Establishing the Foundations of Emotional Intelligence in Care Companion Robots to Mitigate Agitation Among High-Risk Patients With Dementia: Protocol for an Empathetic Patient-Robot Interaction Study.

BACKGROUND: An estimated 6.7 million persons are living with dementia in the United States, a number expected to double by 2060. Persons experiencing moderate to severe dementia are 4 to 5 times more likely to fall than those without dementia, due to agitation and unsteady gait. Socially assistive robots fail to address the changing emotional states associated with agitation, and it is unclear how emotional states change, how they impact agitation and gait over time, and how social robots can best respond by showing empathy. OBJECTIVE: This study aims to design and validate a foundational model of emotional intelligence for empathetic patient-robot interaction that mitigates agitation among those at the highest risk: persons experiencing moderate to severe dementia. METHODS: A design science approach will be adopted to (1) collect and store granular, personal, and chronological data using Personicle (an open-source software platform developed to automatically collect data from phones and other devices), incorporating real-time visual, audio, and physiological sensing technologies in a simulation laboratory and at board and care facilities; (2) develop statistical models to understand and forecast the emotional state, agitation level, and gait pattern of persons experiencing moderate to severe dementia in real time using machine learning and artificial intelligence and Personicle; (3) design and test an empathy-focused conversation model, focused on storytelling; and (4) test and evaluate this model for a care companion robot (CCR) in the community. RESULTS: The study was funded in October 2023. For aim 1, architecture development for Personicle data collection began with a search for existing open-source data in January 2024. A community advisory board was formed and met in December 2023 to provide feedback on the use of CCRs and provide personal stories. Full institutional review board approval was received in March 2024 to place cameras and CCRs at the sites. In March 2024, atomic marker development was begun. For aim 2, after a review of open-source data on patients with dementia, the development of an emotional classifier was begun. Data labeling was started in April 2024 and completed in June 2024 with ongoing validation. Moreover, the team established a baseline multimodal model trained and validated on healthy-person data sets, using transformer architecture in a semisupervised manner, and later retrained on the labeled data set of patients experiencing moderate to severe dementia. In April 2024, empathy alignment of large language models was initiated using prompt engineering and reinforcement learning. CONCLUSIONS: This innovative caregiving approach is designed to recognize the signs of agitation and, upon recognition, intervene with empathetic verbal communication. This proposal has the potential to have a significant impact on an emerging field of computational dementia science by reducing unnecessary agitation and falls of persons experiencing moderate to severe dementia, while reducing caregiver burden. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/55761.

Roles and contributions of companions in healthcare professional-older patient interaction: A systematic review.

OBJECTIVES: Companions commonly participate in medical visits to facilitate the interactions between healthcare professionals (HCPs) and older patients. Multiple studies have investigated the contributions and roles of companions in these triadic interactions. However, no review has synthesized these studies. Therefore, a systematic review was conducted to synthesize the contributions and roles of companions in medical interactions between HCPs and older patients. METHODS: The review adhered to the PRISMA guidelines. Peer-reviewed studies published prior to August 17, 2023 were included if they concentrated on the contributions and roles of companions in medical interactions between HCPs and older patients. Thirteen eligible studies were identified through database and manual searches. The findings of these studies were synthesized using thematic analysis. RESULTS: Four themes emerged: (1) facilitating the delivery of patient information to HCPs; (2) advocating for older patients; (3) taking an active role in medical consultations; and (4) neglecting/excluding older patients from medical consultations. CONCLUSION: The review highlighted the valuable support and potential challenges that companion participation brings to interactions between HCPs and older patients. These findings underscore the importance of enhancing HCPs' communication skills in such triadic consultations.

Staphylococcus pseudintermedius ST2660 isolated from a cat has strong biofilm-forming ability and increases biofilm formation at cat's normal body temperature.

Staphylococcus pseudintermedius has been isolated from dogs, cats, and horses and is also known as an emergent zoonotic agent. We administered orbifloxacin, a fluoroquinolone, to treat bacterial infections of cutaneous wounds caused by excessive grooming of the skin in contact with the subcutaneous port of the subcutaneous ureteral bypass (SUB) system in a cat. However, after 80 days of treatment, a severe abscess was observed in the wound and fluoroquinolone-resistant S. pseudintermedius was isolated from the abscess. The isolate was identified as a novel sequence type (ST) 2660 and contained genes for leukocidins (lukS and lukF), exfoliative toxin (siet), and biofilm regulation (icaA and icaD). The isolate was resistant to macrolide, lincosamide, fluoroquinolone, and tetracycline classes. In addition, the isolate had strong biofilm-forming ability which significantly increased with culturing at 39 °C compared with that at 37 °C, suggesting that the isolate prefers a cats' body temperature as the optimal biofilm growth condition. Notably, the biofilms were increased in the presence of doxycycline with culturing at 39 °C. This study is the first report in Japan on the new sequence type of S. pseudintermedius isolated from a companion animal and clarifies the distinctive virulence of S. pseudintermedius.

Comprehensive profile of the companion animal gut microbiome integrating reference-based and reference-free methods.

The gut microbiome of companion animals is relatively underexplored, despite its relevance to animal health, pet owner health, and basic microbial community biology. Here, we provide the most comprehensive analysis of the canine and feline gut microbiomes to date, incorporating 2639 stool shotgun metagenomes (2272 dog and 367 cat) spanning 14 publicly available datasets (n = 730) and 8 new study populations (n = 1909). These are compared with 238 and 112 baseline human gut metagenomes from the Human Microbiome Project 1-II and a traditionally living Malagasy cohort, respectively, processed in a manner identical to the animal metagenomes. All microbiomes were characterized using reference-based taxonomic and functional profiling, as well as de novo assembly yielding metagenomic assembled genomes clustered into species-level genome bins. Companion animals shared 184 species-level genome bins not found in humans, whereas 198 were found in all three hosts. We applied novel methodology to distinguish strains of these shared organisms either transferred or unique to host species, with phylogenetic patterns suggesting host-specific adaptation of microbial lineages. This corresponded with functional divergence of these lineages by host (e.g., differences in metabolic and antibiotic resistance genes) likely important to companion animal health. This study provides the largest resource to date of companion animal gut metagenomes and greatly contributes to our understanding of the "One Health" concept of a shared microbial environment among humans and companion animals, affecting infectious diseases, immune response, and specific genetic elements.

Cracking the plant VOC sensing code and its practical applications.

Volatile organic compounds (VOCs) are essential airborne mediators of interactions between plants. These plant-plant interactions require sophisticated VOC-sensing mechanisms that enable plants to regulate their defenses against pests. However, these interactions are not limited to specific plants or even conspecifics, and can function in very flexible interactions between plants. Sensing and responding to VOCs in plants is finely controlled by their uptake and transport systems as well as by cellular signaling via, for example, chromatin remodeling system-based transcriptional regulation for defense gene activation. Based on the accumulated knowledge about the interactions between plants and their major VOCs, companion plants and biostimulants are being developed for practical applications in agricultural and horticultural pest control, providing a sustainable alternative to harmful chemicals.

Anaplasma platys and Rickettsia massiliae in Rhipicephalus sanguineus sensu stricto ticks collected on dogs in the Patagonian region of Argentina.

The aim of this study was to examine the presence of tick-borne rickettsial bacteria in Rhipicephalus sanguineus sensu stricto ticks collected from dogs in the Patagonian region of Argentina. Fourteen stray dogs from Valcheta, Río Negro province, Argentina were examined for the presence of R. sanguineus s.s. ticks. Ninety ticks were collected and identified to species level. DNA was extracted and analysed by conventional PCR assays for the presence of tick-borne bacteria belonging to the genera Anaplasma, Ehrlichia and Rickettsia. Thirty-three tick pools were tested by different PCR assays of which 3 were positive for Anaplasmataceae bacteria. From the 3 Anaplasmataceae positive samples, 2 partial 16S rDNA sequences were generated and belonging to Anaplasma platys, the causative agent of canine cyclic thrombocytopenia. Two tick samples were positive in Rickettsia specific PCR assays and were identified by phylogenetic analysis as Rickettsia massiliae, a member of the spotted fever group rickettsiae. The results of this study demonstrate the molecular detection of 2 rickettsial bacteria in R. sanguineus s.s. in a region of Argentina where no data were available so far.

Adaptation and Validation of the Pet Bereavement Questionnaire (PBQ) for Chinese Population.

Despite the increasing prevalence of pet ownership in Chinese societies, standardized tools to assess grief from pet loss remain lacking. Research predominantly focuses on Western populations, creating a gap in understanding pet bereavement in Chinese cultural settings. This study aimed to adapt and validate the Pet Bereavement Questionnaire (PBQ-C) for a Chinese context to create a culturally appropriate assessment tool. A total of 246 participants with companion animal loss experiences were recruited through the university of the research team. They were invited to complete an online survey including the PBQ-C, the Depression subscale of the Depression Anxiety Stress Scales (DASS-21), and the Inventory of Complicated Grief (ICG). Both Exploratory Factor Analysis and Confirmatory Factor Analysis were conducted to examine the psychometric properties of the PBQ-C and the findings supported a three-factor structure-grief, anger, and guilt-aligned with the original PBQ, with three items reassigned to different factors. Despite these adjustments, the PBQ-C demonstrated strong internal consistency, reflecting the reliability of the questionnaire in measuring the same construct across its items; split-half reliability, indicating its ability to produce consistent results when divided into two parts; and concurrent validity, showing that the PBQ-C correlates well with other established measures of grief. The validated PBQ-C provides a culturally sensitive tool for assessing pet bereavement in Chinese society that can promote research and counselling support for this under-researched and under-recognized type of loss of human-animal relationships.

Human-Robot Intimacy: Acceptance of Robots as Intimate Companions.

Depictions of robots as romantic partners for humans are frequent in popular culture. As robots become part of human society, they will gradually assume the role of partners for humans whenever necessary, as assistants, collaborators, or companions. Companion robots are supposed to provide social contact to those who would not have it otherwise. These companion robots are usually not designed to fulfill one of the most important human needs: the one for romantic and intimate contact. Human-robot intimacy remains a vastly unexplored territory. In this article, we review the state-of-the-art research in intimate robotics. We discuss major issues limiting the acceptance of robots as intimate partners, the public perception of robots in intimate roles, and the possible influence of cross-cultural differences in these domains. We also discuss the possible negative effects human-robot intimacy may have on human-human contact. Most importantly, we propose a new term "intimate companion robots" to reduce the negative connotations of the other terms that have been used so far and improve the social perception of research in this domain. With this article, we provide an outlook on prospects for the development of intimate companion robots, considering the specific context of their use.

A Smart Water Bottle and Companion App (HidrateSpark 3) to Improve Bladder-Filling Compliance in Patients With Prostate Cancer Receiving Radiotherapy: Nonrandomized Trial of Feasibility and Acceptability.

BACKGROUND: Patients with prostate cancer undergoing radiation therapy (RT) need comfortably full bladders to reduce toxicities during treatment. Poor compliance is common with standard of care written or verbal instructions, leading to wasted patient value (PV) and clinic resources via poor throughput efficiency (TE). OBJECTIVE: Herein, we assessed the feasibility and acceptability of a smartphone-based behavioral intervention (SBI) to improve bladder-filling compliance and methods for quantifying PV and TE. METHODS: In total, 36 patients with prostate cancer were enrolled in a single-institution, closed-access, nonrandomized feasibility trial. The SBI consists of a fully automated smart water bottle and smartphone app. Both pieces alert the patient to empty his bladder and drink a personalized volume goal, based on simulation bladder volume, 1.25 hours before his scheduled RT. Patients were trained to adjust their volume goal and notification times to achieve comfortably full bladders. The primary end point was met if qualitative (QLC) and quantitative compliance (QNC) were >80%. For QLC, patients were asked if they prepared their bladders before daily RT. QNC was met if bladder volumes on daily cone-beam tomography were >75% of the simulation's volume. The Service User Technology Acceptability Questionnaire (SUTAQ) was given in person pre- and post-SBI. Additional acceptability and engagement end points were met if >3 out of 5 across 4 domains on the SUTAQ and >80% (15/18) of patients used the device >50% of the time, respectively. Finally, the impact of SBI on PV and TE was measured by time spent in a clinic and on the linear accelerator (linac), respectively, and contrasted with matched controls. RESULTS: QLC was 100% in 375 out of 398 (94.2%) total treatments, while QNC was 88.9% in 341 out of 398 (85.7%) total treatments. Of a total score of 5, patients scored 4.33 on privacy concerns, 4 on belief in benefits, 4.56 on satisfaction, and 4.24 on usability via SUTAQ. Further, 83% (15/18) of patients used the SBI on >50% of treatments. Patients in the intervention arm spent less time in a clinic (53.24, SEM 1.71 minutes) compared to the control (75.01, SEM 2.26 minutes) group (P<.001). Similarly, the intervention arm spent less time on the linac (10.67, SEM 0.40 minutes) compared to the control (14.19, SEM 0.32 minutes) group (P<.001). CONCLUSIONS: This digital intervention trial showed high rates of bladder-filling compliance and engagement. High patient value and TE were feasibly quantified by shortened clinic times and linac usage, respectively. Future studies are needed to evaluate clinical outcomes, patient experience, and cost-benefit. TRIAL REGISTRATION: ClinicalTrials.gov NCT04946214; https://www.clinicaltrials.gov/study/NCT04946214.

Companion Tests and Personalized Cancer Therapy: Reaching a Glass Ceiling.

The use of companion diagnostics has become a standard in precision oncology in the context of ongoing therapeutic innovation. However, certain limitations make their application imperfect in current practice. This position paper underscores the need to broaden the notion of companion testing, considering the potential of emerging technologies, including computational biology, to overcome these limitations. This wave of progress should impact not only our representation of the analytical tool itself but also the nature of the tumoral sample under analysis (liquid biopsies). The complex inter-relationship between companion test guided-personalized therapy, and health agency policies for new drug agreements will also be discussed.

Decoding the Gut Microbiome in Companion Animals: Impacts and Innovations.

The changing notion of "companion animals" and their increasing global status as family members underscores the dynamic interaction between gut microbiota and host health. This review provides a comprehensive understanding of the intricate microbial ecology within companion animals required to maintain overall health and prevent disease. Exploration of specific diseases and syndromes linked to gut microbiome alterations (dysbiosis), such as inflammatory bowel disease, obesity, and neurological conditions like epilepsy, are highlighted. In addition, this review provides an analysis of the various factors that impact the abundance of the gut microbiome like age, breed, habitual diet, and microbe-targeted interventions, such as probiotics. Detection methods including PCR-based algorithms, fluorescence in situ hybridisation, and 16S rRNA gene sequencing are reviewed, along with their limitations and the need for future advancements. Prospects for longitudinal investigations, functional dynamics exploration, and accurate identification of microbial signatures associated with specific health problems offer promising directions for future research. In summary, it is an attempt to provide a deeper insight into the orchestration of multiple microbial species shaping the health of companion animals and possible species-specific differences.

A biological age based on common clinical markers predicts health trajectory and mortality risk in dogs.

Predicting aging trajectories through biomarkers of biological aging can guide interventions that optimize healthy lifespan in humans and companion animals. Differences in physiology, genetics, nutrition, and lifestyle limit the generalization of such biomarkers and may therefore require species-specific algorithms. Here, we compared correlations of standard clinical blood parameters with survival probability in humans with those of the two most common mammalian companion animals, cats and dogs, and highlighted universal and species-specific relationships. Based on this comparative analysis, we generated and validated an algorithm that predicts biological age in canines using a longitudinal dataset with health records, blood count, and clinical chemistry from 829 dogs spanning over 12 years. Positive deviations of biological from chronological age (AgeDev) measured by this composite score significantly correlated with a decreased survival probability (hazard ratio = 1.75 per 1 year of AgeDev, p = 3.7e - 06). Importantly, in nearly half of the dogs whose biological age was accelerated by more than 1 year, none or only a single individual marker scored outside its respective reference range, suggesting practical applications for the detection of unfavorable health trajectories. Analyzing samples from a unique 14-year life-long diet restriction study, we show that restricted caloric intake lowers biological age, an effect that can be quantified at midlife years before a difference in survival is observed. Thus, a biological age clock based on clinical blood tests predicts the health trajectories of dogs for use in research and veterinary practice.

The Effects of Pets in Cancer Care: A Case Study.

Humans can form an intense bond with their pets through shared love, attachment, and amusement. Through this case study, nurses can develop an increased understanding of how companion pets affect the quality of life of patie.

Criteria for assessing evidence for biomarker-targeted therapies in rare cancers-an extrapolation framework.

Background: Advances in targeted therapy development and tumor sequencing technology are reclassifying cancers into smaller biomarker-defined diseases. Randomized controlled trials (RCTs) are often impractical in rare diseases, leading to calls for single-arm studies to be sufficient to inform clinical practice based on a strong biological rationale. However, without RCTs, favorable outcomes are often attributed to therapy but may be due to a more indolent disease course or other biases. When the clinical benefit of targeted therapy in a common cancer is established in RCTs, this benefit may extend to rarer cancers sharing the same biomarker. However, careful consideration of the appropriateness of extending the existing trial evidence beyond specific cancer types is required. A framework for extrapolating evidence for biomarker-targeted therapies to rare cancers is needed to support transparent decision-making. Objectives: To construct a framework outlining the breadth of criteria essential for extrapolating evidence for a biomarker-targeted therapy generated from RCTs in common cancers to different rare cancers sharing the same biomarker. Design: A series of questions articulating essential criteria for extrapolation. Methods: The framework was developed from the core topics for extrapolation identified from a previous scoping review of methodological guidance. Principles for extrapolation outlined in guidance documents from the European Medicines Agency, the US Food and Drug Administration, and Australia's Medical Services Advisory Committee were incorporated. Results: We propose a framework for assessing key assumptions of similarity of the disease and treatment outcomes between the common and rare cancer for five essential components: prognosis of the biomarker-defined cancer, biomarker test analytical validity, biomarker actionability, treatment efficacy, and safety. Knowledge gaps identified can be used to prioritize future studies. Conclusion: This framework will allow systematic assessment, standardize regulatory, reimbursement and clinical decision-making, and facilitate transparent discussions between key stakeholders in drug assessment for rare biomarker-defined cancers.

Influenza in feral cat populations: insights from a study in North-East Italy.

Influenza A virus (IAV) can cause high morbidity and mortality in domestic and wild avian species and it is able to infect mammals as well. IAV in cats is sporadic and self-limiting but the recent findings of high pathogenicity avian influenza virus (HPAIV) with genetic signatures of mammalian adaptation, in domestic cats, has raised new concerns about the potential role of cats in the virus ecology. The present study aimed to investigate the circulation of IAV in companion animals' shelters in North-eastern Italy. All samples were collected from feral cats living in feline colonies that were hosted in the companion animals' shelters for the requisite period to administer the veterinary treatments. Between 2021 and 2022, 389 oropharyngeal swabs and 279 sera were collected. All swabs tested negative for IAV and the only one ELISA positive serum sample resulted H5 positive by HI test with a titer of 1:80. Despite the sporadic occurrence of influenza in cats, continuous monitoring is crucial due to the evolving zoonotic nature of the virus.

Text mining for disease surveillance in veterinary clinical data: part two, training computers to identify features in clinical text.

In part two of this mini-series, we evaluate the range of machine-learning tools now available for application to veterinary clinical text-mining. These tools will be vital to automate extraction of information from large datasets of veterinary clinical narratives curated by projects such as the Small Animal Veterinary Surveillance Network (SAVSNET) and VetCompass, where volumes of millions of records preclude reading records and the complexities of clinical notes limit usefulness of more "traditional" text-mining approaches. We discuss the application of various machine learning techniques ranging from simple models for identifying words and phrases with similar meanings to expand lexicons for keyword searching, to the use of more complex language models. Specifically, we describe the use of language models for record annotation, unsupervised approaches for identifying topics within large datasets, and discuss more recent developments in the area of generative models (such as ChatGPT). As these models become increasingly complex it is pertinent that researchers and clinicians work together to ensure that the outputs of these models are explainable in order to instill confidence in any conclusions drawn from them.

A unifying approach to drug-in-polymer solubility prediction: Streamlining experimental workflow and analysis.

This method paper describes currently used experimental methods to predict the drug-in-polymer solubility of amorphous solid dispersions and offers a combined approach for applying the Melting-point-depression method, the Recrystallization method, and the Melting-and-mixing method. It aims to describe and expand on the theoretical basis as well as the analytical methodology of the recently published Melting-and-mixing method. This solubility method relies on determining the relationship between drug loads and the enthalpy of melting and mixing of a crystalline drug in the presence of an amorphous polymer. This relationship is used to determine the soluble drug load of an amorphous solid dispersion from the recorded enthalpy of melting and mixing of the crystalline drug portion in a drug-polymer sample at equilibrium solubility. Due to the complex analytical methodology of the Melting-and-mixing method, a software solution called the Glass Solution Companion app was developed. Using this new tool, it is possible to calculate the predicted drug-in-polymer solubility and Flory-Huggins interaction parameter from experimental samples, as well as to generate the resulting solubility-temperature curve. This software can be used for calculations for all three experimental methods, which would be useful for comparing the applicability of the methods on a given drug-polymer system. Since it is difficult to predict the suitability of these drug-in-polymer solubility methods for a specific drug-polymer system in silico, some experimental investigation is necessary. By optimizing the experimental protocol, it is possible to collect data for the three experimental methods simultaneously for a specific drug-polymer system. These results can then be readily analyzed using the Glass Solution Companion app to find the most appropriate method for the drug-polymer system, and therefore, the most reliable drug-in-polymer solubility prediction.

Exploring microbial diversity and function in companion planting systems of white clover and orchard grass.

Companion planting of white clover (Trifolium repens L.) with orchard grass (Dactylis glomerata L.), a famous hay grass, improves the forage quality of orchard grass. Microbiome profiling techniques can reveal the specific role of white clover companion planting with orchard grass. This study aimed to explore the microbiome distribution and gene functions of rhizosphere and non-rhizosphere soil via companion planting systems of white clover and orchard grass. From metagenomics sequencing analysis, we confirmed the significant role of white clover on soil environment modeling during companion planting with orchard grass. Twenty-eight biomarkers of rhizosphere soil organisms were identified during companion planting, including Proteobacteria, Betaproteobacteria, Flavobacteriia, and Caulobacterales. The number of gene functions of nitrogen and carbon fixation in companion planting was higher than that in single plants, indicating new functional flora for companion planting. We characterized specific rhizosphere effects, typical biomarker flora, and potential regulatory mechanisms for white clover-related companion planting by metagenomics analyses.

Successful Transvenous Extraction of Adult Dirofilaria immitis Parasites from a Naturally Infected Domestic Ferret (Mustela putorius furo).

Heartworm disease caused by Dirofilaria immitis is a serious and underdiagnosed cardiovascular condition in domestic ferrets. Hemodynamic changes caused by parasitization in ferrets cause a potentially fatal syndrome, but its clinical findings and treatment have not yet been standardized. The objective of this study was to describe the clinical case of a successful surgical extraction in a ferret infected by D. immitis. The patient was a 2-year-old, 1.5 kg asymptomatic male domestic ferret. The infection was diagnosed using a commercial test for the detection of D. immitis antigens. Subsequently, their clinical status was evaluated using serological and imaging diagnostic tests, and it was finally decided to perform surgical extraction of the adult worms. The ferret was anesthetized and placed in the left lateral decubitus position to perform a venotomy in the right jugular vein. Endoscopic extraction basket-shaped devices were used in the right atrial cavity under fluoroscopic guidance following the Seldinger endovascular surgery technique. With careful handling, two adult parasites were manually removed. A transthoracic echocardiogram performed after the procedure confirmed the absence of heartworms. The ferret recovered without complications and was discharged within 24 h. In the clinical review, 30 days after surgery, no notable alterations or symptoms were observed. This case report describes the first complete surgical removal of adult D. immitis parasites in a naturally infected ferret.

Exploring Levels of Interspecies Interaction: Expectations, Knowledge, and Empathy in Human-Dog Relationships.

This exploratory study examines the complex dynamics of human-dog relationships and their impact on interspecies communication. Twelve human-dog dyads were studied using narrative interviews to explore how people perceive their relationships with their dogs. In addition, the dyads engaged in a cooperative task to observe interaction dynamics during everyday activities. This study shows that individual expectations frame interactions and that traditional notions of dog ownership are evolving into more family-like relationships. Effective communication relies on a nuanced mix of verbal and non-verbal cues, with empathy emerging as a fundamental element guiding these interactions. Our findings underline the profound influence of human expectations, knowledge and empathy on communication with dogs. They also highlight the critical role of compatibility between human and dog dyads, and emphasize that such compatibility is a key determinant of satisfaction in interspecies relationships. These findings contribute to a deeper understanding of how human factors modulate communication and satisfaction in human-animal interactions.