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GlioStat (patent pending) denotes an invention that addresses the current deficiencies of glioblastoma (GBM) chemotherapy by developing a molecularly imprinted drug reservoir that is specifically designed for post-surgical recovery. The goal of our research was to guarantee the long-term release of the antitumor drug ruxolitinib (RUX), which is specifically designed to target residual infiltrative cancer cells, while simultaneously reducing the risk of adverse effects. In order to achieve this goal, we have successfully developed and characterized four distinctive molecularly imprinted polymers (MIPs), with one of them advancing to in vivo experimentation. The selection of one MIP for further in vivo investigations was guided by the Alamar Blue viability assay on C6 GBM cell cultures, which took into account both the efficacy and the potential toxicity of residual monomers. Over the course of 96 hours, MIP 2 demonstrated the most favorable risk-benefit profile, providing superior efficacy against GBM C6 cells. In contrast, its non-imprinted counterpart (NIP 2) exhibited minimal toxicity. The protocol involved anesthetising the male Wistar rats, immobilising them on a corkboard, without the use of a stereotactic headholder. After shaving the head and local disinfection with iodine solution, we made a linear sagittal incision and exposed the parietal bones. A 3x3 mm burr hole was made with a pneumatic drill in the right parietal bone, revealing the dura mater. Subsequently, we injected 20,000 C6 GBM cells suspended in 5 microliters of solution in the cerebral parenchyma at a depth of 3 mm. Clinical and imaging control was performed. For the animals that developed tumors, a second therapeutic intervention was performed. The rats were anesthetised, disinfected, and readied in the same manner as before. The burr hole was exposed, with the tumor being partially resected via a “microscooping” technique. Next, 5-10 microliters of MIP2 solution (4 mg/mL) were injected into the parenchyma respective of the tumor bed. Five microliters of thrombin solution were then added (100 UI/mL) to form the fibrin network. In comparison to the untreated controls and animals treated with free RUX, animals treated with MIP2 exhibited a substantial increase in survival time during the in vivo evaluation, extending from 20 to 50 days. As such, our research had yielded a potentially life-changing drug delivery system in GBM, with the capacity to significantly increase postoperative survival. More in vivo tests should be conducted to validate our findings.

Introduction. Brain vascular malformations (BVMs) are congenital lesions with evolutive properties that possess a considerable chance of causing intracranial haemorrhage. The most common types are arteriovenous malformations (AVMs), aberrant entanglements of deformed vessels that shunt blood from the arteries directly into the veins, and cavernous malformations (CMs), being mulberry-shaped sinusoid spaces filled with blood. The rate of hemorrhagic stroke varies between these two types of lesions, being the most common form of symptomatic presentation for AVMs, but a much rarer occurrence for CMs. The purpose of our pilot study was to test whether the incidence of intracranial haemorrhage from BVMs varies between seasons, as well as examining a possible causality for this event. Material and methods. We performed a retrospective analysis on the cases of ruptured BVMs of the brain operated by the senior surgeon in our department between January 2008 and December 2019. We then divided the patients according to the type of lesion and gender, based on the month of the year when their pathologies caused the hemorrhagic stroke. We performed Pearson’s chi-square test to verify the relationship between season and rate of rupture of AVMs and CMs, individual month and rate of rupture, season and gender, and individual month and gender. Results. There were 87 ruptured vascular malformations, out of which 71 were AVMs and 16 were CMs. There were 51 males (40 AVMs, 11 CMs) and 36 females (31 AVMs, 5 CMs). The majority of hemorrhagic strokes occurred in the months of July (10 AVVMs, 2 CMs) and December (10 AVMs, 1 CM). We obtained a statistically significant correlation between the summer season and presentation with ruptured cavernous malformation, as well as the male sex and presentation with a ruptured AVM in December, whereas the female sex presented a correlation with ruptured AVMs in the month of March. We also obtained a correlation between the male sex and presenting with a ruptured vascular malformation of any kind in December, as well as the female gender and hemorrhagic stroke from any vascular malformation in the months of January and August. Conclusion. Despite promising statistical results, the relatively low number of cases may not be applicable to a larger patient population. It seems probable that meteorological conditions, especially extreme temperatures, might act as an additional risk factor for hemorrhagic stroke from vascular malformations, however, these findings should be corroborated with supplementary case series from other centres or a large prospective trial.

Background and Objectives: The IDH (isocitrate dehydrogenase) status represents one of the main prognosis factors for gliomas. However, determining it requires invasive procedures and specialized surgical skills. Medical imaging such as MRI is essential in glioma diagnosis and management. Lately, fields such as Radiomics and Radiogenomics emerged as pertinent prediction tools for extracting molecular information out of medical images. These fields are based on Artificial Intelligence algorithms that require external validation in order to evaluate their general performance. The aim of this study was to provide an external validation for the algorithm formulated by Yoon Choi et al. of IDH status prediction using preoperative common MRI sequences and patient age. Material and Methods: We applied Choi’s IDH status prediction algorithm on T1c, T2 and FLAIR preoperative MRI images of gliomas (grades WHO II-IV) of 21 operated adult patients from the Neurosurgery clinic of the Cluj County Emergency Clinical Hospital (CCECH), Cluj-Napoca Romania. We created a script to automate the testing process with DICOM format MRI sequences as input and IDH predicted status as output. Results: In terms of patient characteristics, the mean age was 48.6 ± 15.6; 57% were female and 43% male; 43% were IDH positive and 57% IDH negative. The proportions of WHO grades were 24%, 14% and 62% for II, III and IV, respectively. The validation test achieved a relative accuracy of 76% with 95% CI of (53%, 92%) and an Area Under the Curve (AUC) through DeLong et al. method of 0.74 with 95% CI of (0.53, 0.91) and a p of 0.021. Sensitivity and Specificity were 0.78 with 95% CI of (0.45, 0.96) and 0.75 with 95% CI of (0.47, 0.91), respectively. Conclusions: Although our results match the external test the author made on The Cancer Imaging Archive (TCIA) online dataset, performance of the algorithm on external data is still not high enough for clinical application. Radiogenomic approaches remain a high interest research field that may provide a rapid and accurate diagnosis and prognosis of patients with intracranial glioma.

Background/Aims Mechanical alterations of the spine, which can cause chronic low back pain (LBP), are a frequent indication for spinal fusion. Studies have shown differences between genders in patients’ evaluations of health-related quality of life (HRQoL) after spinal procedures, but results have been conflicting, and some authors have suggested that cultural variation could explain these discrepancies. The objectives of this study were to determine the influence that gender plays on HRQoL, disability, and the correlation between the 2 in people undergoing spinal fusion for chronic LBP at a neurosurgical centre in Eastern Europe. Methods Patients undergoing fusion surgery at a single centre for LBP with a duration of more than 3 months were included. They were evaluated using the Short Form Health Survey version-2.0 (SF-36v2) and Oswestry Low Back Pain Disability Index (ODI) questionnaire preoperatively and 1 year after the surgical procedure to identify differences between genders and to evaluate correlations between disability and quality of life. Results We included 31 female and 30 male patients. The male patients had higher disability scores at the preoperative evaluation, but improved more than females in all domains of disability at the postoperative evaluation. HRQoL improved similarly in both genders. The ODI score showed a strong or moderate correlation with 6 of the domains of the SF-36 in males, but with only 3 domains in females. Surgery had a positive impact on the mental status of more men than women at risk of depression. Conclusion The type of benefit that surgery offers seems to be influenced by gender. While HRQoL improved in both genders, disability decreased significantly more in male patients. Male patients also showed a closer correlation between HRQoL and disability. We conclude that men and women place different importance on specific aspects of their overall quality of life.

Background: Brain arteriovenous malformations (BAVMs) and cerebral cavernous malformations (CCMs) are rare developmental anomalies of the intracranial vasculature, with an irregular tendency to rupture, and as of yet incompletely deciphered pathophysiology. Because of their variety in location, morphology, and size, as well as unpredictable natural history, they represent a management challenge. MicroRNAs (miRNAs) are strands of non-coding RNA of around 20 nucleotides that are able to modulate the expression of target genes by binding completely or partially to their respective complementary sequences. Recent breakthroughs have been made on elucidating their contribution to BAVM and CCM occurrence, growth, and evolution; however, there are still countless gaps in our understanding of the mechanisms involved. Methods: We have searched the Medline (PubMed; PubMed Central) database for pertinent articles on miRNAs and their putative implications in BAVMs and CCMs. To this purpose, we employed various permutations of the terms and idioms: ‘arteriovenous malformation’, ‘AVM’, and ‘BAVM’, or ‘cavernous malformation’, ‘cavernoma’, and ‘cavernous angioma’ on the one hand; and ‘microRNA’, ‘miRNA’, and ‘miR’ on the other. Using cross-reference search; we then investigated additional articles concerning the individual miRNAs identified in other cerebral diseases. Results: Seven miRNAs were discovered to play a role in BAVMs, three of which were downregulated (miR-18a, miR-137, and miR-195*) and four upregulated (miR-7-5p, miR-199a-5p, miR-200b-3p, and let-7b-3p). Similarly, eight miRNAs were identified in CCM in humans and experimental animal models, two being upregulated (miR-27a and mmu-miR-3472a), and six downregulated (miR-125a, miR-361-5p, miR-370-3p, miR-181a-2-3p, miR-95-3p, and let-7b-3p). Conclusions: The following literature review endeavored to address the recent discoveries related to the various implications of miRNAs in the formation and growth of BAVMs and CCMs. Additionally, by presenting other cerebral pathologies correlated with these miRNAs, it aimed to emphasize the potential directions of upcoming research and biological therapies.

Introduction: Metformin (MET), an old anti-diabetic drug, has proven unexpected anti-glioblastoma effects, by impacting cell proliferation, migration and invasion. However, its remarkable anti-cancer efficacy is mainly limited to the use of high millimolar concentrations in in vitro studies, which are hard to be attained in the clinical setting. Aim: The aim of this paper was to synthetize gold nanoparticles loaded with MET and to test if an enhanced drug delivery via nanotechnology could overcome the limitations of small drug concentrations. Materials and Methods: Gold nanoparticles were functionalized with chitosan (GNPc) and loaded with 80 µM of MET. Their size, zeta potential and stability were characterized and their internalization within tumor cells was assayed through dark field microscopy. Three primary glioblastoma stem cell lines were treated with 5, 10 and 20 µg/mL concentrations of nanoparticles and irradiated. The anti-tumoral effect was evaluated through the MTT cell viability assay. Results: MET-GNPc are easily synthetized and have a positive zeta potential, spherical shape and a median size of 26 nm. MET-GNPc have an increased cell internalization and affect the viability of all three glioblastoma cell lines used compared to control and free MET. However, their anti-cancer effect is not statistically different when compared to GNPc, although a slight tendency to a better response may be observed. Conclusion:Despite an increased cell internalization, the small micromolar concentrations of metformin does not bring an additional benefit to chitosan-based GNPs. Novel delivery methods being able to carry a higher drug concentration of metformin should be tested.

Trigeminal schwannomas (TS) are rare tumors that are located in the posterior and middle cranial fossae in about a quarter of the cases. The presentation pattern is different according to the involved compartment and the goal of surgery is complete removal. We present the case of a 35-year old woman who presented a left sided TS extending from the posterior to the middle fossa and cavernous sinus. We review the relevant literature regarding diagnosis and surgical treatment of these tumors.

Meningiomas account for more than 30% of all intracranial brain tumors, with 25% of them originating somewhere along the skull base and about 20% of these located in the posterior fossa. The intimate relation of these tumors with neural and vascular structures make them difficult to treat, both surgically and nonsurgically. Their treatment is further hampered by the lack of definitive recommendations, which is partially due to the fact that there is no general accepted model of classification. The present report proposes a new concept of classification of posterior fossa skull base meningiomas, one that takes into account the intimate relation of these tumors with arachnoid structures, simplifies the overcrowded landscape of their systematization and can be extended to oher skull base locations.

Introduction Most tumoral processes involving the cerebellopontine angle (CPA) are extraneuraxial and usually comprise of vestibular schwannomas and meningiomas, followed by less common lesions such as epidermoid cysts, metastases and arachnoid cysts. Glioblastomas located in the CPA are rarely diagnosed. Uncommonly, intraneuraxial tumors in the CPA may grow in an exophytic manner compressing the surrounding cranial nerves, resembling the clinical picture of a more common extraneuraxial tumour. Clinical Case A 47 year old male presented to our department accusing gait imbalance, vertigo, vomiting and nausea, symptoms that started 2 months prior to admission. Upon neurological examination, the patient additionally presented right facial paresis and hypoesthesia, right sided hypoacusis, hypogeusia and diplopia. A contrast enhanced cerebral MRI revealed a right cerebellopontine angle mass with inhomogenous contrast enhancement, relatively well delineated, exerting mass effect on the cerebellum and pons with reduced perilesional edema but with involvement of the internal acoustic meatus. The indication for surgical removal of the tumour was made. The patient was placed in sitting position and a right retrosigmoid approach was performed using the operating microscope. Upon retraction of the cerebellar hemisphere, a greyish, highly vascularized and soft lesion was seen, exhibiting a spread growth, engulfing the V, VII and VIII nerves, without infiltrating them, resembling anything but a schwannoma. A frozen section of the tumour revealed a surprising result: high grade glioma. The surgical excision continued in a piece-meal fashion, using the ultrasonic aspirator with preservation of the cranial nerves until an almost complete removal was achieved. The immediate postop evolution of the patient was favourable. Nevertheless, the final histopathological diagnosis confirmed a grade IV glioblastoma. Oncological treatmend followed, but the tumour relapsed in 2 months after surgery, the control MRI revealing a multilocular tumoral dissemination in the cerebellum and brainstem which was surgically unsalvageable. Conclusion Glioblastoma of the CPA, manifesting both imagistically and clinically as a vestibular schwannoma is a rare entity but nevertheless extant, that dramatically changes the prognosis and postop evolution of a patient. Physicians involved in the diagnosis and treatment of such tumours must always be suspicious of the usual suspects in the CPA.

Introduction Burkitt lymphoma is a male predominant (3:1 male:female ratio) aggressive B-cell non-Hodgkin lymphoma that can present as a sporadic variant with meningeal involvement in about 20% of cases. Therefore, it can manifest with neurologic deficits due to compression of the spinal cord or spine nerve root. Case Report We report the case of a 6 years-old girl who presented in the emergency department following a traumatic vertebral injury (fall from around 1.5 meters) with no spinal cord involvement. She accused upper back pain, walking and orthostatism difficulties and manifested a light to moderate inferior paraparesis (MCR 3/5) The MRI revealed a space-occupying epidural mass between T1-T4, severely compressing the spinal cord initially thought to be an epidural hematoma. Emergency surgery was performed with duro-radicular decompression and mass excision through a T1-T4 laminotomy followed by a laminoplasty. The unveiled mass was white, minimally vascularized and adherent to the dura raising the suspicion of a tumor. Postoperatively the patient exhibited significant neurological improvement with resolution of the paraparesis and normal gait restoration. Three weeks later, the patient returned with complaints of abnormal gait, lumbar pain radiating in the right lower leg and upon examination a light right lower limb monoparesis (MRC 4/5) following another traumatic event. Emergency MRI of the whole spine with contrast was requested just as the pathologist in charge of the case suggested a diagnosis of Burkitt lymphoma, prompting a whole-body MRI. A severe recurrence was noted at the site of the previous lesion along with a new lumbar lesion, and several intraabdominal, intrathoracic, ovarian tumor sites with diffuse infiltration of the bone marrow. The patient was urgently referred to the pediatric oncology department and started on steroidal anti-inflammatory treatment and chemotherapy. Conclusions Burkitt lymphoma involving the nervous system in children requires increased medical attention during the clinical, histopathological examination and treatment phase, due to the association with advanced disease and, although rare, should be considered as a differential diagnosis in pediatric patients with epidural lesions. The management of such lesions demands a solid collaboration between neurosurgeon, pediatrician, pathologist and oncologist for an early diagnosis and proper treatment.

Introduction Managing intracranial aneurysms in the posterior circulation is particularly challenging due to anatomical complexities and the high risk of rupture. The presence of a large, partially thrombosed aneurysm adds another layer of difficulty. This report details the case of a 66-year-old female patient presenting with a symptomatic intracranial arterial loop and a large, partially thrombosed aneurysm in the posterior circulation, successfully treated through microsurgical clipping. Material and Methods A 66-year-old female with a history of intermittent headaches, vertigo, and diplopia underwent neuroimaging, including computed tomography angiography (CTA) and magnetic resonance imaging (MRI). Imaging revealed a large aneurysm in the posterior circulation, with partial thrombosis and an associated intracranial arterial loop. The patient was scheduled for a craniotomy to perform microsurgical clipping of the aneurysm. Two titanium aneurysm clips were applied to achieve complete occlusion. Results Intraoperative findings confirmed the large, partially thrombosed aneurysm arising from the basilar artery, with a complex arterial loop intricately intertwined with the aneurysm and adjacent neurovascular structures. The first clip was placed to secure the primary inflow, and the second clip provided additional reinforcement. Postoperative imaging demonstrated successful clipping with no residual aneurysm filling. The patient had an uneventful recovery with no immediate postoperative complications. Clinically, the patient reported significant improvement in symptoms, with a complete resolution of headaches and vertigo. Conclusions This case highlights the challenges and considerations in managing large, partially thrombosed aneurysms in the posterior circulation, particularly in the presence of an intracranial arterial loop. Successful management requires precise microsurgical technique and careful intraoperative decision-making. Further research is needed to optimize treatment strategies, potentially incorporating adjunctive endovascular techniques to enhance surgical outcomes.

ObjectiveDecompressive craniectomy (DC) serves as a vital life-saving intervention, demonstrating efficacy in reducing intracranial pressure (ICP). However, its efficacy hinges on meticulous surgical execution, perioperative management, and vigilance toward potential complications. The incidence of complications associated with DC plays a pivotal role in determining its superiority over medical management for patients experiencing intracranial hypertension following traumatic brain injury (TBI).MethodsSevere cases often require more intensive therapy, prolonged mechanical ventilation, and vasopressor treatment. Identifying the optimal moment for early extubation and minimizing vasopressor use is crucial to reducing the risk of complications, including PTH. Our study aims to highlight the potential risks associated with prolonged mechanical ventilation and long-term vasopressor administration. The collected data were demographics, the craniectomy size, the distance from the midline of the craniectomy, the presence or absence of hydrocephalus, duration of mechanical ventilation and vasopressor treatment, and outcome at 30 days.ResultsSeventy-two patients with a mean age of 44.2 (range 5–83) were included in the study, with a median craniectomy size of 119.3 cm2. In our series, craniectomy areas ranged between 30 and 207.5 cm2 and had a similar decrease in midline shift in all cases. We did not observe any associations between the surface of craniectomy and the complication rate (p = 0.6302). There was no association between craniectomy size and mortality rate or length of hospital stay. The most common complication of decompressive craniectomy in our study group was posttraumatic hydrocephalus, with an incidence of 13.8%. Our results showed that craniectomy size did not independently affect PTH development (p = 0.5125). Still, there was a strong correlation between prolonged time of vasopressor treatment (p = 0.01843), period of mechanical ventilation (p = 0.04928), and the development of PTH.ConclusionsThis study suggests that there is no clear correlation between craniectomy size, midline shift reduction, and survival rate. An extended period of vasopressor treatment or mechanical ventilation is linked with the development of posttraumatic hydrocephalus. Further studies on larger series or randomized controlled studies are needed to better define this correlation.

Introduction: Planning cranioplasty (CPL) in patients with suspected or proven post-traumatic hydrocephalus (PTH) poses a significant management challenge due to a lack of clear guidance. Research question: This project aims to create a European document to improve adherence and adapt to local protocols based on available resources and national health systems. Methods: After a thorough non-systematic review, a steering committee (SC) formed a European expert panel (EP) for a two-round questionnaire using the Delphi method. The questionnaire employed a 9-point Likert scale to assess the appropriateness of statements inherent to two sections: ''Diagnostic criteria for PTH'' and ''Surgical strategies for PTH and cranial reconstruction.'' Results: The panel reached a consensus on 29 statements. In the ''Diagnostic criteria for PTH'' section, five statements were deemed ''appropriate'' (consensus 74.2−90.3 %), two were labeled ''inappropriate,'' and seven were marked as ''uncertain.''In the ''Surgical strategies for PTH and cranial reconstruction'' section, four statements were considered ''appropriate'' (consensus 74.2−90.4 %), six were ''inappropriate,'' and five were ''uncertain.'' Discussion and conclusion: Planning a cranioplasty alongside hydrocephalus remains a significant challenge in neurosurgery. Our consensus conference suggests that, in patients with cranial decompression and suspected hydrocephalus, the most suitable diagnostic approach involves a combination of evolving clinical conditions and neuroradiological imaging. The recommended management sequence prioritizes cranial reconstruction, with the option of a ventriculoperitoneal shunt when needed, preferably with a programmable valve. We strongly recommend to adopt local protocols based on expert consensus, such as this, to guide patient care.

Abstract Intracranial epidermoid cysts are benign slow-growing ectodermal inclusions that account for less than 1% of all intracranial tumors. We retrospectively reviewed 36 such cases to evaluate the demographic characteristics, clinical manifestations, anatomical distribution, surgical management, and treatment outcome of these tumors. Additionally, we sought to identify the relationship between median or paramedian cistern tumor localization and clinical parameters, such as recurrence risk, hospitalization duration, and postoperative complication rates. The most frequently observed neurological symptoms were transient headaches (77.8%), dizziness (36.1%), CN VII palsy (19.4%), CN VIII hearing difficulty (19.4%) and cerebellar signs (19.4%). The most common surgical approaches included retrosigmoid (36.1%), subfrontal (19.4%) and telovelar (19.4%) approaches; gross total resection was feasible in 83.3% of cases. The postoperative complication rate was 38.9%. Tumors were more frequently found in the paramedian cisterns (47.2%), followed by the median line cisterns (41.6%). Multivariate analysis revealed that postoperative hydrocephalus and age 10 days). Despite their benign histopathological nature, these tumors have an important clinical resonance, with a high rate of postoperative complications and a degree of recurrence amplified by younger age and hydrocephalus.

IntroductionVentriculomegaly (VM) is a fetal brain malformation which may present independently (isolated form) or in association with different cerebral malformations, genetic syndromes or other pathologies (non-isolated form).MethodsThis paper aims to study the effect of ventriculomegaly on the internal tridimensional architecture of fetal brains by way of Klingler's dissection. Ventriculomegaly was diagnosed using fetal ultrasonography during pregnancy and subsequently confirmed by necropsy. Taking into consideration the diameter of the lateral ventricle (measured at the level of the atrium), the brains were divided into two groups: moderate ventriculomegaly (with atrial diameter between 13 and 15 mm) and severe ventriculomegaly (with atrial diameter above 15 mm).Results and discussionThe results of each dissection were described and illustrated, then compared with age-matched reference brains. In the pathological brains, fascicles in direct contact with the enlarged ventricles were found to be thinner and displaced inferiorly, the opening of the uncinate fasciculus was wider, the fornix was no longer in contact with the corpus callosum and the convexity of the corpus callosum was inverted. We have studied the prevalence of neurodevelopmental delay in children born with ventriculomegaly in the literature and discovered that a normal developmental outcome was found in over 90% of the mild VM cases, approximately 75% of the moderate and 60% in severe VM, with the correlated neurological impairments ranging from attention deficits to psychiatric disorders.

Background and Objectives: Brain arteriovenous malformations AVMs have been consistently regarded as congenital malformations of the cerebral vasculature. However, recent case reports describing “de novo AVMs” have sparked a growing debate on the nature of these lesions. Materials and Methods: We have performed a systematic review of the literature concerning de novo AVMs utilizing the PubMed and Google Academic databases. Termes used in the search were “AVM,” “arteriovenous,” “de novo,” and “acquired,” in all possible combinations. Results: 53 articles including a total of 58 patients harboring allegedly acquired AVMs were identified by researching the literature. Of these, 32 were male (55.17%), and 25 were female (43.10%). Mean age at de novo AVM diagnosis was 27.833 years (standard deviation (SD) of 21.215 years and a 95% confidence interval (CI) of 22.3 to 33.3). Most de novo AVMs were managed via microsurgical resection (20 out of 58, 34.48%), followed by radiosurgery and conservative treatment for 11 patients (18.97%) each, endovascular embolization combined with resection for five patients (8.62%), and embolization alone for three (5.17%), the remaining eight cases (13.79%) having an unspecified therapy. Conclusions: Increasing evidence suggests that some of the AVMs discovered develop some time after birth. We are still a long way from finally elucidating their true nature, though there is reason to believe that they can also appear after birth. Thus, we reason that the de novo AVMs are the result of a ‘second hit’ of a variable type, such as a previous intracranial hemorrhage or vascular pathology. The congenital or acquired characteristic of AVMs may have a tremendous impact on prognosis, risk of hemorrhage, and short and long-term management.