Search Results (220)

Background/Objectives: Sleep quality and daytime sleepiness influence vigilance and motor control, but their joint contribution to injury risk in physically active young adults remains unclear. This study examined sex-specific associations between sleep quality, daytime sleepiness, and injury occurrence in university students. Methods: A cross-sectional sample of 418 students (199 males, 219 females) was analyzed. Sleep quality (PSQI), daytime sleepiness (ESS), and 12-month injury occurrence were assessed with validated questionnaires. Bivariate χ² tests examined individual associations. Sex-stratified log-linear models evaluated classical (multiplicative) interactions between sleep quality (SQ), excessive daytime sleepiness (EDS), and injury (INJ). Additive interaction was assessed using Poisson-derived risk ratios (RR₁₀, RR₀₁, RR₁₁) and synergy indices (RERI, AP, S). Results: Poor sleep quality was significantly associated with injury occurrence (χ² = 4.76, p = 0.029; OR = 1.60, 95% CI: 1.05–2.45), driven primarily by females (χ² = 5.39, p = 0.020; OR = 1.98). In males, interaction plots showed non-parallel slopes and log-linear modeling supported significant two-way dependencies (ΔG² = 18.37, p < 0.001), but the three-way interaction was not significant (p = 0.119). In females, relationships were fully additive (ΔG² = 0.011, p = 0.917). Additive interaction metrics indicated no synergy in males, whereas females showed a mild supra-additive pattern (RR₁₁ = 1.61). Importantly, logistic regression models showed that sleep factors explained only 0.6–1.2% of variance in males and up to 4.3% in females, indicating limited overall predictive value. Poor sleep quality contributed modestly to injury occurrence, while daytime sleepiness added minimal explanatory improvement. Conclusions: Sleep–injury relationships were sex-specific. Poor sleep quality was the most consistent predictor of injury—especially among females—while interaction patterns differed between sexes. Sleep factors contributed modestly to injury risk and should be interpreted within a broader framework of intrinsic determinants in physically active young adults. Full article

Background/Objectives: Multiple sclerosis (MS) is a chronic neurological disease associated not only with motor dysfunction but also with non-motor symptoms such as depression and MS-related fatigue (MSRF). Sensory integration disorders (SID) in MS remain poorly characterized. This study aimed to evaluate the association between SID and depression, MSRF, disability level, disease duration, and disease activity in patients with relapsing–remitting MS (RRMS). Methods: A total of 205 patients with RRMS were assessed using the Daniel Travis sensory integration questionnaire, Beck Depression Inventory (BDI), EDSS, FSMC fatigue scale, and MRI T2-lesion burden. Due to non-normal distribution, non-parametric statistical tests were applied with significance set at p < 0.05. Results: Statistically significant associations were identified between SID and depressive symptoms. Compared with patients without depression, individuals with mild to severe depression showed significantly higher impairment in under-responsiveness/sensory seeking (p = 0.040), sensory discrimination (p = 0.017 for mild; p = 0.011 for severe), sensory-based motor abilities (p = 0.007 for severe), and social–emotional functioning (p = 0.006 for mild; p = 0.014 for severe). Higher disability (EDSS > 3) was associated with impaired sensory discrimination (p = 0.013) and reduced motor abilities (p = 0.000). Longer disease duration was linked to poorer general sensory modulation (≤5 vs. 5–10 years p = 0.038; ≤5 vs. >10 years p = 0.037) and reduced motor abilities (>10 years p = 0.042). Increased disease activity (1 or ≥2 relapses/year) correlated with more severe under-responsiveness/sensory seeking (p = 0.039) and worse social–emotional functioning (p = 0.025 and p = 0.007). No significant association was found between SID and MSRF or MRI T2-lesion count. Conclusions: In conclusion, sensory integration disorders in RRMS are strongly associated with depression, disability level, disease duration, and relapse rate, but not with MSRF. SID assessment may provide additional insight into non-motor symptom burden and disease progression. Full article

Female cancers, including breast and gynecological malignancies, are among the most prevalent oncological conditions worldwide. Advances in screening, diagnosis, and treatment have markedly improved survival, resulting in a growing population of female cancer survivors. Consequently, long-term health and quality of life have become essential aspects of comprehensive cancer care. Among survivorship issues, sleep disturbances—particularly insomnia—are highly prevalent and associated with adverse outcomes including mood and cognitive impairment, fatigue, immune and cardiometabolic dysregulation, and reduced adherence to therapy. Insomnia, defined as difficulty initiating or maintaining sleep or experiencing poor sleep quality with daytime impairment, affects 6–10% of the general population and is more common in women. In cancer survivors, poor sleep quality appears to be three times more frequent, reaching 62% in breast cancer survivors, although these data may be underestimated, especially for other cancer types, due to the small sample size and heterogeneity of the studies. The pathogenesis of insomnia in female cancer patients is multifactorial, involving cancer-related inflammation, hypothalamic–pituitary–adrenal axis dysregulation, neuroimmune alterations, treatment effects, psychological distress, and behavioral factors. Hormonal disruption plays a central role, as oncological treatments are often the cause of iatrogenic menopause, leading to vasomotor symptoms, mood and cognitive disturbances, sexual dysfunction, and genitourinary complaints, all contributing to sleep disruption. Importantly, estrogens and progesterone independently regulate sleep–wake pathways via central mechanisms, influencing sleep quality even in the absence of vasomotor symptoms. Management requires a multidisciplinary approach integrating oncology, gynecology, and sleep medicine. Cognitive Behavioral Therapy for Insomnia (CBT-I) is first-line, while pharmacologic options include benzodiazepines, Z-drugs, SSRIs/SNRIs, melatonin, or new medication like DORAs. Menopausal hormone therapy (MHT) should be considered for premature menopause management in selected women without contraindications, improving both vasomotor symptoms and sleep quality. Emerging neurokinin receptor (NK-R) antagonists show promise, and ongoing trials suggest significant potential even in breast cancer survivors. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) exhibits substantial clinical heterogeneity and poor prognosis in relapsed/refractory (R/R) settings. PRO-MIND is a prospective, multicenter real-world study evaluating tafasitamab–lenalidomide followed by tafasitamab monotherapy in patients with transplant-ineligible R/R DLBCL in Italy. This ad hoc, cross-sectional, baseline analysis aimed to characterize health-related quality of life (HRQoL) and symptom burden before tafasitamab–lenalidomide initiation in the PRO-MIND cohort. Methods: Thirty-eight patients across 30 centers completed the EORTC QLQ-C30 and QLQ-NHL-HG29 questionnaires at pretreatment baseline, prior to starting tafasitamab–lenalidomide. EORTC QLQ-C30 scores (0–100) were compared with age-specific normative values for the Italian general population using Welch’s t-test. Differences of ≥5 points were considered clinically meaningful and ≥10 points clearly clinically important. Effect sizes (Cohen’s d) were calculated to complement p-values for between-group comparisons. Results: Compared with normative data, the PRO-MIND cohort had significantly lower EORTC QLQ-C30 functioning scores for physical (Δ 12.7, p = 0.0135), role (Δ 16.1, p = 0.0168), social (Δ 15.2, p = 0.0019), and cognitive (Δ 8.5, p = 0.0460) functioning. Symptom scales revealed worse fatigue (Δ 14.8, p = 0.0097), insomnia (Δ 13.9, p = 0.0291), appetite loss (Δ 9.4, p = 0.0435), and pain (Δ 8.7, p = 0.0430) in the PRO-MIND cohort versus normative data, with effect sizes in the small-to-moderate range. EORTC QLQ-NHL-HG29 scores indicated a high prevalence of concerns about future health (84.2%), disease recurrence (81.6%), and dependency (78.9%), as well as physical symptoms, including lack of energy (71.1%), sleep difficulties (63.2%), and pain or discomfort (60.5%). Conclusions: This cross-sectional, baseline-only analysis of the PRO-MIND real-world cohort showed that patients with transplant-ineligible R/R DLBCL scheduled to receive tafasitamab–lenalidomide already had pronounced impairments in physical, role, social, and cognitive functioning, along with substantial fatigue, insomnia, pain, appetite loss, and psychological concerns. These baseline benchmarks underscore the importance of systematic HRQoL assessment and targeted supportive interventions focusing on these domains before and during treatment. Future longitudinal PRO-MIND analyses will complement these findings by describing how HRQoL evolves after tafasitamab–lenalidomide initiation. Full article

Background: Physical function, muscle strength, and fatigue are often impaired in patients with multiple sclerosis (MS). This study aimed to assess these parameters and their associations. Methods: This cross-sectional study included patients with relapsing-remitting MS. Physical function was assessed using the dynamic gait index (DGI), two-minute walk test (2MWT), and Expanded Disability Status Scale (EDSS). Muscle strength and fatigue were assessed using a load cell (measured in kgf). Generalized linear models (GLMs) with log link and gamma distribution examined the associations between MS and physical function, muscle strength, and fatigue. In the MS group, GLMs explored links between fatigue, muscle strength, and physical function. Results: Forty-seven individuals participated (18 MS; 27 controls). Patients with MS showed reduced physical function and muscle strength, and higher fatigue. Knee extension fatigue was associated with DGI (Exp β = 0.23; p = 0.03), 2MWT (Exp β = 0.11; p = 0.02), and EDSS (Exp β = 17.17; p < 0.0001); knee flexion fatigue was associated with EDSS (Exp β = 2.45; p = 0.006). Knee flexion and extension strength were also associated with EDSS. Conclusions: Patients with MS show reduced physical function and strength, increased fatigue, and knee muscle performance. The associations between strength, fatigue, and functional outcomes varied in magnitude, with knee-related measures, especially knee extension fatigue, showing the most consistent relationships. Full article

Traumatic brain injury (TBI) is a major global health problem and a leading cause of long-term neurological disability. TBI produces a spectrum of persistent symptoms, including cognitive impairment, mood and behavioral disturbances, sleep disruption, fatigue, and autonomic dysregulation. Chronic pain is among the most debilitating sequelae, affecting physical, emotional, and social functioning. The etiology of post-TBI pain is multifactorial, arising from initial structural and biochemical injury to the nervous system, maladaptive neuroplastic changes, neuroinflammation, and psychological comorbidities that amplify pain perception and chronicity. This review explores the complex pathophysiology of post-TBI pain and outlines a multidisciplinary framework for management. Pain syndromes are classified according to the International Association for the Study of Pain’s mechanistic framework as nociceptive pain (resulting from tissue injury and inflammation), neuropathic pain (due to lesion or disease of the somatosensory nervous system), and nociplastic pain (arising from altered nociceptive processing without clear evidence of tissue or nerve damage). Many patients exhibit mixed pain phenotypes driven by neuroinflammation and central sensitization. Pharmacologic approaches, including anti-inflammatory agents, anticonvulsants, and antidepressants, require cautious titration due to TBI-related comorbidities. Equally essential are non-pharmacologic strategies such as physical and occupational therapy, cognitive behavioral therapy, and neuromodulation techniques, which target both biomechanical and psychosocial contributors. Emerging innovations, machine learning for prognostication, blood biomarkers for structural injury, and neuro-reparative agents, represent the next frontier in personalized management. Effective care for post-TBI pain requires an integrated strategy that combines mechanistic classification, multidisciplinary treatments, and advancing diagnostic technologies. Full article

Background/Objectives: Children with hearing loss (HL) could experience significant fatigue which compromises their performance. The effort related to the combination of HL and visual impairment in children affected by Usher syndrome (USH) could compromise mental health, socio-emotional behavior and academic achievement. The aim of the present study was to analyse the listening effort in USH cases types 1 and 2 and its relation to age, molecular diagnosis, visual field, visual acuity, degree of HL, vestibular impairment and spatial orientation. Methods: This was a retrospective monocentric study. Twenty children with genetically confirmed USH (USH2 in 15/20–75% and USH1 in 5/20–25%), age range 3–17 years (mean 9.6 ± 4.7), underwent: the Vanderbilt fatigue scale questionnaire (VFS), audiological and vestibular assessment including the Oldenburg Matrix test in Italian and video head impulse test (VHIT), sound localization test and ophthalmologic examination. Results: We observed a more pronounced HL and deteriorated vestibular function in those with USH1. They also employed significantly more time and head movements to localize sounds compared to USH2 and had the worst visual field on eye examination. The VFS did not show significant differences between the two groups, with the exception of the physical fatigue reported by parents. Mean VFS was linearly related to age, the hearing threshold of the worse ear, data logging hours of hearing device, time and head movements of the localization test, VHIT asymmetry and balance problems referred by parents and the visual field. USH type 1 had no greater risk of fatigue than USH2. Profound hearing loss, data logging of hearing device < 8 h a day, difficult localization test, balance problems and low retinal sensitivity represented risk factors for listening effort measured with VFS. Conclusions: Listening effort in difficult environments such as school rooms in USH patients is not only associated to hearing function but also to the spatial awareness determined in part by vestibular and visual function. Teachers should be informed and made aware of multiple comorbidities in order to facilitate learning. Full article

This study aimed to investigate the effects of acute exhaustion exercise on cognitive control in young men, a key higher cognitive function for goal-directed behavior. Although long-term regular exercise benefits cognition, the effects of acute exhaustion exercise on cognitive control and its neural mechanisms are not fully understood. 35 male college students completed a Stroop task before and after exhaustion exercise on a cycle ergometer with incremental load. Electroencephalogram data were collected synchronously during the task. Behavioral measures (accuracy, reaction time), Event-Related Potential components (N2, P3 amplitudes and latencies), and Event-Related Spectral Perturbation (energy changes in theta, alpha, beta frequency bands) were analyzed. Results: Behavioral results showed that task accuracy only significantly decreased under the conflict condition (incongruent trials) following exhaustive exercise. ERP analysis revealed that the P3 amplitude at the anterior site (Fz) was significantly reduced post-exercise, but specifically for the incongruent condition, while the N2 amplitude demonstrated a more widespread enhancement. Time–frequency analysis found a significant decrease in alpha-band power over the parietal region after exercise. Theta and beta band activities were not significantly affected by exercise-induced fatigue. Conclusions: Acute exhaustive exercise did not impair early conflict monitoring functions (as indicated by stable N2 component and theta oscillations), but it compromised later higher-order cognitive processes related to attentional resource allocation and conflict resolution (manifested as reduced anterior P3 amplitude), accompanied by decreased efficiency in neural oscillatory activity associated with inhibitory control (reduced alpha power). This suggests that fatigue primarily affects the neural mechanisms of the “implementation” stage rather than the “monitoring” stage in the cognitive control cascade. Full article

Background: Exposure to hypoxia is widely used to enhance training adaptations, but its acute effects on cardiac function remain unclear. Exercise-induced cardiac fatigue (EICF), defined as transient impairments in left ventricular (LV) systolic and diastolic function, has been reported after endurance exercise. Whether moderate hypoxia influences EICF, particularly in athletes, is unknown. Methods: Twenty-four healthy men participated: 12 endurance-trained cyclists (T) and 12 untrained individuals (UT). Each completed two exhaustive cycling tests under normoxia (FiO₂ = 20.9%) and moderate normobaric hypoxia (FiO₂ = 14.4%; ~3000 m). Echocardiography was performed at rest and immediately post-exercise to assess LV systolic and diastolic function. Results: Exhaustive exercise reduced LV diastolic function in both groups, with no significant condition-related differences. Under normoxia, early peak filling velocity (Mitral E) decreased by 21.2% in UT and 23.2% in T, and under hypoxia, by 16.2% in UT and 14.9% in T. Global longitudinal strain (LV GLS) became less negative after exercise under normoxia (UT: +25.2%, T: +30.6%) and hypoxia (UT: +24.8%, T: +20.3%). Athletes exhibited slightly less post-exercise systolic impairment under hypoxia than normoxia, reflected by the maintenance of a more negative LV GLS (∆GLS: 6.87 ± 2.65% in normoxia vs. 4.55 ± 1.86% in hypoxia, p < 0.05). Conclusions: Moderate normobaric hypoxia (~3000 m) did not exacerbate EICF in either group. Athletes showed slightly less post-exercise systolic impairment under hypoxia. Moderate hypoxia may modify the cardiac response to exhaustive exercise, but studies with larger samples and direct preload assessment are needed. Full article

Early-life infections can produce durable changes in immune function and behavior. We propose a mechanistic hypothesis positioning the mechanistic target of rapamycin (mTOR) as the link between peripheral inflammation and central nervous system dysfunction in pediatric post-infectious syndromes. Based on clinical, translational, and experimental literature, we outline a stepwise pathway. First, sustained mTOR activation skews T-cell and macrophage differentiation toward pro-inflammatory and autoimmune states. Second, endothelial mTOR signaling weakens tight junctions and increases vesicular transport, compromising blood–brain barrier integrity. Third, cytokines and sometimes autoreactive cells enter the brain and engage mTOR in microglia and neurons, driving neuroinflammation, impaired synaptic maintenance and plasticity, and neurotransmitter disruption. This framework accounts for features observed in Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and pediatric acute neuropsychiatry syndrome (PANS/PANDAS) and yields testable predictions on pathway activity and barrier permeability. It also motivates targeted interventions that modulate mTOR-related processes in immune and endothelial compartments and within neural circuits in children. So, this article aims to outline a mechanistic framework linking infection-driven mTOR activation to post-infectious neuropsychiatric syndromes. Full article

Background/Objectives: Postural orthostatic tachycardia syndrome (POTS) is a form of dysautonomia characterized by excessive tachycardia during orthostatic stress. It is frequently observed in patients with syncope, Chronic Fatigue Syndrome (CFS), and post-COVID-19 syndrome (PCS), yet the underlying mechanisms may differ across these conditions. This study aimed to assess autonomic nervous system (ANS) function in patients with syncope, CFS of insidious onset, and CFS post-COVID-19 who presented with POTS, and to compare them with age- and sex-matched patients without POTS. Methods: In this retrospective cross-sectional study, 138 patients over 18 years of age were included following head-up tilt testing (HUTT). Patients were divided into six groups: syncope with and without POTS, CFS with insidious onset with and without POTS, and CFS post-COVID-19 with and without POTS. All participants underwent HUTT, cardiovascular reflex testing (CART) by Ewing, five-minute resting ECG with short-term Heart Rate Variability (HRV) analysis, and 24 h Holter ECG monitoring. Results: The prevalence of POTS across groups ranged from 5% to 7%. Female predominance was consistent across all subgroups. In syncope with POTS, hypertensive responses during HUTT, lower rates of normal Valsalva maneuver results, and reduced HF values in short-term HRV suggested baroreceptor dysfunction with sympathetic overdrive. In both CFS subgroups with POTS, CART revealed higher rates of definite parasympathetic dysfunction, along with more frequent extreme blood pressure variation during HUTT and reduced vagally mediated HRV parameters (rMSSD, pNN50). Across groups, no significant differences were observed with regard to long-term HRV across groups. Conclusions: Distinct autonomic profiles were identified in POTS patients depending on the underlying condition. Syncope-related POTS was associated with baroreceptor dysfunction and sympathetic predominance, whereas CFS-related POTS was characterized by parasympathetic impairment and impaired short-term baroreflex regulation. Evaluating dysautonomia patterns across disease contexts may inform tailored therapeutic strategies and improve management of patients with POTS. Full article

Myalgic Encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), is a debilitating and heterogeneous disorder marked by persistent fatigue, post-exertional malaise, cognitive impairment, and multisystem dysfunction. Despite its prevalence and impact, the molecular mechanisms underlying ME remain poorly understood. This review synthesizes current evidence on the role of DNA, both nuclear and mitochondrial, in the susceptibility and pathophysiology of ME. We examined genetic predispositions, including familial clustering and candidate gene associations, and highlighted emerging insights from genome-wide and multi-omics studies. Mitochondrial DNA variants and oxidative stress-related damage are discussed in relation to impaired bioenergetics and symptom severity. Epigenetic modifications, particularly DNA methylation dynamics and transposable element activation, are explored as mediators of gene–environment interactions and immune dysregulation. Finally, we explored the translational potential of DNA-based biomarkers and therapeutic targets, emphasizing the need for integrative molecular approaches to advance diagnosis and treatment. Understanding the DNA-associated mechanisms in ME offers a promising path toward precision medicine in post-viral chronic diseases. Full article

Background: Sleep disturbances in the multiple sclerosis (MS) population are increasingly recognized, but the factors driving this association remain understudied. This study aimed to determine the prevalence and associations of poor sleep quality in the relapsing–remitting MS (RRMS) population receiving disease-modifying therapy (DMT). Methods: We conducted a cross-sectional study that enrolled 399 individuals diagnosed with RRMS on DMT. Data on patient demographics, clinical presentation, and treatment were systematically evaluated. Sleep-related outcomes were assessed using validated questionnaires—the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), STOP-Bang questionnaire, and Hamilton Anxiety Rating Scale (HAM-A). Independent associations of poor sleep were examined using log-binomial regression to estimate risk ratios (RR). Results: Poor sleep was reported in 42% of the participants in our cohort. In multivariable analysis, only insomnia severity (RR = 1.07; 95% CI 1.05–1.09, p < 0.001) and anxiety (RR = 1.02; 95% CI 1.01–1.04, p = 0.001) remained independently associated with poor sleep. Conclusions: Sleep disturbances are common among patients with RRMS. Insomnia severity and anxiety, rather than demographic or disease-related characteristics, showed independent associations with impaired sleep. Routine screening and targeted interventions addressing insomnia and anxiety may improve sleep quality and, consequently, overall quality of life in this population. Full article

Background: Exposure to heat is a growing health concern in the context of climate change. Older adults (people aged 600 years or older) are particularly vulnerable due to age-related physiological changes that compromise thermoregulation. Objective: To systematically review the evidence on thermoregulatory alterations in older adults exposed to heat and their association with adverse clinical outcomes. Methods: Following PRISMA guidelines, a systematic search was conducted in PubMed, Web of Science, ScienceDirect, and Scopus. Twenty-four original studies met the inclusion criteria, including experimental studies in controlled environments and epidemiological studies on heat-related outcomes. Data on study characteristics, thermophysiological responses, clinical outcomes, and methodological quality (assessed with JBI tools) were extracted and synthesized. Results: Experimental studies showed that older adults exhibit reduced sweating and cutaneous vasodilation, attenuated cardiovascular and autonomic adjustments, impaired hydration status, and altered thermal perception. These limitations resulted in greater heat storage, faster increases in core temperature, and a higher risk of dehydration and fatigue compared with younger adults. Epidemiological evidence confirmed a significant association between high ambient temperatures and increased hospitalizations and mortality among older populations, particularly at advanced ages, in women, and in those with comorbidities or socioeconomic vulnerability. Conclusions: Heat exposure and climatic conditions—particularly high ambient temperatures, humidity, and poor air quality—reduce thermoregulatory efficiency and increase risks of dehydration, cardiovascular strain, and mortality in older adults. Integrated public health actions addressing both environmental and physiological factors are essential for preventing heat-related illness among older adults. Full article

Long COVID is frequently accompanied by neurocognitive complaints, yet the combined effects of demographic and clinical factors remain unclear. This study examined individuals six months after their most recent SARS-CoV-2 infection using a Demographic/Infection-History form, a Physical and Neurocognitive Symptom Checklist (binary), and the Post-COVID Cognitive Impairment Scale (memory, attention; 5-point Likert). Participants were recruited through convenience sampling from multiple community and online sources. Inclusion criteria required confirmed prior COVID-19 infection, self-perceived or clinically documented Long COVID symptoms, and no history of neurological or severe psychiatric disorders. The final sample consisted of 212 participants (mean age = 39.7 years, SD = 10.5), of whom 67.9% were female, and most held a master’s (35.4%) or bachelor’s (28.3%) degree. Difficulties with retaining new information (57.8%) and concentrating (52.1%) were the most frequent neurocognitive complaints, while severe fatigue after mild activity (23.2%) and chronic fatigue (22.7%) were the most common physical symptoms. Confusion and decision-making difficulty were more frequent among younger participants; women reported greater difficulty retaining new information, and difficulty concentrating varied by education level. A multivariable regression model explained 7% of the variance in total cognitive complaints, identifying education level (β = −0.18, p < 0.01) and number of physical symptoms (β = 0.19, p < 0.01) as significant predictors. Higher educational attainment was associated with fewer cognitive complaints, whereas a greater burden of physical symptoms predicted higher complaint scores. Persistent cognitive difficulties in Long COVID appear closely related to physical symptom burden and protective factors such as education, rather than to infection frequency or sensory dysfunction duration. Findings highlight the need for routine cognitive screening, fatigue-focused management, and longitudinal multimodal research to elucidate underlying mechanisms and recovery pathways. Full article