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BACKGROUND: Anemia (either pre-existing or hospital-acquired) is considered an independent predictor of mortality in acute coronary syndromes. However, it is still not clear whether anemia should be considered as a marker of worse health status or a therapeutic target. We sought to investigate the relationship between hospital-acquired anemia and clinical and laboratory findings and to assess the association with mortality and major cardiovascular events at long-term follow-up. METHODS: Patients consecutively admitted at Niguarda Hospital between February 2014 and November 2020 for an acute coronary syndrome were included in this cohort analysis and classified as anemic at admission (group A), with normal hemoglobin at admission but developing anemia during hospitalization (hospital-acquired anemia) (group B); and with normal hemoglobin levels throughout admission (group C). RESULTS: Among 1294 patients included, group A included 353 (27%) patients, group B 468 (36%), and group C 473 patients (37%). In terms of cardiovascular burden and incidence of death, major cardiovascular events and bleeding at 4.9-year median follow-up, group B had an intermediate risk profile as compared with A and C. Baseline anemia was an independent predictor of death (hazard ratio 1.51; 95% confidence interval, 1.02-2.25; P = .04) along with frailty, Charlson comorbidity Index, estimated glomerular filtration rate, previous myocardial infarction, and left ventricular ejection fraction. Conversely, hospital-acquired anemia was not associated with increased mortality (hazard ratio 1.18; 95% confidence interval, 0.8-1.75; P = .4). CONCLUSIONS: Hospital-acquired anemia affects one-third of patients hospitalized for acute coronary syndrome and is associated with age, frailty, and comorbidity burden, but was not found to be an independent predictor of long-term mortality.
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Síndrome Coronario Agudo , Anemia , Fragilidad , Humanos , Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/epidemiología , Volumen Sistólico , Fragilidad/complicaciones , Factores de Riesgo , Función Ventricular Izquierda , Anemia/epidemiología , Anemia/etiología , Hemoglobinas , HospitalesRESUMEN
OBJECTIVE: To estimate the incidence and describe clinical characteristics and outcome of GBS in COVID-19 patients (COVID19-GBS) in one of the most hit regions during the first pandemic wave, Lombardia. METHODS: Adult patients admitted to 20 Neurological Units between 1/3-30/4/2020 with COVID19-GBS were included as part of a multi-center study organized by the Italian society of Hospital Neuroscience (SNO). RESULTS: Thirty-eight COVID19-GBS patients had a mean age of 60.7 years and male frequency of 86.8%. CSF albuminocytological dissociation was detected in 71.4%, and PCR for SARS-CoV-2 was negative in 19 tested patients. Based on neurophysiology, 81.8% of patients had a diagnosis of AIDP, 12.1% of AMSAN, and 6.1% of AMAN. The course was favorable in 76.3% of patients, stable in 10.5%, while 13.2% worsened, of which 3 died. The estimated occurrence rate in Lombardia ranges from 0.5 to 0.05 GBS cases per 1000 COVID-19 infections depending on whether you consider positive cases or estimated seropositive cases. When we compared GBS cases with the pre-pandemic period, we found a reduction of cases from 165 to 135 cases in the 2-month study period in Lombardia. CONCLUSIONS: We detected an increased incidence of GBS in COVID-19 patients which can reflect a higher risk of GBS in COVID-19 patients and a reduction of GBS events during the pandemic period possibly due to a lower spread of more common respiratory infectious diseases determined by an increased use of preventive measures.
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COVID-19 , Síndrome de Guillain-Barré , Adulto , Humanos , Masculino , Persona de Mediana Edad , COVID-19/complicaciones , COVID-19/epidemiología , SARS-CoV-2 , Síndrome de Guillain-Barré/diagnóstico , Pandemias , Italia/epidemiologíaRESUMEN
In a world accelerating the energy transition towards renewable sources, high voltage transmission lines represent strategic infrastructure for power delivery. Being slender and low-damped structures, HVTL conductors are affected by wind-induced vibrations that can lead to severe fatigue issues in conductors and other components. Vibration monitoring could represent a key activity to assess the safety level of the line and perform condition-based maintenance activities. This work proposes an innovative approach based on the knowledge of the physical phenomena and smart technological devices. A wireless monitoring system based on MEMS accelerometers and energy harvesting techniques has been designed to measure the fymax parameter in the field, which represents a fatigue indicator useful to identify the different wind-induced phenomena and assess the conductors' strain level. A field test on a Canadian transmission line was used in the check of the efficiency of the system and collection of significant data. Vibrations due to vortex shedding were identified with a maximum value of fymax = 50 m/s, while subspan oscillation and galloping were not observed. We show the novel method can detect the different wind-induced phenomena and pave the way to the development of suitable software able to compute a conductor's residual fatigue life.
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Vibración , Viento , Humanos , Canadá , Programas Informáticos , FatigaRESUMEN
Alzheimer's Disease is the most common cause in the world of progressive cognitive decline. Although many modifiable and non-modifiable risk factors have been proposed, in recent years, neuroinflammation has been hypothesized to be an important contributing factor of Alzheimer's Disease pathogenesis. Neuroinflammation can occur through the combined action of the Central Nervous System resident immune cells and adaptive peripheral immune system. In the past years, immunotherapies for neurodegenerative diseases have focused wrongly on targeting protein aggregates Aß plaques and NFT treatment. The role of both innate and adaptive immune cells has not been fully clarified, but several data suggest that immune system dysregulation plays a key role in neuroinflammation. Recent studies have focused especially on the role of the adaptive immune system and have shown that inflammatory markers are characterized by increased CD4+ Teff cells' activities and reduced circulating CD4+ Treg cells. In this review, we discuss the key role of both innate and adaptive immune systems in the degeneration and regeneration mechanisms in the pathogenesis of Alzheimer's Disease, with a focus on how the crosstalk between these two systems is able to sustain brain homeostasis or shift it to a neurodegenerative condition.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Microglía/metabolismo , Sistema Nervioso Central/metabolismo , HomeostasisRESUMEN
Microalgae that form phytoplankton live and die in a complex microbial consortium in which they co-exist with bacteria and other microorganisms. The dynamics of species succession in the plankton depends on the interplay of these partners. Bacteria utilize substrates produced by the phototrophic algae, while algal growth can be supported by bacterial exudates. Bacteria might also use chemical mediators with algicidal properties to attack algae. To elucidate whether specific bacteria play universal or context-specific roles in the interaction with phytoplankton, we investigated the effect of cocultured bacteria on the growth of 8 microalgae. An interaction matrix revealed that the function of a given bacterium is highly dependent on the cocultured partner. We observed no universally algicidal or universally growth-promoting bacteria. The activity of bacteria can even change during the aging of an algal culture from inhibitory to stimulatory or vice versa. We further established a synthetic phytoplankton/bacteria community with the centric diatom, Coscinodiscus radiatus, and 4 phylogenetically distinctive bacterial isolates, Mameliella sp., Roseovarius sp., Croceibacter sp., and Marinobacter sp. Supported by a Lotka-Volterra model, we show that interactions within the consortium are specific and that the sum of the pairwise interactions can explain algal and bacterial growth in the community. No synergistic effects between bacteria in the presence of the diatom was observed. Our survey documents highly species-specific interactions that are dependent on algal fitness, bacterial metabolism, and community composition. This species specificity may underly the high complexity of the multi-species plankton communities observed in nature. IMPORTANCE The marine food web is fueled by phototrophic phytoplankton. These algae are central primary producers responsible for the fixation of ca. 40% of the global CO2. Phytoplankton always co-occur with a diverse bacterial community in nature. This diversity suggests the existence of ecological niches for the associated bacteria. We show that the interaction between algae and bacteria is highly species-specific. Furthermore, both, the fitness stage of the algae and the community composition are relevant in determining the effect of bacteria on algal growth. We conclude that bacteria should not be sorted into algicidal or growth supporting categories; instead, a context-specific function of the bacteria in the plankton must be considered. This functional diversity of single players within a consortium may underly the observed diversity in the plankton.
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Diatomeas , Flavobacteriaceae , Microalgas , Plancton , Fitoplancton , Ecosistema , Microalgas/microbiologíaRESUMEN
Introduction: The detection in mild cognitive impairment (MCI) of metabolic alterations suggestive of depression and/or of evolution to dementia. Methods: Sixty-nine MCI patients underwent clinical and imaging evaluation including position emission tomography/computed tomography with fluorodeoxy-glucose (FDG-PET/CT). Results: The metabolism mean values in parietal, temporal and pre-cuneus areas were lower in subjects who evolved to dementia, and in frontal and in anterior cingulate areas in depressed subjects. Abnormal metabolism values were higher in the frontal and parietal lobes, and in the precuneus in subjects who evolved to dementia independently from depression. Conclusions: In MCI FDG-PET/CT abnormality patterns suggest the presence of depression or the evolution to dementia.
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BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease that targets acetylcholine receptor (AChR) of the neuromuscular junction. New-onset MG after SARS-CoV-2 vaccination has rarely been reported. CASE PRESENTATION: We report about three patients who presented new-onset myasthenia gravis after receiving mRNA SARS-CoV-2 vaccination. The patients were all males and older than 55 years. All the patients presented with ocular and bulbar symptoms. The interval between vaccine administration and MG onset ranged from 3 days after the first dose to 10 days after the second dose. All the patients had elevated serum AChR antibodies and responded to pyridostigmine. Two out of three patients were successfully treated with IVIG or plasma exchange and with long-term immunosuppression. CONCLUSIONS: MG is a rare disease; clinicians should be aware of possible new-onset MG after SARS-CoV-2 vaccination, especially with the current recommendation of booster doses. The hyperstimulation of the innate immune system or the exacerbation of a subclinical pre-existing MG could be possible explanations.
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Vacunas contra la COVID-19 , COVID-19 , Miastenia Gravis , Anciano de 80 o más Años , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Miastenia Gravis/tratamiento farmacológico , ARN Mensajero , Receptores Colinérgicos , SARS-CoV-2 , VacunaciónRESUMEN
INTRODUCTION: Dementia with Lewy bodies (DLB) may represent a diagnostic challenge, since its clinical picture overlaps with other dementia. Two toolkits have been developed to aid the clinician to diagnose DLB: the Lewy Body Composite Risk Score (LBCRS) and the Assessment Toolkit for DLB (AT-DLB). We aim to evaluate the reliability of these two questionnaires, and their ability to enhance the interpretation of the international consensus diagnostic criteria. METHODS: LBCRS and AT-DLB were distributed to 135 Italian Neurological Centers for Cognitive Decline and Dementia (CDCDs), with the indication to administer them to all patients with dementia referred within the subsequent 3 months. We asked to subsequently apply consensus criteria for DLB diagnosis, to validate the diagnostic accuracy of the two toolkits. RESULTS: A total of 23 Centers joined the study; 1854 patients were enrolled. We found a prevalence of possible or probable DLB of 13% each (26% total), according to the consensus criteria. LBCRS toolkit showed good reliability, with a Cronbach alpha of 0.77, stable even after removing variables from the construct. AT-DLB toolkit Cronbach alpha was 0.52 and, after the subtraction of the "cognitive fluctuation" criterion, was only 0.31. Accuracy, sensitivity, and specificity were higher for LBCRS vs. AT-DLB. However, when simultaneously considered in the logistic models, AT-DLB showed a better performance (p < 0.001). Overall, the concordance between LBCRS positive and AT-DLB possible/probable was of 78.02% CONCLUSIONS: In a clinical setting, the LBCRS and AT-DLB questionnaires have good accuracy for DLB diagnosis.
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Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Enfermedad de Alzheimer/diagnóstico , Diagnóstico Diferencial , Humanos , Italia , Enfermedad por Cuerpos de Lewy/diagnóstico , Reproducibilidad de los ResultadosRESUMEN
Nowadays, railway freight transportation is becoming more and more crucial since it represents the best alternative to road transport in terms of sustainability, pollution, and impact on the environment and on public health. Upgrading the potentiality of this kind of transportation, it would be possible to avoid delays in goods deliveries due to road accidents, traffic jams, and other situation occurring on roads. A key factor in this framework is therefore represented by monitoring and maintenance of the train components. Implementing a real time monitoring of the main components and a predictive maintenance approach, it would be possible to avoid unexpected breakdowns and consequently unavailability of wagons for unscheduled repair activities. As highlighted in recent statistical analysis, one of the elements more critical in case of failure is represented by the brake system. In this view, a real time monitoring of pressure values in some specific points of the system would provide significant information on its health status. In addition, since the braking actions are related to the load present on the convoy, thanks to this kind of monitoring, it would be possible to appreciate the different behavior of the system in case of loaded and unloaded trains. This paper presented an innovative wireless monitoring system to perform brake system diagnostics. A low-power system architecture, in terms of energy harvesting and wireless communication, was developed due to the difficulty in applying a wired monitoring system to a freight convoy. The developed system allows acquiring brake pressure data in critical points in order to verify the correct behavior of the brake system. Experimental results collected during a five-month field test were provided to validate the approach.
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Salud Pública , Monitoreo Fisiológico , Fenómenos FísicosRESUMEN
PURPOSE: Intracerebral hemorrhage (ICH) is an uncommon but deadly event in patients with COVID-19 and its imaging features remain poorly characterized. We aimed to describe the clinical and imaging features of COVID-19-associated ICH. METHODS: Multicenter, retrospective, case-control analysis comparing ICH in COVID-19 patients (COV19 +) versus controls without COVID-19 (COV19 -). Clinical presentation, laboratory markers, and severity of COVID-19 disease were recorded. Non-contrast computed tomography (NCCT) markers (intrahematoma hypodensity, heterogeneous density, blend sign, irregular shape fluid level), ICH location, and hematoma volume (ABC/2 method) were analyzed. The outcome of interest was ultraearly hematoma growth (uHG) (defined as NCCT baseline ICH volume/onset-to-imaging time), whose predictors were explored with multivariable linear regression. RESULTS: A total of 33 COV19 + patients and 321 COV19 - controls with ICH were included. Demographic characteristics and vascular risk factors were similar in the two groups. Multifocal ICH and NCCT markers were significantly more common in the COV19 + population. uHG was significantly higher among COV19 + patients (median 6.2 mL/h vs 3.1 mL/h, p = 0.027), and this finding remained significant after adjustment for confounding factors (systolic blood pressure, antiplatelet and anticoagulant therapy), in linear regression (B(SE) = 0.31 (0.11), p = 0.005). This association remained consistent also after the exclusion of patients under anticoagulant treatment (B(SE) = 0.29 (0.13), p = 0.026). CONCLUSIONS: ICH in COV19 + patients has distinct NCCT imaging features and a higher speed of bleeding. This association is not mediated by antithrombotic therapy and deserves further research to characterize the underlying biological mechanisms.
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COVID-19 , Anticoagulantes , Biomarcadores , COVID-19/complicaciones , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/diagnóstico por imagen , Hematoma/diagnóstico por imagen , Humanos , Estudios RetrospectivosRESUMEN
Several studies focused on the role of vitamin D (vitD) in pain chronification. This study focused on vitD level and pain chronification and extension in headache disorders. Eighty patients with primary headache underwent neurological examination, laboratory exams, including serum calcifediol 25(OH)D, and headache features assessment along with three questionnaires investigating depression, anxiety, and allodynia. The 86.8% of the population had migraine (48% episodic and 52% chronic). The 44.1% of patients had extracranial pain, and 47.6% suffered from allodynia. A vitD deficit, namely a serum 25(OH)D level <20 ng/ml, was detectable in 46.1% of the patients, and it occurred more frequently (p = 0.009) in patients suffering from chronic migraine (CM)-medication overuse migraine (MOH) (62.9%) than in episodic migraine (EM, 25.7%) or tension-type headache (TTH, 11.4%). The occurrence of extracranial pain and allodynia was higher in the CM-MOH than in the EM and in the TTH groups but was not related to the co-occurrence of vitD deficiency (Fisher's exact test p = 0.11 and p = 0.32, respectively). Our findings show that 25(OH)D deficit is also related to chronic headache, probably because of vitD anti-inflammatory and tolerogenic properties, reinforcing the idea of a neuroinflammatory mechanism underpinning migraine chronification.
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OBJECTIVES: Excessive daytime sleepiness (EDS) affects a large percentage of Parkinson's disease (PD) patients, and it is enhanced by dopamine agonist drugs. Currently, there is no treatment of choice for EDS in PD. Our aim was to check the clinical impression that some patients who were given selegiline, a selective inhibitor of monoamine oxidase B, experienced an improvement in their daytime somnolence. METHODS: In the present study, we retrospectively identified 45 Parkinson's disease patients (21 females and 24 males) among those referred to the PD Center in Varese that (a) showed excessive daytime sleepiness, usually developed after the introduction of a dopamine agonist, (b) were given selegiline 10 mg to improve their treatment schedule independently of excessive sleepiness, and (c) in whom the Epworth Sleepiness Scale (ESS) and the Parkinson's Disease Sleep Scale (PDSS) scores were available both before and 3 months after the introduction of selegiline. RESULTS: We compared the corresponding scores (ESS, PDSS, and UPDRS III) evaluated before and 3 months after the introduction of selegiline by the nonparametric Mann-Whitney U test: The differences showed a statistically significant improvement of somnolence but no change in the UPDRS III scores. CONCLUSION: Despite some limitations, our data suggest that selegiline may be a valuable add-on therapy in PD patients to reduce their daytime somnolence.
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Trastornos de Somnolencia Excesiva , Enfermedad de Parkinson , Trastornos de Somnolencia Excesiva/tratamiento farmacológico , Agonistas de Dopamina , Femenino , Humanos , Masculino , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Estudios Retrospectivos , SelegilinaRESUMEN
Smart monitoring systems are currently gaining more attention and are being employed in several technological areas. These devices are particularly appreciated in the structural field, where the collected data are used with purposes of real time alarm generation and remaining fatigue life estimation. Furthermore, monitoring systems allow one to take advantage of predictive maintenance logics that are nowadays essential tools for mechanical and civil structures. In this context, a smart wireless node has been designed and developed. The sensor node main tasks are to carry out accelerometric measurements, to process data on-board, and to send wirelessly synthetic information. A deep analysis of the design stage is carried out, both in terms of hardware and software development. A key role is played by energy harvesting integrated in the device, which represents a peculiar feature and it is thanks to this solution and to the adoption of low power components that the node is essentially autonomous from an energy point of view. Some prototypes have been assembled and tested in a laboratory in order to check the design features. Finally, a field test on a real structure under extreme weather conditions has been performed in order to assess the accuracy and reliability of the sensors.
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D-Serine acts as a co-agonist of N-methyl-D-aspartate receptors (NMDAR) which appear overactivated in AD, while D-aspartate is a modulatory molecule acting on NMDAR as a second agonist. The aim of this work is to clarify whether the levels of these D-amino acids in serum are deregulated in AD, with the final goal to identify novel and precocious biomarkers in AD. Serum levels of L- and D-enantiomers of serine and aspartate were determined by HPLC using a pre-column derivatization procedure and a selective enzymatic degradation. Experimental data obtained from age-matched healthy subjects (HS) and AD patients were statistically evaluated by considering age, gender, and disease progression, and compared. Minor changes were apparent in the serum L- and D-aspartate levels in AD patients compared to HS. A positive correlation for the D-serine level and age was apparent in the AD cohort. Notably, the serum D-serine level and the D-/total serine ratio significantly increased with the progression of the disease. Gender seems to have a minor effect on the levels of all analytes tested. This work proposes that the serum D-serine level and D-/total serine ratio values as novel and valuable biomarkers for the progression of AD: the latter parameter allows to discriminate CDR 2 and CDR 1 patients from healthy (CDR 0) individuals.
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Enfermedad de Alzheimer , Aminoácidos , Ácido Aspártico , Biomarcadores , Humanos , Receptores de N-Metil-D-Aspartato , SerinaRESUMEN
Posterior reversible encephalopathy cases are increasingly being reported in patients affected by COVID-19, but the largest series so far only includes 4 patients. We present a series of 6 patients diagnosed with PRES during COVID-19 hospitalized in 5 Centers in Lombardia, Italy. 5 out of the 6 patients required intensive care assistence and seizures developed at weaning from assisted ventilation. 3 out of 6 patients underwent cerebrospinal fluid analysis which was normal in all cases, with negative PCR for Sars-CoV-2 genome search. PRES occurrence may be less rare than supposed in COVID-19 patients and a high suspicion index is warranted for prompt diagnosis and treatment.
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BACKGROUND: CD4+ T-cell dysregulation occurs in Parkinson's disease (PD); however, it is unknown whether it contributes to PD development. The objective of this study was to investigate transcription factor gene expression in CD4+ T cells in idiopathic rapid eye movement sleep behavior disorder, the strongest risk factor for prodromal PD. METHODS: Expression of transcription factors (TBX21, STAT1, STAT3, STAT4, STAT6, RORC, GATA3, FOXP3, and NR4A2) was measured in CD4+ T cells from 33 polysomnographically confirmed idiopathic rapid eye movement sleep behavior disorder subjects and compared with expression in cells from matched healthy subjects and antiparkinson drugs-naive PD patients. RESULTS: Compared with healthy subjects, idiopathic rapid eye movement sleep behavior disorder subjects and PD patients had lower TBX21, STAT3, and STAT4, and higher FOXP3 expression. TBX21 expression discriminated healthy subjects from idiopathic rapid eye movement sleep behavior disorder subjects and PD patients, but not idiopathic rapid eye movement sleep behavior disorder subjects with PD. CONCLUSIONS: In idiopathic rapid eye movement sleep behavior disorder subjects CD4+ T cells exhibit a peculiar molecular signature strongly resembling cells from PD patients, suggesting early involvement of peripheral immunity in PD. © 2020 International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Trastorno de la Conducta del Sueño REM , Linfocitos T CD4-Positivos , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genética , Trastorno de la Conducta del Sueño REM/genética , Factores de Transcripción TCFAsunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Benserazida/farmacología , Dopaminérgicos/farmacología , Encefalomielitis/tratamiento farmacológico , Levodopa/farmacología , Rigidez Muscular/tratamiento farmacológico , Mioclonía/tratamiento farmacológico , Receptores de Glicina/inmunología , Adulto , Autoanticuerpos , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Benserazida/administración & dosificación , Dopaminérgicos/administración & dosificación , Combinación de Medicamentos , Encefalomielitis/inmunología , Encefalomielitis/fisiopatología , Humanos , Levodopa/administración & dosificación , Masculino , Rigidez Muscular/inmunología , Rigidez Muscular/fisiopatología , Mioclonía/inmunología , Mioclonía/fisiopatologíaRESUMEN
During the COVID-19 outbreak, the Neurology and Stroke Unit (SU) of the hospital of Varese had to serve as a cerebrovascular hub, meaning that the referral area for the unit doubled. The number of beds in the SU was increased from 4 to 8. We took advantage of the temporary suspension of the out-patient clinic and reshaped our activity to guarantee the 24/7 availability of recombinant tissue Plasminogen Activator (rtPA) intravenous therapy (IVT) in the SU, and to ensure we were able to admit patients to the SU as soon as they completed endovascular treatment (EVT). In 42 days, 46 stroke patients were admitted to our hospital, and 34.7% of them underwent IVT and/or EVT, which means that we treated 0.38 patients per day; in the baseline period from 2016 to 2018, these same figures had been 23.5% and 0.23, respectively. The mean values of the door-to-first CT/MRI and the door-to-groin puncture, but not of the onset-to-door and the door-to-needle periods were slightly but significantly longer than those observed in the baseline period in 276 patients. On an individual basis, only one patient exceeded the door-to-groin puncture time limit computed from the baseline period by about 10 min. None of the patients had a major complication following the procedures. None of the patients was or became SARS-CoV2 positive. In conclusion, we were able to manage the new hub-and-spoke system safely and without significant delays. The reshaping of the SU was made possible by the significant reduction of out-patient activity. The consequences of this reduction are still unknown but eventually, this emergency will suggest ways to reconsider the management and the allocation of health system resources.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.