bluuebunny/crossref_metadata_2025 huggingface dataset:
On the contribution of cosmic-ray interactions in the circumgalactic gas to the observed high-energy neutrino flux
Authors: Kalashev Oleg , Martynenko Nickolay , Troitsky Sergey
Published: March 2023

Cosmic rays escaping the Milky-Way disk interact with circumgalactic gas which fills the
virial volume of our Galaxy. These interactions should produce guaranteed fluxes of energetic
diffuse neutrinos and photons observable at the Earth. This neutrino flux would be a plausible
contribution to the spectrum measured by the IceCube neutrino observatory: the energy emitted in
this way is weakly constrained from cascade gamma rays, since the cascades have no time to
develop, but the arrival directions of the neutrinos do not point to the Galactic disk, in
agreement with observations. However, previous studies reported very different estimates of the
corresponding neutrino flux, so it was unclear if this contribution to the observed spectrum is
essential. Here we readdress the calculation of this diffuse neutrino flux component under various
assumptions about the cosmic-ray spectrum and propagation in the circumgalactic medium. We find
that even with these variations, this contribution to the observed neutrino flux remains
subleading provided multimessenger constraints are satisfied.
Spike sorting algorithms and their efficient hardware implementation: a comprehensive survey
Authors: Zhang Tim , Rahimi Azghadi Mostafa , Lammie Corey , Amirsoleimani Amirali , Genov Roman
Published: March 2023

Objective. Spike sorting is a set of techniques used to analyze extracellular neural recordings, attributing individual spikes to individual neurons. This field has gained significant interest in neuroscience due to advances in implantable microelectrode arrays, capable of recording thousands of neurons simultaneously. High-density electrodes, combined with efficient and accurate spike sorting systems, are essential for various applications, including brain machine interfaces (BMIs), experimental neural prosthetics, real-time neurological disorder monitoring, and neuroscience research. However, given the resource constraints of modern applications, relying solely on algorithmic innovation is not enough. Instead, a co-optimization approach that combines hardware and spike sorting algorithms must be taken to develop neural recording systems suitable for resource-constrained environments, such as wearable devices and BMIs. This co-design requires careful consideration when selecting appropriate spike-sorting algorithms that match specific hardware and use cases. Approach. We investigated the recent literature on spike sorting, both in terms of hardware advancements and algorithms innovations. Moreover, we dedicated special attention to identifying suitable algorithm-hardware combinations, and their respective real-world applicabilities. Main results. In this review, we first examined the current progress in algorithms, and described the recent departure from the conventional ‘3-step’ algorithms in favor of more advanced template matching or machine-learning-based techniques. Next, we explored innovative hardware options, including application-specific integrated circuits, field-programmable gate arrays, and in-memory computing devices (IMCs). Additionally, the challenges and future opportunities for spike sorting are discussed. Significance. This comprehensive review systematically summarizes the latest spike sorting techniques and demonstrates how they enable researchers to overcome traditional obstacles and unlock novel applications. Our goal is for this work to serve as a roadmap for future researchers seeking to identify the most appropriate spike sorting implementations for various experimental settings. By doing so, we aim to facilitate the advancement of this exciting field and promote the development of innovative solutions that drive progress in neural engineering research.
The role of the visual field size in artificial vision
Authors: Ghezzi Diego
Published: March 2023

Objective. Artificial vision has been and still is the subject of intense research. The ultimate goal is to help blind people in their daily life. Approaches to artificial vision, including visual prostheses and optogenetics, have strongly focused on restoring high visual acuity for object recognition and reading. Consequently, clinical trials were primarily focused on these parameters. Approach. Alternatively, enlarging the visual field (VF) size could significantly improve artificial vision. Main results. I propose that approaches towards artificial vision address the challenge of creating this rudimental form of sight within a large VF. Significance. Enlarging the VF size will enable users to improve their mobility and perform visually-driven search tasks. Eventually, it could make artificial vision more efficient, comfortable and acceptable from the user’s point of view.
Teaching quantum communications through a hands-on laboratory
Authors: Sebastián-Lombraña A. , Ortiz L. , Brito J.P. , Sáez de Buruaga J. , Vicente R.J. , Méndez R.B. , Artiñano R. , Martín V.
Published: March 2023

Teaching quantum communication is a challenging task when involving different technical and engineering backgrounds. The use of an approach that exploits the knowledge of these profiles, as well as other technological resources available for demonstrations or exercises, enhances this teaching. This paper presents as an example the “Quantum Communications Lab” that took place at the 6th INFIERI Summer School in 2021. In this lab, the access to the Madrid Quantum Communication Infrastructure (MadQCI) was an important resource available.
SiPM array of Xenoscope, a full-scale DARWIN vertical demonstrator
Authors: Peres R.
Published: March 2023

The DARWIN project aims to build and operate a next-generation observatory for dark matter and neutrino physics, featuring a time projection chamber with a proposed active target of 40 t of liquid xenon. As an R&D facility to test fundamental components of the future detector, Xenoscope, a full-scale vertical demonstrator with ∼400 kg of liquid xenon and up to 2.6 m electron drift length, was built at the University of Zurich. Its main objective is to demonstrate electron drift over unprecedented distances in liquid xenon—first in a purity monitor setup with charge readout, followed by a dual-phase time projection chamber. In this second phase, an array of 48 VUV4 MMPCs from Hamamatsu (model S13371-6050CQ-02) with a 12-channel readout will be placed above the liquid xenon column and operated as a light readout for the secondary proportional scintillation signals coming from extracted electrons in the time projection chamber. This work presents the design and development of the silicon photomultiplier array of Xenoscope, covering the structural and electronic design, sensor characterisation at cryogenic temperature and signal simulation.
Editorial: Focus issue on biomaterials approaches to the repair and regeneration of cartilage tissue
Authors: Sun Kang , Liu Bangheng , Wang Dong-An
Published: March 2023

Traditional joint replacement surgery faces the risk of enormous trauma and secondary revision while using medication to relieve symptoms can cause bone thinning, weight gain and interference with the patient’s pain signalling. Medical research has therefore focused on minimally invasive solutions for implanting tissue-engineered scaffolds to induce cartilage regeneration and repair. In cartilage tissue engineering, there are still technical barriers to seed cells, scaffold construction techniques, mechanical properties, and the regulation of the internal environment on the transplanted material. This issue focuses on the development of cartilage repair, cutting-edge discoveries, manufacturing technologies, and the current technological queries still faced in cartilage regenerative medicine research. The articles in this collection cover the coordination of physical and biochemical signals, genes, and regulations by the extracellular environment.
Understanding the social impacts of power outages in North America: a systematic review
Authors: Andresen Adam X , Kurtz Liza C , Hondula David M , Meerow Sara , Gall Melanie
Published: March 2023

As demand for electricity increases on an already strained electrical supply due to urbanization, population growth, and climate change, the likelihood of power outages will also increase. While researchers understand that the number of electrical grid disturbances is increasing, we do not adequately understand how increased power outages will affect a society that has become increasingly dependent on a reliable electric supply. This systematic review aims to understand how power outages have affected society, primarily through health impacts, and identify populations most vulnerable to power outages based on the conclusions from prior studies. Based on search parameters, 762 articles were initially identified, of which only 50 discussed the social impacts of power outages in North America. According to this literature, racial and ethnic minorities, especially Blacks or African Americans, those of lower socioeconomic status, children, older adults, and those living in rural areas experienced more significant impacts from previous power outages. Additionally, criminal activity increased during prolonged power outages with both pro-social and anti-social behaviors observed. Providing financial assistance or resources to replace spoiled goods can reduce crime. Future research on this topic must consider the financial effects of power outages, how power outage impacts seasonally vary, and the different durations of power outage impacts.
Implementation and results of a standardized process for identifying ambulatory pharmacy clinical outcome measures
Authors: McKay Connor , Vest Mary-Haston , Doligalski Christina , Summerlin Charles M , Alexander Maurice D , Deyo Zachariah M , Valgus John M , Waldron Kayla M
Published: March 2023

Purpose

Given the variation in clinical practice, a clinician-centric, standardized process to implement and validate clinical pharmacy outcome measures was developed.

Four specialty clinics with embedded clinic-based pharmacists underwent an iterative process to define, refine, and implement the build of electronic health record functionality for outcome measure data collection and reporting. Starting with a list of identified measures, clinic workgroups met to discuss each measure and identify gaps in measure implementation. Information technology experts created electronic documentation forms with discrete data and reports based on criteria specified by the clinic workgroups. Of 32 outcome measures identified as priorities for demonstrating pharmacists’ impact in previous research, 29 were implemented for routine monitoring through this project. Implementation strategies included identification through existing reporting, development of discrete documentation tools within the electronic health record, and development of new reporting tools from available discrete data fields. Time to implementation decreased from the first to the last pilot clinic implementation, as demonstrated through a 9-day reduction in electronic documentation form development and 31-day reduction in report development turnaround time.

Conclusion

A standardized and reproducible process was developed for the implementation of clinical pharmacy outcomes measures for 4 specialty clinics. The process was successfully utilized to develop measurable outputs for a variety of oncology and nononcology specialty disease states based upon multidisciplinary stakeholder input.
A review of enzyme design in catalytic stability by artificial intelligence
Authors: Ming Yongfan , Wang Wenkang , Yin Rui , Zeng Min , Tang Li , Tang Shizhe , Li Min
Published: March 2023

The design of enzyme catalytic stability is of great significance in medicine and industry. However, traditional methods are time-consuming and costly. Hence, a growing number of complementary computational tools have been developed, e.g. ESMFold, AlphaFold2, Rosetta, RosettaFold, FireProt, ProteinMPNN. They are proposed for algorithm-driven and data-driven enzyme design through artificial intelligence (AI) algorithms including natural language processing, machine learning, deep learning, variational autoencoder/generative adversarial network, message passing neural network (MPNN). In addition, the challenges of design of enzyme catalytic stability include insufficient structured data, large sequence search space, inaccurate quantitative prediction, low efficiency in experimental validation and a cumbersome design process. The first principle of the enzyme catalytic stability design is to treat amino acids as the basic element. By designing the sequence of an enzyme, the flexibility and stability of the structure are adjusted, thus controlling the catalytic stability of the enzyme in a specific industrial environment or in an organism. Common indicators of design goals include the change in denaturation energy (ΔΔG), melting temperature (ΔTm), optimal temperature (Topt), optimal pH (pHopt), etc. In this review, we summarized and evaluated the enzyme design in catalytic stability by AI in terms of mechanism, strategy, data, labeling, coding, prediction, testing, unit, integration and prospect.
Watch and wait after neoadjuvant treatment in rectal cancer: comparison of outcomes in patients with and without a complete response at first reassessment in the International Watch & Wait Database (IWWD)
Authors: Temmink Sofieke J D , Peeters Koen C M J , Bahadoer Renu R , Kranenbarg Elma Meershoek-Klein , Roodvoets Annet G H , Melenhorst Jarno , Burger Jacobus W A , Wolthuis Albert , Renehan Andrew G , Figueiredo Nuno L , Pares Oriol , Martling Anna , Perez Rodrigo O , Beets Geerard L , van de Velde Cornelis J H , Nilsson Per J ,   the International Watch & Wait Database (IWWD) Consortium, Aghili M , Keshvari A , Nouritaromlou M K , Ahlberg M , Kordnejad S , Aleinikov A , Dulskas A , Asoğlu O , Tokmak H , Barroca R G , Caiado A F , Rosa I A L , Breukink S O , Coraglio M F , Iseas S , Creaven B , Winter D C , Zaborowski A , Cunningham C , Gregory E , Custers P A , Geubels B M , DeBrun L , D’Hoore A , Dimofte G , Fechner K , Matzel K , Fernandez L , Herrando A I , Vieira P , Gaertner W B , Madoff R D , Gerard J P , Jacquinot F , Schiappa R , Gollins S , Gonzalez M , Vaccaro C A , Habr-Gama A , São Julião G P , Holman F A , Hompes R , Lameris W , Ketelaers S H J , Rutten H J T , Leitner K , Mazzarisi C , Malcomson L , O’Dwyer S T , Saunders M , Maroli A , Mitchell P , Murad-Regadas S , Pairola A , Pedraza Salazar I , Sanchez Loria F , Pennings A J , Spinelli A , Sun Myint A
Published: March 2023

Background

In rectal cancer, watch and wait for patients with a cCR after neoadjuvant treatment has an established evidence base. However, there is a lack of consensus on the definition and management of a near-cCR. This study aimed to compare outcomes in patients who achieved a cCR at first reassessment versus later reassessment.

Methods

This registry study included patients from the International Watch & Wait Database. Patients were categorized as having a cCR at first reassessment or at later reassessment (that is near-cCR at first reassessment) based on MRI and endoscopy. Organ preservation, distant metastasis-free survival, and overall survival rates were calculated. Subgroup analyses were done for near-cCR groups based on the response evaluation according to modality.

Results

A total of 1010 patients were identified. At first reassessment, 608 patients had a cCR; 402 had a cCR at later reassessment. Median follow-up was 2.6 years for patients with a cCR at first reassessment and 2.9 years for those with a cCR at later reassessment. The 2-year organ preservation rate was 77.8 (95 per cent c.i. 74.2 to 81.5) and 79.3 (75.1 to 83.7) per cent respectively (P = 0.499). Similarly, no differences were found between groups in distant metastasis-free survival or overall survival rate. Subgroup analyses showed a higher organ preservation rate in the group with a near-cCR categorized exclusively by MRI.

Conclusion

Oncological outcomes for patients with a cCR at later reassessment are no worse than those of patients with a cCR at first reassessment.
Gamma auditory steady-state response as a promising electrophysiological biomarker for depression: an in vivo study with chronic unpredictable mild stress (CUS)-induced rats
Authors: He Yuchen , Guo Wanting , Ren Zhengyu , Liang Jianhang , Liu Shuang , Ming Dong
Published: March 2023

Gamma oscillations play a functional role in brain cognitions. Recently, auditory steady-state response (ASSR) has been reported abnormally in depression clinically, particularly in the low-gamma band. However, clinical electroencephalography research has challenges obtaining pure signals straight from the source level, making information isolation and precise localization difficult. Besides, the ASSR deficits pattern remains unclear. Herein, we focused on the origin of ASSR—primary auditory cortex (A1), the central node in the auditory pathway. We assessed the evoked-power and phase-synchronization using local field potentials (LFP) in depression (n = 21) and control (n = 22) rats. Subsequent processing of the received auditory information was examined using event-related potentials (AEPs). Results showed that depressed rats exhibited significant gamma ASSR impairments in peak-to-peak amplitude, inter-trial phase coherence, and signal-to-noise ratio. These deficits were more pronounced during 40-Hz auditory stimuli in right-A1, indicating severe gamma network abnormalities in the right auditory pathway. Besides, increased N2 and P3 amplitudes in depression group were found, indicating excessive inhibitory control and contextual processing. Taken together, these ASSR abnormalities have a high specificity of more than 90% and high sensitivity of more than 80% to distinguish depression under 40-Hz auditory stimuli. Our findings provided an abnormal gamma network in the auditory pathway, as a promising diagnostic biomarker in the future.
Advanced heart failure in adult congenital heart disease: the role of renal dysfunction in management and outcomes
Authors: Krishnathasan Kaushiga , Dimopoulos Konstantinos , Duncan Neill , Ricci Piera , Kempny Alexander , Rafiq Isma , Gatzoulis Michael A , Heng Ee Ling , Blakey Sarah , Montanaro Claudia , Babu-Narayan Sonya V , Francis Darrel P , Li Wei , Constantine Andrew
Published: March 2023

Aims

Previous studies in adult congenital heart disease (CHD) have demonstrated a link between renal dysfunction and mortality. However, the prognostic significance of renal dysfunction in CHD and decompensated heart failure (HF) remains unclear. We sought to assess the association between renal dysfunction and outcomes in adults with CHD presenting to our centre with acute HF between 2010 and 2021.

Methods and results

This retrospective analysis focused on the association between renal dysfunction, pre-existing and on admission, and outcomes during and after the index hospitalization. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. Cox regression analysis was used to identify the predictors of death post-discharge. In total, 176 HF admissions were included (mean age 47.7 ± 14.5 years, 43.2% females). One-half of patients had a CHD of great complexity, 22.2% had a systemic right ventricle, and 18.8% had Eisenmenger syndrome. Chronic kidney disease was present in one-quarter of patients. The median length of intravenous diuretic therapy was 7 (4–12) days, with a maximum dose of 120 (80–160) mg furosemide equivalents/day, and 15.3% required inotropic support. The in-hospital mortality rate was 4.5%. The 1- and 5-year survival rates free of transplant or ventricular assist device (VAD) post-discharge were 75.4% [95% confidence interval (CI): 69.2–82.3%] and 43.3% (95% CI: 36–52%), respectively. On multivariable Cox analysis, CKD was the strongest predictor of mortality or transplantation/VAD. Highly complex CHD and inpatient requirement of inotropes also remained predictive of an adverse outcome.

Conclusion

Adult patients with CHD admitted with acute HF are a high-risk cohort. CKD is common and triples the risk of death/transplantation/VAD. An expert multidisciplinary approach is essential for optimizing outcomes.
Cost of illness in patients with post-treatment Lyme disease syndrome in Belgium
Authors: Willems Ruben , Verhaeghe Nick , Perronne Christian , Borgermans Liesbeth , Annemans Lieven
Published: March 2023

Background

A proportion of patients with Lyme borreliosis (LB) report long-term persisting signs and symptoms, even after recommended antibiotic treatment, which is termed post-treatment Lyme disease syndrome (PTLDS). Consensus on guidance regarding diagnosis and treatment is currently lacking. Consequently, patients suffer and are left searching for answers, negatively impacting their quality of life and healthcare expenditure. Yet, health economic data on PTLDS remain scarce. The aim of this article is therefore to assess the cost-of-illness related to PTLDS, including the patient perspective.

Methods

PTLDS patients (N = 187) with confirmed diagnosis of LB were recruited by a patient organization. Patients completed a self-reported questionnaire on LB-related healthcare utilization, absence from work and unemployment. Unit costs (reference year 2018) were obtained from national databases and published literature. Mean costs and uncertainty intervals were calculated via bootstrapping. Data were extrapolated to the Belgian population. Generalized linear models were used to determine associated covariates with total direct costs and out-of-pocket expenditures.

Results

Mean annual direct costs amounted to €4618 (95% CI €4070–5152), of which 49.5% were out-of-pocket expenditures. Mean annual indirect costs amounted to €36 081 (€31 312–40 923). Direct and indirect costs at the population level were estimated at €19.4 and 151.5 million, respectively. A sickness or disability benefit as source of income was associated with higher direct and out-of-pocket costs.

Conclusions

The economic burden associated with PTLDS on patients and society is substantial, with patients consuming large amounts of non-reimbursed healthcare resources. Guidance on adequate diagnosis and treatment of PTLDS is needed.
Water deficits shape the microbiome of Bermudagrass roots to be Actinobacteria rich
Authors: Hu Jialin , Cyle K Taylor , Miller Grady , Shi Wei
Published: March 2023

There is increasing evidence that microbes can help ameliorate plant growth under environmental stress. Still, it is largely unknown what microbes and potential functions are involved in sustaining turfgrass, the major component of urban/suburban landscapes, under drought. We examined microbial responses to water deficits in bulk soil, rhizosphere, and root endosphere of bermudagrass by applying evapotranspiration (ET)-based dynamic irrigation twice per week during the growing season to create six treatments (0%, 40%, 60%, 80%, 100%, and 120% ET) and respective drought-stressed soil conditions. Bacterial and fungal communities were analyzed via marker gene amplicon sequencing and thereafter drought-reshaped potential functions of the bacterial community were projected. Slight yet significant microbial responses to irrigation treatments were observed in all three microhabitats. The root endophytic bacterial community was most responsive to water stress. No-irrigation primarily increased the relative abundance of root endophytic Actinobacteria, especially the genus Streptomyces. Irrigation at ≤40% ET increased the relative abundances of PICRUSt2-predicted functional genes encoding 1-aminocyclopropane-1-carboxylic acid deaminase, superoxide dismutase, and chitinase in root endosphere. Our data suggest that the root endophytic Actinobacteria are likely the key players to improve bermudagrass fitness under drought by modulating phytohormone ethylene production, scavenging reactive oxygen species, or ameliorating nutrient acquisition.
Gene family expansion and functional diversification of chitinase and chitin synthase genes in Atlantic salmon (Salmo salar)
Authors: Holen Matilde Mengkrog , Vaaje-Kolstad Gustav , Kent Matthew Peter , Sandve Simen Rød
Published: March 2023

Chitin is one of the most abundant polysaccharides in nature, forming important structures in insects, crustaceans, and fungal cell walls. Vertebrates on the other hand are generally considered “nonchitinous” organisms, despite having highly conserved chitin metabolism-associated genes. Recent work has revealed that the largest group of vertebrates, the teleosts, have the potential to both synthesize and degrade endogenous chitin. Yet, little is known about the genes and proteins responsible for these dynamic processes. Here, we used comparative genomics, transcriptomics, and chromatin accessibility data to characterize the repertoire, evolution, and regulation of genes involved in chitin metabolism in teleosts, with a particular focus on Atlantic salmon. Reconstruction of gene family phylogenies provides evidence for an expansion of teleost and salmonid chitinase and chitin synthase genes after multiple whole-genome duplications. Analyses of multi-tissue gene expression data demonstrated a strong bias of gastrointestinal tract expression for chitin metabolism genes, but with different spatial and temporal tissue specificities. Finally, we integrated transcriptomes from a developmental time series of the gastrointestinal tract with chromatin accessibility data to identify putative transcription factors responsible for regulating chitin metabolism gene expression (CDX1 and CDX2) as well as tissue-specific divergence in the regulation of gene duplicates (FOXJ2). The findings presented here support the hypothesis that chitin metabolism genes in teleosts play a role in developing and maintaining a chitin-based barrier in the teleost gut and provide a basis for further investigations into the molecular basis of this barrier.
Recurrent mutation in the ancestry of a rare variant
Authors: Wakeley John , Fan Wai-Tong (Louis) , Koch Evan , Sunyaev Shamil
Published: March 2023

Recurrent mutation produces multiple copies of the same allele which may be co-segregating in a population. Yet, most analyses of allele-frequency or site-frequency spectra assume that all observed copies of an allele trace back to a single mutation. We develop a sampling theory for the number of latent mutations in the ancestry of a rare variant, specifically a variant observed in relatively small count in a large sample. Our results follow from the statistical independence of low-count mutations, which we show to hold for the standard neutral coalescent or diffusion model of population genetics as well as for more general coalescent trees. For populations of constant size, these counts are distributed like the number of alleles in the Ewens sampling formula. We develop a Poisson sampling model for populations of varying size and illustrate it using new results for site-frequency spectra in an exponentially growing population. We apply our model to a large data set of human SNPs and use it to explain dramatic differences in site-frequency spectra across the range of mutation rates in the human genome.
Mosaic Chromosomal Alterations and Human Longevity
Authors: Leshchyk Anastasia , Xiang Qingyan , Andersen Stacy L , Gurinovich Anastasia , Song Zeyuan , Lee Joseph H , Christensen Kaare , Yashin Anatoliy , Wojczynski Mary , Schwander Karen , Perls Thomas T , Monti Stefano , Sebastiani Paola
Published: March 2023

Mosaic chromosomal alterations (mCAs) are structural alterations associated with aging, cancer, cardiovascular disease, infectious diseases, and mortality. The distribution of mCAs in centenarians and individuals with familial longevity is poorly understood. We used MOsaic CHromosomal Alteration (MoChA) to discover mCAs in 2050 centenarians, offspring, and 248 controls from the New England Centenarian Study (NECS) and in 3 642 subjects with familial longevity and 920 spousal controls from the Long-Life Family Study (LLFS). We analyzed study-specific associations of somatic mCAs with age, familial longevity, the incidence of age-related diseases, and mortality and aggregated the results by meta-analysis. We show that the accumulation of mCAs > 100 KB increased to 102 years and plateaued at older ages. Centenarians and offspring accumulated fewer autosomal mCAs compared with controls (relative risk 0.637, p = .0147). Subjects with the APOE E4 allele had a 35.3% higher risk of accumulating autosomal mCAs (p = .002). Males were at higher risk for mCAs compared to females (male relative risk 1.36, p = 5.15e−05). mCAs were associated with increased hazard for cancer (hazard ratio 1.2) and dementia (hazard ratio 1.259) at a 10% false discovery rate. We observed a borderline significant association between mCAs and risk for mortality (hazard ratio 1.07, p = .0605). Our results show that the prevalence of individuals with mCAs does not continue to increase at ages >102 years and factors promoting familial longevity appear to confer protections from mCAs. These results suggest that limited mCA accumulation could be an important mechanism for extreme human longevity that needs to be investigated.
The HSPB1-p62/SQSTM1 functional complex regulates the unconventional secretion and transcellular spreading of the HD-associated mutant huntingtin protein
Authors: Bonavita R , Scerra G , Di Martino R , Nuzzo S , Polishchuk E , Di Gennaro M , Williams S V , Caporaso M G , Caiazza C , Polishchuk R , D’Agostino M , Fleming A , Renna M
Published: March 2023

Conformational diseases, such as Alzheimer, Parkinson and Huntington diseases, are part of a common class of neurological disorders characterized by the aggregation and progressive accumulation of proteins bearing aberrant conformations. Huntington disease (HD) has autosomal dominant inheritance and is caused by mutations leading to an abnormal expansion in the polyglutamine (polyQ) tract of the huntingtin (HTT) protein, leading to the formation of HTT inclusion bodies in neurons of affected patients. Interestingly, recent experimental evidence is challenging the conventional view by which the disease pathogenesis is solely a consequence of the intracellular accumulation of mutant protein aggregates. These studies reveal that transcellular transfer of mutated huntingtin protein is able to seed oligomers involving even the wild-type (WT) forms of the protein. To date, there is still no successful strategy to treat HD. Here, we describe a novel functional role for the HSPB1-p62/SQSTM1 complex, which acts as a cargo loading platform, allowing the unconventional secretion of mutant HTT by extracellular vesicles. HSPB1 interacts preferentially with polyQ-expanded HTT compared with the WT protein and affects its aggregation. Furthermore, HSPB1 levels correlate with the rate of mutant HTT secretion, which is controlled by the activity of the PI3K/AKT/mTOR signalling pathway. Finally, we show that these HTT-containing vesicular structures are biologically active and able to be internalized by recipient cells, therefore providing an additional mechanism to explain the prion-like spreading properties of mutant HTT. These findings might also have implications for the turn-over of other disease-associated, aggregation-prone proteins.
Novel Findings of Early Cardiac Dysfunction in Patients With Childhood-Onset Inflammatory Bowel Disease Using Layer-Specific Strain Analysis
Authors: Akiya Azusa , Takahashi Ken , Akimoto Satoshi , Hosono Yu , Ifuku Mayumi , Iso Takeshi , Yazaki Kana , Shigemitsu Sachie , Jimbo Keisuke , Kudo Takahiro , Ohtsuka Yoshikazu , Shimizu Toshiaki
Published: March 2023

Background

Patients with inflammatory bowel disease (IBD) are at a higher risk of developing cardiovascular diseases than healthy individuals, owing to persistent chronic inflammation and treatment effects. This study aimed to assess left ventricular function in patients with childhood-onset IBD using layer-specific strain analysis and to identify early indicators of cardiac dysfunction in them.

Methods

A total of 47 patients with childhood-onset ulcerative colitis (UC), 20 patients with Crohn’s disease (CD), and 75 age- and sex-matched healthy control subjects were included in this study. Conventional echocardiographic measurements of layer-specific (ie, endocardium, midmyocardium, and epicardium) global longitudinal strain and global circumferential strain (GCS) were evaluated in these participants.

Results

Layer-specific strain analysis showed that global longitudinal strain was lower in all layers for the UC (P < .001) and CD (P < .001) groups, regardless of the age at onset, but that GCS was only lower in the midmyocardial (P = .032) and epicardial (P = .018) layers in the CD group than in the control group. Although the mean left ventricular wall thickness was not significantly different among the groups, it was significantly correlated with the GCS of the endocardial layer in the CD group (ρ= -0.615; P = .004), suggesting that thickening of the left ventricular wall occurred as a compensatory mechanism to maintain the endocardial strain in the CD group layer.

Conclusions

Children and young adults with childhood-onset IBD displayed decreased midmyocardial deformation. Layer-specific strain could also be useful to identify indicators of cardiac dysfunction in patients with IBD.
Effects of 2 and 3 Vaccinations With the Bivalent Human Papillomavirus (HPV) Vaccine on the Prevalence and Load of HPV in Clearing and Persistent Infections in Young Women
Authors: van Eer Kahren , Middeldorp Marit , Dzebisasjvili Tsira , Lamkaraf Najima , de Melker Hester E , Steenbergen Renske D M , King Audrey J
Published: March 2023

Background

Human papillomavirus (HPV) viral load (VL) is associated with persistence, which increases cervical cancer risk. The bivalent vaccine protects against oncogenic HPV-16/18 and cross-protects against several nonvaccine types. We examined the effect of 2-dose (2D) and 3-dose (3D) vaccination on HPV prevalence and VL in clearing infections and persistent infections, 6 years and 12 years postvaccination, respectively.

Methods

Vaginal swabs collected from the “HPV Amongst Vaccinated and Non-vaccinated Adolescents” study (HAVANA, 3D-eligible) and HAVANA-2 (2D-eligble) participants were genotyped for HPV with the SPF10-DEIA-LiPA25 system. HPV VL was measured with type-specific quantitative polymerase chain reaction (qPCR).

Results

HPV-16, -18, -31, -33, and -45 clearing and/or persistent infection prevalence and HPV-16, -18, and -31 VLs in clearing infections were significantly reduced in 3D-vaccinated women compared to unvaccinated women. Except for HPV-11 and -59 clearing infections, no significant VL differences were observed among vaccinated women, ≤6 and >6 years post-vaccination. Infection numbers were low in 2D-eligible women, with no HPV-16/18 in vaccinated women. No VL differences for the remaining types were found.

Conclusions

3D vaccination reduces HPV prevalence in clearing infections and persistent infections and decreases HPV VLs in clearing infections, 12 years post-vaccination for vaccine and several nonvaccine types. 2D-eligible women had low infection numbers, with no HPV-16/18 among vaccinated women.
Development of a local antibiogram for a teaching hospital in Ghana
Authors: Dodoo Cornelius C , Odoi Hayford , Mensah Adelaide , Asafo-Adjei Karikari , Ampomah Ruth , Obeng Lydia , Jato Jonathan , Hutton-Nyameaye Araba , Aku Thelma A , Somuah Samuel O , Sarkodie Emmanuel , Orman Emmanuel , Mfoafo Kwadwo A , Ben Inemesit O , Kpokiri Eneyi E , Abba Fatima , Jani Yogini H
Published: March 2023

Background

Antimicrobial resistance threatens adequate healthcare provision against infectious diseases. Antibiograms, combined with patient clinical history, enable clinicians and pharmacists to select the best empirical treatments prior to culture results.

Objectives

To develop a local antibiogram for the Ho Teaching Hospital.

Methods

This was a retrospective cross-sectional study, using data collected on bacterial isolates from January–December 2021. Samples from urine, stool, sputum, blood, and cerebrospinal fluid (CSF) were considered as well as, aspirates and swabs from wound, ears and vagina of patients. Bacteria were cultured on both enrichment and selective media including blood agar supplemented with 5% sheep blood and MacConkey agar, and identified by both the VITEK 2 system and routine biochemical tests. Data on routine culture and sensitivity tests performed on bacterial isolates from patient samples were retrieved from the hospital’s health information system. Data were then entered into and analysed using WHONET.

Results

In all, 891 pathogenic microorganisms were isolated from 835 patients who had positive culture tests. Gram-negative isolates accounted for about 77% of the total bacterial species. Escherichia coli (246), Pseudomonas spp. (180), Klebsiella spp. (168), Citrobacter spp. (101) and Staphylococcus spp. (78) were the five most isolated pathogens. Most of the bacterial isolates showed high resistance (>70%) to ampicillin, piperacillin, ceftazidime, ceftriaxone, cefotaxime, penicillin G, amoxicillin, amoxicillin/clavulanic acid, ticarcillin/clavulanic acid and trimethoprim/sulfamethoxazole.

Conclusions

The isolates from the various samples were not susceptible to most of the antibiotics used in the study. The study reveals the resistance patterns of E. coli and Klebsiella spp. to some antibiotics on the WHO ‘Watch’ and ‘Reserve’ lists. Using antibiograms as part of antimicrobial stewardship programmes would optimize antibiotic use and preserve their efficacy.
Accuracy of antibacterial indication documentation in an electronic medicines management system
Authors: Yao Wendy , Peel Trisha N , Cairns Kelly A
Published: March 2023

Introduction

Electronic medicines management (EMM) systems are relatively new in the Australian healthcare system. This tertiary hospital network implemented an EMM in 2018, with mandatory documentation of antimicrobial indication when prescribing. Free-text (unrestricted) and pre-defined dropdown (restricted) indications are utilized according to antimicrobial restriction.

Objectives

To determine accuracy of antibacterial indication documentation on the medication administration record (MAR) when prescribing and to evaluate factors influencing accuracy of documentation.

Methods

A random sample of 400 inpatient admissions of ≥24 h, between March and September 2019, with the first antibacterial prescription per encounter reviewed retrospectively. Demographic and prescription details were extracted. Indication accuracy was assessed by comparing MAR documentation with the medical notes (gold standard). Statistical analysis compared factors associated with accuracy of indication using chi-squared and Fisher’s exact tests.

Results

Antibacterials were prescribed in 9708 admissions. Of the 400 patients included (60% male; median age 60 years, IQR 40–73), 225 prescriptions were unrestricted and 175 were restricted. Patients were managed by emergency (118), surgical (178) and medical (104) teams. Overall accuracy of antibacterial indication documentation on the MAR was 86%. A higher accuracy rate was found for the unrestricted proportion compared with the restricted proportion (94.2% versus 75.2%; P < 0.0001). Surgical teams had higher accuracy compared with medical and emergency teams (94.4% versus 78.8% versus 79.7%; P < 0.0001).

Discussion

Antibacterial indication documentation on the MAR when prescribing demonstrated a high rate of accuracy. Multiple factors influenced this accuracy, which requires further study to determine the impact on accuracy, with a view to improve future EMM builds.
Mitigating antimicrobial resistance (AMR) using implementation research: a development funder’s approach
Authors: Khurana Mark P , Essack Sabiha , Zoubiane Ghada , Sreenivasan Nandini , Cordoba Gloria Cristina , Westwood Erica , Dalsgaard Anders , Mdegela Robinson H , Mpundu Mirfin , Scotini Rodrigo , Matondo Augustine B , Mzula Alexanda , Chanishvili Nina , Gogebashvili Dimitri , Beruashvili Maia , Tsereteli Marika , Sooronbaev Talant , Kjærgaard Jesper , Bloch Joakim , Isaeva Elvira , Mainda Geoffrey , Muuka Geoffrey , Mudenda Ntombi B , Goma Fusya Y , Chu Duc-Huy , Chanda Duncan , Chirwa Uchizi , Yamba Kaunda , Kapolowe Kenneth , Fwoloshi Sombo , Mwenge Lawrence , Skov Robert
Published: March 2023

Despite the escalating burden of antimicrobial resistance (AMR), the global response has not sufficiently matched the scale and scope of the issue, especially in low- and middle-income countries (LMICs). While many countries have adopted national action plans to combat AMR, their implementation has lagged due to resource constraints, dysfunctional multisectoral coordination mechanisms and, importantly, an under-recognized lack of technical capacity to adapt evidence-based AMR mitigation interventions to local contexts. AMR interventions should be tailored, context-specific, cost-effective and sustainable. The implementation and subsequent scale-up of these interventions require multidisciplinary intervention-implementation research (IIR). IIR involves both quantitative and qualitative approaches, occurs across a three-phase continuum (proof of concept, proof of implementation and informing scale-up), and across four context domains (inner setting, outer setting, stakeholders and the implementation process). We describe the theoretical underpinnings of implementation research (IR), its various components, and how to construct different IR strategies to facilitate sustainable uptake of AMR interventions. Additionally, we provide real-world examples of AMR strategies and interventions to demonstrate these principles in practice. IR provides a practical framework to implement evidence-based and sustainable AMR mitigation interventions.
Influence of fiber-rich coproducts on nutrient and energy digestibility and utilization in sows
Authors: Wisbech Sigrid J , Jørgensen Henry , Nielsen Tina S , Bach Knudsen Knud E
Published: March 2023

Coproducts from the food and agricultural industries can potentially be used to replace concentrated high-value grain crops in diets for sows. The coproducts are typically high in fiber and with diverse composition. Energy digestibility and utilization are generally high in sows fed fiber-rich feedstuff, but nitrogen digestion and utilization may be compromised. The purpose of this study was to quantify the apparent total tract digestibility (ATTD) of nutrients and utilization of energy and nitrogen in empty nonlactating sows fed with six different fiber-rich coproducts (FRCP). Brewers spent grain (BSG), pea hull (PH), potato pulp (PP), pectin residue (PR), sugar beet pulp (SBP), and seed residue (SR) were mixed into a basal diet (BD) with as high an inclusion level as possible, or the BD was fed solely to eight empty sows in a Youden square incomplete cross-over design. The collection period consisted of a total collection period of 5 d, of which 2 d were in a respiration chamber. The sows had a gross energy (GE) intake between 28.5 and 42.3 MJ/d; greatest for the PH fed sows and lowest for the PP fed sows. The ATTD of dry matter, organic matter, GE, and N did not differ among the BD and the PH and SBP fed sows, while the ATTDs of all nutrients and energy were intermediate for PR and BSG lowest in SR fed sows (P < 0.01). The differences were caused by variation in digestible and metabolizable energy content of the FRCP ingredients, which was lowest for SR, intermediate for PR followed by BSG and greatest for SBP, PP, and PH (P < 0.001). Total heat production (HP) did not differ among treatments but the nonactivity related HP was highest in SR fed sows and lowest in PH and SBP fed sows (P < 0.05). Retention of energy was greatest following the PH and BD (7.42 and 2.19 MJ/d, respectively), intermediate for PP, SBP, and BSG fed sows (−0.22 to −0.69 MJ/d) and lowest for the PR and SR fed sows (−4.26 and −6.17 MJ/d, respectively; P < 0.001). From a sow feeding perspective, SBP and PH have the potential to partly replace high-value grain crops due to high ATTD of all nutrients and because sows can efficiently utilize energy and protein. In contrast, SR and PR show low ATTD of nutrients and energy, thereby compromising the nutritive value. PP and BSG also have the potential to be included in sow diets, but caution should be taken because of compromised N utilization and thereby increased environmental impact.
Effects of dietary crude protein level and sodium butyrate protected by medium-chain fatty acid salts on performance and gut health in weaned piglets
Authors: Sadurní M , Barroeta A C , Sol C , Puyalto M , Castillejos L
Published: March 2023

To reduce the use of antibiotics, research into nutritional strategies designed to improve the gut health of weaned pigs are underway. This study sought to examine the effects of reducing dietary crude protein (CP) and/or supplementing the feed with sodium butyrate protected by the sodium salts of medium-chain fatty acids on the growth performance and gut health of weaned piglets. Ninety-six weaned piglets (Landrace x Large White, 21 days of age) were allotted to four experimental treatments for 14 days. The experimental design was factorial with 2 CP levels and 2 feed-additive doses (0 vs 1 kg/t). Results showed that reducing CP from 22.2 to 18.8% diet had no effect on piglet growth performance parameters during the first post-weaning week (P > 0.05), but did compromise growth in the second week (P = 0.011), impacting on overall growth performance results (P = 0.019). Nonetheless, dietary CP level reduction led to reduce crypt depth (P = 0.036). In addition, Lactobacillus counts that were increased in the ileum (P = 0.032) and reduced in the colon (P = 0.032). Furthermore, apparent ileal digestibility of organic matter (P = 0.026) and fecal consistency (P < 0.05) were improved throughout the experiment. Moreover, in piglets fed diets containing 22.2% CP, the use of the feed-additive tended to improve the gain-to-feed ratio (P = 0.091) compared to those fed supplemented diets containing 18.8% CP. In addition, feed supplementation increased ileal numbers of goblet cells (P = 0.036), as well as apparent ileal digestibility of dry matter (P = 0.057) and organic matter (P = 0.003). Supplementation also had beneficial effects on the microbiota of the colon, increasing Lactobacillus counts (P = 0.006) and diminishing Enterobacteriaceae counts (P = 0.003), as well as affecting microbial metabolite profiles in that acetic acid concentrations tended to be increased (P = 0.088) and valeric acid concentrations were reduced (P = 0.002). These findings support the use of both strategies can improve the gut health of weaned piglets and prompt further research into the possible benefits of combining these two nutritional strategies on gut health and growth performance.