First-trimester screening for pre-eclampsia and small for gestational age : A comparison of the gaussian and Fetal Medicine Foundation algorithms

Pre-eclampsia (PE) and small for gestational age (SGA) can be predicted from the first trimester. The most widely used algorithm worldwide is the Fetal Medicine Foundation (FMF) algorithm. The recently described Gaussian algorithm has reported excellent results although it is unlikely to be externally validated. Therefore, as an alternative approach, we compared the predictive accuracy for PE and SGA of the Gaussian and FMF algorithms. Secondary analysis of a prospective cohort study was conducted at Vall d'Hebron University Hospital (Barcelona) with 2641 singleton pregnancies. The areas under the curve for the predictive performance for early-onset and preterm PE and early-onset and preterm SGA were calculated with the Gaussian and FMF algorithms and subsequently compared. The FMF and Gaussian algorithms showed a similar predictive performance for most outcomes and marker combinations. Nevertheless, significant differences for early-onset PE prediction favored the Gaussian algorithm in the following combinations: mean arterial blood pressure (MAP) with pregnancy-associated plasma protein A, MAP with placental growth factor, and MAP alone. The first-trimester Gaussian and FMF algorithms have similar performances for PE and SGA prediction when applied with all markers within a routine care setting in a Spanish population, adding evidence to the external validity of the FMF algorithm. The first-trimester Gaussian and Fetal Medicine Foundation algorithms have similar predictive performances for pre-eclampsia and small-for-gestational-age fetuses

First-trimester screening for pre-eclampsia and small for gestational age: A comparison of the gaussian and Fetal Medicine Foundation algorithms

Preeclampsia d'inici precoç; Primer trimestreEarly-onset pre-eclampsia; First trimesterPreeclampsia de inicio precoz; Primer trimestreObjective Pre-eclampsia (PE) and small for gestational age (SGA) can be predicted from the first trimester. The most widely used algorithm worldwide is the Fetal Medicine Foundation (FMF) algorithm. The recently described Gaussian algorithm has reported excellent results although it is unlikely to be externally validated. Therefore, as an alternative approach, we compared the predictive accuracy for PE and SGA of the Gaussian and FMF algorithms. Methods Secondary analysis of a prospective cohort study was conducted at Vall d'Hebron University Hospital (Barcelona) with 2641 singleton pregnancies. The areas under the curve for the predictive performance for early-onset and preterm PE and early-onset and preterm SGA were calculated with the Gaussian and FMF algorithms and subsequently compared. Results The FMF and Gaussian algorithms showed a similar predictive performance for most outcomes and marker combinations. Nevertheless, significant differences for early-onset PE prediction favored the Gaussian algorithm in the following combinations: mean arterial blood pressure (MAP) with pregnancy-associated plasma protein A, MAP with placental growth factor, and MAP alone. Conclusions The first-trimester Gaussian and FMF algorithms have similar performances for PE and SGA prediction when applied with all markers within a routine care setting in a Spanish population, adding evidence to the external validity of the FMF algorithm

Confirmation of preeclampsia-like syndrome induced by severe COVID-19: an observational study

COVID-19; Preeclampsia; PregnancyCOVID-19; Preeclampsia; EmbarazoCOVID-19; Preeclampsia; EmbaràsBACKGROUND Since the outbreak of the COVID-19 pandemic, some studies have reported an increased preeclampsia incidence in pregnant women with SARS-CoV-2 infection. Several explanations for this association have been proposed, including a preeclampsia-like syndrome induced by severe COVID-19. This syndrome was described in a small case series and has not been confirmed in larger studies, and its effect on perinatal outcomes has not been studied. OBJECTIVE This study aimed to confirm the preeclampsia-like syndrome because of COVID-19 and to investigate its implications on pregnancy outcomes and prognosis. STUDY DESIGN This was a prospective, observational study conducted in a tertiary referral hospital. The inclusion criteria were pregnant women admitted to the intensive care unit for severe pneumonia because of COVID-19. They were classified into 3 groups based on clinical and laboratory findings: preeclampsia, preeclampsia-like syndrome, and women without preeclampsia features. The 3 cohorts were analyzed and compared at 3 different times: before, during, and after severe pneumonia. The main outcomes were incidence of adverse perinatal outcomes and signs and symptoms of PE, such as hypertension, proteinuria, thrombocytopenia, elevated liver enzymes, and increased angiogenic factors (soluble fms-like tyrosine kinase 1–to–placental growth factor ratio). RESULTS A total of 106 women were admitted to the intensive care unit because of severe pneumonia, and 68 women were included in the study. Of those, 53 (50.0%) did not meet the diagnostic criteria for preeclampsia and remained pregnant after pneumonia (non-preeclampsia); 7 (6.6%) met the diagnostic criteria for preeclampsia, had abnormal (>38) soluble fms-like tyrosine kinase 1–to–placental growth factor ratio (preeclampsia), and delivered during severe pneumonia, and 8 (7.5%) met the diagnostic criteria for preeclampsia, had normal (≤38) soluble fms-like tyrosine kinase 1–to–placental growth factor ratio (preeclampsia like), and did not deliver during pneumonia. Despite not having delivered, most preeclampsia-related features improved after severe pneumonia in women with preeclampsia-like syndrome. Women with preeclampsia had significantly poorer outcomes than women with preeclampsia-like syndrome or without preeclampsia. CONCLUSION More than 50% of women with severe COVID-19 and diagnostic criteria for preeclampsia may not be preeclampsia but a preeclampsia-like syndrome, which may affect up to 7.5% of women with severe COVID-19. Preeclampsia-like syndrome might have similar perinatal outcomes to those of normotensive women with severe pneumonia because of COVID-19. For these reasons, preeclampsia-like syndrome should be excluded by using soluble fms-like tyrosine kinase 1–to–placental growth factor ratio in future research and before making clinical decisions

Mycobacterium manresensis induces trained immunity in vitro

The COVID-19 pandemic posed a global health crisis, with new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants weakening vaccine-driven protection. Trained immunity could help tackle COVID-19 disease. Our objective was to analyze whether heat-killed Mycobacterium manresensis (hkMm), an environmental mycobacterium, induces trained immunity and confers protection against SARS-CoV-2 infection. To this end, THP-1 cells and primary monocytes were trained with hkMm. The increased secretion of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, and IL-10, metabolic activity, and changes in epigenetic marks suggested hkMm-induced trained immunity in vitro. Healthcare workers at risk of SARS-CoV-2 infection were enrolled into the MANRECOVID19 clinical trial (NCT04452773) and were administered Nyaditum resae (NR, containing hkMm) or placebo. No significant differences in monocyte inflammatory responses or the incidence of SARS-CoV-2 infection were found between the groups, although NR modified the profile of circulating immune cell populations. Our results show that M. manresensis induces trained immunity in vitro but not in vivo when orally administered as NR daily for 14 days. Biological sciences; Molecular biology; Immunology; Microbiolog

Mycobacterium manresensis induces trained immunity in vitro

The COVID-19 pandemic posed a global health crisis, with new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants weakening vaccine-driven protection. Trained immunity could help tackle COVID-19 disease. Our objective was to analyze whether heat-killed Mycobacterium manresensis (hkMm), an environmental mycobacterium, induces trained immunity and confers protection against SARS-CoV-2 infection. To this end, THP-1 cells and primary monocytes were trained with hkMm. The increased secretion of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, and IL-10, metabolic activity, and changes in epigenetic marks suggested hkMm-induced trained immunity in vitro. Healthcare workers at risk of SARS-CoV-2 infection were enrolled into the MANRECOVID19 clinical trial (NCT04452773) and were administered Nyaditum resae (NR, containing hkMm) or placebo. No significant differences in monocyte inflammatory responses or the incidence of SARS-CoV-2 infection were found between the groups, although NR modified the profile of circulating immune cell populations. Our results show that M. manresensis induces trained immunity in vitro but not in vivo when orally administered as NR daily for 14 days.The MANRECOVID19 clinical trial has been sponsored by the Reig Jofre Group. This research was funded by the Consorcio Centro de Investigación Biomédica en Red (CIBERES and CIBEREHD) and the European Union’s Horizon 2020 research and innovation programme under grant agreement No 847762. MDH is supported by a Margarita Salas grant from NextGenerationEU. LS-M is supported by Juan de la Cierva fellowship (FJC2019-041213-I). NI-U is supported by the Spanish Ministry of Science and Innovation (grant PID2020-117145RB-I00), EU HORIZON-HLTH-2021-CORONA-01 (grant 101046118), and institutional funding from Grifols, Pharma Mar, HIPRA, Amassence, and Palobiofarma. The Innate Immunity lab and the UTE are accredited by the Catalan Agency for Management of University and Research Grants (2017-SGR-490/2021-SGR-01186, 2021-SGR-00931, and 2017-SGR-500/2021 SGR 00920). IGTP is a member of the CERCA network of institutes supported by the Health Department of the Government of Catalonia.info:eu-repo/semantics/publishedVersio

Famílies botàniques de plantes medicinals

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia, Assignatura: Botànica Farmacèutica, Curs: 2013-2014, Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són els recull de 175 treballs d’una família botànica d’interès medicinal realitzats de manera individual. Els treballs han estat realitzat per la totalitat dels estudiants dels grups M-2 i M-3 de l’assignatura Botànica Farmacèutica durant els mesos d’abril i maig del curs 2013-14. Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pel professor de l’assignatura i revisats i finalment co-avaluats entre els propis estudiants. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

X-linked agammaglobulinemia (XLA) : Phenotype, diagnosis, and therapeutic challenges around the world

Background: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features. Methods: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries. Results: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians. Conclusions: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.Peer reviewe

Característiques comunes i diagnòstic diferencial de la COVID-19 i la preeclàmpsia

INTRODUCCIÓ La preeclàmpsia (PE) és una malaltia multisistèmica pròpia de l'embaràs la fisiopatologia de la qual rau en la insuficiència placentària. Aquesta, es pot apreciar a nivell histopatològic dins l'espectre de la malperfusió vascular materna (MVM); i a nivell analític una de les eines més útils és el balanç entre factors pro-angiogènics i anti-angiogènics, el disbalanç dels quals s'ha relacionat de manera altament específica amb malperfusió placentària. Els factors angiogènics poden ajudar a diferenciar la PE d'altres malalties amb característiques clíniques similars, entre elles el recentment descrit PE-like syndrome induït per COVID-19. L'afectació de la infecció per SARS-CoV-2 sobre la gestació i viceversa ha estat en estudi des de l'inici de la pandèmia i ha suscitat especial interès la troballa d'un augment d'incidència de PE en gestants amb la COVID-19. La descripció del PE-like syndrome induït per COVID-19 suggeria que la clínica compatible amb PE que poden manifestar algunes gestants amb COVID-19 greu podia ser en realitat conseqüència de la infecció. L'objectiu d'aquesta tesi és estudiar els paràmetres d'insuficiència placentària en gestants amb la COVID-19 per contribuir a explicar si l'augment d'incidència de PE es deu a una malperfusió placentària des d'un punt de vista fisiopatològic o si, en canvi, són factors materns i derivats de la pròpia infecció els que relacionen aquestes dues patologies. MATERIAL I MÈTODES Es va dissenyar un estudi prospectiu observacional dut a terme a l'Hospital Vall d'Hebron, centre de referència de gestants amb COVID-19, on es van incloure les gestants admeses a la Unitat de Cures Intensives per una pneumònia per SARS-CoV-2. Es van analitzar els paràmetres d'insuficiència placentària, incloent la ràtio de factors angiogènics i l'anàlisi de la MVM de les gestants que complien criteris de PE i es van analitzar els seus resultats perinatals i materns. Per altra banda, es va realitzar un estudi retrospectiu observacional comparant les gestants diagnosticades de COVID-19 amb les dones que es realitzen un cribratge de PE de primer trimestre en l'àmbit català i es van analitzar els paràmetres que havien contribuït a un major risc de PE de primer trimestre. RESULTATS El 7.5% de les gestants amb COVID-19 greu que complien criteris de PE tenien en realitat un PE-like syndrome, caracteritzat per presentar factors angiogènics placentaris normals i tenir millors resultats materns (menor taxa de cesàries) i neonatals (augment de l'edat gestacional i el pes al néixer). En analitzar les placentes d'aquestes pacients, cap de les del grup PE-like syndrome presentava signes de MVM, en contraposició al 80% de les placentes de gestants amb PE. La proporció de casos amb alt risc de PE en primer trimestre és major en les gestants que desenvoluparan una COVID-19, i si s'analitza quins factors hi ha contribuït més destaquen la obesitat i la hipertensió molt més que paràmetres específics d'insuficiència placentària. CONCLUSIONS El PE-like syndrome induït per COVID-19 és una entitat diferenciada de la PE que explicaria, parcialment, la major incidència de PE observada en gestants amb COVID-19. L'eina més útil per a la seva identificació són els factors angiogènics placentaris, encara que també pot ser confirmat postnatalment per l'absència de MVM. A més, en les gestants amb COVID-19 hi hauria una major predisposició a la PE, deguda principalment a factors de risc materns comuns per al desenvolupament de les dues malalties i no a signes de disfunció placentària.INTRODUCCIÓN La preeclampsia (PE) es una enfermedad multisistémica propia del embarazo cuya fisiopatología radica en la insuficiencia placentaria. Ésta se puede apreciar a nivel histopatológico dentro del espectro de la malperfusión vascular materna (MVM); y a nivel analítico una de las herramientas más útiles es el balance entre factores pro-angiogénicos y anti-angiogénicos, cuyo disbalance se ha relacionado de manera altamente específica con malperfusión placentaria. Los factores angiogénicos pueden ayudar a diferenciar la PE de otras enfermedades con características clínicas similares, entre ellas el recientemente descrito PE-like síndrome inducido por COVID-19. La afectación de la infección por SARS-CoV-2 sobre la gestación y viceversa ha estado en estudio desde el inicio de la pandemia y ha suscitado especial interés el hallazgo de un aumento de incidencia de PE en gestantes con la COVID-19. La descripción del PE-like síndrome inducido por COVID-19 sugería que la clínica compatible con PE que pueden manifestar algunas gestantes con COVID-19 grave podía ser en realidad consecuencia de la infección. El objetivo de esta tesis es estudiar los parámetros de insuficiencia placentaria en gestantes con la COVID-19 para contribuir a explicar si el aumento de incidencia de PE se debe a una malperfusión placentaria desde un punto de vista fisiopatológico o si, en cambio, son factores maternos y derivados de la propia infección quienes relacionan estas dos patologías. MATERIAL Y MÉTODOS Se diseñó un estudio prospectivo observacional llevado a cabo en el Hospital Vall d'Hebron, centro de referencia de gestantes con COVID-19, donde se incluyeron las gestantes admitidas en la Unidad de Cuidados Intensivos por una neumonía por SARS-CoV-2. Se analizaron los parámetros de insuficiencia placentaria, incluyendo el ratio de factores angiogénicos y el análisis de la MVM de las gestantes que cumplían criterios de PE y se analizaron sus resultados perinatales y maternos. Por otro lado, se realizó un estudio retrospectivo observacional comparando las gestantes diagnosticadas de COVID-19 con las embarazadas que se realizan un cribado de PE de primer trimestre en el ámbito catalán y se analizaron los parámetros que habían contribuido a un mayor riesgo de PE de primer trimestre. RESULTADOS El 7.5% de las gestantes con COVID-19 grave que cumplían criterios de PE tenían en realidad un PE-like syndrome, caracterizado por presentar factores angiogénicos placentarios normales y tener mejores resultados maternos (menor tasa de cesáreas) y neonatales (aumento de la edad gestacional y el peso al nacer). Al analizar las placentas de estas pacientes, ninguna de las del grupo PE-like syndrome presentaba signos de MVM, en contraposición al 80% de las placentas de gestantes con PE. La proporción de casos con alto riesgo de PE en primer trimestre es mayor en las gestantes que van a desarrollar una COVID-19, y si se analiza qué factores ha contribuido más destacan la obesidad y la hipertensión mucho más que parámetros específicos de insuficiencia placentaria. CONCLUSIONES El PE-like síndrome inducido por COVID-19 es una entidad diferenciada de la PE que explicaría, parcialmente, la mayor incidencia de PE observada en gestantes con COVID-19. La herramienta más útil para su identificación son los factores angiogénicos placentarios, aunque también puede ser confirmado postnatalmente por la ausencia de MVM. Además, en las gestantes con COVID-19 habría una mayor predisposición a la PE, debida principalmente a factores de riesgo maternos comunes para el desarrollo de ambas enfermedades y no a signos de disfunción placentaria.INTRODUCTION Preeclampsia (PE) is a pregnancy-specific multisystemic disorder whose pathophysiology lies in placental insufficiency. Histopathologically, it's linked to the maternal vascular malperfusion (MVM) spectrum; and analytically, one of the most useful tools is the balance between pro-angiogenic and anti-angiogenic factors, the imbalance of which has been associated in a highly specific way to placental malperfusion. Angiogenic factors can help differentiate PE from other diseases with similar clinical features, including the recently described PE-like syndrome induced by COVID-19. The effect of SARS-CoV-2 infection on pregnancy and vice versa has been under study since the beginning of the pandemic and the finding of an increased incidence of PE in pregnant women with COVID has raised particular interest. The description of PE-like syndrome induced by COVID-19 suggested that the clinical features of PE observed in some pregnant women with severe COVID-19 may actually be a consequence of the infection. The aim of this thesis is to study the parameters of placental insufficiency in pregnant women with COVID-19 in order to explain if the increased incidence of PE is due to placental malperfusion physiopathologically or if it is maternal factors and the infection itself that relate these two pathologies. MATERIAL AND METHODS We designed a prospective observational study carried out at Vall d'Hebron Hospital, reference center for pregnant women with COVID-19. Pregnant women admitted to the Intensive Care Unit for SARS-CoV-pneumonia were included. We analyzed parameters of placental insufficiency, including the ratio of angiogenic factors and MVM of pregnant women who met PE criteria, and analyzed their perinatal and maternal outcomes. On the other hand, we designed an observational retrospective study comparing pregnant women diagnosed with COVID-19 with women undergoing first-trimester PE screening in the Catalan area and analyzed the parameters that had contributed to a greater risk of PE of the first trimester. RESULTS About 7.5% of pregnant women with severe COVID-19 who met PE criteria actually had a PE-like syndrome, characterized by presenting normal placental angiogenic factors and having better maternal outcomes (lower cesarean rate) and better neonatal outcomes (increased gestational age and weight at birth). When analyzing the placentas of these patients, none of the PE-like syndrome group showed signs of MVM, in contrast to 80% of the placentas of pregnant women with PE. The proportion of cases with a high risk of PE in the first trimester is greater in pregnant women who will develop a COVID-19, being obesity and hypertension the risk factors that contributed more to this difference, much more than specific parameters of placental insufficiency. CONCLUSIONS The PE-like syndrome induced by COVID-19 and PE are different conditions, and it would partially explain the higher incidence of PE observed in pregnant women with COVID-19. The most useful tool for its identification is placental angiogenic factors, although it can also be confirmed postnatally by the absence of MVM. In addition, in pregnant women with COVID-19 there would be a greater predisposition to PE, mainly due to common maternal risk factors for the development of both diseases and not to signs of placental dysfunction