Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects.

Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions. We show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also directly triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which bind to sugars on the inner endosomal membrane and then regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, both in vitro and in vivo . We show that rapidly biodegradable ionizable lipids can preferentially create endosomal holes that are smaller in size and reparable by the endosomal sorting complex required for transport (ESCRT) pathway. Ionizable lipids producing such ESCRT-recruiting endosomal holes can produce high expression from cargo mRNA with minimal inflammation. Finally, we show that both routes to non-inflammatory LNPs, either galectin inhibition or ESCRT-recruiting ionizable lipids, are compatible with therapeutic mRNAs that ameliorate inflammation in disease models. LNPs without galectin inhibition or biodegradable ionizable lipids lead to severe exacerbation of inflammation in these models. In summary, endosomal escape induces endosomal membrane damage that can lead to inflammation. However, the inflammation can be controlled by inhibiting galectins (large hole detectors) or by using biodegradable lipids, which create smaller holes that are reparable by the ESCRT pathway. These strategies should lead to generally safer LNPs that can be used to treat inflammatory diseases.

Combination of Physicochemical Tropism and Affinity Moiety Targeting of Lipid Nanoparticles Enhances Organ Targeting.

Two camps have emerged for targeting nanoparticles to specific organs and cell types: affinity moiety targeting and physicochemical tropism. Here we directly compare and combine both using intravenous (IV) lipid nanoparticles (LNPs) designed to target the lungs. We utilized PECAM antibodies as affinity moieties and cationic lipids for physicochemical tropism. These methods yield nearly identical lung uptake, but aPECAM LNPs show higher endothelial specificity. LNPs combining these targeting methods had >2-fold higher lung uptake than either method alone and markedly enhanced epithelial uptake. To determine if lung uptake is because the lungs are the first organ downstream of IV injection, we compared IV vs intra-arterial (IA) injection into the carotid artery, finding that IA combined-targeting LNPs achieve 35% of the injected dose per gram (%ID/g) in the first-pass organ, the brain, among the highest reported. Thus, combining the affinity moiety and physicochemical strategies provides benefits that neither targeting method achieves alone.

Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke.

Effective delivery of mRNA or small molecule drugs to the brain is a significant challenge in developing treatment for acute ischemic stroke (AIS). To address the problem, we have developed targeted nanomedicine to increase drug concentrations in endothelial cells of the blood-brain barrier (BBB) of the injured brain. Inflammation during ischemic stroke causes continuous neuronal death and an increase in the infarct volume. To enable targeted delivery to the inflamed BBB, we conjugated lipid nanocarriers (NCs) with antibodies that bind cell adhesion molecules expressed at the BBB. In the transient middle cerebral artery occlusion mouse model, NCs targeted to vascular cellular adhesion molecule-1 (VCAM) achieved the highest level of brain delivery, nearly two orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles with luciferase-encoding mRNA and Cre-recombinase showed selective expression in the ischemic brain. Anti-inflammatory drugs administered intravenously after ischemic stroke reduced cerebral infarct volume by 62% (interleukin-10 mRNA) or 35% (dexamethasone) only when they were encapsulated in VCAM-targeted NCs. Thus, VCAM-targeted lipid NCs represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS.

Using the traditional microscope for mineral grain orientation determination: A prototype image analysis pipeline for optic-axis mapping (POAM).

This paper reports on the development of an open-source image analysis software 'pipeline' dedicated to petrographic microscopy. Using conventional rock thin sections and images from a standard polarising microscope, the pipeline can classify minerals and subgrains into objects and obtain information about optic-axis orientation. Five metamorphic rocks were chosen to test and illustrate the method. Thin sections were imaged using reflected and cross- and plane-polarised transmitted light. Images were taken at different angles of the polariser and analyser (360° with 10° steps), both with and without the full-lambda plate. The resulting image stacks were analysed with a modular pipeline for optic-axis mapping (POAM). POAM consists of external and internal software packages that register, segment, classify, and interpret the visible light spectra using object-based image analysis (OBIAS). The mapped fields-of-view and grain orientation stereonets of interest are presented in the context of whole-slide images. Two innovations are reported. First, we used hierarchical tree region merging on blended multimodal images to classify individual grains of rock-forming minerals into objects. Second, we assembled a new optical mineralogy algorithm chain that identifies the mineral slow axis orientation. The c-axis orientation results were verified with scanning electron microscopy electron backscattered diffraction (SEM-EBSD) data. For quartz (uniaxial) in a granite mylonite the test yielded excellent correspondence of c-axis azimuth and good agreement for inclination. For orthorhombic orthopyroxene in a deformed garnet harzburgite, POAM produced acceptable results for slow axis azimuth. In addition, the method identified slight anisotropy in garnet that would not be appreciated by traditional microscopy. We propose that our method is ideally suited for two commonly performed tasks in mineralogy. First, for mineral grain classification of entire thin sections scans on blended images to provide automated modal abundance estimates and grain size distribution. Second, for prospective fields of view of interest, POAM can rapidly generate slow axis crystal orientation maps from multiangle image stacks on conventionally prepared thin sections for targeting detailed SEM-EBSD studies.

Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions.

Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up or down-regulate any protein of interest. LNPs have mostly been targeted to specific cell types or organs by physicochemical targeting in which LNP's lipid compositions are adjusted to find mixtures with the desired tropism. Here lung-tropic LNPs are examined, whose organ tropism derives from containing either a cationic or ionizable lipid conferring a positive zeta potential. Surprisingly, these LNPs are found to induce massive thrombosis. Such thrombosis is shown in the lungs and other organs, and it is shown that it is greatly exacerbated by pre-existing inflammation. This clotting is induced by a variety of formulations with cationic lipids, including LNPs and non-LNP nanoparticles, and even by lung-tropic ionizable lipids that do not have a permanent cationic charge. The mechanism depends on the LNPs binding to and then changing the conformation of fibrinogen, which then activates platelets and thrombin. Based on these mechanisms, multiple solutions are engineered that enable positively charged LNPs to target the lungs while ameliorating thrombosis. The findings illustrate how physicochemical targeting approaches must be investigated early for risks and re-engineered with a careful understanding of biological mechanisms.

Out-of-Hospital Cardiac Arrest Following the COVID-19 Pandemic.

Importance: Out-of-hospital cardiac arrest (OHCA) health care provision may be a good indicator of the recovery of the health care system involved in OHCA care following the COVID-19 pandemic. There is a lack of data regarding outcomes capable of verifying this recovery. Objective: To determine whether return to spontaneous circulation, overall survival, and survival with good neurological outcome increased in patients with OHCA since the COVID-19 pandemic was brought under control in 2022 compared with prepandemic and pandemic levels. Design, Setting, and Participants: This observational cohort study was conducted to examine health care response and survival with good neurological outcome at hospital discharge in patients treated following OHCA. A 3-month period, including the first wave of the pandemic (February 1 to April 30, 2020), was compared with 2 periods before (April 1, 2017, to March 31, 2018) and after (January 1 to December 31, 2022) the pandemic. Data analysis was performed in July 2023. Emergency medical services (EMS) serving a population of more than 28 million inhabitants across 10 Spanish regions participated. Patients with OHCA were included if participating EMS initiated resuscitation or continued resuscitation initiated by a first responder. Exposure: The pandemic was considered to be under control following the official declaration that infection with SARS-CoV-2 was to be considered another acute respiratory infection. Main Outcome and Measures: The main outcomes were return of spontaneous circulation, overall survival, and survival at hospital discharge with good neurological outcome, expressed as unimpaired or minimally impaired cerebral performance. Results: A total of 14 732 patients (mean [SD] age, 64.2 [17.2] years; 10 451 [71.2%] male) were included, with 6372 OHCAs occurring during the prepandemic period, 1409 OHCAs during the pandemic period, and 6951 OHCAs during the postpandemic period. There was a higher incidence of OHCAs with a resuscitation attempt in the postpandemic period compared with the pandemic period (rate ratio, 4.93; 95% CI, 4.66-5.22; P < .001), with lower incidence of futile resuscitation for OHCAs (2.1 per 100 000 person-years vs 1.3 per 100 000 person-years; rate ratio, 0.81; 95% CI, 0.71-0.92; P < .001). Recovery of spontaneous circulation at hospital admission increased from 20.5% in the pandemic period to 30.5% in the postpandemic period (relative risk [RR], 1.08; 95% CI, 1.06-1.10; P < .001). In the same way, overall survival at discharge increased from 7.6% to 11.2% (RR, 1.45; 95% CI, 1.21-1.75; P < .001), with 6.6% of patients being discharged with good neurological status (Cerebral Performance Category Scale categories 1-2) in the pandemic period compared with 9.6% of patients in the postpandemic period (RR, 1.07; 95% CI, 1.04-1.10; P < .001). Conclusions and Relevance: In this cohort study, survival with good neurological outcome at hospital discharge following OHCA increased significantly after the COVID-19 pandemic.

Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions.

Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up- or down-regulate any protein of interest. LNPs have been targeted to specific cell types or organs by physicochemical targeting, in which LNP's lipid compositions are adjusted to find mixtures with the desired tropism. In a popular approach, physicochemical targeting is accomplished by formulating with charged lipids. Negatively charged lipids localize LNPs to the spleen, and positively charged lipids to the lungs. Here we found that lung-tropic LNPs employing cationic lipids induce massive thrombosis. We demonstrate that thrombosis is induced in the lungs and other organs, and greatly exacerbated by pre-existing inflammation. This clotting is induced by a variety of formulations with cationic lipids, including LNPs and non-LNP nanoparticles. The mechanism depends on the LNPs binding to fibrinogen and inducing platelet and thrombin activation. Based on these mechanisms, we engineered multiple solutions which enable positively charged LNPs to target the lungs while not inducing thrombosis. Our findings implicate thrombosis as a major barrier that blood erects against LNPs with cationic components and illustrate how physicochemical targeting approaches must be investigated early for risks and re-engineered with a careful understanding of biological mechanisms.

Targeting lipid nanoparticles to the blood brain barrier to ameliorate acute ischemic stroke.

After more than 100 failed drug trials for acute ischemic stroke (AIS), one of the most commonly cited reasons for the failure has been that drugs achieve very low concentrations in the at-risk penumbra. To address this problem, here we employ nanotechnology to significantly enhance drug concentration in the penumbra's blood-brain barrier (BBB), whose increased permeability in AIS has long been hypothesized to kill neurons by exposing them to toxic plasma proteins. To devise drug-loaded nanocarriers targeted to the BBB, we conjugated them with antibodies that bind to various cell adhesion molecules on the BBB endothelium. In the transient middle cerebral artery occlusion (tMCAO) mouse model, nanocarriers targeted with VCAM antibodies achieved the highest level of brain delivery, nearly 2 orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles loaded with either a small molecule drug (dexamethasone) or mRNA (encoding IL-10) reduced cerebral infarct volume by 35% or 73%, respectively, and both significantly lowered mortality rates. In contrast, the drugs delivered without the nanocarriers had no effect on AIS outcomes. Thus, VCAM-targeted lipid nanoparticles represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS. Graphical abstract: Acute ischemic stroke induces upregulation of VCAM. We specifically targeted upregulated VCAM in the injured region of the brain with drug- or mRNA-loaded targeted nanocarriers. Nanocarriers targeted with VCAM antibodies achieved the highest brain delivery, nearly orders of magnitude higher than untargeted ones. VCAM-targeted nanocarriers loaded with dexamethasone and mRNA encoding IL-10 reduced infarct volume by 35% and 73%, respectively, and improved survival rates.

Targeted Nanocarriers Co-Opting Pulmonary Intravascular Leukocytes for Drug Delivery to the Injured Brain.

Ex vivo-loaded white blood cells (WBC) can transfer cargo to pathological foci in the central nervous system (CNS). Here we tested affinity ligand driven in vivo loading of WBC in order to bypass the need for ex vivo WBC manipulation. We used a mouse model of acute brain inflammation caused by local injection of tumor necrosis factor alpha (TNF-α). We intravenously injected nanoparticles targeted to intercellular adhesion molecule 1 (anti-ICAM/NP). We found that (A) at 2 h, >20% of anti-ICAM/NP were localized to the lungs; (B) of the anti-ICAM/NP in the lungs >90% were associated with leukocytes; (C) at 6 and 22 h, anti-ICAM/NP pulmonary uptake decreased; (D) anti-ICAM/NP uptake in brain increased up to 5-fold in this time interval, concomitantly with migration of WBCs into the injured brain. Intravital microscopy confirmed transport of anti-ICAM/NP beyond the blood-brain barrier and flow cytometry demonstrated complete association of NP with WBC in the brain (98%). Dexamethasone-loaded anti-ICAM/liposomes abrogated brain edema in this model and promoted anti-inflammatory M2 polarization of macrophages in the brain. In vivo targeted loading of WBC in the intravascular pool may provide advantages of coopting WBC predisposed to natural rapid mobilization from the lungs to the brain, connected directly via conduit vessels.

Mechanisms by Which Liposomes Improve Inhaled Drug Delivery for Alveolar Diseases.

Diseases of the pulmonary alveolus, such as pulmonary fibrosis, are leading causes of morbidity and mortality, but exceedingly few drugs are developed for them. A major reason for this gap is that after inhalation, drugs are quickly whisked away from alveoli due to their high perfusion. To solve this problem, the mechanisms by which nano-scale drug carriers dramatically improve lung pharmacokinetics using an inhalable liposome formulation containing nintedanib, an antifibrotic for pulmonary fibrosis, are studied. Direct instillation of liposomes in murine lung increases nintedanib's total lung delivery over time by 8000-fold and lung half life by tenfold, compared to oral nintedanib. Counterintuitively, it is shown that pulmonary surfactant neither lyses nor aggregates the liposomes. Instead, each lung compartment (alveolar fluid, alveolar leukocytes, and parenchyma) elutes liposomes over 24 h, likely serving as "drug depots." After deposition in the surfactant layer, liposomes are transferred over 3-6 h to alveolar leukocytes (which take up a surprisingly minor 1-5% of total lung dose instilled) in a nonsaturable fashion. Further, all cell layers of the lung parenchyma take up liposomes. These and other mechanisms elucidated here should guide engineering of future inhaled nanomedicine for alveolar diseases.

Targeted drug delivery to the brain endothelium dominates over passive delivery via vascular leak in experimental intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is one of the most common causes of fatal stroke, yet has no specific drug therapies. Many attempts at passive intravenous (IV) delivery in ICH have failed to deliver drugs to the salvageable area around the hemorrhage. The passive delivery method assumes vascular leak through the ruptured blood-brain barrier will allow drug accumulation in the brain. Here we tested this assumption using intrastriatal injection of collagenase, a well-established experimental model of ICH. Fitting with hematoma expansion in clinical ICH, we showed that collagenase-induced blood leak drops significantly by 4 h after ICH onset and is gone by 24 h. We observed passive-leak brain accumulation also declines rapidly over ∼4 h for 3 model IV therapeutics (non-targeted IgG; a protein therapeutic; PEGylated nanoparticles). We compared these passive leak results with targeted brain delivery by IV monoclonal antibodies (mAbs) that actively bind vascular endothelium (anti-VCAM, anti-PECAM, anti-ICAM). Even at early time points after ICH induction, where there is high vascular leak, brain accumulation via passive leak is dwarfed by brain accumulation of endothelial-targeted agents: At 4 h after injury, anti-PECAM mAbs accumulate at 8-fold higher levels in the brain vs. non-immune IgG; anti-VCAM nanoparticles (NPs) deliver a protein therapeutic (superoxide dismutase, SOD) at 4.5-fold higher levels than the carrier-free therapeutic at 24 h after injury. These data suggest that relying on passive vascular leak provides inefficient delivery of therapeutics even at early time points after ICH, and that a better strategy might be targeted delivery to the brain endothelium, which serves as the gateway for the immune attack on the peri-hemorrhage inflamed brain region.

Scale for contraversive pushing in stroke patients: pusher behavior vs Thalamic astasia differential diagnosis and psychometric properties.

BACKGROUND: : Few studies have investigated the psychometric properties of the Scale for Contraversive Pushing (SCP) in depth, and none have evaluated its ability to establish differential diagnosis between pusher behavior (PB) and thalamic astasia (TA). OBJECTIVES: : To study the ability of the SCP to establish differential diagnosis, its reliability, content, construct, and internal validity in the assessment of subacute stroke patients. METHODS: : 120 individuals were evaluated using the SCP over a four-week period of treatment. Intra- and inter-observer reliability, floor and ceiling effects, minimum detectable change (MDC), internal validity and sensitivity to change were explored. In addition, the Barthel Index and the Trunk Control Test were used to study their correlations with the SCP. RESULTS: : Discriminant validity provides evidence that the correlation between SCP items was large or moderate. Convergent validity demonstrated that the correlation of each item with the total score of the scale was high (at around 0.8). Sensitivity to change was large (W = 0.274). Intra- and inter-observer reliability were excellent (Intraclass Correlation Coefficient > 0.9; k > 0.8), except for items B standing and C sitting (k > 0.7). The MDC was 1.39, and ceiling (8.333%) and floor (15.833%) effects were adequate. Cronbach's alpha (α) was equal to 0.901 (0.874-0.924) and McDonald's Omega (ω) was equal to 0.883 (0.856-0.973), showing excellent internal consistency. CONCLUSIONS: : The SCP is a reliable and valid tool which can successfully establish differential diagnosis between PB and TA and evaluate the changes generated by physiotherapy treatment.

Supramolecular arrangement of protein in nanoparticle structures predicts nanoparticle tropism for neutrophils in acute lung inflammation.

This study shows that the supramolecular arrangement of proteins in nanoparticle structures predicts nanoparticle accumulation in neutrophils in acute lung inflammation (ALI). We observed homing to inflamed lungs for a variety of nanoparticles with agglutinated protein (NAPs), defined by arrangement of protein in or on the nanoparticles via hydrophobic interactions, crosslinking and electrostatic interactions. Nanoparticles with symmetric protein arrangement (for example, viral capsids) had no selectivity for inflamed lungs. Flow cytometry and immunohistochemistry showed NAPs have tropism for pulmonary neutrophils. Protein-conjugated liposomes were engineered to recapitulate NAP tropism for pulmonary neutrophils. NAP uptake in neutrophils was shown to depend on complement opsonization. We demonstrate diagnostic imaging of ALI with NAPs; show NAP tropism for inflamed human donor lungs; and show that NAPs can remediate pulmonary oedema in ALI. This work demonstrates that structure-dependent tropism for neutrophils drives NAPs to inflamed lungs and shows NAPs can detect and treat ALI.

Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE).

Current nucleoside-modified RNA lipid nanoparticle (modmRNA-LNP) technology has successfully paved the way for the highest clinical efficacy data from next-generation vaccinations against SARS-CoV-2 during the COVID-19 pandemic. However, such modmRNA-LNP technology has not been characterized in common pre-existing inflammatory or immune-challenged conditions, raising the risk of adverse clinical effects when administering modmRNA-LNPs in such cases. Herein, we induce an acute-inflammation model in mice with lipopolysaccharide (LPS) intratracheally (IT), 1 mg kg-1, or intravenously (IV), 2 mg kg-1, and then IV administer modmRNA-LNP, 0.32 mg kg-1, after 4 h, and screen for inflammatory markers, such as pro-inflammatory cytokines. ModmRNA-LNP at this dose caused no significant elevation of cytokine levels in naive mice. In contrast, shortly after LPS immune stimulation, modmRNA-LNP enhanced inflammatory cytokine responses, Interleukin-6 (IL-6) in serum and Macrophage Inflammatory Protein 2 (MIP-2) in liver significantly. Our report identifies this phenomenon as inflammation exacerbation (IE), which was proven to be specific to the LNP, acting independent of mRNA cargo, and was demonstrated to be time- and dose-dependent. Macrophage depletion as well as TLR3 -/- and TLR4-/- knockout mouse studies revealed macrophages were the immune cells involved or responsible for IE. Finally, we show that pretreatment with anti-inflammatory drugs, such as corticosteroids, can partially alleviate IE response in mice. Our findings characterize the importance of LNP-mediated IE phenomena in gram negative bacterial inflammation, however, the generalizability of modmRNA-LNP in other forms of chronic or acute inflammatory and immune contexts needs to be addressed.

Monoclonal antibody 2C5 specifically targets neutrophil extracellular traps.

Neutrophils can release DNA and granular cytoplasmic proteins that form smooth filaments of stacked nucleosomes (NS). These structures, called neutrophil extracellular traps (NETs), are involved in multiple pathological processes, and NET formation and removal are clinically significant. The monoclonal antibody 2C5 has strong specificity toward intact NS but not to individual NS components, indicating that 2C5 could potentially target NS in NETs. In this study, NETs were generated in vitro using neutrophils and HL-60 cells differentiated into granulocyte-like cells. The specificity of 2C5 toward NETs was evaluated by ELISA, which showed that it binds to NETs with the specificity similar to that for purified nucleohistone substrate. Immunofluorescence showed that 2C5 stains NETs in both static and perfused microfluidic cell cultures, even after NET compaction. Modification of liposomes with 2C5 dramatically enhanced liposome association with NETs. Our results suggest that 2C5 could be used to identify and visualize NETs and serve as a ligand for NET-targeted diagnostics and therapies.

Oxidative DNA Damage Modulates DNA Methylation Pattern in Human Breast Cancer 1 (BRCA1) Gene via the Crosstalk between DNA Polymerase ß and a de novo DNA Methyltransferase.

DNA damage and base excision repair (BER) are actively involved in the modulation of DNA methylation and demethylation. However, the underlying molecular mechanisms remain unclear. In this study, we seek to understand the mechanisms by exploring the effects of oxidative DNA damage on the DNA methylation pattern of the tumor suppressor breast cancer 1 (BRCA1) gene in the human embryonic kidney (HEK) HEK293H cells. We found that oxidative DNA damage simultaneously induced DNA demethylation and generation of new methylation sites at the CpGs located at the promoter and transcribed regions of the gene ranging from -189 to +27 in human cells. We demonstrated that DNA damage-induced demethylation was mediated by nucleotide misincorporation by DNA polymerase ß (pol ß). Surprisingly, we found that the generation of new DNA methylation sites was mediated by coordination between pol ß and the de novo DNA methyltransferase, DNA methyltransferase 3b (DNMT3b), through the interaction between the two enzymes in the promoter and encoding regions of the BRCA1 gene. Our study provides the first evidence that oxidative DNA damage can cause dynamic changes in DNA methylation in the BRCA1 gene through the crosstalk between BER and de novo DNA methylation.

Síndrome de burnout en médicos y personal paramédico / Burnout syndrome in medical practitioners and paramedic personel

Introduction Burnout syndrome is one of the most studied manifestations of job stress. The burnout concept was used by the first time in the area of psychology by Freudenberger in 1974. This psychologist defined it as a condition of fatigue or frustration that is produced by the commitment to a reason, lifestyle or relationship that does not produce the expected effort. Afterwards, Maslach and Jackson proposed three interrelated dimensions: emotional weariness (EW) which estimates the experience of emotional fatigue for the demands of work; the depersonalization (DP) which measures the answers of impersonal type and negative attitudes towards the patients; and the personal accomplishment (PA) which reflects the personal satisfaction and the competition in the practice of the daily work. These dimensions are joined in the Maslach Burnout Inventory (MBI) that is used to measure the afore mentioned syndrome. Several studies have demonstrated the presence of burnout syndrome among medical and paramedic personnel. The close contact with the patients and the work overload are the main reasons of this syndrome. In a multicentre study carried out among 248 doctors of the United States, 40% presented the syndrome with emotional detriment, which coincides with another study carried out with nurses attending patients with palliative care and marrow transplants. Also, in a study carried out among residents of internal medicine of the University of Washington, there was a prevalence of 76% of professional wear, with an autoperception of a lower quality in the professional care of the patients, after comparing them with non-affected residents. In Mexico, a study that investigated burnout level in a group of 450 medical practitioners, nurses and paramedics of 12 institutions revealed the following information: 10.9% presented emotional weariness, 19.6%, depersonalization, and 74.9, low personal accomplishment. Palmer et al. determined a general prevalence of 44% of the syndrome in anesthesiologists. The work overload and the conflict of values were variables that influenced the presence of this syndrome. At the Instituto Mexicano del Seguro Social, Aranda et al., carried out a study among family physicians, where the prevalence of burnout syndrome was 42.3%. Likewise, Cabrera et al., found that, out of 236 studied nurses, 92 (39%) had information compatible with burnout syndrome, with statistically significant differences for the age and the antiquity in the place after comparing them with nurses without burnout syndrome. The burnout syndrome was considered by the World Health Organization as work risk. Its trascendence is rooted in the impact it has in the labor relation between medical and/or paramedic personnel and the health institutions. For this reason, we considered it important to investigate the presence of this syndrome among the medical and paramedic personnel working at hospital of the Mexican social security. Material and Methods Design: Transversal comparative survey. Population: Of a total population of 240 workers of the health area assigned to a general hospital a sample of 160 was obtained that included doctors, nurses and medical assistants based on an average prevalence of the syndrome in 30%, with an alpha level of 0.05 and a power of 90%. Instrument of evaluation: The survey was based on the following sociodemographic and labor variables: age, marital status, academic level, labor antiquity, antiquity of adscript ion to the hospital, category, service and labor shift. To evaluate the burnout syndrome, the MBI questionnaire was used in its previously validated Spanish version. The afore mentioned instrument is an objective way of measuring and determining the burnout level that a person experiences, in its three subscales: EW, DP and PA. The survey consists of 22 items with a Likert type punctuation scale (0-6), of which 9 valued EW, 5, DP, and 8, PA. With regard to the EW, which values the sensation of being emotionally exhausted by the daily contact with people to whom it is necessary to attend as object of work, a punctuation of 27 or higher indicated a high level; between 19 and 26, moderated; and lower than 19, low. In the subscale DP, which measures the degree in which the response towards the patients is cold, distant and impersonal, punctuations above 10 indicated a high level; from 6 to 9, moderated; lower than 6, low. In the subscale PA, which values the feelings of competition and efficiency for the accomplishment of the work and the relation with the people who are being attended, values above 40 indicated personal high accomplishment; from 34 to 39, intermediate; and under 33, low. In the case of obtaining a low emotional depletion, a low depersonalization and a high personal accomplishment, it was considered that no burnout was present. In the rest of the cases, the presence of burnout syndrome was established. Compilation of the information: From August to December, 2005, the survey was applied to each of the workers, indicating them that they should answer and return it in a term not longer than five days. They were all informed previously about the general objectives of the study and its confidential and anonymous character. The head investigator integrated later on the database. Statistical tests: Descriptive and inferential statistics were carried out. The odds ratio and confidence intervals of 95% were calculated to measure the association between the sociodemographic and labor factors with the professional wear. Results Of 160 workers to whom the survey MBI was applied, only 146 returned it in a complete form. Regarding the frequency and the percentages of the three categories studied with the qualifications of low, average and high for every subscale that composes the burnout syndrome, it was observed that the highest evaluations fit the medical assistants. There was a 19.6% prevalence of burnout syndrome among the groups of doctors with at least one of three disturb subscales. Likewise, it was observed that all medical assistants had an alteration of a minimum of two subscales. The nursing personnel did not present information that constitutes a risk for the development of burnout syndrome. Only four sociodemographic and labor variables were found as risk factors for the presence of burnout syndrome, as well as their relation with each of the subscales composing it. When the variables compared age, labor antiquity and time of adscript ion in the service with each of the subscales of the burnout, we observed that depersonalization appeared in older workers and longer antiquity in the position and the lack of personal accomplishment in workers with longer time in the service. There were no statistically significant differences in the subscale of emotional weariness. Discussion In the last years, burnout syndrome has acquired special relevance, mainly because of the series of repercussions that it has in the labor and personal area. Numerous studies exist on the prevalence of this syndrome in different health professionals, but in present work incorporated medical assistants, since they are those who have the first contact with the patients in our institution.

Introducción El concepto de burnout fue utilizado por primera vez en el ámbito de la psicología por Freudenberger en el año de 1974. Este psicólogo lo definió como un estado de fatiga o frustración que se produce por la dedicación a una causa, forma de vida o relación que no produce el esperado esfuerzo. Más tarde, Maslach y Jackson propusieron tres dimensiones interrelacionadas: el cansancio emocional (CE), la despersonalización (DP) y la realización personal (RP). Estas dimensiones se integran en el cuestionario Maslach Burnout Inventory (MBI) que se utiliza para medir dicho síndrome. Material y métodos Diseño: Encuesta transversal comparativa. Población: Se entregó el cuestionario MBI a 160 trabajadores del área de la salud adscritos al Hospital General de Zona con Medicina Familiar 36 de la Ciudad de Cardel, Veracruz. Instrumento de evaluación: Se construyó una encuesta sobre las siguientes variables sociodemográficas y laborales: edad, estado civil, nivel académico, antigüedad laboral, antigüedad de adscripción al hospital, categoría, servicio y turno laboral. Para evaluar el síndrome de burnout se utilizó el cuestionario MBI en su versión en español. Dicho instrumento consta de 22 ítems con escala de puntuación tipo Likert (0-6), de los cuales 9 valoran CE, 5 la DP y 8 la RP. Recolección de la información: Durante el periodo comprendido de agosto a diciembre del 2006 se entregó el cuestionario a cada uno de los trabajadores de la salud. Pruebas estadísticas: Se realizó estadística descriptiva e inferencial. Se calculó la razón de momios e intervalos de confianza de 95% para medir la asociación entre los factores sociodemográficos y laborales con el desgaste profesional. Resultados De 160 trabajadores a quienes se les entregó el cuestionario MBI, sólo 146 lo regresaron en forma completa. En lo que respecta a la frecuencia y los porcentajes de las tres categorías estudiadas se observó que las evaluaciones más altas corresponden a las asistentes médicas. Hubo una prevalencia del síndrome de burnout entre el grupo de médicos del 19.6% con al menos una de las tres subescalas alteradas. Asimismo se observa que en todas las asistentes médicas hubo alteración de un mínimo de dos subescalas. Sólo se encontraron cuatro variables sociodemográficas y laborales como factores de riesgo para la presencia del síndrome de burnout, así como su relación con cada una de la subescalas que lo componen. Discusión Existen numerosos estudios sobre la prevalencia de este síndrome en diferentes profesionales de la salud, pero en el presente trabajo se incorpora a las asistentes médicas, ya que son quienes tienen un primer contacto con los pacientes en nuestra institución. Las cifras de prevalencia del síndrome de burnout reportadas por otros estudios realizados en México entre el personal médico van desde el 42.3% y 44% hasta 50%; en esta investigación la prevalencia fue menor y la dimensión de cansancio emocional es la más afectada. Entre las variables que se consideraron factores de riesgo en nuestro estudio se encuentra el estado civil. Asimismo, el trabajar en el turno vespertino y ofrecer sus servicio en la consulta externa también estuvieron relacionados con mayor predisposición al síndrome de burnout. Al igual que otros estudios, en esta investigación se encontró un mayor nivel de Burnout en profesionales con mayor edad. En lo que respecta a la DP y RP, éstas se presentaron en trabajadores cuya antigüedad laboral era mayor. En conclusión, la prevalencia del síndrome de burnout entre las asistentes médicas es muy alta y es necesario adoptar medidas para evitar el desarrollo de esta patología.