomal miR-21-5p was enriched in HucMSCs-Exos and could be delivered to macrophages. Additionally, the results indicated that miR-21-5p could directly target the 3’UTR of SPRY2 and activate the phosphorylation of ERK to modify macrophage phenotypes. Mechanistically, exosomal miR-21-5p derived from HucMSCs could promote macrophage M2 polarisation via the SPRY2/ERK axis.

Conclusion

Mesenteric injection of HucMSCs-Exos significantly alleviates mesenteric inflammation and colitis by promoting mesenteric macrophage M2 polarisation, making it a promising approach to treat colitis and suggesting therapeutic potential role of exosomal miR-21-5p in CD.
Boerhaave syndrome: an unusual myocardial infarction mimic—a case report
Authors: Mangeshkar Shaunak , Borkowski Pawel , Shokrekhuda Aspan , Barillas-Lara Maria Irene , Menegus Mark A
Published: July 2024

Background

A rare complication of oesophageal rupture or Boerhaave syndrome is myopericarditis due to leakage of oesophageal contents. This presentation can mimic a myocardial infarction, making diagnosis and management challenging.

Case summary

We present the case of a middle-aged man presenting with chest pain, who was diagnosed with Boerhaave syndrome complicated by myopericarditis, although the presentation was concerning for acute coronary syndrome.

Discussion

Through this case, we aim to highlight an unusual alternative aetiology of findings classically seen in myocardial infarction.
Do farmers prefer result-based, hybrid or practice-based agri-environmental schemes?
Authors: Gars Jared , Guerrero Santiago , Kuhfuss Laure , Lankoski Jussi
Published: July 2024

This study examines farmers’ preferences for practice-based, result-based and hybrid agri-environmental schemes in three countries through a choice experiment conducted by the Organization for Economic Cooperation and Development, focusing on biodiversity, climate and water quality. The results reveal that, in general, farmers tend to prefer practice-based schemes for water quality or climate change mitigation goals over hybrid or result-based schemes. Moreover, the study indicates that only a limited number of hybrid schemes are both preferred by farmers and more socially beneficial compared to equivalent practice- or result-based schemes. These conclusions are further reinforced by a cost-benefit analysis.
First human safety and effectiveness study of defibrillation with a novel patch wearable cardioverter-defibrillator
Authors: Chovanec Milan , Petrů Jan , Hála Pavel , Kralovec Stepan , Thakkar Anjali B , Mathews Kiran , Dinger Maarten , Ullery Steven , Eapen Zubin J , Kumar Uday N , Neužil Petr
Published: July 2024

Aims

Wearable cardioverter-defibrillators (WCDs) are indicated in patients at risk of sudden cardiac arrest who are not immediate candidates for implantable defibrillator therapy. Limitations of existing WCDs include poor compliance and high false alarm rates. The Jewel is a novel patch-WCD (P-WCD) that addresses these limitations with an adhesive-based design for near-continuous wear and a machine learning algorithm designed to minimize inappropriate detections. This was a first-in-human study of the Jewel P-WCD conducted in an electrophysiology (EP) lab to determine the safety and effectiveness of the device in terminating ventricular tachycardia/ventricular fibrillation (VT/VF) with a single shock. The aim was to evaluate the safety and effectiveness of terminating VT/VF with a single shock using the Jewel P-WCD.

Methods and results

This was a first-in-human, prospective, single-arm, single-centre study in patients scheduled for an EP procedure in which VT/VF was expected to either spontaneously occur or be induced. The Jewel P-WCD was placed on consented patients; upon confirmation of VT/VF, a single shock (150 J) was delivered via the device. A group sequential design and Pocock alpha spending function was used to measure the observed proportion of successful VT/VF single-shock terminations. The endpoint was achieved if the lower confidence limit exceeded the performance goal of 62%, using a one-sided lower 97.4% exact confidence bound. Of 18 eligible subjects, 16 (88.9%, 97.4% confidence bound: 65.4%) were successfully defibrillated with a single shock, exceeding the primary endpoint performance goal with no adverse events.

Conclusion

This first-in-human evaluation of the Jewel P-WCD demonstrated the safety and effectiveness of terminating VT/VF.

Clinical Trial Registration

URL: https://clinicaltrials.gov/; Unique identifier: NCT05490459
The correlation between anisogamy and sexual selection intensity—the broad theoretical predictions
Authors: Lehtonen Jussi , Parker Geoff A
Published: July 2024

Darwin and Bateman suggested that precopulatory sexual selection is more intense on males than females, and that this difference is due to anisogamy (i.e., dimorphism in gamete size and number). While a recent paper apparently presents empirical support for this hypothesis, another appears at first sight to present evidence against it. We argue that this is partly due to lack of transparent theoretical predictions, and discuss and analyze sexual selection theory in relation to anisogamy evolution. On one hand, we find that there exists relatively little theory that can directly address all the tested predictions; on the other, the picture painted by current theory indicates that both sets of empirical results broadly match predictions about the causal link between anisogamy and sexual selection, thus reconciling the two apparently opposing claims. We also discuss in a very broad, general sense how anisogamy is expected to affect sexual selection.
Coordination of care reduces conflict and predation risk in a cooperatively breeding bird
Authors: Halliwell Chay , Beckerman Andrew P , Patrick Samantha C , Hatchwell Ben J
Published: July 2024

When two or more individuals cooperate to provision a shared brood, each carer may be able to maximize their payoffs by coordinating provisioning in relation to what others are doing. This investment “game” is not simply a matter of how much to invest but also of the relative timing of investment. Recent studies propose that temporal coordination of care in the forms of alternation (i.e., turn-taking) and synchrony (i.e., provisioning together) function to mitigate conflict between carers and reduce brood predation risk, respectively. Such coordination is widespread in biparental and cooperatively breeding birds, yet the fitness consequences have rarely been empirically tested. Here, we use a long-term study of long-tailed tits Aegithalos caudatus, a facultative cooperatively breeding bird with active coordination of care, to assess the support for these hypothesized functions for coordination of provisioning visits. First, we found evidence that turn-taking mitigates conflict between carers because, in cooperative groups, provisioning rates and offspring recruitment increased with the level of active alternation exhibited by carers and with the associated increase in provisioning rate parity between carers. In contrast, offspring recruitment did not increase with alternation in biparental nests, although it was positively correlated with parity of provisioning between carers, which is predicted to result from conflict mitigation. Second, synchronous nest visits were associated with a reduced probability of nest predation and thus increased brood survival, especially when provisioning rates were high. We attribute this effect to synchrony reducing carer activity near the nest. We conclude that temporal coordination of provisioning visits in the forms of alternation and synchrony both confer fitness benefits on carers and despite being intrinsically linked, these different kinds of coordination appear to serve different functions.
Plasticity-mediated persistence and subsequent local adaptation in a global agricultural weed
Authors: Garrison Ava J , Norwood Lauren A , Conner Jeffrey K
Published: July 2024

Phenotypic plasticity can alter traits that are crucial to population establishment in a new environment before adaptation can occur. How often phenotypic plasticity enables subsequent adaptive evolution is unknown, and examples of the phenomenon are limited. We investigated the hypothesis of plasticity-mediated persistence as a means of colonization of agricultural fields in one of the world’s worst weeds, Raphanus raphanistrum ssp. raphanistrum. Using non-weedy native populations of the same species and subspecies as a comparison, we tested for plasticity-mediated persistence in a growth chamber reciprocal transplant experiment. We identified traits with genetic differentiation between the weedy and native ecotypes as well as phenotypic plasticity between growth chamber environments. We found that most traits were both plastic and differentiated between ecotypes, with the majority plastic and differentiated in the same direction. This suggests that phenotypic plasticity may have enabled radish populations to colonize and then adapt to novel agricultural environments.
Genetic constitution and variability in synthetic populations of intermediate wheatgrass, an outcrossing perennial grain crop
Authors: Bajgain Prabin , Jungers Jacob M , Anderson James A
Published: July 2024

Intermediate wheatgrass (IWG) is a perennial grass that produces nutritious grain while offering substantial ecosystem services. Commercial varieties of this crop are mostly synthetic panmictic populations that are developed by intermating a few selected individuals. As development and generation advancement of these synthetic populations is a multiyear process, earlier synthetic generations are tested by the breeders and subsequent generations are released to the growers. A comparison of generations within IWG synthetic cultivars is currently lacking. In this study, we used simulation models and genomic prediction to analyze population differences and trends of genetic variance in 4 synthetic generations of MN-Clearwater, a commercial cultivar released by the University of Minnesota. Little to no differences were observed among the 4 generations for population genetic, genetic kinship, and genome-wide marker relationships measured via linkage disequilibrium. A reduction in genetic variance was observed when 7 parents were used to generate synthetic populations while using 20 led to the best possible outcome in determining population variance. Genomic prediction of plant height, free threshing ability, seed mass, and grain yield among the 4 synthetic generations showed a few significant differences among the generations, yet the differences in values were negligible. Based on these observations, we make 2 major conclusions: (1) the earlier and latter synthetic generations of IWG are mostly similar to each other with minimal differences and (2) using 20 genotypes to create synthetic populations is recommended to sustain ample genetic variance and trait expression among all synthetic generations.
The Protestant Origins of the German Garden City, 1848–1910
Authors: Heckmann-Umhau Philipp
Published: July 2024

The garden city is one of the most enduring concepts in the history of modern urban planning. At the beginning of the twentieth century, garden city movements emerged in Britain, France, the United States, and Japan—and in Germany. While the German garden city is often viewed as a later adaption of the British type, its real origins are more complex. This article situates the genesis of the German garden city project within the larger framework of nineteenth-century Protestant thought and practice. It places the intellectual, institutional and legal innovations that prefigured the twentieth-century garden city in Protestant social reform, providing a longer-term perspective on its rich and diverse intellectual origins. The German garden city, it is argued, should be considered on its own terms, rather than merely as a derivative of the British type.
Enhancing Care for Older Adults and Dementia Patients With Large Language Models: Proceedings of the National Institute on Aging—Artificial Intelligence & Technology Collaboratory for Aging Research Symposium
Authors: Abadir Peter M , Battle Alexis , Walston Jeremy D , Chellappa Rama
Published: July 2024

Large Language Models (LLMs) stand on the brink of reshaping the field of aging and dementia care, challenging the one-size-fits-all paradigm with their capacity for precision medicine and individualized treatment strategies. The “Large Pre-Trained Models with a Focus on AD/ADRD and Healthy Aging” symposium, organized by the National Institute on Aging and the Johns Hopkins Artificial Intelligence & Technology Collaboratory for Aging Research, served as a platform for exploring this potential. The symposium brought together diverse experts to discuss the integration of LLMs in aging and dementia care. They highlighted the roles LLMs can play in clinical decision support and predictive analytics, while also addressing critical ethical concerns including bias, privacy, and the responsible use of artificial intelligence (AI). The discussions focused on the need to balance technological advancement with ethical considerations in AI deployment. In conclusion, the symposium projected a future where LLMs not only revolutionize healthcare practices but also pose significant challenges that require careful navigation.
Younger Older Americans and Sarcopenic Obesity: The Moderating Role of Living Alone
Authors: Bae Youngjoon
Published: July 2024

Objectives

Previous studies have indicated that compared to older adults, younger older adults (e.g., baby boomers) are more susceptible to obesity, but their risk decreases as they age. However, there is a lack of research on how individuals experience sarcopenic obesity, which increases in later life and is a mortality risk factor. This study examined how younger cohorts of older Americans and their demographic traits are related to sarcopenic obesity.

Methods

Generalized estimating equations were used to analyze participants aged 65 years and older, stratified by sex using data from the 2006–2016 Health and Retirement Study, with survey weights (n = 2,896 men and n = 4,268 women).

Results

The findings indicate that the youngest cohort (born between 1948 and 1953) had greater odds of sarcopenic obesity than older cohorts (born before 1931). However, the youngest cohort did not have significantly different risks from those born between 1931 and 1947. Unexpectedly, the youngest cohort of older women living alone tended not to have sarcopenic obesity compared to the older cohorts living alone. These results remained significant even after adjusting for various covariates, including marital status, race, education level, wealth, and other factors.

Discussion

This paper contributes to the existing literature on population health and demographic change in 2 ways. First, the risk of sarcopenic obesity is higher among younger cohorts of older Americans relative to older cohorts (born before 1931). Second, living alone may not necessarily be considered a worse health condition, particularly for younger female cohorts.
‘The Hideous Old Lady of Fashion’: dressing the ageing body in Victorian Britain
Authors: Ellis Ruby
Published: July 2024

This article explores how the biological realities and cultural constructions of ageing combined to influence a daily decision taken by Victorian women: what to wear. The cartoons found in Punch, and the guidance given by fashion papers and journalistic and literary sources highlight the individualized experience of dressing the ageing body, and the knowledge and skill needed to chart a course of compromise between ageing and the expectations that came with longer-held identities such as class, gender and sexuality. The difficulties in navigating this transition demonstrate how ageing was an art, and doing it well was a merit.
Metformin Is Associated With Improved Inflammatory Bowel Disease Outcomes in Patients With Type 2 Diabetes Mellitus: A Propensity-Matched Cohort Study
Authors: Petrov Jessica C , Desai Aakash A , Kochhar Gursimran S , Crosby Sheena K , Kinnucan Jami A , Picco Michael F , Hashash Jana G , Farraye Francis A
Published: July 2024

Background

Metformin exerts anti-inflammatory properties through a positive effect on oxidative stress, gut barrier integrity, and the gut microbiota. Our aim was to evaluate the influence of metformin on inflammatory bowel disease (IBD) outcomes in patients with type 2 diabetes mellitus (T2DM).

Methods

We conducted a retrospective cohort study using the TriNetX database in patients with IBD and T2DM who initiated metformin vs oral hypoglycemics or insulin (control cohort) between August 31, 2002, and August 31, 2022. One-to-one propensity score matching was performed. Primary outcomes were need for intravenous (IV) steroid use or IBD-related surgery within 1, 2, and 3 years after metformin initiation.

Results

Our cohorts included 1323 patients with ulcerative colitis (UC) (mean age 58.7 ± 12.2 years, 50.1% female, 77.3% White) and 1278 patients with Crohn’s disease (CD) (mean age 56.3 ± 12.6 years, 58.2% female, 76.5% White). At 1 year, patients with UC and CD were less likely to require IV steroids (UC: adjusted odds ratio [aOR], 0.45; 95% confidence interval [CI], 0.34-0.59; P < .01; CD: aOR, 0.67; 95% CI, 0.53-0.85; P < .01). The decreased need for IV steroids persisted in all metformin groups at 2 and 3 years. Patients with CD were at a lower risk for IBD-related surgery at year 1 (aOR, 0.5; 95% CI, 0.31-0.81; P < .01), and this finding persisted at 3 years (aOR, 0.62; 95% CI, 0.43-0.89; P < .01). Metformin did not affect risk for surgery in patients with UC.

Conclusions

Patients with IBD and T2DM on metformin had a decreased likelihood of worse IBD outcomes.
Initiation of knowledge and technology transfer from academia to industry: opportunity recognition and transfer channel choice
Authors: Huegel Matthias , Doerr Philip , Kalthaus Martin
Published: July 2024

Transferring knowledge and technology from academia to industry is usually understood as a process. While previous research focuses on phenomena along the process and its outcomes, the starting point of the process—the initiation of a transfer activity—remains unstudied. We conceptualize this initiation as a simultaneous recognition of a transfer opportunity and the choice of a transfer channel and provide first empirical insights into the initiation of the transfer process. We use survey data from 1149 scientists from the German state of Thuringia and their activities in science–industry collaboration, intellectual property rights, and spin-off creation. We employ seemingly unrelated regressions to account for selection and multiple channel choices in our econometric approach. Our results show a positive relationship between scientists’ different kinds of prior knowledge and the probability of recognizing a transfer opportunity. Contrary to our expectations, scientific impact reduces the likelihood of recognizing a transfer opportunity. For the choice of the transfer channel, the results show a positive relationship between choosing the spin-off channel and risk willingness, as well as basic research. Applied research increases the likelihood of choosing intellectual property rights as a channel. Furthermore, role models are positively associated with these two channels.
Bias due to coarsening of time intervals in the inference for the effectiveness of colorectal cancer screening
Authors: Karmakar Bikram , Zauber Ann G , Hahn Anne I , Lau Yan Kwan , Doubeni Chyke A , Joffe Marshall M
Published: July 2024

Background

Observational studies are frequently used to estimate the comparative effectiveness of different colorectal cancer (CRC) screening methods due to the practical limitations and time needed to conduct large clinical trials. However, time-varying confounders, e.g. polyp detection in the last screening, can bias statistical results. Recently, generalized methods, or G-methods, have been used for the analysis of observational studies of CRC screening, given their ability to account for such time-varying confounders. Discretization, or the process of converting continuous functions into discrete counterparts, is required for G-methods when the treatment and outcomes are assessed at a continuous scale.

Development

This paper evaluates the interplay between time-varying confounding and discretization, which can induce bias in assessing screening effectiveness. We investigate this bias in evaluating the effect of different CRC screening methods that differ from each other in typical screening frequency.

Application

First, using theory, we establish the direction of the bias. Then, we use simulations of hypothetical settings to study the bias magnitude for varying levels of discretization, frequency of screening and length of the study period. We develop a method to assess possible bias due to coarsening in simulated situations.

Conclusions

The proposed method can inform future studies of screening effectiveness, especially for CRC, by determining the choice of interval lengths where data are discretized to minimize bias due to coarsening while balancing computational costs.
Substrate Interactions and Free-Swimming Dynamics in the Crayfish Escape Response
Authors: de Pablo L X , Carleton A , Modarres-Sadeghi Y , Clotfelter E D
Published: July 2024

Synopsis

The caridoid or “tail flip” escape behavior of decapod crustaceans is a model system in neurobiology, but many aspects of its biomechanics are not well understood. To understand how the freshwater virile crayfish Faxonius virilis interacts with the substrate during the tail flip, we studied tail-flip hydrodynamics and force generation for free-moving animals standing on substrate, as well as tethered animals held at different distances from the substrate. We found no significant differences in force generation when distance from substrate was varied. Particle image velocimetry revealed that vortex formation was similar at all distances, but there were notable differences in interactions between shed vortices and substrate at different distances. Negative vorticity (clockwise flow of water) was observed in tethered animals interacting with the substrate but was largely absent in free-swimming animals. We found no evidence of ground effects enhancing tail flip performance in either tethered or free-swimming individuals, as peak force generation occurred before vortex shedding. This study contributes to our understanding of the crayfish escape response and highlights the need for more work that incorporates free-swimming animals and complex environments in the study of crustacean biomechanics.
A microbiological and genomic perspective of globally collected Escherichia coli from adults hospitalized with invasive E. coli disease
Authors: Arconada Nuin Enya , Vilken Tuba , Xavier Basil Britto , Doua Joachim , Morrow Brian , Geurtsen Jeroen , Go Oscar , Spiessens Bart , Sarnecki Michal , Poolman Jan , Bonten Marc , Ekkelenkamp Miquel , Lammens Christine , Goossens Herman , Glupczynski Youri , Van Puyvelde Sandra ,   COMBACTE-NET Consortium/EXPECT Study Group, Leten Gert , Van Mieghem Sofie , Violette Madison , Munshi Sonal , Aitabi Moussa , Azzini Anna Maria , Righi Elda , Salerno Nicola Duccio , Cascio Giuliana Lo , Cremonini Eleonora , Pascual Álvaro , Espíndola Reinaldo , Palomo Virginia , Barraud Olivier , Walker Sarah V , Akai Naomi , Kimura Risa , Lakatos Louis , De Blacam Killian , Thaden Joshua , Ruffin Felicia , Dagher Michael
Published: July 2024

Objectives

Escherichia coli can cause infections in the urinary tract and in normally sterile body sites leading to invasive E. coli disease (IED), including bacteraemia and sepsis, with older populations at increased risk. We aimed to estimate the theoretical coverage rate by the ExPEC4V and 9V vaccine candidates. In addition, we aimed at better understanding the diversity of E. coli isolates, including their genetic and phenotypic antimicrobial resistance (AMR), sequence types (STs), O-serotypes and the bacterial population structure.

Methods

Blood and urine culture E. coli isolates (n = 304) were collected from hospitalized patients ≥60 years (n = 238) with IED during a multicentric, observational study across three continents. All isolates were tested for antimicrobial susceptibility, O-serotyped, whole-genome sequenced and bioinformatically analysed.

Results

A large diversity of STs and of O-serotypes were identified across all centres, with O25b-ST131, O6-ST73 and O1-ST95 being the most prevalent types. A total of 45.4% and 64.7% of all isolates were found to have an O-serotype covered by the ExPEC4V and ExPEC9V vaccine candidates, respectively. The overall frequency of MDR was 37.4% and ST131 was predominant among MDR isolates. Low in-patient genetic variability was observed in cases where multiple isolates were collected from the same patient.

Conclusions

Our results highlight the predominance of MDR O25b-ST131 E. coli isolates across diverse geographic areas. These findings provide further baseline data on the theoretical coverage of novel vaccines targeting E. coli associated with IED in older adults and their associated AMR levels.
Penicillin-binding protein 3 sequence variations reduce susceptibility of Pseudomonas aeruginosa to β-lactams but inhibit cell division
Authors: Glen Karl A , Lamont Iain L
Published: July 2024

Background

β-lactam antibiotics, which inhibit penicillin-binding protein 3 (PBP3) that is required for cell division, play a key role in treating P. aeruginosa infections. Some sequence variations in PBP3 have been associated with β-lactam resistance but the effects of variations on antibiotic susceptibility and on cell division have not been quantified. Antibiotic efflux can also reduce susceptibility.

Objectives

To quantify the effects of PBP3 variations on β-lactam susceptibility and cell morphology in P. aeruginosa.

Methods

Nineteen PBP3 variants were expressed from a plasmid in the reference strain P. aeruginosa PAO1 and genome engineering was used to construct five mutants expressing PBP3 variants from the chromosome. The effects of the variations on β-lactam minimum inhibitory concentration (MIC) and cell morphology were measured.

Results

Some PBP3 variations reduced susceptibility to a variety of β-lactam antibiotics including meropenem, ceftazidime, cefepime and ticarcillin with different variations affecting different antibiotics. None of the tested variations reduced susceptibility to imipenem or piperacillin. Antibiotic susceptibility was further reduced when PBP3 variants were expressed in mutant bacteria overexpressing the MexAB-OprM efflux pump, with some variations conferring clinical levels of resistance. Some PBP3 variations, and sub-MIC levels of β-lactams, reduced bacterial growth rates and inhibited cell division, causing elongated cells.

Conclusions

PBP3 variations in P. aeruginosa can increase the MIC of multiple β-lactam antibiotics, although not imipenem or piperacillin. PBP3 variations, or the presence of sub-lethal levels of β-lactams, result in elongated cells indicating that variations reduce the activity of PBP3 and may reduce bacterial fitness.
The use of fosfomycin in infections caused by multidrug-resistant pathogens, especially pneumonia in children: a five-year retrospective single-centre experience
Authors: Dizi Işık Aylin , Akkoç Gülşen , Ergenç Zeynep , Yılmaz Seyhan , Aslan Tuncay Sevgi , Parlak Burcu , Canizci Erdemli Pınar , Büyüktaş Aytaç Didem , Abacı Çapar M Çağla , Öcal Demir Sevliya , Kepenekli Eda
Published: July 2024

Background

Fosfomycin is gaining increasing attention for its activity against MDR or XDR pathogens. Currently, IV fosfomycin is a potential option for treating various infections, including urinary tract infections, pneumonia and skin infections when first-line treatments fail.

Objectives

To evaluate the demographic, clinical, microbiological and treatment modality of children received IV fosfomycin to treat infections caused by MDR pathogens since there are few data on the use of fosfomycin in children.

Methods

This study was conducted retrospectively with patients under 18 years of age who were treated with IV fosfomycin for at least 72 h due to infections caused by MDR pathogens between January 2019 and October 2023 at Marmara University Pendik Training and Research Hospital, İstanbul, Türkiye. Data on demographic and clinical features, microbiological findings, treatment modalities and side effects were evaluated.

Results

Twenty-five children, for a total of 32 cases of infection episodes, with a mean age of 11.4 ± 3.92 years who received IV fosfomycin were included. The most frequent comorbidity was chronic pulmonary diseases, and the most common infection needed for IV fosfomycin was MDR Pseudomonas aeruginosa pneumonia. In all cases, fosfomycin was administered in combination with other antibiotics, mainly meropenem–colistin (68.7%) or meropenem (15.6%). Twenty-two (71.9%) cases had favourable clinical responses at the end of therapy.

Conclusions

Our results suggest that IV fosfomycin may be an effective treatment option for MDR pathogens in the paediatric population. Nevertheless, careful stewardship is necessary to maintain efficacy and reduce antimicrobial resistance selection risk.
Epidemiology of carbapenem-resistant Klebsiella pneumoniae in China and the evolving trends of predominant clone ST11: a multicentre, genome-based study
Authors: Shi Qiucheng , Ruan Zhi , Zhang Ping , Hu Huangdu , Han Xinhong , Wang Zhengan , Lou Tao , Quan Jingjing , Lan Wei , Weng Rui , Zhao Dongdong , Du Xiaoxing , Yu Yunsong , Jiang Yan
Published: July 2024

Objectives

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major nosocomial infectious pathogen with rapidly increasing prevalence. The genomic epidemiological characteristics of CRKP nationwide, especially the evolving trends within the predominant clones, should be evaluated clearly.

Methods

We collected 3415 K. pneumoniae strains from 28 hospitals across China. Antimicrobial susceptibility testing and WGS were performed. Subsequent genomic analyses, including sequence typing, K-locus (KL) identification, antimicrobial resistance gene screening, and virulence score assessment were performed. The phylogenetic relationship of clonal group 11 was determined based on core-genome analysis, and the presence of the pLVPK-like virulence plasmid in ST11 isolates was confirmed using plasmid core-gene analysis. Additionally, the trends of the ST11 lineage with different KL types on a global scale were investigated using Beast2.

Results

Of the K. pneumoniae strains, 708 were identified as CRKP isolates (20.7%), of which 97.7% were MDR. ST11 was the predominant clone, and KPC-2 was the prevalent carbapenemase in China, although the prevalence of specific clones and carbapenemases varied by geographic region. Among ST11 isolates, KL47 and KL64 were the predominant KL types, and KL64 gradually replaced KL47, with a higher percentage of KL64 isolates harbouring the pLVPK-like plasmid. Global genome data showed a significant increase in the effective population size of KL64 over the last 5 years.

Conclusions

The prevalence of CRKP was very high in certain regions in China. The increasing convergence of virulence and resistance, particularly in ST11-KL64 isolates, should be given more attention and further investigation.
Defining optimal sulbactam regimens for treatment of Acinetobacter baumannii pneumonia and impact of blaOXA-23 on efficacy
Authors: Abouelhassan Yasmeen , Nicolau David P , Abdelraouf Kamilia
Published: July 2024

Objectives

We evaluated the efficacies of human-simulated regimens (HSRs) of two clinically utilized sulbactam regimens: 1 g q6h 0.5 h infusion (maximum FDA-approved dosage) and 3 g q8h 4 h infusion (high-dose, prolonged-infusion regimen), against Acinetobacter baumannii in a translational murine model.

Methods

Thirty-two clinical A. baumannii isolates were investigated, of which 16 were sulbactam resistant (MIC ≥ 16 mg/L), 6 were sulbactam intermediate (MIC = 8 mg/L) and 10 were sulbactam susceptible (MIC ≤ 4 mg/L). Efficacies of the two sulbactam HSRs were assessed in the neutropenic murine pneumonia model. Changes in log10 cfu/lungs at 24 h compared with 0 h controls were measured, and efficacy was defined as achieving 1 log kill relative to baseline. WGS of the isolates and bioinformatics analysis were performed to explore potential associations between the genomic backgrounds and the in vivo responses.

Results

Eleven isolates harboured blaOXA-23, of which 10 were sulbactam resistant, 1 was sulbactam intermediate while none was sulbactam susceptible. Both sulbactam HSRs achieved >1 log kill against sulbactam-susceptible isolates. Against sulbactam-intermediate and sulbactam-resistant isolates, lack of efficacy correlated with the presence of the blaOXA-23 gene; sulbactam 1 g HSR and 3 g HSR did not show efficacy against 11/11 and 9/11 blaOXA-23-positive isolates, respectively, while efficacy was observed against all 11 blaOXA-23-negative sulbactam-intermediate and sulbactam-resistant isolates (i.e. harbouring other resistance genes).

Conclusions

A sulbactam high-dose prolonged-infusion regimen provides comparable activity to the standard dose against isolates currently considered sulbactam susceptible. However, the activity against isolates with intermediate and resistant susceptibility could be predicted by the detection of blaOXA-23. Enhancing detection capabilities of common diagnostic modalities to include OXA-23 can improve patient outcome.
Clinical, pharmacological, and qualitative characterization of drug–drug interactions in pregnant women initiating HIV therapy in Sub-Saharan Africa
Authors: Kiiza Daniel , Rostami-Hochaghan Danial , Alhassan Yussif , Seden Kay , Reynolds Helen , Kaboggoza Julian P , Taegtmeyer Miriam , Chen Tao , Challenger Elizabeth , Malaba Thokozile , Wang Duolao , Else Laura , Hern Faye , Sharp Jo , Neary Megan , Dilly Penchala Sujan , Waitt Catriona , Orrell Catherine , Colbers Angela , Myer Landon , Owen Andrew , Rannard Steve , Khoo Saye , Lamorde Mohammed
Published: July 2024

Background

We investigated the impact of Drug–Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs.

Methods

Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure.

Results

The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%–13.9%) and iron (4%–6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (−21%; P = 0.0271) and C24 (−53%; P = 0.0028).

Conclusions

The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.
Extraction of sleep information from clinical notes of Alzheimer’s disease patients using natural language processing
Authors: Sivarajkumar Sonish , Tam Thomas Yu Chow , Mohammad Haneef Ahamed , Viggiano Samuel , Oniani David , Visweswaran Shyam , Wang Yanshan
Published: July 2024

Objectives

Alzheimer’s disease (AD) is the most common form of dementia in the United States. Sleep is one of the lifestyle-related factors that has been shown critical for optimal cognitive function in old age. However, there is a lack of research studying the association between sleep and AD incidence. A major bottleneck for conducting such research is that the traditional way to acquire sleep information is time-consuming, inefficient, non-scalable, and limited to patients’ subjective experience. We aim to automate the extraction of specific sleep-related patterns, such as snoring, napping, poor sleep quality, daytime sleepiness, night wakings, other sleep problems, and sleep duration, from clinical notes of AD patients. These sleep patterns are hypothesized to play a role in the incidence of AD, providing insight into the relationship between sleep and AD onset and progression.

Materials and Methods

A gold standard dataset is created from manual annotation of 570 randomly sampled clinical note documents from the adSLEEP, a corpus of 192 000 de-identified clinical notes of 7266 AD patients retrieved from the University of Pittsburgh Medical Center (UPMC). We developed a rule-based natural language processing (NLP) algorithm, machine learning models, and large language model (LLM)-based NLP algorithms to automate the extraction of sleep-related concepts, including snoring, napping, sleep problem, bad sleep quality, daytime sleepiness, night wakings, and sleep duration, from the gold standard dataset.

Results

The annotated dataset of 482 patients comprised a predominantly White (89.2%), older adult population with an average age of 84.7 years, where females represented 64.1%, and a vast majority were non-Hispanic or Latino (94.6%). Rule-based NLP algorithm achieved the best performance of F1 across all sleep-related concepts. In terms of positive predictive value (PPV), the rule-based NLP algorithm achieved the highest PPV scores for daytime sleepiness (1.00) and sleep duration (1.00), while the machine learning models had the highest PPV for napping (0.95) and bad sleep quality (0.86), and LLAMA2 with finetuning had the highest PPV for night wakings (0.93) and sleep problem (0.89).

Discussion

Although sleep information is infrequently documented in the clinical notes, the proposed rule-based NLP algorithm and LLM-based NLP algorithms still achieved promising results. In comparison, the machine learning-based approaches did not achieve good results, which is due to the small size of sleep information in the training data.

Conclusion

The results show that the rule-based NLP algorithm consistently achieved the best performance for all sleep concepts. This study focused on the clinical notes of patients with AD but could be extended to general sleep information extraction for other diseases.