A systematic review on the efficacy of adjunctive surgical strategies during microvascular decompression for trigeminal neuralgia without intraoperative evidence of neurovascular conflict.

Aim of the present study was to conduct a comprehensive review of surgical strategies that can be offered to patients with trigeminal neuralgia undergoing microvascular decompression (MVD) surgery and without intraoperative evidence of neurovascular conflict, with a high pre-operative suspicion of conflict lacking intraoperative confirmation, or individuals experiencing recurrence after previous treatment. This systematic review followed established guidelines (PRISMA) to identify and critically appraise relevant studies. The review question was formulated according to the PICO (P: patients; I: intervention; C: comparison; O: outcomes) framework as follows. For patients with trigeminal neuralgia (P) undergoing MVD surgery (I) without demonstrable preoperative neurovascular conflict, high suspicion of conflict but no intraoperative confirmation or recurrence after previous treatment (C), do additional surgical techniques (nerve combing, neurapraxia, arachnoid lysis) (O) improve pain relief outcomes (O)? The search of the literature yielded a total of 221 results. Duplicate records were then removed (n = [76]). A total of 143 papers was screened, and 117 records were excluded via title and abstract screening; 26 studies were found to be relevant to our research question and were assessed for eligibility. Upon full-text review, 17 articles were included in the review, describing the following techniques; (1) internal neurolysis (n = 6) (2) arachnoid lysis/adhesiolysis (n = 2) (3) neurapraxia (n = 3) (4) partial rhizotomy of the sensory root (n = 4) (5) pontine descending tractotomy (n = 2). The risk of bias was assessed using the ROBINS-I (Risk of Bias in Non-randomized Studies - of Interventions) assessment tool. While the described techniques hold promise, further research is warranted to establish standardized protocols, refine surgical approaches, and comprehensively evaluate long-term outcomes.

Telomerase inhibition in malignant gliomas: a systematic review.

Glioblastoma (GBM) is the most frequent adult malignant brain tumour and despite different therapeutic efforts, the median overall survival still ranges from 14 to 18 months. Thus, new therapeutic strategies are urgently needed. However, the identification of cancer-specific targets is particularly challenging in GBM, due to the high heterogeneity of this tumour in terms of histopathological, molecular, genetic and epigenetic features. Telomerase reactivation is a hallmark of malignant glioma. An activating mutation of the hTERT gene, encoding for the active subunit of telomerase, is one of the molecular criteria to establish a diagnosis of GBM, IDH-wildtype, in the 2021 WHO classification of central nervous system tumours. Telomerase inhibition therefore represents, at least theoretically, a promising strategy for GBM therapy: pharmacological compounds, as well as direct gene expression modulation therapies, have been successfully employed in in vitro and in vivo settings. Unfortunately, the clinical applications of telomerase inhibition in GBM are currently scarce. The aim of the present systematic review is to provide an up-to-date report on the studies investigating telomerase inhibition as a therapeutic strategy for malignant glioma in order to foster the future translational and clinical research on this topic.

Longitudinal global transcriptomic profiling of preclinical systemic sclerosis reveals molecular changes associated with disease progression.

OBJECTIVE: To investigate peripheral blood cell (PBCs) global gene expression profile of SSc at its preclinical stage (PreSSc) and to characterize the molecular changes associated with progression to a definite disease over time. MATERIAL AND METHODS: Clinical data and PBCs of 33 participants with PreSSc and 16 healthy controls (HCs) were collected at baseline and follow-up (mean 4.2 years). Global gene expression profiling was conducted by RNA sequencing and a modular analysis was performed. RESULTS: Comparison of baseline PreSSc to HCs revealed 2889 differentially expressed genes. Interferon signalling was the only activated pathway among top over-represented pathways. Moreover, 10 modules were significantly decreased in PreSSc samples (related to lymphoid lineage, cytotoxic/NK cell, and erythropoiesis) in comparison to HCs. At follow-up, 14 subjects (42.4%) presented signs of progression (evolving PreSSc) and 19 remained in stable preclinical stage (stable PreSSc). Progression was not associated with baseline clinical features or baseline PBC transcript modules. At follow-up stable PreSSc normalized their down-regulated cytotoxic/NK cell and protein synthesis modules while evolving PreSSc kept a down-regulation of cytotoxic/NK cell and protein synthesis modules. Transcript level changes of follow-up vs baseline in stable PreSSc vs evolving PreSSc showed 549 differentially expressed transcripts (336 up and 213 down) with upregulation of the EIF2 Signalling pathway. CONCLUSIONS: Participants with PreSSc had a distinct gene expression profile indicating that molecular differences at a transcriptomic level are already present in the preclinical stages of SSc. Furthermore, a reduced NK signature in PBCs was related to SSc progression over time.

Mental health and the effects on methylation of stress-related genes in front-line versus other health care professionals during the second wave of COVID-19 pandemic: an Italian pilot study.

Healthcare workers experienced high degree of stress during COVID-19. Purpose of the present article is to compare mental health (depressive and Post-Traumatic-Stress-Disorders-PTSD-symptoms) and epigenetics aspects (degree of methylation of stress-related genes) in front-line healthcare professionals versus healthcare working in non-COVID-19 wards. Sixty-eight healthcare workers were included in the study: 39 were working in COVID-19 wards (cases) and 29 in non-COVID wards (controls). From all participants, demographic and clinical information were collected by an ad-hoc questionnaire. Depressive and PTSD symptoms were evaluated by the Patient Health Questionnaire-9 (PHQ-9) and the Impact of Event Scale-Revised (IES-R), respectively. Methylation analyses of 9 promoter/regulatory regions of genes known to be implicated in depression/PTSD (ADCYAP1, BDNF, CRHR1, DRD2, IGF2, LSD1/KDM1A, NR3C1, OXTR, SLC6A4) were performed on DNA from blood samples by the MassARRAY EpiTYPER platform, with MassCleave settings. Controls showed more frequent lifetime history of anxiety/depression with respect to cases (χ2 = 5.72, p = 0.03). On the contrary, cases versus controls presented higher PHQ-9 (t = 2.13, p = 0.04), PHQ-9 sleep item (t = 2.26, p = 0.03), IES-R total (t = 2.17, p = 0.03), IES-R intrusion (t = 2.46, p = 0.02), IES-R avoidance (t = 1.99, p = 0.05) mean total scores. Methylation levels at CRHR1, DRD2 and LSD1 genes was significantly higher in cases with respect to controls (p < 0.01, p = 0.03 and p = 0.03, respectively). Frontline health professionals experienced more negative effects on mental health during COVID-19 pandemic than non-frontline healthcare workers. Methylation levels were increased in genes regulating HPA axis (CRHR1) and dopamine neurotransmission (DRD2 and LSD1), thus supporting the involvement of these biological processes in depression/PTSD and indicating that methylation of these genes can be modulated by stress conditions, such as working as healthcare front-line during COVID-19 pandemic.

CSF neuron-specific enolase as a biomarker of neurovascular conflict severity in drug-resistant trigeminal neuralgia: a prospective study in patients submitted to microvascular decompression.

BACKGROUND: Although neurovascular conflict (NVC) is the most widely accepted cause of trigeminal neuralgia (TN), few articles have analyzed molecular and biochemical mechanisms underlying TN. In the present study, we dosed neuron-specific enolase (NSE) on serum and CSF samples of 20 patients submitted to microvascular decompression (MVD) and correlated these findings with the type of NVC. METHODS: Blood samples were obtained preoperatively and 48 h after MVD. CSF from trigeminal cistern was intraoperatively obtained. NSE levels were measured using the Diasorin kit (LIAISON®NSE). NVC was classified as "contact" or "trigeminal nerve distortion/indentation" or "trigeminal root atrophy" based on MRI and intraoperative findings. Clinical outcome was measured by acute pain relief (APR) and Barrow Neurological Institute (BNI) scale at last available follow-up (FU; 6.40 ± 5.38 months). RESULTS: APR was obtained in all patients. A statistically significant BNI reduction was obtained at latest FU (p < 0.0001). Serum NSE levels significantly decreased following MVD (from 12.15 ± 3.02 ng/mL to 8.95 ± 2.83 ng/mL, p = 0.001). The mean CSF NSE value was 48.94 ng/mL, and the mean CSF/serum NSE rate was 4.18 with a strong correlation between these two variables (p = 0.0008). CSF NSE level in "trigeminal root atrophy" group was significantly higher compared to "contact" (p = 0.0045) and "distortion/indentation" (p = 0.010) groups. CONCLUSION: NSE levels seem to be related to the etiopathology and severity of NVC. A significant reduction of serum NSE levels could be related to the resolution of the NVC and clinical TN improvement.

Resection versus biopsy for management of primary central nervous system lymphoma: a meta-analysis.

The role of surgery in the management of primary central nervous system lymphomas (PCNSL) is currently confined to diagnosis. However, over recent years, an increasing number of papers have suggested a possible positive prognostic impact of surgery in selected cases. The present work aims to perform a meta-analysis of the available literature evidence. A meta-analysis with meta-regression on the role of surgical resection compared to biopsy in the management of PCNSL was conducted according to the PRISMA statement, searching MEDLINE via PubMed and Embase. The random effect model was used. The quality of evidence was assessed using the GRADE framework. After screening 1395 records, we included 11 papers in our analysis. Patients who underwent surgical resection harbored superficial and single-lesion tumors. At 1-, 2-, and 5-year follow-up, progression-free survival did not differ between the two groups, while overall survival favored resection, even if in a non-significant fashion. Meta-regression analysis showed that the overall survival rate at 2 years, but not at 1 or 5 years, was significantly influenced by tumor location. There were no differences in terms of age, sex, Karnofsky performance status, adjuvant therapy, or procedure-related complications. Overall, the quality of evidence is low. The results of the present meta-analysis do not change the current standard of care for PCNSL. However, surgery could be non-inferior to biopsy with an acceptable risk profile in selected patients harboring single and superficial lesions. The low quality of evidence prompts future randomized studies.

Methods and Principles of the Intraoperative Neurophysiologic Monitoring in Neurosurgery.

Intraoperative neurophysiologic monitoring (IONM) is an innovation introduced in neurosurgery in the past decades. It aims to support and guide the neurosurgeon to obtain the best surgical result possible, preventing the occurrence of neurological deficits. The somatosensory evoked potentials (SSEP) assess the integrity of the sensory pathways monitoring the dorsal column-medial lemniscus pathway during spine and cerebral surgery. Motor evoked potentials (MEPs) provide information on the integrity of the motor pathway monitoring the efferent motor pathways from the motor cortex to the muscle through corticospinal (or corticobulbar) tracts. Free-running EMG is the standard technique to monitor peripheral nerves, roots, or cranial motor nerves during surgery. Intraoperative EMG signals are activated during cranial motor nerves damaging or after an irritative stimulus. The duration, morphology, and persistence of EMG reflects the severity of neural injury. Nerve mapping consists of recording muscle activations given by direct nerve stimulation. This technique makes use of a stimulation probe available to the neurosurgeon which allows administering current directly to the nervous tissue (nerves, roots, etc.). Intraoperative neurophysiological monitoring (IONM) represents the standard of care during many procedures, including spinal, intracranial, and vascular surgeries, where there is a risk of neurological damage. Close communication and collaboration between the surgical team, neurophysiologist, and anesthesiologist is mandatory to obtain high-quality neuromonitoring, thus preventing neurologic injuries and gaining the best surgical "safe" results.

Atlantoaxial Anterior Transarticular Screw Fixation: Indications and Surgical Technique.

Posterior atlantoaxial screw fixation is a widely adopted therapeutic option for C1-C2 instability secondary to fractures or dislocation, degenerative diseases, or tumors at this level. Anterior transarticular screw fixation (ATSF) is an effective alternative to the posterior approaches, presenting several advantages despite being scarcely known and rarely chosen.In this chapter, we describe the ATSF step by step, illustrating its variations reported in literature, and we critically analyze the several advantages and contraindications of this technique. Moreover, we provide a list of tips and tricks on the surgical procedure, including critical operating room settings-the result of more than 10 years of experience in the field by a senior author.ATSF is a valid strategy for the treatment of different diseases occurring at the level of the atlantoaxial complex that needs consideration. Given the significant learning curve of this strategy, some hints may be essential to begin introducing this technique in the personal armamentarium of a spine surgeon so that they can perform ATSF safely and effectively.

Does Laminectomy Affect Spino-Pelvic Balance in Lumbar Spinal Stenosis? A Study Based on the EOS X-Ray Imaging System.

PURPOSE: Lumbar spinal stenosis (LSS) is a degenerative disorder causing the forward bending of the trunk and pelvic retroversion with the consequent loss of lumbar lordosis; surgical treatment is intended to enlarge the canal and foramina and decompress the nerve roots. The purpose of our study is to determine whether and to what extent facet-sparing laminectomy affects the spino-pelvic balance. METHODS: The spino-pelvic balance of 26 patients was analysed before and after surgery through the EOS X-ray Imaging System. The following parameters were considered: thoracic kyphosis (TK), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT) and sacral slope (SS). Clinical data were expressed in numeric values according to the Oswestry Disability Index (ODI), the visual analogue scale (VAS) and the modified Japanese Orthopaedic Association (mJOA) scoring system. RESULTS: Significant SS decreases and PT increases were noticed after surgery, without modification in LL, axial vertebral rotation (AVR) and the general alignment. Pain and disability had a significant improvement, as represented by a decrease in scores on the VAS and ODI scales and an increase in scores on the mJOA functional scale. CONCLUSION: The most important parameter seems to be a congruence between pelvic and spinal parameters, which achieves an economic posture with the physiologic position of the axis of gravity. According to the literature, a standard sagittal balance (SB) has not been defined.

Percutaneous Balloon Compression for Trigeminal Neuralgia. A Comparative Study Between the Fluoroscope Guided and Neuronavigated Technique.

Percutaneous balloon compression (PBC) is a safe and effective procedure in the treatment of trigeminal neuralgia (TN) due to its simplicity, low cost and the possibility of being repeated in case of pain recurrence. Foramen ovale (FO) cannulation is accomplished with the assistance of intraoperative C-arm fluoroscopy. Recently, several authors have reported successful application of intraoperative CT navigation as well. The reported advantages of CT navigation are linked to better spatial orientation and the low rate of attempts for FO cannulation. However, these advantages should be considered in the face of concerns regarding increased radiation dose to the patient and its possible adverse effects. Here we compared the fluoroscopic guided and neuronavigated PBC techniques in terms of efficacy and radiological exposure. We retrospectively analyzed 37 patients suffering for TN and submitted to PBC. We observed a significant improvement of pain at 1 month FU compared with the pre-operative in both groups (p < 0.0001 and p < 0.0001, respectively). A significant increase in radiation exposure was found in the neuronavigated group compared with the fluoroscopy group (p < 0.0001). We suggest the use of neuronavigated PBC only in selected cases, such as patients with multiple previous operations, in whom a difficult access can be pre-operatively hypothesized.

Spinal Cord High-Frequency Stimulation. The Current Experience and Future Directions.

Spinal cord stimulation (SCS) is a neuromodulation technology that has emerged as a valid treatment for chronic intractable neuropathic pain. After conventional tonic SCS, new waveforms of stimulation, like high frequency (HF), have proved that they can provide safe and effective pain relief. In addition, SCS is now being utilized more broadly as a potential treatment for a range of indications, including motor disorders and spasticity. Our study presents a retrospective analysis of 20 patients with heterogenous aetiologies of neuropathic pain treated with HF stimulation, after a standardized protocol in a temporary trial. We observed a significant improvement in pain relief according to comparisons of numerical rating scale (NRS) scores before the procedure, after the clinical trial and at latest follow-up. Two unusual clinical cases were also reported, and the pertinent literature was discussed.

Spinal Epidural Atypical Meningioma: Case Report and Review of the Literature.

Spinal atypical meningiomas are rare, and those whose main extension is in the epidural space are anecdotal. Here, we report a case of a young woman presenting with sensory disturbances and a radiological diagnosis of a dorsal epidural sleeve-like mass. The surgical resection of the lesion allowed the decompression of the spinal cord and led to the histopathological diagnosis of atypical meningioma. At the 3-month follow-up, her neurological recovery was complete. Because of the gross total removal of the lesion, adjuvant radiotherapy was not performed: At the 2-year follow-up, no recurrence of disease was detected. A comprehensive literature review was performed, and just two more case reports on epidural atypical meningiomas were found in the English literature. Through this case report and literature review, we described a rare manifestation of spinal meningioma that entered into a differential diagnosis for extradural spinal lesions, such as secondary malignancies.

Toward the End of the Funnel: The Ventriculus Terminalis-The State of Art of an Ancient Entity with a Recent History.

PURPOSE: The ventriculus terminalis (VT), also called the fifth ventricle, is a small cavity containing cerebrospinal fluid (CSF) that is in the conus medullaris in continuity with the central canal of the spinal cord. In adults, persistent VT is a very rare entity, and the diagnosis is incidental in most cases. Rarely, VT may become symptomatic for still-uncertain reasons but most often for its cystic dilatation. The management of these selected cases is still controversial and sometimes associated with unsatisfactory outcomes. METHODS: We performed a critical review of the existing literature on the management of symptomatic VT in adults. The etiology, pathophysiology, and treatment of VT are presented and discussed, focusing on the best timing for surgery. RESULTS: Conservative management, marsupialization, or the placement of a T drain have been reported. The existing classifications describe the most correct approach for each clinical presentation, but scarce importance has been given to the delay from symptoms' onset to surgical treatment. CONCLUSION: Although different cases have been described in the literature, this rare pathology remains unknown to most neurosurgeons.

Reliability of intraoperative visual evoked potentials (iVEPs) in monitoring visual function during endoscopic transsphenoidal surgery.

OBJECTIVE: To refine a reliable and reproducible intraoperative visual evoked potentials (iVEPs) monitoring protocol during endoscopic transsphenoidal surgery. To assess the reliability of baseline iVEPs in predicting preoperative visual status and perioperative iVEP variation in predicting postoperative visual outcome. METHODS: Sixty-four patients harboring tumors of the pituitary region were included. All patients underwent endoscopic endonasal approach (EEA) with iVEPs monitoring, using a totally intravenous anesthetic protocol. Ophthalmological evaluation included visual acuity and visual field studies. RESULTS: Preoperatively, visual acuity was reduced in 86% and visual field in 76.5% of cases. Baseline iVEPs amplitude was significantly correlated with preoperative visual acuity and visual field (p = 0.001 and p = 0.0004, respectively), confirming the reliability of the neurophysiological/anesthetic protocol implemented. Importantly, perioperatively the variation in iVEPs amplitude was significantly correlated with the changes in visual acuity (p < 0.0001) and visual field (p = 0.0013). ROC analysis confirmed that iVEPs are an accurate predictor of perioperiative visual acuity improvement, with a 100% positive predictive value in patients with preoperative vision loss. CONCLUSIONS: iVEPs during EEA is highly reliable in describing preoperative visual function and can accurately predict postoperative vision improvement. SIGNIFICANCE: iVEPs represent a promising resource for carrying out a more effective and safe endoscopic transsphenoidal surgery.

An Overview of Recent Advances in Anterior Cervical Decompression and Fusion Surgery.

Anterior cervical diskectomy and fusion (ACDF) has evolved significantly in the last few years with the aim of enhancing effectiveness and safety while reducing hospitalization and healthcare-related costs. Transitioning from iliac crest autografts to allografts minimizes donor-site complications like pain, infections, and hematoma. Allograft options, such as polyetheretherketone (PEEK) and tantalum, vary in their osteoinductive properties and elastic modulus, influencing fusion rates, time, and the rate of subsidence. Recently introduced zero-profile cages offer bone fixation through screws, resulting in reduced blood loss, improved spinal alignment, and decreased complications like dysphagia and adjacent segment disease. Intraoperative neuromonitoring (IONM) has gained widespread use. The North American Spine Society (NASS) 2023 recommendations endorse IONM in cervical deformity corrections and myelopathy cases. Insufficient studies hinder clear radiculopathy recommendations, but emerging research supports IONM for patients at greater risk of C5 nerve root injury or positional injury. Advancements in hemostatic agents, such as gelatin sponges, oxidized cellulose, and fibrin sealants, contribute to safety by reducing postoperative hematoma rates and eliminating the need for drainage. Innovations like the exoscope, endoscope, and computed-tomography (CT) navigation have transformed surgical practices. Exoscopes are emerging as an alternative to microscopes, offering benefits like a smaller footprint, adjustable positioning, lower costs, and shared intraoperative views for educational purposes. The use of endoscope offers the possibility of performing a minimally invasive technique with improved results in terms of cosmesis and patient-perceived outcome. CT navigation can be useful in high-risk procedures, such as cervical plate placement for major instability. This paper provides an overview of cutting-edge technologies in ACDF surgery, emphasizing cage materials and designs, safety measures, and operating room advancements. It also highlights areas for future research, underlining the procedure's continuous evolution.

Neuromodulation for Brain Tumors: Myth or Reality? A Narrative Review.

In recent years, research on brain cancers has turned towards the study of the interplay between the tumor and its host, the normal brain. Starting from the establishment of a parallelism between neurogenesis and gliomagenesis, the influence of neuronal activity on the development of brain tumors, particularly gliomas, has been partially unveiled. Notably, direct electrochemical synapses between neurons and glioma cells have been identified, paving the way for new approaches for the cure of brain cancers. Since this novel field of study has been defined "cancer neuroscience", anticancer therapeutic approaches exploiting these discoveries can be referred to as "cancer neuromodulation". In the present review, we provide an up-to-date description of the novel findings and of the therapeutic neuromodulation perspectives in cancer neuroscience. We focus both on more traditional oncologic approaches, aimed at modulating the major pathways involved in cancer neuroscience through drugs or genetic engineering techniques, and on electric stimulation proposals; the latter is at the cutting-edge of neuro-oncology.

Predictors of response to vagus nerve stimulation in drug resistant epilepsy.

LETTER TO EDITOR Keywords.

Choosing Wisely in clinical practice: Embracing critical thinking, striving for safer care.

In recent years, the Choosing Wisely and Less is More campaigns have gained growing attention in the medical scientific community. Several projects have been launched to facilitate confrontation among patients and physicians, to achieve better and harmless patient-centered care. Such initiatives have paved the way to a new "way of thinking." Embracing such a philosophy goes through a cognitive process that takes into account several issues. Medicine is a highly inaccurate science and physicians should deal with uncertainty. Evidence from the literature should not be accepted as it is but rather be translated into practice by medical practitioners who select treatment options for specific cases based on the best research, patient preferences, and individual patient characteristics. A wise choice requires active effort into minimizing the chance that potential biases may affect our clinical decisions. Potential harms and all consequences (both direct and indirect) of prescribing tests, procedures, or medications should be carefully evaluated, as well as patients' needs and preferences. Through such a cognitive process, a patient management shift is needed, moving from being centered on establishing a diagnosis towards finding the best management strategy for the right patient at the right time. Finally, while "thinking wisely," physicians should also "act wisely," being among the leading actors in facing upcoming healthcare challenges related to environmental issues and social discrepancies.

Prognostic value of copeptin and mid-regional proadrenomedullin in COVID-19-hospitalized patients.

BACKGROUND: Biomarkers are used for diagnosis, risk stratification and medical decisions. Copeptin and mid-regional proadrenomedullin (MR-proADM) are markers of stress and endothelial function, respectively, which have been studied in pneumonia, sepsis and septic shock. This study aimed to assess whether copeptin and MR-proADM could predict coronavirus disease 2019 (COVID-19) in-hospital outcomes, that is multi-system complications, length of stay and mortality. METHODS: Copeptin and MR-proADM were assessed at admission in 116 patients hospitalized with COVID-19. Data were retrospectively extracted from an online database. The primary endpoint was in-hospital mortality. The secondary endpoints were in-hospital complications, the composite outcome 'death, or admission to intensive care unit, or in-hospital complications', and length of stay. The predictive power was expressed as area under the receiver operator characteristic curve (AUROC). RESULTS: Copeptin was increased in non-survivors (median 29.7 [interquartile range 13.0-106.2] pmol/L) compared to survivors (10.9 [5.9-25.3] pmol/L, p < 0.01). The AUROC for mortality was 0.71, with a hazard ratio of 3.67 (p < 0.01) for copeptin values > 25.3 pmol/L. MR-proADM differentiated survivors (0.8 [0.6-1.1] nmol/L) from non-survivors (1.5 [1.1-2.8] nmol/L, p < 0.001) and yielded a AUROC of 0.79 and a hazard ratio of 7.02 (p < 0.001) for MR-proADM values > 1.0 nmol/L. Copeptin and MR-proADM predicted sepsis (AUROC 0.95 and 0.96 respectively), acute kidney injury (0.87 and 0.90), the composite outcome (0.69 and 0.75) and length of stay (r = 0.42, p < 0.001, and r = 0.46, p < 0.001). CONCLUSIONS: Admission MR-proADM and copeptin may be implemented for early risk stratification in COVID-19-hospitalized patients to help identify those eligible for closer monitoring and care intensification.

The role of hypoxia and inflammation in the regulation of iron metabolism and erythropoiesis in COVID-19: The IRONCOVID study.

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis.