A potential complication of pharmacotherapy for a given patient is the possibility of various side effects of drugs, which are manifested in many ways and constitute iatrogenic causes of diseases. Among the systemic side effects of drugs, there are also those involving the urinary tract, although these are less reported in the literature. The use of numerous drugs—especially of anticholinergics or drugs with anticholinergic potential, opioid analgesics, non-steroidal anti-inflammatory drugs, antidepressants, first-generation antipsychotics (classic neuroleptics) and selected cardiovascular drugs , as well as others—may increase the risk of developing urological disorders, such as urinary retention or incontinence, urinary tract infections, urolithiasis, erectile dysfunction in men and retroperitoneal fibrosis. The purpose of this paper is to characterise the abovementioned drug-induced disorders of the lower urinary tract on the basis of a non-systematic literature review. The primary goal of pharmacotherapy is to be effective and safe. Attaining this goal is related to demonstrating an acceptable risk–benefit ratio of the drugs that are currently on the pharmaceutical market. However, this fact does not mean that the use of drugs is immune to side effects that can be manifested in various systems and organs, including the kidneys and urinary tract. Therefore, lower urinary tract disorders may be drug-induced disturbances.The term “side effect of the drug”, also known as “adverse drug reaction” is defined in different ways. The World Health Organization (WHO) defines an adverse drug reaction (ADR) as “a response to a medicine which is noxious and unintended, and which occurs at doses normally used in man” . ADR wasAnother commonly accepted definition of an ADR is that of Ivor Ralph Edwards: “an appreciably harmful or unpleasant reaction, caused by an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or the alteration of the dosage regimen, or the withdrawal of the product” . A similThe occurrence of ADRs is a significant clinical problem because ADRs are considered a cause of unscheduled hospital admissions that may persist after hospital discharge. Between 5% and 10% of patients are estimated to suffer from an ADR at admission, during admission or upon discharge, despite various preventative efforts . In summThe classes of drugs that are regarded as being associated with the highest occurrence of ADRs include agents used in the treatment of cardiovascular disorders ; antiplatelets; warfarin and other anticoagulants; antipsychotic agents; non-opioid and opioids analgesics; cytotoxics; immunosuppressants; antidiabetics; and antibiotics ,13.per os route and pass through the digestive tract, gastrointestinal disturbances  are common types of ADRs. Various dermatological disorders are also frequent adverse drug reactions [Since many drugs are administered via the eactions . Howevereactions .Among the drug-related disturbances of the urinary system (SOC1300) distinguished in this report, 11 were distinguished as predominantly affecting the kidneys and urinary tract: glomerular vasomotor disorder; glomerulonephritis (acute or chronic); nephritis interstitial (acute or chronic); nephropathy analgesic; nephropathy toxic; nephrotic syndrome; kidney failure; acute kidney failure; kidney tubular disorder; kidney vasculitis; and urinary retention (UR).Some of these disturbances are potentially severe , or affect the kidney in a significant way as part of a systemic disorder . The main mechanisms by which drugs cause kidney dysfunction include pre-kidney effects ; obstructive uropathy ; allergic or immunological damage ; and direct nephrotoxicity  .The list of drug-induced urinary tract disorders mentioned above does not include many lower urinary tract disorders other than UR, although the report mentions that drugs can also have adverse effects on the bladder or urothelium, such as haemorrhagic cystitis or carcinoma of the urinary tract.The PubMed database searches, performed in June 2023 and limited to English-language records from the last 10 years, used the search terms “adverse drug reactions” and “lower urinary tract” or “urological” yielded 170 and 576 results, respectively. At the same time, when searching the PubMed database for records relating to dermatological or gastroenterological adverse drug reactions, a much larger number of publications was found . Thus, the performed query indicates that drug-induced urological disorders are less known and less reported in the literature.Therefore, the aim of the review was to discuss the most recognised, in the author’s opinion, drug-induced, adverse lower urinary tract disturbances described in the literature: urinary retention or incontinence, urinary tract infections, urolithiasis, erectile dysfunction and retroperitoneal fibrosis. The intention of the author was to organise and collect information on the above-mentioned urological disorders, discussing their potential drug-induced causes. This paper is based on the literature references covering adverse drug reactions in the form of lower urinary tract disturbances found through Medline/PubMed searches. In addition, the query was supplemented with references to key urological and pharmacological texts mentioned in the articles originally obtained during the literature review. It should also be emphasised that the drug-induced background of the urological disturbances described in this review is one of the elements of the broadly understood differential diagnosis of these disorders. Urological ADRs, like any other ADRs, are difficult to identify, and their diagnosis is based on the exclusion of other, organic or functional potential causes of the observed disorders, as well as on the demonstration of the existence of a cause-and-effect relationship between the observed disorder and the use of a given drug. It is also important to demonstrate the resolution or recurrence of the diagnosed urological disorders in the case of discontinuation of treatment, as well as during re-exposure to the drug used, respectively. Thus, this review describes the potential mechanisms predisposing to the development of urological ADR, which does not mean that in each case of using a specific drug the observed disorders are undoubtedly drug-induced.The most important function of the kidneys and urinary tract is the excretion of urine containing metabolic wastes and drugs with their metabolites, which is one of the vital functions of the human body. The voiding process is under the control of complex peripheral neural pathways that are, in turn, coordinated by cell groups in the spinal cord, brainstem and brain. There are two complementary stages: the storage of urine inside the bladder (“filling”) and (2) the elimination of urine through micturition, involving bladder emptying and urinary outlet  . The stoDuring bladder filling, the distention of the smooth muscle and urothelium evoke afferent activity. The afferents from stretch and volume receptors located at myelinated Aδ sensory fibres are conveyed via the pelvic (parasympathetic nervous system) and hypogastric nerves (sympathetic nervous system), whereas the pudendal (somatic nervous system) and hypogastric nerves carry impulses from the neck of the bladder and the urethra. Moreover, in some conditions such as overactive bladder or urinary tract infections, afferent activity also involves unmyelinated C-sensory fibres, which physiologically have a high mechanical threshold but respond to many neurotransmitters and other inflammatory mediators. These neuromodulators lower the threshold for bladder contraction and provoke symptoms such as urgency, an increased frequency of urination and urinary incontinence (UI). The afferent signals are carried to the spinal cord and then via the spinothalamic tract to the periaqueductal gray (PAG) matter and pontine micturition centre , which is located in the medial dorsal pons, close to, or includes the lateral dorsal tegmental nucleus and locus coeruleus. The role of the PAG in the control of the bladder function encompasses both downstream connections, as well as connections with the higher brain centres involved in decision-making and initiation of urination ,18.The higher brain centres of micturition communicate with the PMC through the PAG matter to either provoke or suppress the voiding reflex. Along with bladder distention, the afferent signal from the stretch receptors of the bladder reaches the pons, which subsequently notifies the brain. This afferent signal results in a perception of bladder fullness or the desire to urinate. The higher brain  determines the appropriateness of initiating the voiding reflex. Mostly, the higher brain suppresses PMC by transmitting reciprocal inhibitory signals via the PAG matter. It abolishes the urge to urinate and allows delaying voiding until finding a socially acceptable place and time. The voiding is initiated in an appropriate time and place, when the suppression of the PMC disappears, enabling a micturition reflex activation . The effThus, it can be concluded that the expulsion of urine requires the proper coordination of the contraction and relaxation of the bladder and bladder outlet, respectively, coordinated by the CNS. Both UR and incontinence belong to the “lower urinary tract symptoms; LUTS”, a term that encompasses all urinary symptoms, namely, voiding, storage, and post-voiding ,22. LUTSThe inability to generate efficient bladder emptying leads to UR. It is a clinical condition that is classified as acute or chronic. Acute UR is characterised by a rapid onset associated with suprapubic pain and the inability to urinate. Conversely, chronic UR is not associated with pain due to the fact that small amounts of urine still may be exposed from the body. Paradoxically, patients with chronic UR can present symptoms of UI, occurring after exceeding the critical amount of urine and intravesical pressure. The incidence of UR is higher in men compared to women and shows an increasing trend with age . UR may Considering the complex mechanism of voiding outlined above, it is possible to identify classes of drugs which can interfere with this process, resulting in either UR or UI. The mutual afferent and efferent signalling between the bladder and urethra and the CNS, contributing to urinary retention, is disturbed by opioid drugs (by affecting opioid receptors); non-opioid analgesics (by affecting tachykinin receptors); benzodiazepines (by affecting GABA receptors); and serotonin reuptake inhibitors (by potentiating serotonin-dependent increased sympathetic activity that increases bladder compliance). On the other hand, drugs with the ability to antagonise muscarinic receptors (anticholinergics) impair the cholinergic mediated contractility of the bladder. Similarly, bladder contractility is impaired by calcium channel blockers through a direct effect on smooth muscle through the inhibition of calcium channels. Drug-induced urinary retention may also result from the stimulation of alpha-1 adrenergic receptors, which leads to contraction of the internal urethral sphincter and impairment of urinary outflow. A schematic representation of the above mechanisms contributing to potential drug-induced urinary retention is shown in Taking into account the autonomic control of urination, it can be concluded that drugs affecting the mutual communication between the CNS and the lower urinary tract, those inhibiting the parasympathetic system (muscarinic M3 receptor antagonists) as well as those stimulating the sympathetic system  may disturb the micturition process, contributing to drug-induced UR ,28. It sThe opposite disorder to UR is UI. It is a condition characterised by the involuntary loss of urine. UI can be diagnosed in childhood and may resolve itself with growth; however, it usually occurs in patients over 40 years of age and increases with ageing . UI is rUI can be an isolated problem, or it can be the result of an underlying disease affecting the nervous system and the autonomic control of urination, such as stroke, myelomeningoceles, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis or neuropathies. Moreover, there are some specific causes of male UI, including benign prostatic hyperplasia, prostate cancer and related surgery or radiation therapies. These types of UI are collectively named incontinence after prostate treatment (IPT) . In the According to the pathophysiological premises described above, numerous drug groups can theoretically induce UI. However, drug-induced UI has been well evidenced for only a few classes (listed in An uncomplicated urinary tract infection (UTI) is an infection of the lower urinary tract (urethra and bladder), developing in patients without structural abnormality and comorbidities, such as diabetes, immunocompromised state, pregnancy, kidney transplants, the presence of a urinary catheter or other factors predisposing them to a complicated course of the infection. It is commonly known as cystitis or lower UTI, and it manifests itself with typical symptoms including urinary frequency, urgency, suprapubic discomfort and dysuria. UTI is usually caused by enteric coliforms that typically inhabit the periurethral vaginal introitus, with Escherichia coli as the main etiological factor constituting the vast majority of UTIs, followed by Klebsiella, and other organisms . Uncomplicated UTI involves the bladder starting with the invasion of the bladder mucosal wall by bacteria using adhesins on their surface, which allow them to attach to the urothelial mucosal surface. In addition, a short urethra makes it easier for the uropathogen to invade the urinary tract; thus, UTIs are significantly more common in women. Estimates indicate that 40% to 60% of women will have a UTI episode at least once in their lives, which means that UTIs are observed four times more frequently in females than males. A UTI may also progress to further complications: increasing the risk of urinary calculi development, UI, chronic prostatitis and affecting the upper urinary tract  ,37. The Moreover, the complementary mechanism contributing to UTI is urine stagnation and retention secondary to urinary stone formation in the urinary tract, as well as the intensification and promotion of the bacterial colonisation of urine (as a result of drugs that intensify glycosuria) . The druMoreover, cystitis may be non-infectious and occur in the form of severe, hemorrhagic damage to the bladder. Thus, drugs that cause the development of the so-called chemical cystitis (CC) and its complication–hemorrhagic cystitis (HC)–deserve special attention. CC is caused by different chemical agents, including chemotherapeutic or immunologic drugs, such as cyclophosphamide or ifosfamide (oxazophosphorine compounds), mitomycin C, anaesthetic agent–ketamine, tiaprofenic acid, danazol or agents administered intravesically . CC/HC shares similar symptoms with other types of cystitis, presenting suprapubic pain, dysuria, urinary frequency, urinary urgency, and hematuria (microscopic or macroscopic). The pathogenesis of cyclophosphamide and ifosfamide-induced HC is associated with the corrosive liver product called acrolein, which is a by-product formed during the metabolism of oxazaphosphorines. Acrolein is filtered by the kidneys and consequently accumulates in the bladder where it induces a complex reaction with pyroptotic effects in the urothelium, resulting in ulceration and the exposure of the muscularis mucosa and the blood vessels. Moreover, acrolein can break down proteins and damages DNA structure, which results in a metabolite that causes apoptosis. An important element of the pathophysiology of HC caused by oxazaphosphorines is also the intensification of oxidative stress and the overproduction of highly reactive oxygen and nitrogen-free radicals . A detaiUrolithiasis  is a relatively common clinical entity and research indicates that the general prevalence of the disease varies between 1–5% in Asia, 5–9% in Europe, 13% in the USA to even 20% in Middle Eastern countries ,51. AccoTaking into account the main pathomechanism, two main types of drug-induced urinary stones can be distinguished. They are shown in The first group includes stones composed principally of the drug itself and/or its metabolites excreted into the urine. They are poorly soluble compounds, for which the kidneys are the main route of elimination. Therefore, in accordance with the general pathophysiology of urolithiasis, these drugs may, in supersaturated urine, be characterised by exceeding the solubility equilibrium. The second group of drug-induced urinary stones are those classified as a sub-type of “metabolic stones”, due to the fact that treatment with these drugs contributes to the development of metabolic disturbances that facilitate the crystallisation of endogenous lithogenic substances. Many drugs may induce urinary stone development by affecting the pH of urine (in such a way that the solubility of many endogenous substances decreases), the alternation of the glomerular filtration and tubular secretion/reabsorption of the endogenous substances, or impairing the balance and action of crystallisation promoters/inhibitors ,58,59,60There are many causes of erectile dysfunction (ED) development in men, including pathophysiological  and psychological factors. However, there are also iatrogenic causes of ED, including drugs. Several drug-dependent mechanisms can be implicated as potentially contributing to the ED development. Among them, there is an antiandrogenic effect, hyperprolactinemia development, a decrease in the level of androgens, disorders of autonomic innervation or impaired peripheral circulation. They are shown in Numerous drugs may affect sexual functioning with important consequences related to patients’ quality of life. Sexual dysfunction in men can also worsen treatment results by decreasing a patient’s adherence to a programme of medication. This is of special importance in the case of drugs which are required to be precisely administered to evoke a desired pharmacological effect, e.g., anti-HIV medications, anticonvulsants or immunosuppressants. Moreover, given the embarrassing nature of ED, the true incidence of this ADR appears to be unknown and underestimated. ED is the main reason for the premature termination of antidepressant treatment, which should normally last at least 6 months. Approximately 42% of men discontinue antidepressant treatment after the development of disturbances to their sexual desire, ejaculation and orgasm . ED is aRetroperitoneal fibrosis (RPF) is a rare condition that is characterised by chronic inflammatory of, and fibrosis in the retroperitoneum, resulting in a midline plaque, usually at the aortic bifurcation. The gross appearance of RPF is that of a smooth, flat, tan-coloured dense mass that encases the retroperitoneal structures, usually centred at the fourth and fifth lumbar vertebrae. The extensive fibrotic process often affects the ureters and may lead to ureteric obstruction. RPF is observed in patients aged 40–60 years, with male predominance . The total incidence of the disease is estimated to be 1 per 200,000 to 500,000 per year . The cliA review of clinical reports on adverse drug reactions manifesting in the lower urinary tract suggests that they are most often observed in clinical practice after treatment with centrally acting drugs. A systematic review using a meta-analysis by Trinchieri et al. , analysiFor sertraline, the literature review also revealed case reports of patients with sertraline-induced both UR  and UI ,78. The The literature review also revealed a case of a 62-year-old patient with a past medical history notable for bipolar I disorder, nephrogenic diabetes insipidus, and metastatic colorectal cancer presenting with a chief complaint of non-radiating suprapubic abdominal pain. This patient was initially treated with lithium, but due to the development of nephrogenic insipidus, the therapy was changed to lamotrigine, and three weeks before the onset of the UR episode, to olanzapine. In the course of the differential diagnosis process, it was concluded that the cause of UR observed in the patient was the antimuscarinic effect of olanzapine associated with impaired micturition . OlanzapOpioids are a group of drugs whose use is also associated with an increased risk of UR in real clinical practice. In a prospective study, Panicker et al.  showed tBenzodiazepines are the next class of centrally acting drugs whose use is also associated with voiding disturbances. In a prospective study by Landi et al., it was demonstrated that 475 individuals (21% of patients aged 60–74 years and 38% aged > 75 years) currently on a regimen of benzodiazepines presented with UI. The estimated global risk of UI during treatment with benzodiazepines was nearly 45%, and the effect was mainly associated with agents with a long half-life elimination . On the Drug-induced UI in real clinical practice was also studied by the Hall et al.  in a popAmong cardiovascular drugs, the group most often reported in the literature in the context of inducing voiding disorders are calcium channel blockers. These drugs affect voiding by impairing the detrusor muscle to create enough contractile force. In a cross-sectional Elhebir et al.  study, aWhen considering drugs predisposing to urinary tract infections, the group most frequently described in clinical reports are sodium-glucose co-transporter 2 (SGLT2) inhibitors (gliflozins). In an observational Uitrakul et al.  study caFor anti-infective chemotherapeutics, a detailed study by Tasian et al.  showed aIn the case of drug-induced ED, case studies are dominated by patients using drugs causing autonomic imbalance. Thus, drugs like beta-blockers (nonselective), alpha-blockers, anticholinergic drugs and other affecting the adrenergic and cholinergic system, along with other antihypertensive drugs, are most often cited as being responsible for ED. Similarly, clinical reports indicate the involvement of centrally acting drugs in the development of drug-induced ED. Clinical cases ,95,96 diThe drug-related entities of retroperitoneal fibrosis were reported for hydralazine, hydrochlorothiazide and ampicillin therapy , as wellIn conclusion, the use of many drugs may contribute to the development of iatrogenic disorders of the kidneys and urinary tract. Pharmacotherapy implemented in a patient may cause various LUTS: UR or UI, UTIs, urolithiasis, ED or RPF. Among the drugs that may predispose to urological disorders, centrally acting drugs, antihypertensive agents, selected antibacterial chemotherapeutics, gliflozins and drugs affecting autonomic nervous system are most often mentioned in clinical reports.The review of the literature indicates that adverse drug reactions manifesting themselves in the urinary tract are less frequently reported compared to, e.g., gastroenterological or dermatological drug side effects. The use of many drugs listed in this review may be also the potential cause of the increased risk of urological disorder development. Their diagnosis is difficult because it requires the exclusion of other potential organic and functional causes of the observed symptoms. Thus, knowledge of drug-induced urinary tract disorders is important for physicians who, in the course of diagnostic procedures, must remember to consider the possible drug-related background of the observed urological abnormalities, as well as for pharmacists providing a medication use review for the patient in terms of pharmacovigilance and recognising less common adverse drug reactions. Finally, the possibility of the drug-induced development of lower urinary tract disturbances is important for patients themselves, as these disorders reduce patients′ therapeutic adherence. Therefore, patients should be counselled to notify their healthcare provider if they notice urinary symptoms.


Fires are common in Mediterranean soils and constitute an important driver of their evolution. Although fire effects on vegetation dynamics are widely studied, their influence on the assembly rules of soil prokaryotes in a small-scale environment has attracted limited attention. In the present study, we reanalyzed the data from Aponte et al. (2022) to test whether the direct and/or indirect effects of fire are reflected in the network of relationships among soil prokaryotes in a Chilean sclerophyllous ecosystem. We focused on bacterial (genus and species level) co-occurrence patterns in the rhizospheres and bulk soils in burned and unburned plots. Four soils were considered: bulk-burnt (BB), bulk-unburnt (BU), rhizosphere-burnt (RB), and rhizosphere-unburnt (RU). The largest differences in network parameters were recorded between RU and BB soils, while RB and BU networks exhibited similar values. The network in the BB soil was the most compact and centralized, while the RU network was the least connected, with no central nodes. The robustness of bacterial communities was enhanced in burnt soils, but this was more pronounced in BB soil. The mechanisms mainly responsible for bacterial community structure were stochastic in all soils, whether burnt or unburnt; however, communities in RB were much more stochastic than in RU. Mediterranean climate is found in regions surrounding the Mediterranean Sea, the western coast of California, central Chile, southwestern South Africa, and southwestern Australia. Annual precipitation ranges from 275 to 950 mm, with over 65% falling during the six coldest months . The aboIn MTEs, overgrazing and fire are major drivers of ecological convergence ,7. Fire Fire frequency and severity are key factors directly affecting plant and soil responses ,18. PostAlthough the complete recovery of soil quality requires many years ,25, the Recently, the debate on the forces that govern the composition and structure of ecological communities has focused on the concepts of determinism and stochasticity . DetermiCo-occurrence network analysis has recently gained popularity in analyzing biota relationships . Since cSpecifically, the hypotheses tested were the following: (a) the accumulated dead material along with the fire-produced charcoal is key in shaping network architecture, (b) the contribution of deterministic and stochastic processes in shaping networks’ architectures, as well as network robustness varies across small spatial scales (rhizosphere vs. bulk soil), and (c) the stochastic control is expected to prevail in burnt soils since stochasticity is enhanced during the early post-fire period.The analyzed data in this study were obtained from a prior study conducted by Aponte et al.  in the PSoil DNA was isolated using the DNeasy PowerSoil DNA isolation kit  according to the manufacturer’s instructions. Bacteria and Archaea were identified using the prokaryotic primer set 515f  and 806p-value as the mean of the permutation distribution under the bootstrap distribution, using 1000 iterations for each distribution [p-values of different similarity/dissimilarity measures supporting the same link were merged using Brown’s method and corrected for multiple testing using Benjamini–Hochberg’s procedure [p-value below 0.05.We analyzed OTUs co-occurrence patterns in bulk-burnt (BB), bulk-unburnt (BU), rhizosphere-burnt (RB), and rhizosphere-unburnt (RU) soils by the CoNet software , which iribution . Unstablrocedure ,52. FinaThe architecture of each network was portrayed as an undirected, weighted network of microbes’ spatial co-occurrence. The valued matrices  were analyzed and visualized using the network analysis . Specifreal) is equal to or close to the estimated length of a random counterpart (L) and its clustering coefficient  is significantly higher than its random counterpart (CInull). The coefficient of small-worldness (S) is calculated as the ratio of  to , and a value of S higher than 1 classifies the network as small world. Accordingly, values of the ratio S  = / higher than 1 classify the network to the class of small-world networks [t-test.A real network is characterized as ‘Small-world’ if its shortest path length (Lnetworks . The resK2/K > 2). The index, the K is the average degree of the network, and K2 is the average of the square of degrees. The larger the positive value of Networks’ robustness to disturbances was evaluated using random graph theory . To do si is the ith eigenvalue of the adjacency matrix. Τhe larger the value of Another class of alternative indices with an enhanced ability to distinguish between networks is based on considering the eigenvalues of the Laplacian and/or adjacency matrices . In thisEI) was estimated according to Klein et al. [i were averaged separately for each one, and the Shannon entropy (uncertainty) associated with averages were calculated  and lower for Alphaproteobacteria (0.31).The similarity between bacterial communities’ genera and species was tested by the Bray–Curtis index . As regaAs can be realized from Based on the number of nodes, the network was of larger size in the bulk soil of burned plots and smaller in the rhizosphere network of burned plots . The rhiPseudorhoplanes [Hippea [Piscinibacter aquaticus [Adhaeribacter [Geodermatophilus [Skermanella [Roseomonas [Paenibacillus brasilliensis [Alterococcus [Umezawaea [Roseomonas, Skermanella, Paenibacillus, as well as the bioprotectant Umezawaea and the decomposer Alterococcus, were recorded.Based on their degree of centrality, the most influential nodes were categorized into putative functional guilds  that was inserted into the soil [The values of network parameters varied between sampling points  although not greatly, (except for the robustness index). The larger differences in network parameters were recorded between the unburnt rhizosphere and the burnt bulk soil. Burnt rhizosphere and unburnt bulk soil values were similar and intermediate. The network in the burnt bulk soil was the most compact and centralized, with the highest number of nodes, ties, average neighborhood size, and % degree centralization compared to the other networks. In contrast, the unburnt rhizosphere network had the lowest values of the calculated parameters (except for the number of nodes), resulting in a less connected network lacking central nodes. Apparently, the differences between network parameters cannot be attributed exclusively to fire, as the lethal effect of fire on soil microorganisms is limited since the temperature increase caused by low-severity fires in the first few centimeters of Mediterranean soils is generally low , and thethe soil ,13. The the soil  found inThe incorporation of charcoal into burnt soil increases the structural and functional complexity of the soil and consequently is expected to modify positively or negatively the complexity of the relationships between soil microorganisms. Furthermore, the release of root exudates, which causes significant changes in the carbon and nitrogen cycles, alters the competitive balance between microbes . These pConcerning burnt rhizospheres, we assumed enhanced heterogeneity which could be attributed partly to a fresh litter of variable provenance, partly to the addition of habitats owing to charcoal and partly to the increased activity of the fast-regenerating and fire-adapted herbaceous plants ,31. The Actinomycetes (similarity 100%) and Alphaproteobacteria (similarity 31%) and network metrics. Actually, a large amount of litter of variable provenance and age has accumulated on the surface of the unburnt bulk soils, whereas on the surface of the burned rhizosphere, the amount of litter was less and less diversified. Furthermore, the charcoal in the rhizospheres of burned soils likely sequestered a part of root exudates [Despite habitat differences between burnt and unburnt plots, the configuration of relationships between bacteria in the rhizospheres of the burned soils and in the bulk soil of the unburned areas showed similarities regarding both the community composition of exudates , limitinexudates , permit Ferrenberg et al.  proposedThe balance between stochasticity and determinism in regulating bacterial communities can also be discussed in terms of modularity and small-world properties that are considered important in terms of network robustness and stability . Our resThe metacommunity architecture, which was common for all networks, seems to fit well with the diversified mosaic of shrubby and herbaceous vegetation, voids, stones, and outcropping rocks of the Mediterranean habitats , but wheAs aforementioned, it is argued that metacommunity architecture leads to increased resilience of the microbial communities against disturbance. Following the approach of Mayfield and Levine , we posiWe concluded that the architectural features  found in all four networks were likely related to the adversities of the Mediterranean environments and their mosaic spatial pattern. Fire similarly affected some architectural features in either the rhizosphere or the bulk soil. The networks in the burnt areas contained more co-occurring taxa, were less fragmented, had lower null ties, exhibited stronger local organization, and had larger neighborhoods. Thus, at first glance, they were more complex and met all the criteria to be considered more stable than the networks in unburnt areas. However, the robustness of the networks was the product of the joint effect of fire and the small spatial arrangement of samples; fire increased robustness, but this was more pronounced in burnt bulk soil. The mechanisms mainly responsible for bacterial community structure were stochastic in all soils, either burnt or unburnt, a fact that contrasts with one of our initial hypotheses. The contribution of stochasticity changed in rhizosphere soils; networks in burnt rhizospheres were much more stochastic than in unburnt rhizospheres. Mechanisms controlled stochasticity related to the abundance and quality of litter, the variability in microclimatic variables, the presence/absence of charcoal, the unlimited dispersal, and the intrinsic environmental heterogeneity of the Mediterranean soils. Overall, our study provides valuable insights into the complexity and robustness of bacterial networks in burnt Mediterranean soils; however, distinguishing the fire effect from the rhizosphere effect is difficult and highlights the need for further research to disentangle the effects of these two agents on bacterial community structure.


Neuroinflammation has a significant impact on different pathologies, such as stroke or spinal cord injury, intervening in their pathophysiology: expansion, progression, and resolution. Neuroinflammation involves oxidative stress, damage, and cell death, playing an important role in neuroplasticity and motor dysfunction by affecting the neuronal connection responsible for motor control. The diagnosis of this pathology is performed using neuroimaging techniques and molecular diagnostics based on identifying and measuring signaling molecules or specific markers. In parallel, new therapeutic targets are being investigated via the use of bionanomaterials and electrostimulation to modulate the neuroinflammatory response. These novel diagnostic and therapeutic strategies have the potential to facilitate the development of anticipatory patterns and deliver the most beneficial treatment to improve patients’ quality of life and directly impact their motor skills. However, important challenges remain to be solved. Hence, the goal of this study was to review the implication of neuroinflammation in the evolution of motor function in stroke and trauma patients, with a particular focus on novel methods and potential biomarkers to aid clinicians in diagnosis, treatment, and therapy. A specific analysis of the strengths, weaknesses, threats, and opportunities was conducted, highlighting the key challenges to be faced in the coming years. Neuroinflammation is a highly complex process characterized by the activation of various glial cells and the release of proinflammatory mediators in the central nervous system (CNS) . It deveSpinal cord injury (SCI) involves the physical and/or functional disruption of neuronal connections in the spinal cord, affecting the integrity of electrical and chemical signals necessary for proper motor, sensory, and autonomic function . This anThe multidisciplinary approach to addressing neuroinflammation in the context of SCI and stroke is significantly enhanced by state-of-the-art diagnostic techniques. Neuroimaging techniques have emerged as fundamental tools for the accurate assessment of neuroinflammation. Magnetic resonance imaging (MRI) , computeIn the therapeutic field, the incorporation of electrostimulation and bionanomaterials has arisen as cutting-edge strategies. Electrostimulation has emerged as a highly promising technique to precisely modulate neuronal activity and mitigate the inflammatory responses characteristically observed in SCI and stroke . This thNeuroinflammation includes several pathological processes, ranging from altered morphology of glial cells to invasion and destruction of tissues by immune cells migrating from the periphery ,24,25,26Microglia cells are the main recipients of peripheral inflammatory signals reaching the brain. Once activated, an inflammatory cascade is initiated with the release of chemokines, cytokines, and reactive oxygen and nitrogen species , triggering the activation of astrocytes and, thus, amplifying the inflammatory signal within the CNS. Several astrocyte functions will be altered, resulting in the dysregulation of neurotrophic factor production, transporter function, and neurotransmitter synthesis. The toxic effects of overexposure to cytokines also affect oligodendrocytes, with subsequent apoptosis and demyelination of neurons. Thus, excessive release of proinflammatory mediators together with incorrect neurotransmitter reuptake, decreased release of neurotrophic factors, and oxidative stress cause damage to neuronal plasticity, leading to neurodegeneration and apoptosis  Figure . Strokes are those disorders that produce functional and structural neuronal alterations in different areas of the brain due to maintained hypoxia, a consequence of an abrupt variation (interruption or reduction) in cerebral circulation in such regions . Thus, s-Ischemic stroke (80%): Occurs because of a decrease and insufficiency of blood supply to the CNS, causing a circumscribed area of cerebral infarction. Depending on their etiology, strokes can be subclassified as thrombotic due to the formation of a blood clot in an area of the brain and embolic because of the formation of a blood clot in another cerebral artery that subsequently travels to the brain. When the symptoms last less than 24 h, it is called a transient ischemic attack TIA ,36)..36]).-Hemorrhagic stroke (20%): Is due to parenchymal and/or subarachnoid bleeding. Generally, they are caused by arterial hypertension (AHT), aneurysm ruptures, and or arteriovenous malformations .Strokes can be classified into two subtypes based on the cause that determines the presence of the pathology: Depending on the affected area, the altered functions will vary, although it is very common that the stroke involves the pyramidal system, causing a first motor neuron or upper motor neuron syndrome . The cliFollowing ischemia, a neuropathological cascade of mechanisms is activated that triggers innate and potentially adaptive inflammatory and immune responses in the central and peripheral nervous systems. This activation leads to the extension and deterioration of the brain injury .+ T cells (helper) [+ T cells (cytotoxic) [The progression and increase in neuroinflammation are directly linked to the immune system, as reflected by the increase in damage-associated molecular patterns (DAMPs) to nuclear or cytosolic proteins observed after stroke . Thus, c(helper)  and CD8+totoxic) .Importantly, in the acute phase, immediately after stroke, neuroinflammation may play an endogenous neuroprotective role by phagocytizing leukocytes brain cells and increasing immune cell signaling . This acMoreover, it is necessary to highlight the role that neuroinflammation plays in the integrity of the blood–brain barrier (BBB) and vice versa . Disrupt-Cause: Traumatic or non-traumatic.-Mechanism of injury: Hyperflexion, flexion with rotation, hyperextension, or compression.-Level of injury: Cervical, dorsal, or/and lumbosacral.-Extension: Complete or incomplete.SCI is a pathological process of any etiology that affects the spinal cord and causes transitory or permanent impairment of motor, sensory, and autonomic function . The annThe assessment of motor and sensory functions is performed according to international standards via the American Spinal Injury Association (ASIA) Impairment Scale . The proIt is important to know the extension of the SCI since incomplete SCI causes specific syndromes: Scheiner´s syndrome, anterior spinal artery syndrome , spinal SCI shows different clinical phases. The first is the spinal shock phase, immediately after the injury, which extends up to the second and eighth weeks ,54. ThisFollowing SCI, a range of vascular, cellular, and molecular alterations originate in the CNS and produce imbalances between immune cells and modulatory factors resulting from neuroinflammation secondary to trauma . AlthougAcute neuroinflammation develops in several stages . In the BBB is a highly specialized structure that separates the peripheral blood from the CNS and protects the brain from the entry of potentially harmful substances and immune cells . The BBBThe close relationship between neuroplasticity and neuroinflammation in the context of SCI should be emphasized. The presence of edema and an increase in BBB permeability, as well as the release of proinflammatory cytokines, chemokines, and ROS, affect neuronal reorganization in the area of the lesion . LikewisMitochondria are recognized as powerhouses, present in virtually all eukaryotic cells. They are dynamic organelles that constantly fuse and divide to regulate their shape, size, number, and bioenergetic function . In factIn this sense, oxidative stress derived from the increase in the ROS production at the neuronal level and in cells of the peripheral system causes a decrease in the generation of ATP that will eventually lead to a lack of energy at times of increased energy demand, for example, in neuronal activity to modulate synaptic connections and neuronal plasticity  or underCytokines and chemokines are cell signaling molecules that play a crucial role in regulating the immune response and communication between different cell types in the body. However, in the context of SCI and stroke, the interaction of these molecules can have both beneficial and detrimental effects on neuroinflammation .In certain situations, cytokines and chemokines can be beneficial in the response to SCI and stroke. They can recruit immune system cells and migrate to the site, which is essential to eliminate damaged tissues and toxic substances, as well as to initiate repair. However, overexpression or dysregulation of certain cytokines and chemokines can have detrimental effects. Excessive cytokine release causes excessive attraction of inflammatory cells to the site of injury and can lead to the formation of a toxic environment and excessive scarring that hinders neuronal regeneration. It also contributes to a chronic inflammatory environment. Thus, if the inflammatory response persists in an uncontrolled manner, it can contribute to secondary neuronal death and worsening damage.Thus, cytokines and chemokines are molecules with a significant influence on neuroinflammation. Their role is complex and depends on the amount and type of molecules released, as well as their interaction with the cellular environment. Therefore, the balance between cytokines and chemokines is crucial in neuroinflammation associated with SCI and stroke. Biological markers or biomarkers were defined by the Biomarkers Definitions Working Group of the National Institutes of Health as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”. In essence, biomarkers are measurable molecules, structures, or processes present in organisms, which are evaluated to gather objective information about a patient’s health, differentiating physiological events from pathological ones, including their optimal treatment and disease subtype. Thereby, biomarkers are a crucial tool in diagnosis laboratories since they predict patient’s prognosis by monitoring their disease and treatment response ,15,16. Biomarker analysis should be reproducible, precise, reliable, accurate, easy to interpret, cost-effective, exhibit high sensitivity and specificity, and add information on top of clinical variables ,103. LikWhen considering the stroke condition, biomarkers must stem from damaged brain tissues, encompassing specific damage markers and broader systemic indicators related to inflammation . For cliNevertheless, proteins and laboratory parameters are not the only possible biomarkers to be employed in stroke diagnosis. Recent findings indicate that some RNA expressed in peripheral blood cells is correlated with stroke. Additionally, some of those nucleic acids differentiate the stroke cause (ischemic from hemorrhagic stroke) and its etiology  . Some exRegarding SCI biomarkers , these mSimilarly to stroke, SCI can trigger alterations in miRNAs from exosomes, which may serve as prognosis indicators for acute SCI . Among tAdditionally, neuroimaging biomarkers could serve as a prognosis indicator of SCI. For example, intramedullary lesion , iron deIn line with these biomarkers, several techniques have been developed for their measurement and evaluation. In order to detect proteins such as CRP, BNP, NSE, or S100B, the prevailing method is Enzyme-linked immunosorbent assay (ELISA) . ELISA tWithin the scope of RNA detection, techniques such as reverse transcription-polymerase chain reaction (RT-PCR) or real-time RT-PCR , northern blot, and nuclease protection (NP) assays may be employed. Among these, PCR analysis stands out as the most sensitive and established technique, even though they are not devoid of challenges ,150.Conventional PCR capitalized on the inherent capability of DNA polymerase enzymes to synthesize new DNA strands, utilizing a DNA template to complementarily fabricate the new strand. The commonly employed enzyme for this purpose is Taq DNA polymerase. Additionally, this technique employs specific primers to initiate the addition of required first nucleotides, as these enzymes can only synthesize the DNA strand onto a preexisting 3º-OH group. Moreover, these primers facilitate the selection of the DNA region to be copied and amplified via the hybridization phenomenon. As a result of the PCR reaction, the selected region is copied in amplicons . In RT-PEqually important are non-conventional approaches that are currently under investigation, as they hold the potential to surpass the performance of conventional methods and introduce novel strategies for the management of stroke and SCI. In this framework, noteworthy examples encompass antibody microarray (AbMAs) , electroThe use of biomarkers involves certain limitations linked to different factors. One of the main difficulties lies in the detection of interferences from other molecules in screening assays, which can lead to false positive or false negative results. This error can be used by cross-reactions with similar molecules or the presence of compounds that mask the signal of the selected biomarker . AnotherPET is based on the administration of a molecule labeled with a radioactive isotope, i.e., a radioactive tracer, which has an affinity for a specific biological target. In this way, the tracer is absorbed by the cells, depending on their metabolic activity, and accumulates in the selected area of the body . The posIn the context of neuroinflammation, PET is able to detect and quantify the activity of activated immune cells, microglia, and macrophages ,163. TheHowever, PET has limitations in identifying individual cells and small areas of inflammation .MRI is an imaging technique that allows visualization of brain anatomy and can also indicate the presence, location, and severity of an inflamed area of the brain . MRI is In order to detect neuroinflammation, specific imaging sequences such as the T1-weighted imaging sequence are used . This maMRI is also used in combination with iron oxide nanoparticles to detect immune cell activation . The nanCerebral vascular permeability magnetic resonance imaging (PVC-MRI) is an advanced imaging technique that allows quantification and visualization of BBB permeability in the brain . The tecCT is an imaging technique that uses X-rays to create cross-sectional or axial images of internal body structures . It is bAs specific CT techniques for neuroinflammation, contrast-enhanced CT stands out. For this purpose, a highly radiodense iodinated contrast agent is administered, which appears white on the X-ray images . After aCEUS is a real-time imaging technique that uses contrast microbubbles, gas-filled particles introduced intravenously that are able to circulate through the blood vessels. These microbubbles act as sound reflectors due to their acoustic properties. The images are generated by the presence of a transducer that emits high-frequency sound waves into the tissue and receives the echo signals that are reflected .In the case of neuroinflammation, the microbubbles interact with inflammatory molecules, allowing visualization of the dynamics of inflammation and the changes generated in vascular permeability . SpecifiElectrical stimulation (ES) is a technique based on the controlled application of electrical currents through the body, tissue, or specific structures, influencing the electrical activity of cells and tissues . In the The use of electrical signals has demonstrated findings that highlight the potential of electrical stimulation as a strategy to regulate microglial function and inflammatory response . These aOn the one hand, it has been observed that the use of an electrical signal causes reorganization of the cytoskeleton in nerve and glial cells as an adaptive response to the electrical stimulus  with a pIn turn, it has been shown to have a significant impact on cellular metabolism for energy production and in the regulation of metabolic homeostasis . ES incr2+) channels play an essential role, and their hyperactivity contributes to increased excitability [2+ ion channels [In addition, alteration of ion channels contributes to changes in neuronal excitability . Calciumtability . These ctability . In thistability . Furtherchannels . In thischannels ,215,216.channels . It can channels . In addiAfter tissue damage, the immune system relies on phagocytosis to remove the altered structures, making it an essential process. Microglial phagocytosis interconnects processes related to the inflammatory response when the latter is not regulated and in balance . This reFurthermore, it is essential to recognize that the influence of ES is not limited only to the reduction in neuroinflammation. In the context of SCI, the application of electric fields plays a crucial role in the regeneration of the affected neural pathways . In thisTherefore, ES is a promising treatment technique for neuroinflammation since it is capable of modulating neuronal activity, reorganizing the cytoskeleton , influenThe application of ES in the treatment of neuroinflammation entails challenges and limitations that must be addressed. Despite promising initial results, it is important to note that both the heterogeneity of neuroinflammation processes and the variability in patient response introduce substantial technical challenges. The challenges underscore the need for precise targeting of ES to specific brain areas, which in turn highlights the necessity of standardizing treatment protocols in such a diverse field . FurtherNanoparticles have emerged as a promising tool, especially for the treatment of neuroinflammation-related disorders. Nanoparticles are structures with dimensions within the nanometer scale, which allows them to overcome biological barriers and selective penetration into specific brain areas. They also have the capacity to encapsulate and release therapeutic agents in a controlled manner . In turn-oDissolution and diffusion method: For hydrophobic drugs. Dissolution occurs in the lipid core or polymer matrix during the manufacture of the nanoparticle .oEncapsulation method: For hydrophilic drugs, which are encapsulated in the aqueous core. For this, the drug and the nanoparticle material are emulsified in an organic solvent, and then the solvent is removed .oSurface adsorption: For small molecules or substances with an affinity for the surface of the nanoparticle material. The drug is adsorbed directly on the surface .oPhysical methods: Co-precipitation involves the simultaneous formation of nanoparticles and drug precipitates within the nanoparticles during a physical or chemical process . Freeze-Drug loading: takes place in the interior or membrane, depending on the solubility of the drugs. It involves the encapsulation of hydrophobic or hydrophilic therapeutic agents. For this, it is necessary to select the most suitable nanoparticle for the application, which depends on factors such as the chemical naturalization of the drug, the desired release, and the mechanism of administration . The loa-Administration: Generally, they are administered via intravenous or local injection into the area affected by neuroinflammation .-Targeting of inflamed areas: They are specifically designed to target an area of the brain affected by neuroinflammation to increase treatment efficacy and reduce potential side effects. To this end, the nanoparticle surface is functionalized with specific markers that may include proteins, receptors, or adhesion molecules that are expressed in greater quantities on inflammatory cells . For thi-Controlled release: Drug release is performed gradually to prolong the therapeutic effect and reduce the need for frequent dosing. It is accomplished via modification of the nanoparticle matrix, selection of specific polymers, or surface engineering . The rel-Anti-inflammatory action: Released drugs act on inflammatory cells, reducing the response. They can inhibit the production of proinflammatory cytokines using anti-inflammatory drugs or specific molecules that block cytokine signaling , such as-Biodegradation: They are broken down into non-toxic products and eliminated from the body naturally. Biodegradation can take place using different mechanisms: hydrolysis, hepatic metabolism, phagocytosis by phagocytic cells, and lipid exchange .The mechanism of action of nanoparticles in the treatment of neuroinflammation involves several key steps:-oLiposomes: Lipid vesicles that are composed of a lipid bilayer surrounding an internal water cavity. The bilayer is composed of two layers of lipid molecules, with lipid tail structures towards the center and the heads towards the outside. This type of amphiphilic structure allows liposomes to be compatible with hydrophobic and hydrophilic substances. Depending on the manufacturing conditions and composition, different types of liposomes can be obtained. Unimamellar liposomes (LUV) are used for gene therapy, multi-mamellar liposomes (MLV) are used for research and pharmaceutical applications with high drug loads, and finally, miscellaneous liposomes are used for the release of drugs at different rates or locations within the organism ,245.oLipid micelles: Nanometric structures formed by lipid molecules arranged in the form of micelles. They do not have an internal aqueous cavity since the lipid heads are oriented outward and the lipid tails inward in a spherical structure .Lipid nanoparticles: are a type of bionanomaterial composed of a lipid bilayer surrounding an aqueous or lipid core, forming a membrane-like structure surrounding the drug core. They are usually between 0.05 and 5 nanometers in size, allowing them to be administered at the cellular and subcellular levels . The adv-oPEG-coated gold nanoparticles: Ability to cross the BBB .oPEG-coated dendrimer nanoparticles: Dendrimers are branched polymers that, when coated with PEG, improve their circulation properties and reduce immunogenicity, facilitating their arrival in the brain .oPoly(lactide-co-glycolic) (PLGA) nanoparticles coated with PEG: PLGA has a great capacity to degrade into biocompatible products and be eliminated naturally by the body, reducing toxicity and gradual release of the encapsulated drug. Being PEG-coated increases their stability and time in circulation .oPEG-coated liposomes and micelles: Lipid vesicles that the PEG coating makes them more stable .oHydrogel nanoparticles: Composed of hydrophilic polymers such as PEG or arginine, which are chemically cross-linked to form a three-dimensional network structure. Significant amounts of water are retained within the network, conferring gel-like properties .Polymeric nanoparticles: Colloidal systems composed of polymers. They are manufactured using different methods, such as emulsification, solvent evaporation, emulsion polymerization, and nanoprecipitation ,247. The-3O4). Their diameter can vary depending on the desired application but never exceeds the nanometer scale [oSuper magnetic iron oxide nanoparticles (SPIONs): Used in MR techniques to visualize areas of brain inflammation and diagnosis of neuroinflammatory diseases .oMultifunctional iron oxide nanoparticles: Controlled release of anti-inflammatory drugs or magnetic hyperthermia .oLipid-coated iron oxide nanoparticles: Encapsulation and delivery of drugs into the brain in a controlled and stable manner ,256.oIron oxide nanoparticles for gene transport: Delivery of therapeutic genes to areas of brain inflammation. Functionalized with DNA or RNA sequences that regulate the expression of genes involved in neuroinflammation .Iron oxide nanoparticles (NPOH): Composed of iron oxide crystals, generally magnetite  that can be synthesized as spheres, nanocapsules, nanotubes, and/or complex structures. The internal structure of NPS can be porous or non-porous, depending on the desired application. Their main advantage is the ability to combine diagnostics and therapy by being able to function as contrast agents and therapy delivery simultaneously [oMesoporous silica nanoparticles (MSN): They present a porous structure with internal channels that allow for greater drug loading capacity and sustained release .oSilica nanoparticles functionalized with antibodies or peptides: Allows specific binding to biomarkers or cells .oMagnetic silica nanoparticles: Contain an iron oxide core coated with silica, which allows them to be guided to areas of the brain by means of external magnetic fields .oAntioxidant-loaded silica nanoparticles: To combat oxidative damage.oSilica nanoparticles with imaging agents: Incorporate fluor surfactants or contrast agents for MRI .oMultifunctional silica nanoparticles: Combine several features .Silica nanoparticles (SNP): Nanoparticles composed mainly of silicon dioxide  nanoparticles: Cross the BBB .oFunctionalized peptide nanoparticles: Precise delivery of therapeutic agent and reduction in side effects .oImmunoglobulin G (IgG) nanoparticles: Modulation of immune response in CSN .Protein nanoparticles: Composed mainly of proteins or peptides that can be natural or specifically designed for the application. Their size generally ranges from 1 to 100 nanometers, and their morphology can be spherical, nanotubes, or vesicles .oAlbumiThe variety of nanoparticles available, such as lipid, polymeric, iron oxide, silica, and protein nanoparticles, offers a broad selection of therapeutic and strategic options for the treatment of neuroinflammation . Not to Bionanomaterials, within the realm of neuroinflammation treatment, present a highly auspicious perspective. However, it is imperative to acknowledge that their development and application confront challenges and limitations. Primarily, the BBB stands as an impediment to the selective and secure penetration of bionanomaterials into cerebral tissue . MoreoveNeuroinflammation is an immune-mediated phenomenon characterized by an inflammatory response in the CSN that is postulated to be a critical component in the pathogenesis and progression of CSI and stroke ,5,6. ThiDespite notable advances in the development of neuroimaging and biomarker-based diagnostic techniques in the context of neuroinflammation, there is a need to focus research on the evolution of specific biomarkers and the implementation of real-time neuroimaging techniques to understand the complex dynamics of neuroinflammation. This will enable early and accurate detection, which in turn will facilitate more timely and personalized treatment. The integration of clinical and neuroimaging data through the application of artificial intelligence (AI) emerges as a key tool in the analysis of complex data, identifying subtle patterns, and predicting therapeutic responses with greater accuracy. This synergy provides a comprehensive view of the effects of neuroinflammation on brain anatomy and function ,183,184.In the same vein, considerable limitations and challenges have been identified in current therapies for neuroinflammation, particularly in relation to the use of bionanomaterials and ES. The field of bionanomaterials occupies a pivotal role in the design of highly biocompatible and targeted therapies for the CNS . The stuFinally, future research in this field could lead to significant advances in the prevention and treatment of spinal cord injury and stroke, thus improving the quality of life of patients .


Blunt thoracic aortic injury (BTAI) is a potentially fatal condition that needs prompt recognition and expedited management. Clinical manifestations of BTAI are not straight forwarding and may be misdiagnosed. The grade of aortic injury is an important determinant of perioperative mortality and morbidity, as well as the indication of treatment, along with the presence of concomitant lesions of other involved organs. The mainstay of treatment nowadays for hemodynamically stable patients who survive the trauma scene is represented by delayed endovascular repair whenever anatomically and clinically feasible. Endovascular repair, in fact, is burdened by lower perioperative mortality and morbidity rates if compared to open surgical repair, but concerns remain about the need for long-term surveillance and radiation exposure in patients who are at a younger age than patients treated for the aneurysmal disease. The aim of the paper is to provide an update on the diagnostic modalities and strategies of treatment for patients affected by BTAI. Blunt thoracic aortic injury (BTAI) may occur in patients who sustain thoracic trauma with rapid deceleration, either from high-speed motor vehicle collision or falls from a significant height . The aorThe reason why the aortic isthmus is the most affected zone lies in the relative weakness of this segment of transition between the more mobile ascending aorta and arch and the relatively fixed descending thoracic aorta, which is furthermore trapped between anterior and posterior bony structures, leading to focal rupture .From a histologic point of view, the aortic rupture occurs first as intimal and medial injury, followed by the adventitial rupture that can occur during an unpredictable interval of time ranging from seconds to years . If the BTAI is then a serious condition that can rapidly lead to death, but the clinical presentation features sometimes lack sensitivity and specificity and pose challenges to physicians dealing with such situations. Prompt diagnostic evaluation, often with a multidisciplinary approach, as well as appropriate treatment, is mandatory to reduce mortality and morbidity rates in those who are able to arrive at the hospital.The aim of this paper is then to provide a narrative review of the literature about the most frequent clinical presentations of BTAI and to provide an update on the diagnostic modalities and strategies of treatment for patients affected by BTAI.The trauma patient who can present a BTAI may arrive at the Emergency Department (ED) with a complaint of chest pain, interscapular pain, or difficulty breathing. One-third of the patients present with hypotension, and about 40% of them may present with an altered state of consciousness .Nevertheless, the patient may present with lethal lesions and may not survive after immediate arrival at the ED. Dinh et al. , in theiPatients who are victims of BTAI are predominantly young or mid-aged males since the most represented mechanism of injury is usually road traffic accidents .The history of thoracic trauma should always be investigated in patients who arrive in ED after a motor vehicle collision or a fall. In particular, the steering wheel or seatbelt imprint on the surface of the skin should suggest a thoracic trauma with a rapid deceleration. Left subclavicular hematoma and a previously unknown cardiac murmur also can be associated with BTAI but are not typical.On physical examination, patients may also present bilateral hyposphygmia of femoral pulses with increased pressure of the upper extremities. Arrhythmia, low blood pressure, tachycardia, and signs of peripheral vascular shutdown may suggest the presence of severe hypotensive status.The trauma patient may also present other associated injuries with respect to the different mechanisms of damage. Commonly associated injuries include head, lung, and heart contusions, intra-abdominal hemorrhage, bone fractures , and diaphragmatic rupture ,8. ScaleLaboratory tests are not specific for BTAI, but they can reflect the general severity of the injury; for example, the presence of acute blood loss or the presence of acute kidney injury.At plain anteroposterior chest X-ray, indirect signs can be noted, such as a wide mediastinum, abnormal aortic arch imprint, deviation of the trachea, and bone fractures.All of them, however, are not specific for BTAI; therefore, further imaging testing is required. Crapps et al. analyzed the results of 708 patients with confirmed BTAI injuries, and they described that the most consistent single finding identified at plan chest X-ray was widened mediastinum, but this finding was present in 27.7% of all confirmed BTAIs and in about half of the patients who presented with a high-grade injury .Early diagnosis of BTAI is crucial to reduce mortality rates, particularly in severely diseased patients. Boutin et al., in fact, in their multicenter retrospective study, found that the time to diagnosis increased with the severity of the aortic injury and the clinical severity of the patients .While a whole-body multidetector computed tomographic scan (CT) is often performed in the acute management of trauma patients  when susIn particular, CE-CT is recommended for the diagnosis of BTAI in hemodynamically stable patients, while TEE is a valuable alternative for hemodynamically unstable patients who require prompt bedside assessment. On the other side, transthoracic echocardiography is not indicated for BTAI .Both CE-CT and TEE can identify early sub adventitial aortic injuries with comparable diagnostic accuracies. CE-CT of the chest, in particular, is a highly sensitive and specific test for BTAI, having a reported sensitivity of 95–100% and a negative predictive value of 100% . It can TEE can provide a similar evaluation in hemodynamically unstable patients who cannot be moved safely from the Emergency Department or from the Operating Room . In the At TEE, an irregular intraluminal flap can be seen traversing the lumen of the aortic isthmus in the transverse view , as wellThe presence of a mediastinal hematoma can also be accurately diagnosed using TEE , as wellNevertheless, the guidelines strongly recommend CE-CT to diagnose BTAI because of its availability, rapidity, and ability to diagnose additional intra-thoracic injuries .Thoracic aortography is not used for the diagnosis of BTAI, given the greater invasiveness and the lower sensitivity in comparison to CE-CT . MagnetiIntravascular ultrasound (IVUS) can be a valuable tool when used at the time of endovascular repair of stable patients since it facilitates accurate endograft sizing and graft deployment .Grade I: Intimal tear.Grade II: Intramural hematoma.Grade III: Pseudoaneurysm.Grade IV: Rupture.Several classification schemes for grading the severity of aortic injury have been proposed , but theIn addition, the term “minimal aortic injury” has been used to describe relatively small lesions, such as isolated intimal defects less than 1 cm without periaortic mediastinal hematoma . While sThe clinical presentation and the hemodynamic status of the patient, together with the grade of aortic injury, are all main determinants of the indication of treatment, as well as of the timing of treatment .More specifically, injury grade is a predictor of aortic-related mortality among patients with BTAIs , in partAs a general rule, patients with BTAIs should be treated at a trauma center that has experienced and expert professionals and opportune facilities for perioperative care. If this level of care is not available at the department to which the patient has come, the patient should be stabilized and transferred to a more suitable facility.The common principles of general trauma management include a careful evaluation of the vital signs for the prompt identification of life-threatening injuries, according to the basic rules of Advanced Trauma Life Support .The trauma team should include the general surgeon, the emergency physician, the orthopedic surgeon and the critical care/anesthesia specialist on call, and at least two trained nurses and two paramedics. Patent with cervical spine precautions should be established, followed by the administration of supplemental oxygen as appropriate, with a target of achieving 94–98% saturation. If tension pneumothorax is detected, immediate drainage should be performed to relieve the tension . Then, h“Minimal” injuries can be managed conservatively with safe results .In such cases, the approach consists primarily of antihypertensive therapy, which should be initiated on admission with intravenous beta blockers or negative inotropic drugs (such as esmolol) to achieve a systolic blood pressure lower than 100 mmHg and a heart rate < 100 beats per minute. This approach has the main goal of reducing the risk of extending the injury and reducing the volume of blood loss in case of aortic rupture. Some studies have observed a reduction in mortality in patients treated with antihypertensive therapy  comparedIn patients in whom beta blockers are contraindicated, a calcium channel blocker, such as diltiazem, can be used. If beta-blocker therapy is not enough to control systolic blood pressure, a vasodilator such as nitroprusside can be used in combination. There is no consensus about the optimal duration of antihypertensive therapy.Nevertheless, the target for systolic blood pressure in case of concomitant head injury is 110 mmHg. Hypotension should, in fact, be avoided to maintain cerebral perfusion .Then, the patient should undergo serial imaging during follow-up, mainly using a chest CE-CT scan . HoweverBased upon the principles of Advanced Trauma Life Support (ATLS), hemodynamically unstable trauma patients (such as Grade IV aortic injuries) should undergo emergent surgical exploration to determine and control the source of life-threatening hemorrhage. In the case of thoracic aortic injury, the use of the resuscitative endovascular balloon occlusion of the aorta (REBOA) is contraindicated.According to major trauma association guidelines , hemodynHigh-risk patients with favorable anatomy may better benefit from endovascular rather than open repair ,19.In such cases also, delayed repair should be the choice whenever feasible. Romijn et al., in fact, in their propensity-score analysis of 548 matched patients submitted to Thoracic Endovascular Aortic Repair (TEVAR) for BTAI, found that immediate (<24 h) repair was associated with a two-fold higher mortality if compared to delayed repair (>24 h), even after adjusting for the injury grade .Over the past 30 years, the preferred approach for the treatment of thoracic aortic diseases has moved from open repair to the less invasive use of endovascular stent grafts .This concept also applies to the treatment of BTAIs, where the preference is toward endovascular repair whenever possible . Open suThe endovascular procedure for the treatment of BTAIs is similar to what is performed for other aortic thoracic injuries, with reported technical success rates ranging from 80 to 100% .Similar to what happens for the endovascular treatment of aortic dissections or thoracic aneurysms, the placement of the endovascular graft can be aided by the use of intravascular ultrasound and/or transesophageal echocardiography .In particular, the use of trans-esophageal echocardiography (TOE) may be considered for the guidance of wire placement via the dissected aorta, for endoleak assessment, and/or for the detection of cannulation injury. The benefit of TOE in these scenarios is well supported by evidence .Furthermore, similar to the treatment of aneurysmal disease, spinal fluid drainage may be used to prevent spinal cord ischemia in case of long (>20 cm) endograft coverage, if there has been a previous abdominal aortic repair, or in case area of possible coverage of the artery of Adamkievicz.Nevertheless, the endovascular treatment of BTAIs deserves particular considerations that mainly concern the sizing of the endovascular graft and the management of intraoperative anticoagulation.As for the first issue, it is worth keeping in mind that thoracic stent graft devices were originally designed to treat aneurysmal diseases, and about 20 to 30% of them are not suited to the narrow and tight angulation of the aortic arch, which is typical of the younger patients who present with BTAI . FurtherNeschis et al., in their experience, about 43 patients aged in mean 44 years treated for BTAI, reported an average aortic diameter of about 23 mm, ranging from 19 to 30 mm .® (CTAG) thoracic stent graft , and the Medtronic Valiant Captivia™   , Table 1To ensure an optimal proximal landing zone, coverage of the left subclavian artery may be required, particularly when the injury is located at the level of the aortic isthmus.In such cases, the revascularization of the subclavian artery using an extra-anatomic bypass should be performed to reduce the risk of neurologic complications . In factSome peculiar cases, such as the presence of a “bovine” aortic arch, are associated with a consistent geometric pattern, which identifies hostile proximal landing zones for endograft deployment, namely Zone 3 and Zone 0 in the Type I arch. This mandates a specific amendment to thoracic endovascular aortic repair planning, requiring, for example, the need for a total debranching of the supra-aortic trunks to ensure a safer proximal landing zone  or the uThe second issue concerns the indication for anticoagulation. In particular, the administration of unfractionated heparin (UFH) during endovascular repair of BTAI is controversial, and patients with traumatic aortic injury may present significant associated injuries, such as intracranial hemorrhage or splenic injury, that may contraindicate anticoagulation. In such circumstances, an endovascular repair can be performed without the use of heparin, without significant adverse consequences .Nevertheless, Makaloski et al., in their retrospective analysis of 36 patients submitted to TEVAR for BTAI, found that, in patients with hemodynamic stability and no severe associated injuries, systemic anticoagulation can be safely performed with no intraoperative bleeding or thromboembolic complications in the early postoperative period .Open surgical repair of BTAI is similar to open repair of thoracic aortic aneurysm, keeping, however, in mind some peculiarities.The first concerns the site of the incision, which is based on the location of the pathology and the need to obtain a safe proximal aortic cross-clamping control. Isolated BTAIs occurring at the aortic isthmus require, for example, a thoracotomy incision in the fourth intercostal space and aortic cross-clamping just distal to the left subclavian artery or between the left common carotid artery and the left subclavian artery.Then, active perfusion of the distal aorta, through either left atrial-femoral bypass or femoral venous-to-femoral arterial cardiopulmonary bypass, may be performed to reduce the incidence of perioperative paraplegia , even inOpen surgical repair of the aorta may also be preliminary to a secondary endovascular intervention, such as when treating complex lesions involving the aortic arch and the descending thoracic aorta. In such cases, the “Frozen Elephant Trunk” (FET) technique may be used to perform the two-staged approach to repair the complex lesion. New branched hybrid grafts, such as the Thoraflex, the Cronus , the Evita Open Neo , and the J graft (now Frozenix) , are currently available on the market. They enable the reimplantation of the supra-aortic vessels separately using prefabricated vascular branches, and a side graft allows direct cannulation for antegrade distal perfusion during arch replacement .Furthermore, hybrid surgery combining rapid resuscitative thoracotomy, direct suturing of the aortic lesion, and completion of endovascular treatment may be used as a safe treatment strategy in complex cases .The introduction of endovascular techniques over open repair for the treatment of BTAIs has dramatically improved perioperative outcomes . The repIrrespective of the chosen technique, the main reported perioperative complications to include spinal cord ischemia and stroke.Spinal cord ischemia, which may result in paraparesis or paraplegia, remains a significant concern, particularly after open repair, where it has been reported in up to 9% percent of cases . On the Perioperative stroke is another potentially devastating complication, especially if the aortic injury is proximal to the origin of the left subclavian artery.Similarly to spinal cord ischemia, the incidence of perioperative stroke has been reported to be lower (1%) in patients who underwent endovascular repair when compared to patients undergoing open surgical repair (4.5%) . These rIn patients who survive hospital discharge, mid and long-term outcomes after both open and endovascular repair of BTAIs are satisfying , with ovCheng et al.  reportedIn addition, among new-generation endografts, the Conformable GORE TAG (CTAG) thoracic stent graft  has proven to be a safe, effective, and durable option for the treatment of patients with BTAIs, with a reported survival rate of 89% at 5 years .Recently, Gennai et al. performed a systematic review and meta-analysis of long-term reintervention following thoracic endovascular repair for BTAIs. They reported an overall late survival of 95.6% up to 60 months, and they found that aortic reinterventions were rarely required and tended to occur within the first and after the fifth year from the initial procedure .Furthermore, endovascular repair of BTAI seems to not present the sex-based outcome disparities observed after thoracic aortic aneurysm repair, as demonstrated by Rastogi et al., who found no significant association between sex and perioperative outcomes or long-term mortality after TEVAR for BTAIs. The authors explained this contrast by differences in the pathology, demographics, and anatomic factors in these patients .However, the benefit of endovascular repair over open surgical repair in the perioperative period may be counteracted by its unknown long-term effect in a predominantly younger population.One of the main concerns, in fact, is about the need for long-term graft surveillance, which is mandatory given the fact that following endograft placement for BTAI, the “healthy diameter” of the aorta undergoes remodeling and increases, the more the amount of endograft oversizing . FurtherThoracic aortic surveillance is usually performed with chest contrast-enhanced CT, which may pose a challenge for both radiation exposure and contrast-induced nephropathy.The optimal follow-up program is still not defined and may vary by the institution .Long-term data about outcomes of blunt aortic injuries managed nonoperatively are limited.Blunt thoracic aortic injury is a life-threatening problem that requires a high index of suspicion based on the mechanism of injury and a prompt diagnosis in trauma centers with appropriate facilities. In people who survive the traumatic event, endovascular treatment has become the mainstay of treatment whenever feasible, with lower perioperative results if compared to open surgery and promising long-term outcomes. Concerns remain about the need for long-term surveillance after endovascular grafting.


Head pose estimation is an important technology for analyzing human behavior and has been widely researched and applied in areas such as human–computer interaction and fatigue detection. However, traditional head pose estimation networks suffer from the problem of easily losing spatial structure information, particularly in complex scenarios where occlusions and multiple object detections are common, resulting in low accuracy. To address the above issues, we propose a head pose estimation model based on the residual network and capsule network. Firstly, a deep residual network is used to extract features from three stages, capturing spatial structure information at different levels, and a global attention block is employed to enhance the spatial weight of feature extraction. To effectively avoid the loss of spatial structure information, the features are encoded and transmitted to the output using an improved capsule network, which is enhanced in its generalization ability through self-attention routing mechanisms. To enhance the robustness of the model, we optimize Huber loss, which is first used in head pose estimation. Finally, experiments are conducted on three popular public datasets, 300W-LP, AFLW2000, and BIWI. The results demonstrate that the proposed method achieves state-of-the-art results, particularly in scenarios with occlusions. The rapid development of artificial intelligence and the increasing prevalence of intelligent living have led to an increasing demand for robots to serve people in their daily lives. As an important component of service robot co-navigation, head pose estimation can provide information on human attention direction and intent, assisting robots in analyzing human behavior, and enabling them to possess the capability of social-aware navigation .Head pose estimation refers to inferring the orientation of the head from a given image. It can be represented by a 3D vector that includes the pitch, roll, and yaw angles . In receHead pose estimation from an image requires learning a mapping of two-dimensional space and three-dimensional space. Traditional head pose estimation methods use face localization and image cropping to reduce the influence of image-independent backgrounds on the detection target, mainly by using face alignment to similarly match the target image to the image sample . HoweverHead pose estimation utilizes a single RGB image since it can be regarded as a classification problem. Most of the methods proposed in the past five years for head pose estimation are based on machine learning and convolutional/deep neural networks . CompareIn this paper, we argue that head pose estimation methods suffer from low estimation accuracy and poor occlusion detection in complex environments. Therefore, we consider the limitations of the loss of spatial structure information and the inadequate generalization ability of capsule networks. To overcome these limitations, we propose a head pose estimation method based on an improved capsule network and attention-guided regression loss to enhance the accuracy of head pose estimation.(1)We propose a detection model that combines CNN and capsule network for head pose estimation. The model includes feature extraction, feature mapping, and feature aggregation modules. A multi-level output structure backbone network is used to extract spatial structure and semantic information at different levels for improved estimation accuracy.(2)In order to obtain more effective and representative features, we apply an improved feature extraction module to enhance the spatial weight of feature extraction, which can obtain more spatial information and significantly improve the feature extraction performance and network efficiency for capturing the main features.(3)To address the problem of loss of spatial structure information, we utilize an improved capsule network with reduced number of capsules and parameters to enhance the network’s generalization ability. Moreover, we optimize the regression loss to improve the model’s robustness.(4)To validate the effectiveness of the proposed method, we conduct tests and ablation experiments on the AFLW2000 and BIWI datasets. The results demonstrated that the performance of our method outperformed previous methods significantly.Specifically, the contributions of our work are as follows:Head pose estimation, as a critical technology in computer vision, has attracted extensive attention and research. Various methods for head pose estimation have been proposed up to now based on different types of data including 2D color images, 3D images, and depth images. Methods based on 3D images and depth images require special equipment, such as depth cameras or stereo cameras, which are expensive and computationally complex, making real-time applications difficult . TherefoFacial landmark detection is used to establish the mapping relationship between 3D space and 2D images for estimating head pose . Dlib 2 employedThe accurate estimation of head pose based on facial landmarks and model matching requires sufficient accuracy in both facial detection and feature point labeling. However, due to a high complexity, computational cost, and low efficiency of the model, it is difficult to accurately estimate head pose using classification training methods. In practical applications, the accuracy of facial feature point detection can be significantly reduced by various interfering factors such as lighting changes, complex backgrounds, head rotation, and occlusion , which cThe landmark-freed methods train on different samples of poses to obtain a vector description of the target pose sample, which represents a mapping between the pose and its features. By converting the head pose recognition problem into a classification or regression problem , it estaThe deep learning-based models for head pose estimation employ an end-to-end recognition approach, which enables fast image processing, excellent high-dimensional feature extraction, strong generalization, and the extraction of the main features of head pose estimation tasks. However, this method faces the ambiguity of the Euler angle representation of head pose in a wide range of angles. Moreover, occlusion and multi-target detection significantly affect the accuracy of head pose estimation and result in the loss of target detection. In this section, we first formulate head pose estimation problem . Then, wTypically, head pose estimation can be represented as a regression problem-based image. We use a set of trained facial images The proposed network model is illustrated in Firstly, we employ multitask cascaded convolution neural network (MTCNN)  to detecDetecting faces and face alignment from images is challenging in varying unconstrained environments. Different lighting conditions, visual variations of faces and extreme head pose variations are the main challenges in correctly detecting faces from images . TherefoIn deep convolution neural networks, attention mechanisms can refine feature maps to achieve better performance. To extract more effective features from the input face image, we design to introduce an efficient GAB that reduces information loss and amplifies cross-spatial-channel interactions across all three dimensions of importance. This module can improve the extraction efficiency of key features and the performance of deep neural networks. The structure diagram of GAM is shown in The channel-attention sub-module uses 3D alignment to retain information, and then it uses a multi-layer perceptron to amplify the channel-space dependencies across dimensions. Finally, the original alignment is recovered, and a set of channel weights is generated after a sigmoid activation function to represent the weights of the feature mapping between channels. An enhanced feature map can be obtained by multiplying the weights with the input feature map. The channel attention sub-module is illustrated in In the spatial attention sub-module, two convolution layers are used for spatial information fusion and the same reduction ratio as in the channel attention sub-module to focus spatial information. Also, pooling is removed to further preserve feature mapping. The spatial attention sub-module is illustrated in After the above feature extraction module, we obtain the feature maps milar to , we forcThe next step is to perform fine-grained structure mapping to obtain more representative features Regarding the aggregation module, we first consider CNNs because their convolutional structures can effectively capture existing features. However, CNNs rely on large amounts of data and layers with feature mappings to complete learning and updates, which may not be very efficient. When capturing relationships between feature attributes, CNNs may cause feature detectors to lose the precise target information from input images. Capsule networks provide a good solution, as they can extend current convolutional networks to efficiently encode all affine transformations of features and have better generalization capabilities.To overcome the limitations of the CNN method, we adopt the capsule network for feature aggregation. However, the capsule network requires training a large number of parameters, leading to low utilization efficiency and insufficient inherent generalization ability in expressing feature transformations. To address this problem, we use the linear combination and self-attention routing mechanism (SARM) . UtiliziAs shown in For the loss function of the regression model, TriNet  employs To address this problem, we propose a novel regression loss function ber loss  and L2 rIn this section, we provide a detailed account of the experimental procedure and results. The first part describes the experimental setup, while the second part introduces the dataset and evaluation metrics used in the experiments. The third part presents experimental results to test the effectiveness of the proposed network. Finally, we compare the experimental results with those of typical head pose estimation algorithms to further validate the performance of our method.The experiments are performed on a computer with an Intel Xeon Gold 5118 CPU and Nvidia RTX 5000 GPU. We use Keras with TensorFlow 1.10.0 backend to implement the proposed network. To make a fair comparison, we apply random cropping and random scaling to training images by following the data augmentation strategies in training from FSA-Net  and TriNIn 300W-LP: The 300W-LP dataset is a combined dataset containing eight small datasets. It has a total of 122,450 images and contains samples of large-angle head poses, and the images are labeled with the Euler angles rotated during the image processing. This dataset is currently the largest publicly available dataset in the field of head pose estimation and has been chosen for the training of head pose estimation models proposed in recent years.AFLW2000: The AFLW2000 dataset consists of 2000 images selected from the AFLW dataset, with most of its sample being portraits of people in natural scenes. The images in the AFLW2000 dataset include variations in the pose of people in different scenes and brightness, covering people of different ages and ethnicities. It has pretty accurate face pose annotation providing ground-truth 3D faces and the corresponding 68 landmarks. Therefore, we test the model using the AFLW2000 dataset to verify the generalization capability of the model.BIWI: The BIWI dataset is a publicly available dataset commonly used in the field of head pose estimation, with approximately 15,000 images. The dataset contains 24 videos of head poses from 20 test subjects . In addition to RGB frames, the dataset also provides the depth image for each frame. Ground-truth is provided in the form of the 3D location of the head and its rotations.(1)In our first protocol, we follow the convention by using the 300W-LP dataset for training and AFLW2000 and BIWI datasets for testing. When evaluating on the BIWI dataset, we do not use tracking and only consider using MTCNN  face det(2)For the second protocol, we follow the convention by FSA-Net  and randFor comparison with state-of-the-art methods, we follow the same training and testing setup as mentioned in Hopenet , FSA-NetIn all the experiments above, we evaluate the performance of all methods using MAE. For each method, MAE for yaw, pitch, and roll is separately calculated and then taking the average for overall evaluation.We explore the performance variation of the model using different loss functions, namely MAE, Huber loss and We test each of the three loss functions by incorporating them into the improved model, where “In protocol 1, the features of the training and test datasets are completely different, with the training dataset being synthetic and the test dataset being real. The landmark-free approach can better accommodate the domain differences between training and testing. As a result, the landmark-free approach performs better than the landmark-based approach on both the AFLW2000 and BIWI datasets.To fully understand the performance of the proposed network, we compare the proposed method with other state-of-the-art methods in terms of model size, parameters, and computation time. For a fair comparison, all networks are tested on the same target platform. To further validate the effectiveness of our proposed method, we present a visualization comparison between different methods. In this study, we propose a method for head pose estimation that shares a similar feature mapping module with FSA-Net. To demonstrate the effectiveness of our proposed method, we select a subset of images with significant occlusions from the AFLW2000 dataset. In addition, to strengthen the persuasive power of our experiments, we refer to the visualization results of Zhu . Based oIn this section, we conducted ablation experiments to investigate the impact of different modules  on the performance of our proposed model. The proposed method was trained on the 300W-LP dataset and tested on the AFLW2000 and BIWI datasets for the three modules. We then used 70% of the BIWI dataset as a training set and 30% as a test set. The experimental results for the different datasets are shown in To avoid loss of spatial information and improve the estimation accuracy of head pose under occlusion, in this paper, we propose a head pose estimation model based on a fusion of a convolutional neural network and capsule network. We adopt a feature extraction network with a multi-level output structure and introduce GAB to enhance the spatial weight of feature extraction, which can obtain more spatial information. The capsule network can retain and transmit spatial information. We improve the capsule network with SARM to significantly reduce the number of capsules and trainable parameters, effectively improving the model’s performance and solving the problem of loss of spatial structural information. In addition, to enhance the robustness of the model, we have utilized Huber loss for head pose estimation for the first time, which has better performance compared to methods based on multiple loss functions. The collaborative fusion of convolutional neural networks and capsule networks facilitates the extraction and preservation of both spatial and semantic features, resulting in better detection of head pose.This study conducts experiments on AFLW2000 and BIWI datasets, comparing the proposed method with previous methods. The results demonstrate that the proposed model exhibits more advanced performance in cases of significant angle deviations and occlusions. In future work, we will primarily focus on real-time head pose detection for analysis in social interactions. To achieve this, we will investigate lightweight network architectures to further improve computational speed and optimize the model parameters. Additionally, we intend to incorporate multimodal information, such as depth and temporal cues, for head pose estimation, with the aim of enhancing the performance of the network.