Osakidetza

The prevalence and related clinical features of obstructive sleep apnea-hypopnea (OSAH) in the general population were estimated in a two-phase cross-sectional study. The first phase, completed by 2,148 subjects (76.9%), included a home survey, blood pressure, and a portable respiratory recording, whereas in the second, subjects with suspected OSAH (n = 442) and a subgroup of those with normal results (n = 305) were invited to undergo polysomnography (555 accepted). Habitual snoring was found in 35% of the population and breathing pauses in 6%. Both features occurred more frequently in men, showed a trend to increase with age, and were significantly associated with OSAH. Daytime hypersomnolence occurred in 18% of the subjects and was not associated with OSAH. An apnea-hypopnea index (AHI) > or = 10 was found in 19% of men and 15% of women. The prevalence of OSAH (AHI > or = 5) increased with age in both sexes, with an odds ratio (OR) of 2.2 for each 10-yr increase. AHI was associated with hypertension after adjusting for age, sex, body mass index, neck circumference, alcohol use, and smoking habit. This study adds evidence for a link between OSAH and hypertension.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

BACKGROUND: Colonoscopy and fecal immunochemical testing (FIT) are accepted strategies for colorectal-cancer screening in the average-risk population. METHODS: In this randomized, controlled trial involving asymptomatic adults 50 to 69 years of age, we compared one-time colonoscopy in 26,703 subjects with FIT every 2 years in 26,599 subjects. The primary outcome was the rate of death from colorectal cancer at 10 years. This interim report describes rates of participation, diagnostic findings, and occurrence of major complications at completion of the baseline screening. Study outcomes were analyzed in both intention-to-screen and as-screened populations. RESULTS: The rate of participation was higher in the FIT group than in the colonoscopy group (34.2% vs. 24.6%, P<0.001). Colorectal cancer was found in 30 subjects (0.1%) in the colonoscopy group and 33 subjects (0.1%) in the FIT group (odds ratio, 0.99; 95% confidence interval [CI], 0.61 to 1.64; P=0.99). Advanced adenomas were detected in 514 subjects (1.9%) in the colonoscopy group and 231 subjects (0.9%) in the FIT group (odds ratio, 2.30; 95% CI, 1.97 to 2.69; P<0.001), and nonadvanced adenomas were detected in 1109 subjects (4.2%) in the colonoscopy group and 119 subjects (0.4%) in the FIT group (odds ratio, 9.80; 95% CI, 8.10 to 11.85; P<0.001). CONCLUSIONS: Subjects in the FIT group were more likely to participate in screening than were those in the colonoscopy group. On the baseline screening examination, the numbers of subjects in whom colorectal cancer was detected were similar in the two study groups, but more adenomas were identified in the colonoscopy group. (Funded by Instituto de Salud Carlos III and others; ClinicalTrials.gov number, NCT00906997.).

OBJECTIVES: To assess the association between gender and suicide attempt/death and identify gender-specific risk/protective factors in adolescents/young adults. METHODS: Systematic review (5 databases until January 2017). Population-based longitudinal studies considering non-clinical populations, aged 12-26 years, assessing associations between gender and suicide attempts/death, or evaluating their gender risk/protective factors, were included. Random effect meta-analyses were performed. RESULTS: Sixty-seven studies were included. Females presented higher risk of suicide attempt (OR 1.96, 95% CI 1.54-2.50), and males for suicide death (HR 2.50, 95% CI 1.8-3.6). Common risk factors of suicidal behaviors for both genders are previous mental or substance abuse disorder and exposure to interpersonal violence. Female-specific risk factors for suicide attempts are eating disorder, posttraumatic stress disorder, bipolar disorder, being victim of dating violence, depressive symptoms, interpersonal problems and previous abortion. Male-specific risk factors for suicide attempt are disruptive behavior/conduct problems, hopelessness, parental separation/divorce, friend's suicidal behavior, and access to means. Male-specific risk factors for suicide death are drug abuse, externalizing disorders, and access to means. For females, no risk factors for suicide death were studied. CONCLUSIONS: More evidence about female-specific risk/protective factors of suicide death, for adolescent/young adults, is needed.

Throughout this article, the reader will notice combinations of superscripted letters and numbers (eg, "Cricoid Pressure ALS-CPR&A-007B "). These callouts are hyperlinked to evidence-based worksheets, which were used in the development of this article. An appendix of worksheets, applicable to this article, is located at the end of the text. The worksheets are available in PDF format and are open access. The topics reviewed by the International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force are grouped as follows: (1) airway and ventilation, (2) supporting the circulation during cardiac arrest, (3) periarrest arrhythmias, (4) cardiac arrest in special circumstances, (5) identifying reversible causes, (6) postresuscitation care, (7) prognostication, and (8) organ donation. Defibrillation topics are discussed in Part 6.

INTRODUCTION: Few studies have examined the clinical, neuropsychological and pharmacological factors involved in the functional outcome of bipolar disorder despite the gap between clinical and functional recovery. METHODS: A sample of 77 euthymic bipolar patients were included in the study. Using an a priori definition of low versus good functional outcome, based on the psychosocial items of the Global Assessment of Functioning (GAF, DSM-IV), and taking also into account their occupational adaptation, the patients were divided into two groups: good or low occupational functioning. Patients with high (n = 46) and low (n = 31) functioning were compared on several clinical, neuropsychological and pharmacological variables and the two patient groups were contrasted with healthy controls (n = 35) on cognitive performance. RESULTS: High- and low-functioning groups did not differ with respect to clinical variables. However, bipolar patients in general showed poorer cognitive performance than healthy controls. This was most evident in low-functioning patients and in particular on verbal memory and executive function measures. CONCLUSIONS: Low-functioning patients were cognitively more impaired than highly functioning patients on verbal recall and executive functions. The variable that best predicted psychosocial functioning in bipolar patients was verbal memory.

RATIONALE: The incidence of obesity hypoventilation syndrome (OHS) may be increasing in parallel with the present obesity epidemic. Despite extensive noninvasive ventilation (NIV) and continuous positive airway pressure (CPAP) use in patients with OHS, information regarding efficacy is limited. OBJECTIVES: We performed a large, multicenter randomized controlled study to determine the comparative efficacy of NIV, CPAP, and lifestyle modification (control group) using daytime PaCO2 as the main outcome measure. METHODS: Sequentially screened patients with OHS with severe sleep apnea were randomized into the above-mentioned groups for a 2-month follow up. Arterial blood gas parameters, clinical symptoms, health-related quality-of-life assessments, polysomnography, spirometry, 6-minute-walk distance, dropouts, compliance, and side effects were evaluated. Statistical analysis was performed using intention-to-treat analysis, although adjustments for CPAP and NIV compliance were also analyzed. MEASUREMENTS AND MAIN RESULTS: In total, 351 patients were selected, and 221 were randomized. NIV yielded the greatest improvement in PaCO2 and bicarbonate, with significant differences relative to the control group but not relative to the CPAP group. In the CPAP group, PaCO2 improvement was significantly different than in the control group only after CPAP compliance adjustment. Additionally, clinical symptoms and polysomnographic parameters improved similarly with NIV and CPAP relative to the control. However, some health-related quality-of-life assessments, the spirometry, and 6-minute-walk distance results improved more with NIV than with CPAP. Dropouts were similar between groups, and compliance and secondary effects were similar between NIV and CPAP. CONCLUSIONS: NIV and CPAP were more effective than lifestyle modification in improving clinical symptoms and polysomnographic parameters, although NIV yielded better respiratory functional improvements than did CPAP. Long-term studies must demonstrate whether this functional improvement has relevant implications. Clinical trial registered with www.clinicaltrials.gov (NCT01405976).

In the search for biomarkers of synapse loss associated with Alzheimer's disease (AD), we used shotgun proteomics to identify a panel of 9 synaptic proteins detectable in human cerebrospinal fluid (CSF). Expression at the human synapse was verified using super resolution microscopy. Using SRM, we monitored the panel in CSF from 3 independent clinical cohorts. We report 6 synaptic biomarkers that demonstrate changes in preclinical AD prior to markers of neurodegeneration, which could have clinical value for assessing disease progression.

INTRODUCTION: The application of an autologous plasma rich in growth factors is beneficial in restoring connective tissues, as shown by clinical evidence in oral surgery and more recently in arthroscopic anterior cruciate ligament reconstruction and two cases of ruptured Achilles tendon in professional athletes. This is attributed to the slow delivery of growth factors from harvested platelets that have been activated by endogenous thrombin promoted by the addition of calcium chloride. PURPOSE: This case report describes a new application of this therapy in the arthroscopic treatment of a large, nontraumatic avulsion of articular cartilage in the knee of an adolescent soccer player. METHODS: After arthroscopic reattachment of the large (>2 cm) loose chondral body in its crater in the medial femoral condyle, autologous plasma rich in growth factors was injected into the area between the crater and the fixed fragment. RESULTS AND CONCLUSION: Despite the extremely poor prognosis of the case, complete articular cartilage healing was considerably accelerated, and the functional outcome was excellent, allowing a rapid resumption of symptom-free athletic activity. This technique opens new perspectives for human tissue regeneration.

COVID-19 is a systemic infection that exerts significant impact on the metabolism. Yet, there is little information on how SARS-CoV-2 affects metabolism. Using NMR spectroscopy, we measured the metabolomic and lipidomic serum profile from 263 (training cohort) + 135 (validation cohort) symptomatic patients hospitalized after positive PCR testing for SARS-CoV-2 infection. We also established the profiles of 280 persons collected before the coronavirus pandemic started. Principal-component analysis discriminated both cohorts, highlighting the impact that the infection has on overall metabolism. The lipidomic analysis unraveled a pathogenic redistribution of the lipoprotein particle size and composition to increase the atherosclerotic risk. In turn, metabolomic analysis reveals abnormally high levels of ketone bodies (acetoacetic acid, 3-hydroxybutyric acid, and acetone) and 2-hydroxybutyric acid, a readout of hepatic glutathione synthesis and marker of oxidative stress. Our results are consistent with a model in which SARS-CoV-2 infection induces liver damage associated with dyslipidemia and oxidative stress.

BACKGROUND: Physical activity promotion is a priority, but contribution of physicians' interventions is unclear. The effectiveness of the PEPAF ("Experimental Program for Physical Activity Promotion"), which was implemented exclusively by physicians in routine primary care from October 2003 to December 2004, was assessed. METHODS: Fifty-six Spanish family physicians were randomized to either the intervention (n = 29) or standard care (n = 27) arm of the trial. The physicians recruited 4317 physically inactive patients (2248 for intervention and 2069 for control protocols) from a systematic sample after assessing their physical activity in routine practice. Intervention physicians provided advice to all patients and a physical activity prescription to the subgroup attending an additional appointment (30%). The main outcome measure was the change in physical activity measured by blinded nurses using the 7-Day Physical Activity Recall. Secondary outcomes included cardiorespiratory fitness and health-related quality of life. RESULTS: At 6 months, intervention patients increased physical activity more than controls (adjusted difference, 18 min/wk [95% confidence interval, 6-31 min/wk]; metabolic equivalent tasks x hours per week, 1.3 [95% CI, 0.4-2.2]). The proportion of the population achieving minimal physical activity recommendations was 3.9% higher in the intervention group (1.2%-6.9%; number needed to treat, 26). No differences were found in secondary outcomes. The effect of intervention was positively modified in subjects older than 50 years (P < or = .01) and in the prescription subgroup (P < .001). CONCLUSIONS: Family physicians were effective for increasing physical activity of primary care patients. Overall clinical effect was small but relevant for population public health. Within the intervention program, clinically relevant effects were seen in patients receiving a physical activity prescription. Trial Registration clinicaltrials.gov Identifier: NCT00131079.

BACKGROUND: The Minnesota Living with Heart Failure Questionnaire (MLHFQ) is one of the most widely used health-related quality of life questionnaires for patients with heart failure (HF). It provides scores for two dimensions, physical and emotional, and a total score. However, there are some concerns about its factor structure and alternatives have been proposed, some including a third factor representing a social dimension. The objectives of the present study were to analyze the internal structure of the MLHFQ and the unidimensionality of the total score, and to compare the different factor structures proposed. METHODS: The MLHFQ was given to 2565 patients with HF. The structural validity of the questionnaire was assessed by confirmatory factor analysis (CFA), and Rasch analysis. These two approaches were also applied to the alternative structures proposed. RESULTS: The CFA results for the hypothesized model of two latent factors and the Rasch analysis confirmed the adequacy of the physical and emotional scales. Rasch analysis for the total score showed only two problematic items. The results of the CFA for other two-factor structures proposed were not better than the results for the original structure. The Rasch analyses applied to the different social factors yielded the best results for Munyombwe's social dimension, composed of six items. CONCLUSIONS: Our results support the validity of using the MLHFQ physical, emotional and total scores in patients with HF, for clinical practice and research. In addition, they confirmed the existence of a third factor, and we recommend the use of Munyombwe's social factor.

OBJECTIVE: To assess the association and magnitude of the effect of early exposure to different types of interpersonal violence (IPV) with suicide attempt and suicide death in youths and young adults. METHOD: We searched six databases until June 2015. Inclusion criteria were as follows: (1) assessment of any type of IPV as risk factor of suicide attempt or suicide: (i) child maltreatment [childhood physical, sexual, emotional abuse, neglect], (ii) bullying, (iii) dating violence, and (iv) community violence; (2) population-based case-control or cohort studies; and (3) subjects aged 12-26 years. Random models were used for meta-analyses (Reg: CRD42013005775). RESULTS: From 23 682 articles, 29 articles with 143 730 subjects for meta-analyses were included. For victims of any IPV, OR of subsequent suicide attempt was 1.99 (95% CI: 1.73-2.28); for child maltreatment, 2.25 (95% CI: 1.85-2.73); for bullying, 2.39 (95% CI: 1.89-3.01); for dating violence, 1.65 (95% CI: 1.40-1.94); and for community violence, 1.48 (95% CI: 1.16-1.87). Young victims of IPV had an OR of suicide death of 10.57 (95% CI: 4.46-25.07). CONCLUSION: Early exposure to IPV confers a risk of suicide attempts and particularly suicide death in youths and young adults. Future research should address the effectiveness of preventing and detecting early any type of IPV exposure in early ages.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

BACKGROUND: The long-term recovery rate of chemosensitive functions in coronavirus disease 2019 patients has not yet been determined. METHOD: A multicentre prospective study on 138 coronavirus disease 2019 patients was conducted. Olfactory and gustatory functions were prospectively evaluated for 60 days. RESULTS: Within the first 4 days of coronavirus disease 2019, 84.8 per cent of patients had chemosensitive dysfunction that gradually improved over the observation period. The most significant increase in chemosensitive scores occurred in the first 10 days for taste and between 10 and 20 days for smell. At the end of the observation period (60 days after symptom onset), 7.2 per cent of the patients still had severe dysfunctions. The risk of developing a long-lasting disorder becomes significant at 10 days for taste (odds ratio = 40.2, 95 per cent confidence interval = 2.204-733.2, p = 0.013) and 20 days for smell (odds ratio = 58.5, 95 per cent confidence interval = 3.278-1043.5, p = 0.005). CONCLUSION: Chemosensitive disturbances persisted in 7.2 per cent of patients 60 days after clinical onset. Specific therapies should be initiated in patients with severe olfactory and gustatory disturbances 20 days after disease onset.

BACKGROUND: The adequate information about the functional capacity of elderly populations is a key for the comprehensive assessment of their health status and autonomy. The Lawton IADL (instrumental activities of daily living) Scale is a very often used scale to assess independent living skills, but has never been validated for its use in Spanish-speaking populations. The purpose of this study was to assess the validity, the reliability, and responsiveness of this widely used scale. METHODS: The validation was based on a prospective cohort of 1,965 patients aged 65 or over who suffered an accidental fall with a hip or wrist fracture as a result. These patients were followed up six months after the production of the fracture. Cronbach's alpha was used to assess reliability, and exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) for the construct validity. Convergent and discriminant validity were examined by the correlation of the IADL Scale with the Barthel Index, SF-12, WOMAC short form, and QuickDASH questionnaires. Known-groups validity was also studied comparing IADL Scale according to different groups, and responsiveness was assessed by means of effect sizes. RESULTS: The mean age was 80.04 years (SD 8.04). The Cronbach alpha coefficient was 0.94. In the EFA, factor loadings ranged from 0.67 to 0.90, and CFA confirmed the homogeneity of the construct. Regarding the convergent validity, all correlation coefficients were higher than 0.40. Significant differences were found according to different groups, supporting known-groups validity. Responsiveness parameters showed moderate to large changes (effect sizes, 0.79 and 0.84 among patients classified as worsened). CONCLUSIONS: These results confirm that the Spanish version of the Lawton IADL Scale has excellent reliability and validity and a moderate to large sensitivity to change. This study provides a proper validation, not only of the Spanish version of the Lawton IADL Scale, but also of the original instrument.

OBJECTIVE: To assess the safety and symptomatic changes of IA injections of platelet-rich plasma (PRP) in patients with OA of the hip. METHODS: Forty patients affected by monolateral severe hip OA were included in the study. Each joint received three IA injections of PRP, which were administered once a week. The primary end point was meaningful pain relief, which was described as a reduction in pain intensity of at least 30% from baseline levels as evaluated by the WOMAC subscale at 6-months post-treatment. The visual analogue scale (VAS) and Harris hip score subscale for pain were used to verify the results. Secondary end points included changes in the level of disability of at least 30% and the percentage of positive responders, i.e. the number of patients that achieved a >30% reduction in pain and disability. RESULTS: Statistically significant reductions in VAS, WOMAC and Harris hip subscores for pain and function were reported at 7 weeks and 6 months (P < 0.05). Twenty-three (57.5%) patients reported a clinically relevant reduction of pain (45%, range 30-71%) as assessed by the WOMAC subscale. Sixteen (40%) of these patients were classified as excellent responders who showed an early pain reduction at 6-7 weeks, which was sustained at 6 months, and a parallel reduction of disability. Side effects were negligible and were limited to a sensation of heaviness in the injection site. CONCLUSIONS: This preliminary non-controlled prospective study supported the safety, tolerability and efficacy of PRP injections for pain relief and improved function in a limited number of patients with OA of the hip.

Background Research suggests that lesbian, gay and bisexual (LGB) adolescents have a higher risk of suicidal behaviours than their heterosexual peers, but little is known about specific risk factors. Aims To assess sexual orientation as a risk factor for suicidal behaviours, and to identify other risk factors among LGB adolescents and young adults. Method A systematic search was made of six databases up to June 2015, including a grey literature search. Population-based longitudinal studies considering non-clinical populations aged 12–26 years and assessing being LGB as a risk factor for suicidal behaviour compared with being heterosexual, or evaluating risk factors for suicidal behaviour within LGB populations, were included. Random effect models were used in meta-analysis. Results Sexual orientation was significantly associated with suicide attempts in adolescents and youths (OR=2.26, 95% CI 1.60–3.20). Gay or bisexual men were more likely to report suicide attempts compared with heterosexual men (OR=2.21, 95% CI 1.21–4.04). Based on two studies, a non-significant positive association was found between depression and suicide attempts in LGB groups. Conclusions Sexual orientation is associated with a higher risk of suicide attempt in young people. Further research is needed to assess completed suicide, and specific risk factors affecting the LGB population.

IMPORTANCE OF THE FIELD: The therapeutic use of platelet-rich plasma (PRP) is an autologous biotechnology that relies on the local delivery of a wide range of growth factors and cytokines with the aim of enhancing tissue healing. Understanding both tendon healing and PRP therapies is an area of research that is critically important in developing optimal formulations and protocols to achieve the intended therapeutic effects. AREAS COVERED IN THIS REVIEW: We summarise recent information on the mechanisms inherent to the earliest response to tendon injury. We then describe the positive effect of PRP therapies on tendon healing. Research on tendinopathy has produced several biological hypotheses based on histopathological, biochemical and clinical findings showing that cell apoptosis, angiofibroblastic features or abnormal biochemical adaptations underlie the condition. WHAT THE READER WILL GAIN: The article provides insights into early healing mechanisms and the influence of PRP therapies on inflammation, cell migration, angiogenesis and the proliferation and synthesis of extracellular matrix. The knowledge gained helps to better understand and optimize tendon therapies. TAKE HOME MESSAGE: The use of endogenous therapies has a positive effect on experimental tendon healing. However, several obstacles need to be addressed to optimise medical practice in this field.

•Circulating EV-proteins allow for CCA risk prediction, early and differential (vs. HCC) diagnosis, and prognostication.•Serum CRP/FIBRINOGEN/FRIL levels discriminated patients with early-stage PSC-CCA from those with PSC.•Most pan-CCA biomarkers are mainly expressed in malignant cholangiocytes within human CCA tumours.•Serum CRP/FIBRINOGEN/FRIL/PIGR levels predict CCA development in patients with PSC before radiological tumour evidence.•The abundance of EV-proteins COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V independently predict patients’ overall survival. Background & AimsCholangiocarcinoma (CCA), heterogeneous biliary tumours with dismal prognosis, lacks accurate early diagnostic methods especially important for individuals at high-risk (i.e. those with primary sclerosing cholangitis [PSC]). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs).MethodsEVs from patients with isolated PSC (n = 45), concomitant PSC-CCA (n = 44), PSC who developed CCA during follow-up (PSC to CCA; n = 25), CCAs from non-PSC aetiology (n = 56), and hepatocellular carcinoma (n = 34) and healthy individuals (n = 56) were characterised by mass spectrometry. Diagnostic biomarkers for PSC-CCA, non-PSC CCA, or CCAs regardless of aetiology (Pan-CCAs) were defined and validated by ELISA. Their expression was evaluated in CCA tumours at a single-cell level. Prognostic EV biomarkers for CCA were investigated.ResultsHigh-throughput proteomics of EVs identified diagnostic biomarkers for PSC-CCA, non-PSC CCA, or Pan-CCA, and for the differential diagnosis of intrahepatic CCA and hepatocellular carcinoma, which were cross-validated by ELISA using total serum. Machine learning-based algorithms disclosed CRP/FIBRINOGEN/FRIL for the diagnosis of PSC-CCA (local disease [LD]) vs. isolated PSC (AUC = 0.947; odds ratio [OR] =36.9) and, combined with carbohydrate antigen 19-9, overpowers carbohydrate antigen 19-9 alone. CRP/PIGR/VWF allowed the diagnosis of LD non-PSC CCAs vs. healthy individuals (AUC = 0.992; OR = 387.5). It is noteworthy that CRP/FRIL accurately diagnosed LD Pan-CCA (AUC = 0.941; OR = 89.4). Levels of CRP/FIBRINOGEN/FRIL/PIGR showed predictive capacity for CCA development in PSC before clinical evidence of malignancy. Multi-organ transcriptomic analysis revealed that serum EV biomarkers were mostly expressed in hepatobiliary tissues, and single-cell RNA sequencing and immunofluorescence analysis of CCA tumours showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EV prognostic biomarkers, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively and positively with patients’ survival, respectively.ConclusionsSerum EVs contain protein biomarkers for the prediction, early diagnosis, and prognostication of CCA that are detectable using total serum, representing a tumour cell-derived liquid biopsy tool for personalised medicine.Impact and implicationsThe accuracy of current imaging tests and circulating tumour biomarkers for cholangiocarcinoma (CCA) diagnosis is far from satisfactory. Most CCAs are considered sporadic, although up to 20% of patients with primary sclerosing cholangitis (PSC) develop CCA during their lifetime, constituting a major cause of PSC-related death. This international study has proposed protein-based and aetiology-related logistic models with predictive, diagnostic, or prognostic capacities by combining two to four circulating protein biomarkers, moving a step forward into personalised medicine. These novel liquid biopsy tools may allow the (i) easy and non-invasive diagnosis of sporadic CCAs, (ii) identification of patients with PSC with higher risk for CCA development, (iii) establishment of cost-effective surveillance programmes for the early detection of CCA in high-risk populations (e.g. PSC), and (iv) prognostic stratification of patients with CCA, which, altogether, may increase the number of cases eligible for potentially curative options or to receive more successful treatments, decreasing CCA-related mortality. Cholangiocarcinoma (CCA), heterogeneous biliary tumours with dismal prognosis, lacks accurate early diagnostic methods especially important for individuals at high-risk (i.e. those with primary sclerosing cholangitis [PSC]). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs). EVs from patients with isolated PSC (n = 45), concomitant PSC-CCA (n = 44), PSC who developed CCA during follow-up (PSC to CCA; n = 25), CCAs from non-PSC aetiology (n = 56), and hepatocellular carcinoma (n = 34) and healthy individuals (n = 56) were characterised by mass spectrometry. Diagnostic biomarkers for PSC-CCA, non-PSC CCA, or CCAs regardless of aetiology (Pan-CCAs) were defined and validated by ELISA. Their expression was evaluated in CCA tumours at a single-cell level. Prognostic EV biomarkers for CCA were investigated. High-throughput proteomics of EVs identified diagnostic biomarkers for PSC-CCA, non-PSC CCA, or Pan-CCA, and for the differential diagnosis of intrahepatic CCA and hepatocellular carcinoma, which were cross-validated by ELISA using total serum. Machine learning-based algorithms disclosed CRP/FIBRINOGEN/FRIL for the diagnosis of PSC-CCA (local disease [LD]) vs. isolated PSC (AUC = 0.947; odds ratio [OR] =36.9) and, combined with carbohydrate antigen 19-9, overpowers carbohydrate antigen 19-9 alone. CRP/PIGR/VWF allowed the diagnosis of LD non-PSC CCAs vs. healthy individuals (AUC = 0.992; OR = 387.5). It is noteworthy that CRP/FRIL accurately diagnosed LD Pan-CCA (AUC = 0.941; OR = 89.4). Levels of CRP/FIBRINOGEN/FRIL/PIGR showed predictive capacity for CCA development in PSC before clinical evidence of malignancy. Multi-organ transcriptomic analysis revealed that serum EV biomarkers were mostly expressed in hepatobiliary tissues, and single-cell RNA sequencing and immunofluorescence analysis of CCA tumours showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EV prognostic biomarkers, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively and positively with patients’ survival, respectively. Serum EVs contain protein biomarkers for the prediction, early diagnosis, and prognostication of CCA that are detectable using total serum, representing a tumour cell-derived liquid biopsy tool for personalised medicine.