Assessing the role of vitamin D in the prevention and management of chronic rhinosinusitis: a systematic review and meta-analysis.

Loneliness can be considered among the most pressing health challenges affecting humans at present. The latest findings of the World Health Organization (WHO) indicate that loneliness affects one in six individuals and that, on average, around 100 people worldwide die every hour due to loneliness-related causes (). Loneliness refers to the subjective and aversive experience of being alone. The frustration of the need for belonging () may exhibit a functional characteristic in the short term (); however, in the long term, loneliness can lead to destructive emotional-affective (), metabolic, and immunological processes (). In particular, chronic loneliness is associated with higher risks of mental (, , ), cardiovascular () and neurodegenerative (–) diseases. The prevalence of loneliness in the general population is estimated at 11.1% in Western European countries and has been observed to be even higher in lower-income countries (, ). Loneliness coincides with depression in the general population. A study focused on the general population of older persons in England revealed that, among people with severe loneliness, 3.3% of these individuals (vs. 1.1% of individuals with low/moderate loneliness) demonstrated clinically relevant depression, and 45.2% (vs. 13% of individuals with low/moderate loneliness) exhibited measurable depressive symptoms (). Another representative population study conducted in Germany revealed that among individuals who reported depression in a self-assessment using the Patient Health Questionnaire, 52.6% reported pronounced loneliness, 30.5% reported moderate loneliness, 19.3% reported minimal loneliness, and only 5.2% reported no loneliness at all (). Compared with other health consequences that have been investigated, the associations between loneliness and negative health outcomes are most apparent with respect to mental health (). In conjunction with another meta-analysis conducted by Erzen and Cikrikci (), the authors reported moderate effects of loneliness on depression. Suicidal tendencies and loneliness are also significantly related (, ). The relationship between depression and experiences of loneliness is likely to be bidirectional. However, in non-clinical study populations, longitudinal studies have suggested evidence of a relatively stronger predictive influence of loneliness on depression (, ). To our knowledge, there is currently no reliable data regarding the prevalence and clinical relevance of loneliness among patients with clinical depression. The pathophysiological pathways underlying the adverse health effects of loneliness remain incompletely understood. It is very likely that the best-described pathophysiological mechanism through which loneliness is linked to health involves the chronic overactivation of the hypothalamic-pituitary–adrenal axis (HPA axis) triggered by psychosocial stress. This activation leads to increased glucocorticoid release and resistance; subsequently, numerous consequences are induced, including mitochondrial dysfunction and inflammatory dysregulation, hyperglycemia, and increased vascular resistance (). At the neurotrophic level, findings suggest that the interaction of loneliness and brain-derived neurotrophic factor (BDNF) is crucial for neuroplasticity and problem-focused coping (, ). While cortisol is one of several factors involved in suppressing BDNF expression () opposing mechanisms that upregulate BDNF expression, such as physical activity, are also well documented (). Moreover, loneliness is bidirectionally associated with sleep disturbances, including daytime dysfunction such as fatigue, low energy, and sleepiness () and is related to sleep fragmentation (). Additional mechanisms, such as poorer health behaviors (e.g., reduced physical activity), affective and neuronal dysregulation (involving the cognitive control model) (, , ), and fewer compensation mechanisms such as a lack of social support (known as the buffer hypothesis) culminate in a vicious cycle (). Importantly, much of the biological evidence remains correlational and does not permit causal inferences.