Relation and effect of resilience on burnout in nurses: A literature review and meta-analysis.

AIM: To study the relation between burnout and resilience and to identify the profile of nurses presenting this quality. BACKGROUND AND INTRODUCTION: Healthcare professionals are subject to high rates of burnout. Resilience could be an important factor in preventing or alleviating this condition. METHODS: The PubMed, ProQuest, Scopus and ScienceDirect databases were consulted in February 2022 using the equation 'burnout AND resilience AND nurs*'. The inclusion criteria applied were that the texts should describe quantitative studies, be published in English or Spanish, in any year, and be directly related to the question considered. The meta-analysis was performed using StatsDirect statistical software. RESULTS: Analysis of the 29 studies shows that among the dimensions of burnout, nurses are especially prone to emotional exhaustion, and are less affected by depersonalisation and low personal accomplishment. Those who score highly for resilience tend to have longer service experience, acceptable salaries and less work overload. Meta-analysis reveals an inverse correlation between resilience and burnout (r = -0.41; n = 2750), exhaustion (r = -0.27; n = 6966) and depersonalisation (r = -0.23; n = 6115). CONCLUSION: Many nurses present low levels of resilience and suffer from burnout syndrome. The application of programmes to enhance their resilience would help prevent burnout and optimise the potential to provide quality health care. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Resilience is inversely correlated with burnout, depersonalisation and emotional exhaustion. Accordingly, healthcare organisations should develop and implement evidence-based programmes to foster nurses' resilience and thus reduce their susceptibility to burnout.

Synthesis and interaction with growth factors of sulfated oligosaccharides containing an anomeric fluorinated tail.

Compounds that mimic the biological properties of glycosaminoglycans (GAGs) and can be more easily prepared than the native GAG oligosaccharides are highly demanded. Here, we present the synthesis of sulfated oligosaccharides displaying a perfluorinated aliphatic tag at the reducing end as GAG mimetics. The preparation of these molecules was greatly facilitated by the presence of the fluorinated tail since the reaction intermediates were isolated by simple fluorous solid-phase extraction. Fluorescence polarization competition assays indicated that the synthesized oligosaccharides interacted with two heparin-binding growth factors, midkine (MK) and FGF-2, showing higher binding affinities than the natural oligosaccharides, and can be therefore considered as useful GAG mimetics. Moreover, NMR experiments showed that the 3D structure of these compounds is similar to that of the native sequences, in terms of sugar ring and glycosidic linkage conformations. Finally, we also demonstrated that these derivatives are able to block the MK-stimulating effect on NIH3T3 cells growth.

Normal Infrarenal Aortic Diameter in Men and Women in a Mediterranean Area.

BACKGROUND: Infrarenal aortic diameter (AD) values currently considered normal are based on measurements from epidemiologic studies performed over 20 years ago. Knowledge of expected normal AD is important for understanding the relevance of abdominal aortic dilatation. The aim of this study was to define contemporary reference values for normal infrarenal AD and build a predictive model based on individual features. METHODS: A cross-sectional study of participants in a population-based screening program for abdominal aortic aneurysm (AAA) was performed in a healthcare district with 400,000 inhabitants. Men and women aged 65 years were invited to participate. Cardiovascular (CV) risk factors, family history of AAA, personal history of other aneurysms, CV disease, and anthropometric parameters were evaluated. The largest anteroposterior inner-inner diameter of the infrarenal aorta was measured by ultrasound. Multiple linear regressions were used to determine independent predictors of AD. The best-fit model was obtained by randomly selecting 70% of the sample and validating the results in the remaining 30%. RESULTS: A total of 4,730 people (2,089 men and 2,641 women) were invited. The participation rate was 50.4% for men and 44.0% for women. Mean AD (standard deviation, SD) was 16.51 (3.2) mm in the overall group, 17.91 (3.51) mm in men, and 15.25 (2.32) mm in women (P < 0.001). Male sex (P < 0.001), body surface area (P < 0.001), smoking habit (P = 0.012), and history of arterial aneurysms (P = 0.013) were independently associated with increased AD. Dyslipidemia was associated with decreased AD (P < 0.001). The findings were used to build a model for predicting AD based on individual characteristics. CONCLUSIONS: ADs in our study population are smaller than those described in classic epidemiological studies. Men have a significantly larger diameter than women and the strongest predictor of increased AD is body surface area. A greater understanding of factors associated with AD will help predict expected sizes in individual members of the population.

Autonomy with responsibility ¿Is informed consent just a signature on a paper? Evaluation in patients who underwent spine's surgery.

PURPOSE: To evaluate the information that patients undergoing spine surgery truly receive and assimilate when they sign their informed consent documents. METHODS: This was a retrospective study on patients who underwent spine arthrodesis or spine discectomy. Patients were given a full explanation of the surgical technique to be employed and its potential risks before they were included on the surgical waiting list. Before surgery, they were asked to sign an informed consent form. The studied variables included whether patients read the informed consent form, whether they recalled the surgical technique used or the spinal segment operated, whether they were aware of the surgical risks involved, and if they had looked for information about their procedure elsewhere. Answers were analyzed by age and educational level. RESULTS: Of a total of 458 total patients, only 51.9% answered all the questions. Sixty-three percent of patients said they had read the informed consent document before surgery. Although 91.6% of patients were aware of the spine segment operated, only 73.5% remembered the surgical technique employed. A total of 63.9% of patients could recall the vertebral levels operated. 39.1% were not aware of the surgical risks involved, and only 16.0% of patients admitted having looked for additional information. A statistically significant correlation was found between the search for additional information and young age (p < 0.001) on the one hand, and high educational level on the other (p = 0.023). CONCLUSION: Even though obtaining informed consent is an important procedure before spinal surgery, almost 40% of the patients in this study underwent surgery without reading the informed consent document or being aware of the risks posed by the procedure.

Uremic Toxins Induce THP-1 Monocyte Endothelial Adhesion and Migration through Specific miRNA Expression.

Atherosclerosis is initiated by the activation of endothelial cells that allows monocyte adhesion and transmigration through the vascular wall. The accumulation of uremic toxins such as indoxyl sulphate (IS) and p-cresol (PC) has been associated with atherosclerosis. Currently, miRNAs play a crucial role in the regulation of monocyte activation, adhesion, and trans-endothelial migration. The aim of the present study is to evaluate the effect of IS and PC on monocyte adhesion and migration processes in monocytes co-cultured with endothelial cells as well as to determine the underlying mechanisms. The incubation of HUVECs and THP-1 cells with both IS and PC toxins resulted in an increased migratory capacity of THP-1 cells. Furthermore, the exposure of THP-1 cells to both uremic toxins resulted in the upregulation of BMP-2 and miRNAs-126-3p, -146b-5p, and -223-3p, as well as the activation of nuclear factor kappa B (NF-κB) and a decrease in its inhibitor IĸB. Uremic toxins, such as IS and PC, enhance the migratory and adhesion capacity of THP-1 cells to the vascular endothelium. These toxins, particularly PC, contribute significantly to uremia-associated vascular disease by increasing in THP-1 cells the expression of BMP-2, NF-κB, and key miRNAs associated with the development of atherosclerotic vascular diseases.

Long-Term Assessment of a Set of CO2 Concentration Sensors in an In-Use Office Building.

The measurement of the CO2 concentration has a wide range of applications. Traditionally, it has been used to assess air quality, with other applications linked to the experimental assessment of occupancy patterns and air renewal rates. More recently, the worldwide dissemination of COVID-19 establishing a relationship between infection risk and the mean CO2 level has abruptly led to the measurement of the CO2 concentration in order to limit the spread of this respiratory disease in the indoor environment. Therefore, the extensive application of this measurement outside of traditional air quality assessment requires an in-depth analysis of the suitability of these sensors for such modern applications. This paper discusses the performance of an array of commercial wall-mounted CO2 sensors, focusing on their application to obtain occupancy patterns and air renovation rates. This study is supported by several long-term test campaigns conducted in an in-use office building located in south-eastern Spain. The results show a spread of 19-101 ppm, with a drift of 28 ppm over 5 years, an offset of 2-301 ppm and fluctuations up to 80 ppm in instantaneous measurements not related to concentration changes. It is proposed that values averaged over 30 min, using a suitable reference value, be used to avoid erroneous results when calibration is not feasible.

The Interaction between Chondroitin Sulfate and Dermatan Sulfate Tetrasaccharides and Pleiotrophin.

Pleiotrophin (PTN) is a neurotrophic factor that participates in the development of the embryonic central nervous system (CNS) and neural stem cell regulation by means of an interaction with sulfated glycosaminoglycans (GAGs). Chondroitin sulfate (CS) is the natural ligand in the CNS. We have previously studied the complexes between the tetrasaccharides used here and MK (Midkine) by ligand-observed NMR techniques. The present work describes the interactions between a tetrasaccharide library of synthetic models of CS-types and mimetics thereof with PTN using the same NMR transient techniques. We have concluded that: (1) global ligand structures do not change upon binding, (2) the introduction of lipophilic substituents in the structure of the ligand improves the strength of binding, (3) binding is weaker than for MK, (4) STD-NMR results are compatible with multiple binding modes, and (5) the replacement of GlcA for IdoA is not relevant for binding. Then we can conclude that the binding of CS derivatives to PTN and MK are similar and compatible with multiple binding modes of the same basic conformation.

Prevalence, levels and related factors of burnout in nurse managers: A multi-centre cross-sectional study.

AIMS: The aims of this study are to analyse the prevalence and levels of burnout syndrome in nurse managers and to evaluate the relationship between burnout and related sociodemographic, occupational and psychological factors. BACKGROUND: Burnout syndrome, defined as an emotional response to chronic stress, is a major problem among nurse managers. METHODS: The study was conducted using a cross-sectional survey design and data collected by the Maslach Burnout Inventory, the revised NEO Five Factor Inventory and the Educational-Clinical Questionnaire for Anxiety and Depression. The sample population consisted of 86 nurse managers from different hospitals from the Public Health Service of Andalusia, Spain. RESULTS: A total of 22.4% of the participants presented high levels of emotional exhaustion, 21% experienced depersonalisation and 57.6% had little sense of personal accomplishment. Working long shifts was related to burnout. Emotional exhaustion and depersonalization were predicted by depression, while personal accomplishment was predicted by conscientiousness, agreeableness and openness. CONCLUSIONS: A total of 34.1% of the participants presented high levels of burnout, manifested by feelings of low personal accomplishment. Psychological and occupational factors play an important role in the development of this syndrome. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers should seek to detect burnout among staff and colleagues matching the risk profile for this condition and promote interventions to prevent it.

Midkine Interaction with Chondroitin Sulfate Model Synthetic Tetrasaccharides and Their Mimetics: The Role of Aromatic Interactions.

Midkine (MK) is a neurotrophic factor that participates in the embryonic central nervous system (CNS) development and neural stem cell regulation, interacting with sulfated glycosaminoglycans (GAGs). Chondroitin sulfate (CS) is the natural ligand in the CNS. In this work, we describe the interactions between a library of synthetic models of CS-types and mimics. We did a structural study of this library by NMR and MD (Molecular Dynamics), concluding that the basic shape is controlled by similar geometry of the glycosidic linkages. Their 3D structures are a helix with four residues per turn, almost linear. We have studied the tetrasaccharide-midkine complexes by ligand observed NMR techniques and concluded that the shape of the ligands does not change upon binding. The ligand orientation into the complex is very variable. It is placed inside the central cavity of MK formed by the two structured beta-sheets domains linked by an intrinsically disordered region (IDR). Docking analysis confirmed the participation of aromatics residues from MK completed with electrostatic interactions. Finally, we test the biological activity by increasing the MK expression using CS tetrasaccharides and their capacity in enhancing the growth stimulation effect of MK in NIH3T3 cells.

Congenital dyserythropoietic anemia types Ib, II, and III: novel variants in the CDIN1 gene and functional study of a novel variant in the KIF23 gene.

Congenital dyserythropoietic anemias (CDA) are disorders characterized by ineffective erythropoiesis and morphological anomalies in erythrocytes and erythroblasts. The purpose of this study is to identify the gene variants in patients diagnosed with CDA. We analyzed five unrelated patients and two siblings with a targeted panel of genes to CDA: CDAN1, CDIN1, SEC23B, KIF23, KLF1, and GATA1 genes. We found three novel variants in the CDIN1 gene (p.Leu136Val, p.Tyr247Cys, and p.Ile273Thr), four known variants in the SEC23B gene (p.Arg14Trp, p.Arg554Ter, p.Asp239Gly, and p.Ser436Leu), and one novel variant in the KIF23 gene (p.Leu945Trpfs*31). The in silico analysis of novel variants predict that they are pathogenic and, the in vitro study confirms the functional impact of the KIF23 variant on the protein location.

Defibrotide in hematopoietic stem cell transplantation: A multicenter survey study of the Spanish Hematopoietic Stem Cell Transplantation Group (GETH).

BACKGROUND: Defibrotide is approved in European Union for the treatment of severe sinusoidal obstruction syndrome (SOS) after HSCT. However, it has also been used for SOS prophylaxis, moderate SOS and in other complications such as transplant-associated thrombotic microangiopathy (TAM). The objective of this study was to evaluate current uses, effectiveness and safety of defibrotide in patients with HSCT. METHODS: This multicenter, retrospective study included patients treated with defibrotide for any indication at 28 HSCT centers of the Grupo Español de Trasplante Hematopoyetico (GETH) including the pediatric subgroup Grupo Español de Trasplante de Medula en Niños (GETMON). RESULTS: Three hundred and eighty eight patients treated with defibrotide between January 2011 and December 2018 were included. 253 patients were children, and 135 patients were adults. In total, 332 transplants were allogeneic, and the remainder were autologous. Main indications for defibrotide use were severe/very severe SOS in 173 patients, SOS prophylaxis in 135 patients, moderate SOS in 41 patients, TAM in six patients and suspected SOS in 33 patients. Overall survival (OS) at day +100 in the SOS prophylaxis group was 89% (95% CI, 87%-91%). In the group of patients with moderate and severe/very severe SOS, the OS at day +100 was 80% (95% CI, 74%-86%) and 62% (95% CI, 59%-65%), respectively (P = .0015). With a longer follow-up, median of 2 years (4 months-7 years), OS was 63% (95% CI, 59%-67%) in the SOS prophylaxis patients. OS for patients with moderate and severe/very severe SOS groups was 53% (95% CI, 47%-61%) and 26% (95% CI, 22%-30%), respectively (P = .006). 191 patients died, and SOS was the main cause of death in 23 patients (12%). CONCLUSIONS: Defibrotide has an acceptable safety profile with an improved response in severe/very severe SOS compared with historical controls, mainly in pediatric patients. Use of defibrotide for prophylaxis may improve prognosis of patients at high risk of complications due to endothelial damage such as those who receive a second transplant. SOS has an important impact on the HSCT long-term survival, as can be concluded from our study.

Unexpected Cause of Persistent Microcytosis and Neurological Symptoms in a Child: Niemann-Pick Disease Type C.

Atypical microcytic anemias are rare diseases of iron/heme metabolism that can be diagnostically challenging. We report the case of a 2-year-old twin boy with neurodevelopmental delay and persistent microcytosis in whom atypical microcytic anemias was initially suspected. He had low blood iron and transferrin saturation with normal/high ferritin despite iron therapy. Hemoglobinopathies were excluded by conventional/DNA studies. Hepcidin was high but iron-refractory-iron-deficiency anemia was ruled out by a genetic panel. Bone marrow aspiration revealed foamy cells and iron depletion. A genetic study confirmed the diagnosis of Niemann-Pick disease type C which was finally considered the origin of microcytosis through anemia of chronic disease.

Thoracic Anesthesia during the COVID-19 Pandemic: 2021 Updated Recommendations by the European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) Thoracic Subspecialty Committee.

The novel coronavirus pandemic has radically changed the landscape of normal surgical practice. Lifesaving cancer surgery, however, remains a clinical priority, and there is an increasing need to fully define the optimal oncologic management of patients with varying stages of lung cancer, allowing prioritization of which thoracic procedures should be performed in the current era. Healthcare providers and managers should not ignore the risk of a bimodal peak of mortality in patients with lung cancer; an imminent spike due to mortality from acute coronavirus disease 2019 (COVID-19) infection, and a secondary peak reflecting an excess of cancer-related mortality among patients whose treatments were deemed less urgent, delayed, or cancelled. The European Association of Cardiothoracic Anaesthesiology and Intensive Care Thoracic Anesthesia Subspecialty group has considered these challenges and developed an updated set of expert recommendations concerning the infectious period, timing of surgery, vaccination, preoperative screening and evaluation, airway management, and ventilation of thoracic surgical patients during the COVID-19 pandemic.

Comaneci device-assisted embolization of wide-necked carotid aneurysms with an unfavorable ratio.

BACKGROUND: Endovascular treatment is the technique of choice for most intracranial aneurysms. However, the treatment of morphologically complex wide-necked aneurysms with an unfavorable anatomy is still a therapeutic challenge. The purpose of the study is to describe the initial experience with the Comaneci embolization assist device for the treatment of wide-necked aneurysms with an unfavorable ratio for direct embolization. METHODS: We report a retrospective single-center analysis taken from a prospective database of consecutive aneurysms of the anterior circulation treated using the Comaneci device in the period from March 2017 to March 2019. RESULTS: Eighteen aneurysms were collected from 16 patients (9 women and 7 men) treated using the Comaneci device. The mean age was 48.4 years (range 36-81). Twelve patients had SAH, three were incidental aneurysms and one had compressive symptoms. A complete asymptomatic occlusion rate of 88.8% was obtained. The major complication rate was 5.55%. CONCLUSION: The Comaneci embolization assist device is a safe, effective option for endovascular treatment of complex aneurysms with an unfavorable ratio.

European Association of Cardiothoracic Anesthesiology (EACTA) Cardiothoracic and Vascular Anesthesia Fellowship Curriculum: First Edition.

This special article summarizes the design and certification process of the European Association of Cardiothoracic Anesthesiology (EACTA) Cardiothoracic and Vascular Anesthesia (CTVA) Fellowship Program. The CTVA fellowship training includes a two-year curriculum at an EACTA-accredited educational facility. Before fellows are accepted into the program, they must meet a number of requirements, including evidence of a valid license to practice medicine, a specialist degree examination in anesthesiology, and appropriate language skills as required in the host centers. The CVTA Fellowship Program has 2 sequential and complementary levels of training-both with a modular structure that allows for individual planning and also takes into account the differing national healthcare needs and requirements of the 36 countries represented in EACTA. The basic training period focuses on the anesthetic management of patients undergoing cardiac, thoracic, and vascular surgery and related procedures. The advanced training period is intended to deepen and to extend the clinical and nontechnical skills that fellows have acquired during the basic training. The goal of the EACTA fellowship is to produce highly trained and competent perioperative physicians who are able to care for patients undergoing cardiac, thoracic, and vascular anesthesia.

Thoracic Anesthesia of Patients With Suspected or Confirmed 2019 Novel Coronavirus Infection: Preliminary Recommendations for Airway Management by the European Association of Cardiothoracic Anaesthesiology Thoracic Subspecialty Committee.

The novel coronavirus has caused a pandemic around the world. Management of patients with suspected or confirmed coronavirus infection who have to undergo thoracic surgery will be a challenge for the anesthesiologists. The thoracic subspecialty committee of European Association of Cardiothoracic Anaesthesiology (EACTA) has conducted a survey of opinion in order to create recommendations for the anesthetic approach to these challenging patients. It should be emphasized that both the management of the infected patient with COVID-19 and the self-protection of the anesthesia team constitute a complicated challenge. The text focuses therefore on both important topics.

Identification of New Potential LncRNA Biomarkers in Hirschsprung Disease.

Hirschsprung disease (HSCR) is a neurocristopathy defined by intestinal aganglionosis due to alterations during the development of the Enteric Nervous System (ENS). A wide spectrum of molecules involved in different signaling pathways and mechanisms have been described in HSCR onset. Among them, epigenetic mechanisms are gaining increasing relevance. In an effort to better understand the epigenetic basis of HSCR, we have performed an analysis for the identification of long non-coding RNAs (lncRNAs) by qRT-PCR in enteric precursor cells (EPCs) from controls and HSCR patients. We aimed to test the presence of a set lncRNAs among 84 lncRNAs in human EPCs, which were previously related with crucial cellular processes for ENS development, as well as to identify the possible differences between HSCR patients and controls. As a result, we have determined a set of lncRNAs with positive expression in human EPCs that were screened for mutations using the exome data from our cohort of HSCR patients to identify possible variants related to this pathology. Interestingly, we identified three lncRNAs with different levels of their transcripts (SOCS2-AS, MEG3 and NEAT1) between HSCR patients and controls. We propose such lncRNAs as possible regulatory elements implicated in the onset of HSCR as well as potential biomarkers of this pathology.

ChIP-Seq-Based Approach in Mouse Enteric Precursor Cells Reveals New Potential Genes with a Role in Enteric Nervous System Development and Hirschsprung Disease.

Hirschsprung disease (HSCR) is a neurocristopathy characterized by intestinal aganglionosis which is attributed to a failure in neural crest cell (NCC) development during the embryonic stage. The colonization of the intestine by NCCs is a process finely controlled by a wide and complex gene regulatory system. Several genes have been associated with HSCR, but many aspects still remain poorly understood. The present study is focused on deciphering the PAX6 interaction network during enteric nervous system (ENS) formation. A combined experimental and computational approach was performed to identify PAX6 direct targets, as well as gene networks shared among such targets as potential susceptibility factors for HSCR. As a result, genes related to PAX6 either directly (RABGGTB and BRD3) or indirectly (TGFB1, HRAS, and GRB2) were identified as putative genes associated with HSCR. Interestingly, GRB2 is involved in the RET/GDNF/GFRA1 signaling pathway, one of the main pathways implicated in the disease. Our findings represent a new contribution to advance in the knowledge of the genetic basis of HSCR. The investigation of the role of these genes could help to elucidate their implication in HSCR onset.

Simultaneous Angioplasty and Mechanical Thrombectomy in Tandem Carotid Occlusions. Incidence of Reocclusions and Prognostic Predictors.

OBJECTIVES: The best revascularization technique for tandem carotid occlusions is not clearly defined. The primary objective of this study is to describe our technical and clinical results, analyzing the main predictors of functional independence. The secondary objective is the analysis of stent reocclusion rate. METHODS: A single-center series of 250 mechanical thrombectomies in the anterior circulation was studied. A subsequent analysis of 40 carotid occlusions was performed. The demographics, etiology, angiographic results, antithrombotic drugs, and 3-month follow-up were registered. A bivariate analysis was performed to establish the association of the study variables with major clinical complications (death, symptomatic hemorrhagic transformation and early recurrence) and the functional prognosis. In addition, the relationship between the preprocedure antiaggregation regimen and the reocclusions was studied, as well as its clinical impact. Independent predictive factors were studied using a multivariate logistic regression model. RESULTS: Complete recanalization was achieved in 30 cases (75%). Simultaneous stent placement was decided in 32 cases (80%). Functional independence was reached in 19 cases (47.5%), and 3 (7.5%) died at 3 months. Seven major complications were reported (17.5%). In patients with satisfactory revascularization where a carotid stent was used, 9 reocclusions (28.1%) were detected during the follow-up, 2 of them symptomatic. The only factor related independently with functional independence was the administration of single antiaggregation (odds ratio = .31; 95% confidence interval .002-.595; P = .021). CONCLUSIONS: Urgent endovascular treatment of tandem carotid occlusions has shown to be effective and safe in our series. The administration of single antiaggregation is a predictor of functional independence. In patients treated with carotid stent, the reocclusion rate is high, but generally asymptomatic.

Substitution Rates Predicted by Stability-Constrained Models of Protein Evolution Are Not Consistent with Empirical Data.

Protein structures strongly influence molecular evolution. In particular, the evolutionary rate of a protein site depends on the number of its native contacts. Stability-constrained models of protein evolution consider this influence of protein structure on evolution by predicting the effect of mutations on the stability of the native state, but they currently neglect how mutations affect the protein structure. These models predict that buried protein sites with more native contacts are more constrained by natural selection and less variable, as observed. Nevertheless, previous work did not consider the stability against compact misfolded conformations, although it is known that the negative design that destabilizes these misfolded conformations influences protein evolution significantly. Here, we show that stability-constrained models that consider misfolding predict that site-specific sequence entropy and substitution rate peak at amphiphilic sites with an intermediate number of contacts, as these sites are less constrained than exposed sites with few contacts whose hydrophobicity must be limited. This result holds both for a mean-field model with independent sites and for a pairwise model that takes as a reference the wild-type sequence, but it contrasts with the observations that indicate that the entropy and the substitution rate decrease monotonically with the number of contacts. Our work suggests that stability-constrained models overestimate the tolerance of amphiphilic sites against mutations, either because of the limits of the free energy function or, more importantly in our opinion, because they do not consider how mutations perturb the native protein structure.