mRNA therapeutics encapsulated in lipid nanoparticles (LNPs) offer promising avenues for treating various diseases. While mRNA vaccines anticipate immunogenicity, the associated reactogenicity of mRNA-loaded LNPs poses significant challenges, especially in protein replacement therapies requiring multiple administrations, leading to adverse effects and suboptimal therapeutic outcomes. Historically, research has primarily focused on the reactogenicity of mRNA cargo, leaving the role of LNPs understudied in this context. Adjuvanticity and pro-inflammatory characteristics of LNPs, originating at least in part from ionizable lipids, may induce inflammation, activate toll-like receptors (TLRs), and impact mRNA translation. Knowledge gaps remain in understanding LNP-induced TLR activation and its impact on induction of animal sickness behavior. We hypothesized that ionizable lipids in LNPs, structurally resembling lipid A from lipopolysaccharide, could activate TLR4 signaling via MyD88 and TRIF adaptors, thereby propagating LNP-associated reactogenicity. Our comprehensive investigation utilizing gene ablation studies and pharmacological receptor manipulation proves that TLR4 activation by LNPs triggers distinct physiologically meaningful responses in mice. We show that TLR4 and MyD88 are essential for reactogenic signal initiation, pro-inflammatory gene expression, and physiological outcomes like food intake and body weight─robust metrics of sickness behavior in mice. The application of the TLR4 inhibitor TAK-242 effectively reduces the reactogenicity associated with LNPs by mitigating TLR4-driven inflammatory responses. Our findings elucidate the critical role of the TLR4-MyD88 axis in LNP-induced reactogenicity, providing a mechanistic framework for developing safer mRNA therapeutics and offering a strategy to mitigate adverse effects through targeted inhibition of this pathway.

BACKGROUND: Chronic pain often clusters in families, where parents and their offspring both experience chronic pain conditions. Young children of parents with irritable bowel syndrome (IBS) represent an at-risk group for the development of abdominal pain, disability, and excess health care visits in later childhood. Parental solicitous responses to children\'s expressions of discomfort and maternal modeling of their own illness behavior contribute to a greater focus on somatic sensations, leading to illness behaviors in children. This randomized controlled trial will test the effectiveness of an early preventive web-based psychosocial intervention (REACH)[TM] vs. an educational web-based safety comparison condition delivered to parents with IBS to alter parental responses and lead to improved child health and decreased health care costs.
METHODS: Parents with IBS who have children ages 4-7 years are recruited via community-based approaches (e.g., social media advertisements, school electronic distribution, research networks) and health care providers. The target sample is 460 parents randomized to REACH, a web-based social learning and cognitive behavior therapy (SLCBT) intervention or an educational web-based safety comparison condition (EC). Participants will be assessed at baseline, 6-week (immediate post-intervention), 6-month, 12-month, and 18-month follow-up periods (months post-completion of intervention). The primary outcome is change in parental solicitous/protective behaviors. Secondary outcomes include parent risk and protective factors, child health and symptom outcomes, and health care utilization and cost savings.
CONCLUSIONS: This study adapts a validated, parent-delivered intervention to treat chronic pain in children to a web-based application designed to prevent the development of chronic pain in very young, high-risk children. If successful, this strategy can both prevent adverse sequelae of this condition from developing as well as be widely accessible. Furthermore, the availability of a prevention model for parent training could result in significant short- and long-term health benefits across a broad spectrum of conditions.
BACKGROUND: ClinicalTrials.gov NCT05730491. Registered on February 15, 2023.

UNASSIGNED: Longitudinal data on how acute respiratory illness (ARI) affects behavior, namely school or work participation, and nonpharmaceutical intervention (NPI) usage before and during the COVID-19 pandemic is limited. The authors assessed how ARIs and specific symptoms affected school, work, and health-related behaviors over time.
UNASSIGNED: From November 2019 to June 2021, participating households with children in King County, Washington, were remotely monitored for ARI symptoms weekly. Following ARIs, participants reported illness-related effects on school, work, and NPI use. Using logistic regression with generalized estimating equations, the authors examined associations between symptoms and behaviors.
UNASSIGNED: Of 1,861 participants, 581 (31%) from 293 households reported 884 ARIs and completed one-week follow-up surveys. Compared with the prepandemic period, during the period of the pandemic pre-COVID-19 vaccine, ARI-related school (56% vs 10%, p<0.001) absenteeism decreased and masking increased (3% vs 28%, p<0.001). After vaccine authorization in December 2020, more ARIs resulted in masking (3% vs 48%, p<0.001), avoiding contact with non-household members (26% vs 58%, p<0.001), and staying home (37% vs 69%, p<0.001) compared with the prepandemic period. Constitutional symptoms such as fever were associated with work disruptions (OR=1.91; 95% CI=1.06, 3.43), staying home (OR=1.55; 95% CI=1.06, 2.27), and decreased contact with non-household members (OR=1.58; 95% CI=1.05, 2.36).
UNASSIGNED: This remote household study permitted uninterrupted tracking of behavioral changes in families with children before and during the COVID-19 pandemic, identifying increased use of some NPIs when ill but no additional illness-associated work or school disruptions.

In ectothermic vertebrates, behavioral fever, where an individual actively seeks warmer areas, seems to be a primary response to pathogens. This is considered a broad and evolutionarily conserved response among vertebrates. Recent population declines in amphibians are associated with an increase of infectious disease driven largely by climate change, habitat degradation, and pollution. Immediate action through research is required to better understand and inform conservation efforts. The literature available, does not provide unifying concepts that can guide adequate experimental protocols and interpretation of data, especially when studying animals in the field. The aim of this review is to promote common understanding of terminology and facilitating improved comprehension and application of key concepts about the occurrence of both sickness behavior or behavioral fever in ectothermic vertebrates. We start with a conceptual synthesis of sickness behavior and behavioral fever, with examples in different taxa. Through this discussion we present possible paths to standardize terminology, starting from original use in endothermic tetrapods which was expanded to ectothermic vertebrates, particularly amphibians and reptiles. This conceptual expansion from humans (endothermic vertebrates) and then to ectothermic counterparts, gravitates around the concept of \'normality\'. Thus, following this discussion, we highlight caveats with experimental protocols and state the need of a reference value considered normal (RVCN), which is different from experimental control and make recommendations regarding experimental procedures and stress the value of detailed documentation of behavioral responses. We also propose some future directions that could enhance interaction among disciplines, emphasizing relationships at different levels of biological organization. This is crucial given the increasing convergence of fields such as thermal physiology, immunology, and animal behavior due to emerging diseases and other global crises impacting biodiversity.

OBJECTIVE: Approximately one in five adults experiences chronic pain, often in co-occurrence with depression, insomnia, anxiety, and lower self-rated health. Elevated levels of cytokines, e.g. tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10), have been identified in patients with chronic pain. Depression, insufficient sleep, poor self-rated health, and pain intensity have also been associated with inflammatory biomarkers. This study aimed to investigate the interrelationships between inflammatory biomarkers and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity in patients with chronic pain.
METHODS: Self-report questionnaires and blood samples analyzed for plasma levels of inflammatory biomarkers were collected from 80 adult patients with chronic pain. Associations between inflammatory biomarkers (TNF-α, IL-6, IL-8, IL-10, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity, were analyzed using bivariate Spearman rank correlation coefficients and regression analyses.
RESULTS: Participants were mainly women (72.5 %), with a mean age of 50.8 years, and a reported mean pain duration of 16.7 years. There were significant correlations between insomnia and CRP (rs =.26, p <.05); sex and ESR (rs =.29, p <.05); age and IL-6 (rs =.29, p <.05) and IL-8 (rs =.30, p <.05); BMI and IL-6 (rs =.50, p <.001), CRP (rs =.63, p <.001) and ESR (rs =.42, p <.001). Ratings of depression were positively and significantly related to ratings of sickness behavior and anxiety (β =.32 and β =.40, respectively), explaining 49 % of the total variance in depression ratings. Insomnia was positively and significantly related to sickness behavior (β =.37) explaining 31 % of the total variance in insomnia ratings. Inflammatory biomarkers, however, did not contribute significantly to the models.
CONCLUSIONS: Participants reported high levels of symptoms, yet the associations between these ratings and the inflammatory biomarkers were either absent or weak. Also, despite high levels of self-reported sickness behavior, overall the inflammatory status remained within the normal range. Ratings of sickness behavior contributed more than inflammatory markers in explaining ratings of depression and insomnia. The present results point to the complexity of chronic pain, and the challenges of identifying biomarkers that explain symptomatology.

OBJECTIVE: The current study aims to assess the level of acceptance of their illness in patients diagnosed with type 2 diabetes mellitus, determine whether the self-hardiness of patients with type 2 diabetes mellitus can serve as a predictive factor for their illness acceptance and health-behaviors, and Explore variations in illness acceptance, health-behaviors, and self-hardiness in relation to socio-demographic factors among patients with type 2 diabetes mellitus.
METHODS: A descriptive correlational study was carried out at Al-Rifia Teaching Hospital, and and Imam Al-Qiam Health Center. the study was started from 15th October, 2023 to 3th March, 2024. Purposive sample (non-probability) of 200 patients with type 2 diabetes (male and female). by the used of questionnaire and interviews techniques, data are collected from those who diagnosed with diabetes mellitus. the study instrument consisted of four parts: part one the sociodemographic sheet, part two concerned illness acceptance which composed of 22 items, part three health behaviors which composed of 22 items, and part four concerned self-hardiness which composed of 25 items.
RESULTS: The study results revealed that the who participated in this study their age 55-64 years old and constituted 64 (32.0%), more than half of participants were male patients with type 2 diabetes mellitus 109 (54.5%), where revealed (79.5%) exhibited that the neutral acceptance level as described by mean score (±SD) = 2.075, health-behaviors among patients with type 2 diabetes, findings illustrated that the (51.0%) of patients with type 2 diabetes mellitus exhibited that they follow good health-behaviors level, and good Self-Hardiness among Patients with Type 2 diabetes, in addition, there is a high significant relationship between illness acceptance, health behaviors and patients self-hardness at p-value (< 0.005).
CONCLUSIONS: should support people with educational initiatives and assist them in accepting their sickness and taking an active role in managing it, Psychological support to resolve disease-related problems, cope with difficulties and develop positive attitudes towards the disease.

Infections frequently cause behavioral changes, known as sickness behavior. In a recent study,1 Yipp and collaborators discovered a sensory circuit that is activated by a bacterial lipopolysaccharide during lung infection and drives sickness behaviors independent of inflammation. Biofilm-producing bacteria, however, avoid activating this lung-brain circuit, resulting in infection without sickness behavior.

Social withdrawal is a well-established part of sickness behavior, but in some contexts sick animals might gain from keeping close instead of keeping away. For instance, sick individuals are more willing to be near known individuals who can provide care and safety (close others) compared to when healthy. Yet, interactions with some strangers might also be beneficial (i.e., healthcare professionals), but it is not known how sickness interplay with social behavior towards such individuals. Here, we assessed if sickness affects perception of caregivers, and developed a new task, the Caregiver Perception Task (CgPT). Twenty-six participants performed the CgPT, once after an injection of lipopolysaccharide (LPS, 0.8 ng/kg body weight, n = 24), and once after an injection of saline (n = 25), one hour and forty-five minutes post-injection. During the task, participants watched short video clips of three types of caregivers: a healthcare professional taking care of a sick individual, a healthcare professional not taking care of a sick individual, and a non-healthcare professional taking care of their sick adult child or partner. After each video clip, the likability, trustworthiness, professionalism, and willingness to interact with and receive care from the caregiver were rated on visual analogue scales. Results showed that participants injected with saline rated healthcare professionals who did not take care of a sick individual less positively on all aspects compared to healthcare professionals who took care of a sick individual. Moreover, compared to saline, LPS increased the participants\' willingness to receive care from healthcare professionals and non-healthcare professionals providing care, but not from healthcare professionals not providing care. Thus, our results indicate that sick individuals may approach unknown individuals with potential to provide care and support.

Storylines of Family Medicine is a 12-part series of thematically linked essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In \'V: ways of thinking-honing the therapeutic self\', authors present the following sections: \'Reflective practice in action\', \'The doctor as drug-Balint groups\', \'Cultivating compassion\', \'Towards a humanistic approach to doctoring\', \'Intimacy in family medicine\', \'The many faces of suffering\', \'Transcending suffering\' and \'The power of listening to stories.\' May readers feel a deeper sense of their own therapeutic agency by reflecting on these essays.

Administration of low-dose lipopolysaccharide (LPS) to healthy humans is a translational approach to analyze the effects of acute systemic inflammation and sickness behavior. Although studies documented that LPS-induced inflammation can alter social behavior, its impact on empathy remains poorly understood. In this double-blind, placebo-controlled study, 52 healthy female volunteers received an intravenous injection of either LPS (0.4 ng/kg body weight) or placebo and completed the Social Interaction Empathy Task (SIET) two hours after injection. Physiological responses (blood pressure, heart rate, body temperature, cytokines, cortisol) were analyzed along with sickness symptoms and mood before and after LPS or placebo administration. LPS application led to significant increases in plasma cytokines and sickness symptoms as well as low mood. Moreover, volunteers receiving LPS showed significantly less empathy for other\'s psychological pain than those who received placebo. Furthermore, LPS-injected volunteers with more severe sickness symptoms displayed higher pain ratings in the first-person perspective. Thus, low-grade inflammation reduces empathy for other\'s psychological pain which might reflect an adaptive strategy to save energy by not responding empathetically when sick oneself.