METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer.

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translation control and tumour biology.

The role of m6A, m5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities.

RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N6-methyladenosine (m6A), 5-methylcytosine (m5C) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.

Medulloblastoma subgroups remain stable across primary and metastatic compartments.

Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary-metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology.

The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues.

Recent advancements have illuminated the critical role of RNA modifications in post-transcriptional regulation, shaping the landscape of gene expression. This review explores how tRNA modifications emerge as critical players, fine-tuning functionalities that not only maintain the fidelity of protein synthesis but also dictate gene expression and translation profiles. Highlighting their dysregulation as a common denominator in various cancers, we systematically investigate the intersection of both cytosolic and mitochondrial tRNA modifications with cancer biology. These modifications impact key processes such as cell proliferation, tumorigenesis, migration, metastasis, bioenergetics and the modulation of the tumor immune microenvironment. The recurrence of altered tRNA modification patterns across different cancer types underscores their significance in cancer development, proposing them as potential biomarkers and as actionable targets to disrupt tumorigenic processes, offering new avenues for precision medicine in the battle against cancer.

[Patient with testosterone deficit syndrome and dyslipemia]. / Paciente con SDT y dislipemia.

We define dyslipemia as the abnormally elevated presence of lipids in the blood. The main ones are hypercholesterolemia (cholesterol over 240 mg/dl), hypertrigliceridemia (triglicerides level over 200 mg/dl) and hipo-alphalipoproteinemia (High density lipoproteins,also called HDL Cholesterol, below 40 mg/dl). The presence of excessive lipids contributes to arteriosclerosis and they are an independent cardiovascular risk factor. It may be primary, if they have genetic origin and they are not associated with other diseases, but in most cases they are secondary to other pathological entities such as diabetes, hypothyroidism, obesity and metabolic syndrome (MS). In our current society, sedentary lifestyle and unadequatelly hypercaloric diets are making obesity and MS prevalences grow, and their relation to dyslipemias has become tighter. Obesity is related with all the criteria for MS. But obesity is not at all synonymous of MS. On the one hand neither fat distribution is the same in all individualas nor confers the same risk. Accordingly, we know that abdominal localization of fat is related to higher intensity of insulin resistance (IR) and MS. On the other hand, it seems that certain components of MS are determined by genetic factors, since there are morbid obese persons that are metabolically healthy and other patients develop insulin resistance without obesity. So that, it seems that the excess in visceral adiposity in the presence of certain genetic factors would be the most related cause of the appearance of peripheral insulin resistance and diabetes mellitus, hyperlipidemia (increase of very low density pipoproteins (VLDL), decrease of highdensity lipoproteins (HDL) arterial hypertension, and hypogonadotropic hypogonadism, composing what we call metabolic syndrome. In this scenario, we urologists are being first-hand witnesses.On the one hand, and in relation with cardiovascular risk factors, we know that all of them, and independently,not only can produce erectile dysfunction due to endothelial dysfunction, but also it generally appears years before the cardiovascular event. On the other hand, and in relation to the hypogonadotropic hypogonadism of patients with MS, we urologists may contributein greatly to the detection of patients with MS whose only symptom is erectile dysfunction or diminished libido, but specially we may play a key role in the improvement of these patients, since it is known that testosterone replacement therapy has a major potential to diminish or stop the progression of MS or its cardiovascular effects. Testosterone treatment not only improves the lipid profile, hypertension, insulin resistance, or reduces the abdominal circumference, but also it may help to get a better adherence to diet and exercise, so contributing to change unhealthy lifestyle habits whch are the origin of the problem.

Beliefs, attitudes and feelings about work among healthcare workers and teachers during the fifth wave of COVID-19.

OBJECTIVE: To compare the beliefs, attitudes and feelings about work of healthcare professionals (HCPs) and teachers living in the Canary Islands (Spain) during the COVID-19 pandemic. METHODS: The study had two parts. In Part 1, the Delphi technique was used to adapt a questionnaire. Part 2 was a cross-sectional, comparative study, performed from August 31st to October 25th, 2021 using the questionnaire online distributed to samples of HCPs and teachers. The questionnaire had three dimensions each separated into three sections (i.e., beliefs [coping ability, prevention and organisation]; attitudes [risks, commitments, and obligations]; feelings about work [burnout, support and work satisfaction]). RESULTS: In total 1423 questionnaires were available for analysis, 640 from teaching staff and 783 from HCPs. Significant differences were found in eight of the nine sections. HCPs had a more positive attitude towards work compared with teachers, but had more negative beliefs and feelings about work. In addition, by comparison with teachers, HCPs were more committed to their work, more predisposed to take risks and fulfill their obligations, even though our sample of teachers felt more supported and satisfied at work. CONCLUSIONS: Our results show that the pandemic caused a greater negative impact on job satisfaction of HCPs compared with teachers because they felt less supported by their superiors, which had a greater impact on their psychological health.

A comparative study of differences between parents and teachers in the evaluation of environmental sensitivity.

Introduction: The inextricable bond between humans and the environment underscores the pivotal significance of environmental sensitivity. This innate trait encompasses a wide array of ways individuals perceive, process, and react to various internal and external stimuli. The evaluation of this trait in children is generally conducted by parents. However, little is known about the concordance of the parents reports with those conducted by others, such as teachers. Children's behavior assessment is a current and relevant issue and finding out more positive results could make improvements in different contexts, such as home, clinics and schools. Objective: This study examines agreements and discrepancies between parents and teachers as raters of environmental sensitivity in Spanish children. Methods: Participants were 124 parents and eight teachers of youngsters between 3 and 10 years, who completed a paper survey providing information about parental and school variables and environmental sensitivity. Results: Parents and teachers mostly differ when rating environmental sensitivity, being parents the raters who score higher levels of this trait than teachers. Also, poor intra-class coefficients of reliability are found in both the items of HSCS, the dimensions and the general factor of environmental sensitivity among the informants. Conclusion: The present investigation provides novel findings related to inter-rater assessment on environmental sensitivity and how these different informants could affect in the report. This study also highlights the need of making and validating new and specific tools to assess environmental sensitivity for teachers.

Attitudes and Feelings towards the Work of Teachers Who Had a School Nurse in Their Educational Center during the COVID-19 Pandemic.

The objective of this study was to analyze the influence of the availability of a health professional on the beliefs, attitudes, and work feelings of teaching staff when facing the COVID-19 pandemic. This is a two-phase study: In the first one, the Delphi technique was used to update an instrument used by the authors in a previous investigation in 2020. The second phase was a cross-sectional, descriptive, and comparative study, carried out through an electronic questionnaire distributed among the teaching staff of the Autonomous Community of the Canary Islands (Spain), during the first two months of the 2021/22 academic year, in the midst of the fifth wave of COVID-19. Data were analyzed using Pearson's chi-squared test and the linear trend test. The reasons for advantages were analyzed and the dimensions of the questionnaire were compared between the groups studied (with or without a healthcare professional in the center). Out of 640 teachers in the study, 14.7% (n = 94) stated that they had a reference professional with health training in their educational center (a school nurse) for the management of possible cases of COVID-19. Significant differences were found in five of the nine dimensions studied between the groups of teachers analyzed. Teachers who had a health professional, specifically a nurse, during the pandemic indicated that they felt safer in their educational center, as they perceived that they had more personal protective equipment (OR = 2.03, [95% CI: 1.23-3.35]; p = 0.006). They were also more committed (OR = 1.89, [95% CI: 1.04-3.46]; p = 0.038) with their educational work and assumed more obligations (OR = 1.87, [95% CI: 1.01-3.44]; p = 0.045) and risks (OR = 2.82, [95% CI: 1.13-7.07]; p = 0.027). In addition, they presented fewer feelings of burnout (OR = 0.63, [95% CI: 0.41-0.98]; p = 0.041). These results indicate that having nurses in educational centers improves teachers' ability to cope with a pandemic situation.

The Influence of Emotional Regulation and Cognitive Flexibility on Sleep Habits in Spanish Children and Adolescents through the Lens of Parents.

BACKGROUND: Previous research studies have suggested the importance of studying the relationship between emotional regulation and sleep habits. Some investigations have especially focused on how emotional regulation could impact sleep habits in children and adolescents. Therefore, these researchers have stated there exists a two-way direction in this relationship. OBJECTIVE: This study aimed to analyze the influence of emotional regulation on sleep habits in Spanish children and adolescents and the mediating role of anxiety in this relationship. METHOD: Participants were 953 Spanish parents who completed the assessment protocol according to their children and adolescents' information. RESULTS: The results revealed moderate-strong correlations between emotional regulation problems and sleep habit disturbances (r = 0.375, p < 0.001), trait (r = 0.488, p < 0.001) anxiety, and state (r = 0.589, p < 0.001) anxiety. Additionally, emotional regulation showed a direct impact on sleep habits (ß = 0.011, p = 0.005). Trait and state anxiety demonstrated a significant mediating role in the relationship between emotional regulation and sleep habits. CONCLUSIONS: Emotional regulation may have an impact on sleep habits during childhood and adolescence, suggesting the importance of early intervention focused on the emotions management and the prevention of sleep habit disturbances.

Anxiety, sleep habits and executive function during the COVID-19 pandemic through parents' perception: a longitudinal study.

The present study therefore aims to examine trait and state anxiety, sleep habits and executive functioning during 1 year and a half of the COVID-19 pandemic in children and adolescents through the lens of parents. Assessments were conducted at three different times: April 2020 (T1), October 2020 (T2) and October 2021 (T3). The main sample included 953 children and adolescents aged 6 to 18 years, and scales were used to assess anxiety (STAIC), sleep habits (BEARS) and executive functioning (BRIEF-2). The results showed that 6 months after the outbreak of the pandemic, state and trait anxiety, sleep disturbances and executive dysfunctions increased significantly. One and a half year later, trait anxiety and sleep disturbances have been maintained, while state anxiety and executive dysfunction have decreased their scores obtaining scores similar to those of April 2020. In conclusion, there has been a further decrease in children and adolescents' mental health since the beginning of the pandemic, and it seems to remain at the present time, such as trait anxiety as a part of the personality.

"Long-term oncologic outcomes and risk factors for distant recurrence after pathologic complete response following neoadjuvant treatment for locally advanced rectal cancer. A nationwide, multicentre study".

BACKGROUND: Pathologic complete response (pCR) after multimodal treatment for locally advanced rectal cancer (LARC) is used as surrogate marker of success as it is assumed to correlate with improved oncologic outcome. However, long-term oncologic data are scarce. METHODS: This retrospective, multicentre study updated the oncologic follow-up of prospectively collected data from the Spanish Rectal Cancer Project database. pCR was described as no evidence of tumour cells in the specimen. Endpoints were distant metastases-free survival (DMFS) and overall survival (OS). Multivariate regression analyses were run to identify factors associated with survival. RESULTS: Overall, 32 different hospitals were involved, providing data on 815 patients with pCR. At a median follow-up of 73.4 (IQR 57.7-99.5) months, distant metastases occurred in 6.4% of patients. Abdominoperineal excision (APE) (HR 2.2, 95%CI 1.2-4.1, p = 0.008) and elevated CEA levels (HR = 1.9, 95% CI 1.0-3.7, p = 0.049) were independent risk factors for distant recurrence. Age (years) (HR 1.1; 95%-CI 1.05-41.09; p < 0.001) and ASA III-IV (HR = 2.0; 95%-CI 1.4-2.9; p < 0.001), were the only factors associated with OS. The estimated 12, 36 and 60-months DMFS rates were 96.9%, 91.3%, and 86.8%. The estimated 12, 36 and 60-months OS rates were 99.1%, 94.9% and 89.3%. CONCLUSIONS: The incidence of metachronous distant metastases is low after pCR, with high rates of both DMFS and OS. The oncologic prognosis in LARC patients that achieve pCR after neoadjuvant chemo-radiotherapy is excellent in the long term.

Effectiveness of a cognitive behavioral intervention in patients with medically unexplained symptoms: cluster randomized trial.

BACKGROUND: Medically unexplained symptoms are an important mental health problem in primary care and generate a high cost in health services.Cognitive behavioral therapy and psychodynamic therapy have proven effective in these patients. However, there are few studies on the effectiveness of psychosocial interventions by primary health care. The project aims to determine whether a cognitive-behavioral group intervention in patients with medically unexplained symptoms, is more effective than routine clinical practice to improve the quality of life measured by the SF-12 questionary at 12 month. METHODS/DESIGN: This study involves a community based cluster randomized trial in primary healthcare centres in Madrid (Spain). The number of patients required is 242 (121 in each arm), all between 18 and 65 of age with medically unexplained symptoms that had seeked medical attention in primary care at least 10 times during the previous year. The main outcome variable is the quality of life measured by the SF-12 questionnaire on Mental Healthcare. Secondary outcome variables include number of consultations, number of drug (prescriptions) and number of days of sick leave together with other prognosis and descriptive variables. Main effectiveness will be analyzed by comparing the percentage of patients that improve at least 4 points on the SF-12 questionnaire between intervention and control groups at 12 months. All statistical tests will be performed with intention to treat. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors or factors that might alter the effect recorded will be taken into account in this analysis. DISCUSSION: This study aims to provide more insight to address medically unexplained symptoms, highly prevalent in primary care, from a quantitative methodology. It involves intervention group conducted by previously trained nursing staff to diminish the progression to the chronicity of the symptoms, improve quality of life, and reduce frequency of medical consultations. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov, number NCT01484223 [http://ClinicalTrials.gov].

Feelings of the health personnel in Spain, towards their work, after five waves of the COVID-19 pandemic.

Health personnel have faced highly adverse circumstances in the workplace since the beginning of the COVID-19 pandemic. Prolonged exposure to stressful situations at work is considered to affect the physical, psychological, and emotional health of these workers, as well as job performance. The objective of this study was to analyze the beliefs, attitudes, and feelings of health personnel from one Spanish region towards their work after five waves of the COVID-19 pandemic. A Cross-sectional descriptive study was carried out using an electronic questionnaire, adapted, and validated through the Delphi technique. A convenience sampling of 783 was recruited among health personnel from the Canary Islands during the fifth wave of the pandemic in September 2021. Bivariate analyzes have been performed by the Chi-square test accepting statistical significance (p 0.050). The 94.3% (n=738) of the respondents considered the pandemic to have highlighted the shortcomings of the Spanish health system. A clear level of exhaustion and/or a reduction in the level of commitment can be observed in these workers as the pandemic continues, as participants reported feeling both mentally and physically exhausted when finishing their shifts, and even "burned out by their work". This study highlights the resilience and vocation of healthcare professionals, who even considering the effects of the pandemic would choose the same profession. On the other hand, these professionals felt undervalued by their institutions, and almost one of every five, precised psychological support in some point during the health crisis.

Psychometric Properties of the Spanish Version of the Highly Sensitive Child Scale: The Parent Version.

Environmental sensitivity is the ability to perceive, register and process information about the environment, which differs among children and adolescents. The Highly Sensitive Child (HSC) scale has been used to assess environmental sensitivity in youngsters. The HSC scale is a short and 12-item adapted version of the Highly Sensitive Person (HSP) scale. The aim of this pilot study is to transculturally adapt the Highly Sensitive Child (HSC) scale, and to analyze its factorial structure, reliability and validity. First, a transcultural adaptation was conducted by bilingual experts. Second, once the questionnaire was translated, the psychometric properties were analyzed. The Spanish version of the HSC scale was administered to parents answering about information of 141 children between 6 and 10 years old. The Spanish version of the Emotionality, Activity and Sociability Survey (EAS) was also applied. The results of the confirmatory factor analysis confirmed the three-factor structure of sensitivity in our Spanish sample. This structure included the following dimensions: (1) Ease of Excitation (EOE), (2) Low Sensory Threshold (LST), and (3) Aesthetic Sensitivity (AES). Moreover, both Cronbach's α and McDonald's ω values indicated that the Spanish version of the HSC scale was a reliable measure of environmental sensitivity, as a general factor of sensitivity (α = 0.84), and even in its three dimensions: EOE (α = 0.86), LST (α = 0.77) and AES (α = 0.73). Finally, the correlations for convergent validity showed positive associations, especially among the three dimensions of SPS and Emotionality (EOE r = 0.351; LST r = 0.274; AES r = 0.259), which was one of the domains of the EAS survey. The pilot study provided interesting results, which showed a reliable and valid replication of the original structure of sensitivity in the Spanish samples.

The Need for Psychological Support of Health Workers during the COVID-19 Pandemic and the Influence on Their Work.

The aim of this research was to analyze how the need for psychological support of health workers (HCWs) influenced the beliefs, perceptions and attitudes towards their work during the COVID-19 pandemic and to predict the need of psychological assistance. A descriptive transversal study was conducted based on a self-administered questionnaire distributed to health professionals working in the Canary Islands, Spain. The data were analyzed using Pearson's chi-squared test and the linear trend test. The correlation test between ordinal and frequency variables was applied using Kendall's Tau B. Multiple logistic regression was used to predict dichotomous variables. The sample included 783 health professionals: 17.8% (n = 139) of them needed psychological or psychiatric support. Being redeployed to other services influenced the predisposition to request psychological help, and HCWs who required psychological support had more negative attitudes and perceptions towards their work. After five waves of COVID-19, these HCWs reported to be physically, psychologically and emotionally exhausted or even "burned out"; they did not feel supported by their institutions. The commitment of health personnel to fight against the COVID-19 pandemic decreased after the five waves, especially among professionals who required psychological support.

Assessment Strategies to Evaluate the Mediterranean Lifestyle: A Systematic Review.

The Mediterranean Lifestyle (MLS) has been related to better health and quality of life. However, there is no consensus on how to assess this lifestyle. The main objective of this work was to systematically review the methodology used in different studies on the evaluation of the MLS. The specific objectives were (1) to analyze the MLS components evaluated in previous studies, (2) to explore the assessment instruments available for the analysis of the MLS, and (3) to identify the psychometric properties of these instruments. The search was carried out using the PubMed, Scopus, Web of Science, and ScienceDirect databases with the purpose of identifying those published articles in which the MLS was assessed. The review included 26 studies linked to the assessment of the MLS. Of these studies, only four exclusively used a tool to analyze MLS components globally. These studies included two questionnaires and three different indexes. None of them, however, evaluated all of the recognized MLS components, and food preparation was the least frequently evaluated component. Given the clear importance of analyzing MLS adherence and the lack of consensus in previous research, an evaluation tool needs to be created to comprehensively assess all of the MLS dimensions by means of appropriate psychometric properties.

Attitudes and beliefs of Spanish healthcare professionals during the COVID-19 pandemic.

During the COVID-19 pandemic, healthcare professionals are taking the risk of becoming infected or infecting their families. Spain is the country with the highest number of infected healthcare professionals worldwide. Our aim was to study the attitudes and beliefs of these professionals during the current pandemic. Descriptive study conducted by using an online questionnaire-based on an earlier one-which was sent to healthcare professionals at the national level, during the week March 20-27, 2020. Healthcare professionals returned 971 completed questionnaires. A total of 803 (82.7%) participants thought that they did not have suitable PPEs (Personal Protective Equipment) to protect them from infection with COVID-19. In addition, even 229 (23.58%) agreed to go on working even if they were not. In spite of this, 606 (62.4%) of them were ready to work, even with a higher-than-usual risk of becoming infected at work and getting ill. Remarkably high professional commitment has been observed among Spanish healthcare workers in the current pandemic. They were ready to work even when many of them considered that they did not have suitable PPEs, and were thus taking a higher than usual infection risk. However, they put the health of their relatives before their duties at work.

Control of Leiodes cinnamomeus (Coleoptera: Leiodidae) in Cultivated Black Truffle Orchards by Kairomone-Based Mass Trapping.

The monoculture situation of truffle cultivation is favoring the appearance of pests that would not be economically important in naturally balanced forest ecosystems. The most prominent of them is the European truffle beetle Leiodes cinnamomeus (Panzer) (Coleoptera: Leiodidae), for which there are no effective control methods capable of reducing its populations. The potential of the mass trapping technique against this beetle, based on adapted pitfall traps and the semiochemical methyl disulfide as an attractant, is explored in the present work. Two trap densities (40 and 80 traps/ha) were tested in 2-yr field trials carried out in the region of Teruel (Spain) with black truffle cultivation tradition. Kairomone dispensers were placed in the field immediately before adult outbreak and remained active there throughout the season. The efficacy of each treatment was measured according to the reduction in beetle populations and the damaged truffles in the center of the treated areas. The results showed that both trapping densities reduced adult populations (mean 57% catch reduction), but 80 traps/ha were needed to significantly lower damage parameters (>40% reduction), percentage of attacked truffles and number of galleries/g truffle. The cost effectiveness of these treatments and possible improvements are discussed.

Relationship between Sensory Processing and Quality of Life: A Systematic Review.

BACKGROUND: Sensory processing has been described as the ability to register, modulate, and organize sensory information to respond to environmental demands. Different theoretical approaches have studied the differential characteristics of sensory processing, such as Dunn's model. From this framework, high sensitivity in sensory processing has been described as responses to stimuli from environment quite often due to a rapid activation of the central nervous system. It should be noted that the association between high sensitivity in sensory processing and health outcomes obtained in different studies are not homogeneous, so it is necessary to develop a review of this research in order to clarify the relationship between sensory processing and quality of life. METHODS: We conducted a systematic review of the relevant studies using the PubMed, ScienceDirect, Scopus, and ProQuest databases to assess how sensory processing patterns are related to quality of life. RESULTS: Fourteen studies concerning sensory processing and quality of life were included in the review. Some studies indicate negative, moderate, and significant correlations between these variables in which high sensitivity is related to a poor quality of life in the population studied. CONCLUSIONS: High sensitivity in sensory processing could have a negative impact on quality of life, thereby facilitating a fluctuation in well-being, daily functioning, and health.