Promoting antifungal stewardship through an antifungal multidisciplinary team in a paediatric and adult tertiary centre in the UK.

Background: Invasive fungal infections (IFIs) present significant challenges, especially among immunocompromised patients, with associated high morbidity, mortality and significant economic impact. Diagnostic difficulties and the emergence of antifungal resistance necessitates enhanced antifungal stewardship (AFS) efforts. Methods: We report outcomes from a review of our multidisciplinary approach to AFS, based in a 1300-bed teaching hospital in the South-West of England. Retrospectively reviewing all adult and paediatric cases over 12 months in 2022, we investigated demographics, diagnosis, antifungal therapy and adherence to AFS advice, including clinical, mycological, financial and teamwork metrics. Data were extracted from our AFS database, supported by pharmacy records. Results: The AFS multidisciplinary team (MDT) reviewed 111 patients, with 30 day and 1 year mortality of 22.7% and 35.4%, respectively. IFIs classified as proven accounted for 26%, with fungal pathogens identified in 36.3% of cases. Antifungal consumption (by 25.1%) and expenditure (by 59.9%) decreased from 2018 to 2022. The AFS MDT issued 324 recommendations, with a 93% acceptance rate. Conclusions: Our approach to AFS, centred around a weekly MDT, demonstrated improvements in IFI management, antifungal consumption and cost-efficiency. This single-centre study highlights the value of a comprehensive, collaborative approach to AFS involving experts in mycology, infection, radiology, antifungal therapies and clinical teams. The programme's success in paediatric and adult populations and the near-universal acceptance of its recommendations show its potential as a model for replication. It represents a model for enhancing patient care and AFS practices, with future directions aimed at expanding service reach and the integration of further rapid diagnostic modalities.

Health and economic impacts of Lassa vaccination campaigns in West Africa.

Lassa fever is a zoonotic disease identified by the World Health Organization (WHO) as having pandemic potential. This study estimates the health-economic burden of Lassa fever throughout West Africa and projects impacts of a series of vaccination campaigns. We also model the emergence of "Lassa-X" - a hypothetical pandemic Lassa virus variant - and project impacts of achieving 100 Days Mission vaccination targets. Our model predicted 2.7M (95% uncertainty interval: 2.1M-3.4M) Lassa virus infections annually, resulting over ten years in 2.0M (793.8K-3.9M) disability-adjusted life years (DALYs). The most effective vaccination strategy was a population-wide preventive campaign primarily targeting WHO-classified "endemic" districts. Under conservative vaccine efficacy assumptions, this campaign averted $20.1M ($8.2M-$39.0M) in lost DALY value and $128.2M ($67.2M-$231.9M) in societal costs (International dollars 2021). Reactive vaccination in response to local outbreaks averted just one-tenth the health-economic burden of preventive campaigns. In the event of Lassa-X emerging, spreading throughout West Africa and causing approximately 1.2M DALYs within two years, 100 Days Mission vaccination averted 22% of DALYs given a vaccine 70% effective against disease, and 74% of DALYs given a vaccine 70% effective against both infection and disease. These findings suggest how vaccination could alleviate Lassa fever's burden and assist in pandemic preparedness.

PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells.

The differentiation of naive and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase-delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B lineage cells have not. In the present study, we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens. The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, prompting our investigation of roles for this kinase in antibody responses. Using mouse immunization models, we found that PI3Kγ functions cell intrinsically within activated B cells in a kinase activity-dependent manner to transduce signals required for the transcriptional program supporting differentiation of ASCs. Furthermore, ASC fate choice coincides with upregulation of PIK3CG expression and is impaired in the context of PI3Kγ disruption in naive B cells on in vitro CD40-/cytokine-driven activation, in memory B cells on toll-like receptor activation, or in human tonsillar organoids. Taken together, our study uncovers a fundamental role for PI3Kγ in supporting humoral immunity by integrating signals instructing commitment to the ASC fate.

"Not me!" a qualitative, vignette-based study of nurses' and physicians' reactions to spiritual distress on neuro-oncological units.

PURPOSE: People with primary malignant brain tumors experience serious health-related suffering caused by limited prognosis and high symptom burden. Consequently, neuro-oncological healthcare workers can be affected emotionally in a negative way. The aim of this study was to analyze the attitudes and behavior of nurses and physicians when confronted with spiritual distress in these patients. METHODS: Neurospirit-DE is a qualitative vignette-based, multicenter, cross-sectional online survey that was conducted in Bavaria, Germany. Reflexive thematic analysis was used for data analysis. RESULTS: A total of 143 nurses and physicians working in neurological and neurosurgical wards in 46 hospitals participated in the survey. The participants questioned if the ability to provide spiritual care can be learned or is a natural skill. Spiritual care as a responsibility of the whole team was highlighted, and the staff reflected on the appropriate way of involving spiritual care experts. The main limitations to spiritual care were a lack of time and not viewing spiritual engagement as part of the professional role. Some were able to personally benefit from spiritual conversations with patients, but many participants criticized the perceived emotional burden while expressing the imminent need for specific training and team reflection. CONCLUSIONS: Most neuro-oncological nurses and physicians perceive spiritual care as part of their duty and know how to alleviate the patient's spiritual distress. Nonetheless, validation of spiritual assessment tools for neuro-oncology and standardized documentation of patients' distress, shared interprofessional training, and reflection on the professional and personal challenges faced when confronted with spiritual care in neuro-oncology require further improvement and training.

Occupational exposure to pesticides and neurobehavioral outcomes. Impact of different original and recalled exposure measures on the associations.

BACKGROUND: Several measures of occupational exposure to pesticides have been used to study associations between exposure to pesticides and neurobehavioral outcomes. This study assessed the impact of different exposure measures for glyphosate and mancozeb on the association with neurobehavioral outcomes based on original and recalled self-reported data with 246 smallholder farmers in Uganda. METHODS: The association between the 6 exposure measures and 6 selected neurobehavioral test scores was investigated using linear multivariable regression models. Exposure measures included original exposure measures for the previous year in 2017: (i) application status (yes/no), (ii) number of application days, (iii) average exposure-intensity scores (EIS) of an application and (iv) number of EIS-weighted application days. Two additional measures were collected in 2019: (v) recalled application status and (vi) recalled EIS for the respective periods in 2017. RESULTS: Recalled applicator status and EIS were between 1.2 and 1.4 times more frequent and higher for both pesticides than the original application status and EIS. Adverse associations between the different original measures of exposure to glyphosate and 4 neurobehavioral tests were observed. Glyphosate exposure based on recalled information and all mancozeb exposure measures were not associated with the neurobehavioral outcomes. CONCLUSIONS: The relation between the different original self-reported glyphosate exposure measures and neurobehavioral test scores appeared to be robust. When based on recalled exposure measures, associations observed with the original exposure measures were no longer present. Therefore, future epidemiological studies on self-reported exposure should critically evaluate the potential bias towards the null in observed exposure-response associations.

Measurement of Spiritual Wellbeing in an Australian Hospital Population Using the Functional Assessment of Chronic Illness Therapy: Spiritual Wellbeing Scale (FACIT-Sp-12).

Spiritual wellbeing is known to be a predictor of increased patient coping in hospital settings. Therefore, access to a valid and reliable measure of spiritual wellbeing amongst general hospital patients is highly recommended. The aim of this study was to investigate the dimensionality, reliability, and validity of the Functional Assessment of Chronic Illness Therapy Spiritual Wellbeing scale (FACIT-Sp-12) in a heterogeneous cohort of hospital patients. A cross-sectional survey was administered to 897 adult patients across six hospitals in Sydney, Australia. Confirmatory factor analysis for the three-factor FACIT-12-Sp indicated a poor fit, but after removal of Item 12, the three-factor FACIT-11-Sp presented a good fit to the data. Reliability testing indicated acceptable to good internal consistency. Validity was supported by statistically significant differences between patients who considered themselves 'both spiritual and religious' and 'not religious or spiritual'. While some caution should be taken when using the FACIT-Sp due to several limitations, nevertheless, in a general hospital population in Australia, the three-factor FACIT-11-Sp indicated good dimensionality, reliability, and validity.

Plasma ctDNA enables early detection of temozolomide resistance mutations in glioma.

Background: Liquid biopsy based on circulating tumor DNA (ctDNA) is a novel tool in clinical oncology, however, its use has been limited in glioma to date, due to low levels of ctDNA. In this study, we aimed to demonstrate that sequencing techniques optimized for liquid biopsy in glioma patients can detect ctDNA in plasma with high sensitivity and with potential clinical utility. Methods: We investigated 10 glioma patients with tumor tissue available from at least 2 surgical operations, who had 49 longitudinally collected plasma samples available for analysis. Plasma samples were sequenced with CAPP-seq (AVENIO) and tissue samples with TSO500. Results: Glioma-derived ctDNA mutations were detected in 93.8% of plasma samples. 25% of all mutations detected were observed in plasma only. Mutations of the mismatch repair (MMR) genes MSH2 and MSH6 were the most frequent circulating gene alterations seen after temozolomide treatment and were frequently observed to appear in plasma prior to their appearance in tumor tissue at the time of surgery for recurrence. Conclusions: This pilot study suggests that plasma ctDNA in glioma is feasible and may provide sensitive and complementary information to tissue biopsy. Furthermore, plasma ctDNA detection of new MMR gene mutations not present in the initial tissue biopsy may provide an early indication of the development of chemotherapy resistance. Additional clinical validation in larger cohorts is needed.

Human biomonitoring and toxicokinetics as key building blocks for next generation risk assessment.

Human health risk assessment is historically built upon animal testing, often following Organisation for Economic Co-operation and Development (OECD) test guidelines and exposure assessments. Using combinations of human relevant in vitro models, chemical analysis and computational (in silico) approaches bring advantages compared to animal studies. These include a greater focus on the human species and on molecular mechanisms and kinetics, identification of Adverse Outcome Pathways and downstream Key Events as well as the possibility of addressing susceptible populations and additional endpoints. Much of the advancement and progress made in the Next Generation Risk Assessment (NGRA) have been primarily focused on new approach methodologies (NAMs) and physiologically based kinetic (PBK) modelling without incorporating human biomonitoring (HBM). The integration of toxicokinetics (TK) and PBK modelling is an essential component of NGRA. PBK models are essential for describing in quantitative terms the TK processes with a focus on the effective dose at the expected target site. Furthermore, the need for PBK models is amplified by the increasing scientific and regulatory interest in aggregate and cumulative exposure as well as interactions of chemicals in mixtures. Since incorporating HBM data strengthens approaches and reduces uncertainties in risk assessment, here we elaborate on the integrated use of TK, PBK modelling and HBM in chemical risk assessment highlighting opportunities as well as challenges and limitations. Examples are provided where HBM and TK/PBK modelling can be used in both exposure assessment and hazard characterization shifting from external exposure and animal dose/response assays to animal-free, internal exposure-based NGRA.

Effect of a Spiritual Care Training Program to Build Knowledge, Competence, Confidence and Self-awareness Among Australian Health and Aged Care Staff: An Exploratory Study.

The aim of this study was to evaluate a new spiritual care training program with health and aged care staff. A four-module program was delivered to 44 participants at a large Catholic health and aged care provider in Australia. Pre, post and 6 week follow-up surveys were administered and included measures of spiritual care competency, confidence, perspectives of spirituality and spiritual care, spiritual well-being, and satisfaction. Paired sample t-tests showed total scores of participants' spiritual well-being, spiritual care competency and confidence significantly improved following the training and were largely maintained at follow-up. Perspectives on spirituality and spiritual care did not significantly change over time.

"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease.

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

Australian Patient Preferences for Discussing Spiritual Issues in the Hospital Setting: An Exploratory Mixed Methods Study.

While there is high patient acceptance for clinical staff discussing issues regarding spirituality with hospital inpatients, it is not clear which staff member patients prefer for these discussions. This unique exploratory study investigated inpatient preferences regarding which staff member should raise the topic of spirituality. A cross-sectional survey was conducted with inpatients at six hospitals in Sydney, Australia (n = 897), with a subset invited to participate in qualitative interviews (n = 41). Pastoral care staff (32.9%) were the preferred staff members with whom to discuss spiritual issues, followed by doctors (22.4%). Qualitative findings indicated that individual characteristics of the staff member are more important than their role.

Factors influencing occupational exposure to pyrethroids and glyphosate: An analysis of urinary biomarkers in Malaysia, Uganda and the United Kingdom.

BACKGROUND: Long-term exposure to pesticides is often assessed using semi-quantitative models. To improve these models, a better understanding of how occupational factors determine exposure (e.g., as estimated by biomonitoring) would be valuable. METHODS: Urine samples were collected from pesticide applicators in Malaysia, Uganda, and the UK during mixing/application days (and also during non-application days in Uganda). Samples were collected pre- and post-activity on the same day and analysed for biomarkers of active ingredients (AIs), including synthetic pyrethroids (via the metabolite 3-phenoxybenzoic acid [3-PBA]) and glyphosate, as well as creatinine. We performed multilevel Tobit regression models for each study to assess the relationship between exposure modifying factors (e.g., mixing/application of AI, duration of activity, personal protective equipment [PPE]) and urinary biomarkers of exposure. RESULTS: From the Malaysia, Uganda, and UK studies, 81, 84, and 106 study participants provided 162, 384 and 212 urine samples, respectively. Pyrethroid use on the sampling day was most common in Malaysia (n = 38; 47%), and glyphosate use was most prevalent in the UK (n = 93; 88%). Median pre- and post-activity 3-PBA concentrations were similar, with higher median concentrations post-compared to pre-activity for glyphosate samples in the UK (1.7 to 0.5 µg/L) and Uganda (7.6 to 0.8 µg/L) (glyphosate was not used in the Malaysia study). There was evidence from individual studies that higher urinary biomarker concentrations were associated with mixing/application of the AI on the day of urine sampling, longer duration of mixing/application, lower PPE protection, and less education/literacy, but no factor was consistently associated with exposure across biomarkers in the three studies. CONCLUSIONS: Our results suggest a need for AI-specific interpretation of exposure modifying factors as the relevance of exposure routes, levels of detection, and farming systems/practices may be very context and AI-specific.

Facilitators for increasing dental attendance of people from vulnerable groups: a rapid review of evidence relevant to the UK.

Objective To rapidly review facilitators of access for vulnerable groups and to evaluate their effectiveness.Methods Data sources: MEDLINE via Ovid. Publications in English from 2000. DATA SELECTION: Research involving 'vulnerable groups' relevant to UK health systems, with a primary outcome of increasing attendance. DATA EXTRACTION: One author extracted and tabulated data. These were audited by a second author. DATA SYNTHESIS: A narrative synthesis was produced.Results Data from 31 studies were available for ten vulnerable groups: people with learning, physical or sensory disabilities (n = 8); people experiencing homelessness (n = 6); prisoners (n = 4); asylum-seekers and refugees (n = 3); people living in socioeconomically deprived areas (n = 3); people with severe mental health conditions (n = 2); vulnerable children (n = 2); dependent older people (n = 1); Gypsy, Roma or Traveller groups (n = 1); and people with drug dependency (n = 1). Many facilitators involved organisational reform and more integration of health, social and other services. Other facilitators included: modification of premises; team development and skill-mix use; and awareness of needs and flexible services to meet them. Few studies evaluated effectiveness.Conclusion Although facilitators for access for vulnerable groups have been proposed, there is little evidence to support or refute their effectiveness. Efforts are needed to promote access for vulnerable groups in the UK with evaluation plans embedded.

A dataset of small-mammal detections in West Africa and their associated micro-organisms.

Rodents, a globally distributed and ecologically important mammalian order, serve as hosts for various zoonotic pathogens. However, sampling of rodents and their pathogens suffers from taxonomic and spatial biases. This affects consolidated databases, such as IUCN and GBIF, limiting inference regarding the spillover hazard of zoonotic pathogens into human populations. Here, we synthesised data from 127 rodent trapping studies conducted in 14 West African countries between 1964 and 2022. We combined occurrence data with pathogen screening results to produce a dataset containing detection/non-detection data for 65,628 individual small mammals identified to the species level from at least 1,611 trapping sites. We also included 32 microorganisms, identified to the species or genus levels, that are known or potential pathogens. The dataset is formatted to Darwin Core Standard with associated metadata. This dataset can mitigate spatial and taxonomic biases of current databases, improving understanding of rodent-associated zoonotic pathogen spillover across West Africa.

Self-reported and urinary biomarker-based measures of exposure to glyphosate and mancozeb and sleep problems among smallholder farmers in Uganda.

OBJECTIVE: We aim to showcase the impact of applying eight different self-reported and urinary biomarker-based exposure measures for glyphosate and mancozeb on the association with sleep problems in a study among 253 smallholder farmers in Uganda. METHODS: The questionnaire-based exposure measures included: (1) the number of application days of any pesticide in the last 7 days (never, 1-2; >2 days) and six glyphosate and mancozeb-specific measures: (2) application status over the last 12 months (yes/no), (3) recent application status (never, last 7 days and last 12 months), (4) the number of application days last 12 months, (5) average exposure-intensity scores (EIS) and (6) EIS-weighted number of application days in last 12 months. Based on 384 repeated urinary biomarker concentrations of ethylene thiourea (ETU) and glyphosate from 84 farmers, we also estimated (7) average biomarker concentrations for all 253 farmers. Also in the 84 farmers the measured pre-work and post-work biomarker concentrations were used (8). Multivariable logistic regression models were used to assess the association between the exposure measures and selected Medical Outcomes Study Sleep Scale (MOS-SS) indices (6-item, sleep inadequacy and snoring). RESULTS: We observed positive associations between (1) any pesticide application in the last 7 days with all three MOS-SS indices. Glyphosate application in the last 7 days (3) and mancozeb application in the last 12 months (3) were associated with the 6-item sleep problem index. The estimated average urinary glyphosate concentrations showed an exposure-response association with the 6-item sleep problem index and sleep inadequacy in the same direction as based on self-reported glyphosate application in the last 7 days. In the analysis with the subset of 84 farmers, both measured and modelled post-work urinary glyphosate concentration showed an association with snoring. CONCLUSIONS: Self-reported, estimated average biomarker concentrations and measured urinary biomarker exposure measures of glyphosate and mancozeb showed similar exposure-response associations with sleep outcomes.

A novel COVID-19 program, delivering vaccines throughout rural and remote Australia.

Background: The Royal Flying Doctor Service of Australia (RFDS) established a unique SARS-CoV-2 vaccination program for vaccinating Australians that live in rural and remote areas. This paper describes the preparation and response phases of the RFDS response. Methods: This study includes vaccinations conducted by the RFDS from 01 January 2021 until 31 December 2021 when vaccines were mandatory for work and social activities. Prior to each clinic, we conducted community consultation to determine site requirements, patient characteristics, expected vaccination numbers, and community transmission rates. Findings: Ninety-five organizations requested support. The majority (n = 60; 63.2%) came from Aboriginal Community Controlled Health Organizations. Following consultation, 360 communities were approved for support. Actual vaccinations exceeded expectations (n = 70,827 vs. 49,407), with a concordance correlation coefficient of 0.88 (95% CI, 0.83, 0.93). Areas that reported healthcare workforce shortages during the preparation phase had the highest population proportion difference between expected and actual vaccinations. Areas that reported high vaccine hesitancy during the preparation phase had fewer than expected vaccines. There was a noticeable increase in vaccination rates in line with community outbreaks and positive polymerase chain reaction cases [r (41) = 0.35, p = 0.021]. Engagement with community leaders prior to clinic deployment was essential to provide a tailored response based on community expectations.

Spirituality is "sometimes just a hug": A conceptual analysis from the perspective of nursing students.

OBJECTIVES: Definitions of spirituality abound; however, the importance of context and need for better understanding within health-care practice has been emphasized. In particular, the understanding of spirituality for nurses has been shown to have an impact both professionally and personally. METHODS: This study used a conceptual analysis to explore the understanding of spirituality by German-speaking nurses in an educational context. RESULTS: A total of 91 nursing students (83.5% female, 16.5% male) took the spiritual care course between January 2022 and January 2023. The majority of participants (n = 63, 69.6%) were in the 26- to 40-year age bracket, 50 (54.9%) identified themselves as Christian, 15 (16.5%) chose other, 12 (13.2%) atheist, 6 (6.6%) humanist or agnostic, and 2 (2.2%) Buddhist. A conceptual analysis of nursing students' written responses to the question "What is spirituality to me?" was conducted. Two overarching categories were identified. The first category was titled "What aspects or characters are linked to spirituality?" and included 5 subcategories: people, life, experience, a sense of security, and capacity. The second category was titled "How is spirituality experienced, practiced and lived?" and included 5 subcategories: sometimes just a hug, to align one's life with that purpose, to be content with myself, conscious attention to oneself, and demarcation from religion. These subcategories were interrelated to one another. SIGNIFICANCE OF RESULTS: These findings have implications for how spirituality is introduced in nursing education.

The oral health of adults attending dental practices in England in 2018: a report of a novel method and findings.

Introduction National surveys of the oral health of adults are conducted decennially. For reasons of feasibility and cost, these only provide accurate information at large geographical areas. To address this, a survey of adults attending dental practices in England was undertaken.Aim To describe and discuss the survey method and findings.Method A clinical examination and questionnaire survey was conducted in a sample of English dental practices.Results Questionnaires (n = 16,572) and clinical examinations (n = 14,270) were completed with patients from 1,173 dental practices. Poorer oral health disproportionately affected older adults and those from more socioeconomically deprived areas. Over one in three from more deprived areas had untreated caries compared with one in five in the less deprived (36.2% vs 19.9%) and impacts of oral problems were nearly three times higher in the more deprived areas (27.9% vs 11.0%). Of those receiving NHS care, 28.7% and 46.2% reported they would struggle/be unable to pay a Band 2 and Band 3 NHS patient charge, respectively.Conclusion It is feasible to undertake a survey of adults in dental practices but care must be taken generalising the findings to the general population and comparing them with other surveys undertaken using different methods.

Differing taxonomic responses of mosquito vectors to anthropogenic land-use change in Latin America and the Caribbean.

Anthropogenic land-use change, such as deforestation and urban development, can affect the emergence and re-emergence of mosquito-borne diseases, e.g., dengue and malaria, by creating more favourable vector habitats. There has been a limited assessment of how mosquito vectors respond to land-use changes, including differential species responses, and the dynamic nature of these responses. Improved understanding could help design effective disease control strategies. We compiled an extensive dataset of 10,244 Aedes and Anopheles mosquito abundance records across multiple land-use types at 632 sites in Latin America and the Caribbean. Using a Bayesian mixed effects modelling framework to account for between-study differences, we compared spatial differences in the abundance and species richness of mosquitoes across multiple land-use types, including agricultural and urban areas. Overall, we found that mosquito responses to anthropogenic land-use change were highly inconsistent, with pronounced responses observed at the genus- and species levels. There were strong declines in Aedes (-26%) and Anopheles (-35%) species richness in urban areas, however certain species such as Aedes aegypti, thrived in response to anthropogenic disturbance. When abundance records were coupled with remotely sensed forest loss data, we detected a strong positive response of dominant and secondary malaria vectors to recent deforestation. This highlights the importance of the temporal dynamics of land-use change in driving disease risk and the value of large synthetic datasets for understanding changing disease risk with environmental change.