Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function.

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb(-/-) anti-inflammatory macrophages ameliorated colitis induction by WT CD4(+) T cells in Rag2(-/-)Il10rb(-/-) mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.

Anal trauma caused by bull-horn injury.

BACKGROUND: Bullfighting festivals are commonly performed at Spain. Perineal trauma due to bull-horn injury is associated with high morbidity due to sphincteric associated lesions METHODS: We report a case of 37-year-old male patient with anal trauma due to a bull-horn injury involving the sphincter complex, treated in our Emergency department RESULTS: Urgent surgery was performed with primary sphincteroplasty, without performing a colostomy. The associated complication was a partial dehiscence of the surgical wound (Clavien-Dindo I). No transfusions, re-interventions or readmissions were registered. The degree of incontinence at discharge and after 12 month follow-up, according to the Wexner scale was 8 points and 2 points, respectively. CONCLUSIONS: The main treatment of bull-horn injuries is extensive surgical debridement, antibiotic therapy, and lavage of the area. In cases involving the anal sphincter, primary sphincteroplasty is recommended. The modern trend does not include the systematic performance of a colostomy however, it has been described in cases with catastrophic wounds and urological lesions associated.

Cosmetic and personal care product use, urinary levels of parabens and benzophenones, and risk of endometriosis: results from the EndEA study.

AIM: To explore the relationship of urinary concentrations of different congeners of benzophenones and parabens with the utilization of cosmetics and personal care products (PCPs) and their impact on the risk of endometriosis, and to evaluate the influence of oxidative stress on associations found. METHODS: This case-control study comprised a subsample of 124 women (35 cases; 89 controls). Endometriosis was confirmed (cases) or ruled out (controls) by laparoscopy, with visual inspection of the pelvis and biopsy of suspected lesions (histological diagnosis). Urinary concentrations of benzophenone-1 (BP-1), benzophenone-3 (BP-3), 4-hydroxibenzophenone (4-OH-BP), methyl- (MeP), ethyl- (EtP), propyl- (PrP), and butyl-paraben (BuP), and biomarkers of oxidative stress [lipid peroxidation (TBARS) and total antioxidant power (TAP)] were quantified. Information was gathered on the frequency of use of cosmetics and PCPs. Associations between the frequency of cosmetics/PCP use, urinary concentrations of benzophenones and parabens, oxidative stress, and endometriosis risk were explored in logistic and linear multivariable regression analyses. RESULTS: The frequency of utilization of certain cosmetics and PCPs was significantly associated with urinary concentrations of benzophenones and parabens. After adjustment for potential confounders, the risk of endometriosis was increased in women in the second versus first terciles of MeP (OR = 5.63; p-value<0.001), BP-1 (OR = 5.12; p-value = 0.011), BP-3 (OR = 4.98; p-value = 0.008), and Æ©BPs (OR = 3.34; p-value = 0.032). A close-to-significant relationship was observed between TBARS concentrations and increased endometriosis risk (OR = 1.60, p-value = 0.070) and an inverse association between TAP concentrations and this risk (OR = 0.15; p-value = 0.048). Oxidative stress results did not modify associations observed between benzophenone/paraben exposure and endometriosis risk. CONCLUSIONS: Our findings indicate that the frequency of cosmetics and PCP utilization is a strong predictor of exposure to certain benzophenone and paraben congeners. These compounds may increase the risk of endometriosis in an oxidative stress-independent manner. Further studies are warranted to corroborate these findings.

Contraindications to intravenous thrombolysis in prehospital triage of thrombectomy candidates.

BACKGROUND AND PURPOSE: The existence of contraindications to intravenous thrombolysis (IVT) is considered a criterion for direct transfer of patients with suspected acute stroke to thrombectomy-capable centers in the prehospital setting. Our aim was to assess the utility of this criterion in a setting where routing protocols are defined by the Madrid - Direct Referral to Endovascular Center (M-DIRECT) prehospital scale. METHODS: This was a post hoc analysis of the M-DIRECT study. Reported contraindications to IVT were retrospectively collected from emergency medical services reports and categorized into late window, anticoagulant treatment and other contraindications. Final diagnosis and treatment rates were compared between patients with and without reported IVT contraindications and according to anticoagulant treatment or late window categories. RESULTS: The M-DIRECT study included 541 patients. Reported IVT contraindications were present in 227 (42.0%) patients. Regarding final diagnosis no significant differences were found between patients with or without reported IVT contraindications: ischaemic stroke (any) 65.6% vs. 62.1%, ischaemic stroke with large vessel occlusion (LVO) 32.2% vs. 28.3%, hemorrhagic stroke 15.4% vs. 15.6%, stroke mimic 18.9% vs. 22.3% respectively. Amongst patients with LVO, endovascular thrombectomy (EVT) was performed less often in the presence of IVT contraindications (56.2% vs. 74.2%). M-DIRECT-positive patients had higher rates of LVO and EVT compared with M-DIRECT-negative patients independent of reported IVT contraindications. CONCLUSIONS: Reported IVT contraindications alone do not increase EVT likelihood and should not be considered to determine routing in urban stroke networks.

Measuring the Kinetics of Neutral Pair Evaporation from Cluster Ions of Ionic Liquid in the Drift Region of a Differential Mobility Analyzer.

Singly charged clusters [C+A-]nC+ or [C+A-]nA- of two salts [C+A-] are produced by electrospray ionization of alcohol solutions of the ionic liquids 1-ethyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate (EMI-FAP) and 1,2-dimethyl-3-propylimidazolium-methide (DMPI-Me). The rate of neutral pair evaporation into [C+A-] + [C+A-]n-1C+ or [C+A-]n-1A- is studied in atmospheric pressure as a function of temperature T for the positive trimer ion (n = 2) of DMPI-Me and the negative trimer ion of EMI-FAP. The trimer is separated from all other electrosprayed ions in a first differential mobility analyzer (DMA1) and then transferred through a cooled tube to a second DMA whose drift gas is kept at a controlled temperature (25 °C < T < 100 °C). Singular characteristics of the DMA are a residence time τ of ∼0.1 to 1 ms, with essentially uniform temperature and τ. The decomposition occurring within DMA2 results in a complex mobility spectrum associated with dimer product ions, with apparent mobilities intermediate between those of the dimer and the trimer, depending on the product of the reaction rate k and τ. A theoretical expression yielding k from the shape of the collected mobility spectrum is obtained by accounting for the deterministic reactive, convective, and diffusive evolutions of the parent and product ions within DMA2. Observed and predicted mobility spectra agree well, yielding the reaction rate k with little ambiguity. Activation energies near 1 eV are determined for both trimer ions. Paradoxically, the evaporation process substantially heats up the cluster ion product. The theory developed enables measuring decay times much smaller and much larger than the residence time in the DMA.

Psychosocial repercussion of migraine: is it a stigmatized disease?

INTRODUCTION: Stigma manifests both in prejudices and rejection from society towards patients who suffer from a specific pathology, and by patient's internalization of this discrimination, with the consequent repercussions on their state of mind and quality of life. The aim of the study was to quantify the stigma associated with migraine and analyze whether it is related to the clinical-demographic characteristics of the patients, as well as the possible impact on their daily lives. MATERIALS AND METHODS: The stigma scale for chronic illness (SSCI) and other questionnaires were administered to 56 patients with episodic migraine (EM), 18 with chronic migraine (CM), and 21 with epilepsy, as a control group. RESULTS: The mean SSCI score was higher (51.6 ± 15.0) in the CM group than in the EM (45.0 ± 13.5) and epilepsy (47.6 ± 15.5) groups, without reaching statistical significance. In addition, the score was higher in patients who were unemployed, divorced, and in those who had migraine with aura. A statistically significant correlation was found between the SSCI score and the impact of migraine on daily life, the presence of stress, anxiety and depression, and low self-esteem. CONCLUSIONS: There is a stigma around migraine in our society, which seems to be more prevalent in patients with certain socio-demographic characteristics, and that is related to stress, mood alterations, and low self-esteem. Trying to reduce stigma could contribute to improve the control of migraine and reduce the impact of the disease at a socio-economic level.

Risk factors and comorbidities associated with severe aortic stenosis: a case-control study. / Factores de riesgo y comorbilidades asociadas a la estenosis aórtica grave: estudio de casos y controles.

BACKGROUND AND OBJECTIVE: Aortic stricture (AS) is one of the most prevalent cardiovascular diseases in individuals 65 years of age or older. A number of epidemiological studies have suggested that certain cardiovascular risk factors (CRFs) and comorbidities could be associated with AS. The aim of this study was to evaluate the association between CRFs and comorbidities and severe symptomatic AS in individuals 65 years of age or older in a Spanish healthcare region. PATIENTS AND METHODS: We conducted an epidemiological case-control study from a single primary care centre. We collected information on exposure to CRFs and comorbidities and determined their association with AS, employing adjusted odds ratios (OR) and multiple logistic regression models. RESULTS: The study included 102 cases (mean age, 77.6 years) and 221 controls (mean age, 75.5 years). The CRFs significantly associated with severe symptomatic AS were hypercholesterolaemia (OR, 2.67; p<.001), tobacco use (OR, 2.60; p<.001), hypertension (OR, 2.41; p=.010) and low HDL cholesterol readings (OR, 2.20; p=.007). The comorbidities significantly associated with severe symptomatic AS were carotid stenosis (OR, 14.5; p=.017), stroke (OR, 4.14; p=.024), chronic renal failure (OR, 3.78; p<.001) and low haemoglobin levels (OR, 0.76; p<.001). CONCLUSIONS: Hypercholesterolaemia, tobacco use, arterial hypertension and low HDL cholesterol levels are the CRFs with a greater risk of severe AS. Furthermore, this disease is associated with a number of comorbidities (chronic renal failure, stroke, carotid stenosis and low haemoglobin levels), which could be markers of AS.

Virus Size Analysis by Gas-Phase Mobility Measurements: Resolution Limits.

Electrospraying (ES) dissolved viral particles, followed by charge reduction and size analysis with a differential mobility analyzer (DMA), offers a flexible size-analysis tool for small particles in solution. The technique relies on pioneering work by Kaufman and colleagues, commercialized by TSI, and often referred to as GEMMA. However, viral studies with TSI's GEMMA have suffered from limited resolving power, possibly because of imperfections in either the instrument (DMA or charge reduction) or the sample solution preparation. Here, we explore the limits of the resolution achievable by GEMMA, taking advantage of (i) cleaner charge reduction methods and (ii) DMAs of higher resolving power. Analysis of the literature provides indications that mobility peak widths (fwhm) of 2% or less may be achieved by combining careful sample preparation with improved instrumentation. Working with purified PP7 bacteriophage particles small enough to be classifiable by existing high-resolution DMAs, we confirm that fairly narrow viral mobility peaks may be obtained (relative full width at half-maximum fwhm <5%). Comparison of spectra of a given apian virus sample obtained with TSI's GEMMA and our improved instrumentation confirms that one critical limitation is the DMA. This is further verified by narrow peaks from murine parvovirus, norovirus, and encephalomyelitis virus samples, obtained in our improved GEMMA with little sample preparation, directly from infected cell cultures. Classification of purified large (60 nm) coliphage PR772 particles leads to broad peaks, due to both viral degradation and limited intrinsic resolution of the DMAs used to cover the range of such large particles. We conclude that improved DMAs suitable for high-resolution analysis of particles larger than 30 nm need to be developed to determine the intrinsic mobility width of viral particles.

T follicular helper cells restricted by IRF8 contribute to T cell-mediated inflammation.

The follicular helper T cell (TFH) are established regulators of germinal center (GC) B cells, whether TFH have pathogenic potential independent of B cells is unknown. Based on in vitro TFH cell differentiation, in vivo T cell transfer animal colitis model, and intestinal tissues of inflammatory bowel disease (IBD) patients, TFH and its functions in colitis development were analyzed by FACS, ChIP, ChIP-sequencing, WB, ELISA and PCR. Herein we demonstrate that intestinal tissues of patients and colon tissues obtained from Rag1-/- recipients of naïve CD4+ T cells with colitis, each over-express TFH-associated gene products. Adoptive transfer of naïve Bcl6-/- CD4+ T cells into Rag1-/- recipient mice abrogated development of colitis and limited TFH differentiation in vivo, demonstrating a mechanistic link. In contrast, T cell deficiency of interferon regulatory factor 8 (IRF8) resulted in augmentation of TFH induction in vitro and in vivo. Functional studies showed that adoptive transfer of IRF8 deficient CD4+ T cells into Rag1-/- recipients exacerbated colitis development associated with increased gut TFH-related gene expression, while Irf8-/-/Bcl6-/- CD4+ T cells abrogated colitis, together indicating that IRF8-regulated TFH can directly cause colon inflammation. Molecular analyses revealed that IRF8 suppresses TFH differentiation by inhibiting transcription and transactivation of the TF IRF4, which is also known to be essential for TFH induction. Our documentation showed that IRF8-regulated TFH can function as B-cell-independent, pathogenic, mediators of colitis suggests that targeting TFH could be effective for treatment of IBD.

Vitamin effects on the immune system: vitamins A and D take centre stage.

Vitamins are essential constituents of our diet that have long been known to influence the immune system. Vitamins A and D have received particular attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. We present and discuss our current understanding of the essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation and proliferation, T-helper-cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response. Finally, we discuss the clinical potential of vitamin A and D metabolites for modulating tissue-specific immune responses and for preventing and/or treating inflammation and autoimmunity.

Reaching a Vapor Sensitivity of 0.01 Parts Per Quadrillion in the Screening of Large Volume Freight.

The feasibility of detecting explosives in the atmosphere at concentrations as low as 0.01 ppq hinges on the poorly known question of what interfering species exist at these or higher concentrations. To clarify the issue, hundreds of samples of ambient air, either clean or loaded with explosives (from lightly contaminated environments) have been collected in fiberglass/stainless steel filters coated with Tenax-GR, thermally desorbed at variable temperature, and ionized with Cl- via secondary electrospray (SESI). They are analyzed with a narrow-band mobility filter (SEADM's P5 DMA) and a triple quadrupole mass spectrometer (Sciex's 5500), configured in series to transmit precursor and fragment ions of the explosives Nitroglycerin, PETN, RDX, and TNT. Blanks were sampled outdoors at a rural site (Boecillo, Valladolid, Spain), and loads were sampled at diverse locations. For RDX and TNT, atmospheric background inhibits detection below 1 part/trillion (ppt) without mobility filtering. This interference was drastically reduced by the DMA, allowing detection up to 1 part/quadrillion (ppq). Further sensitivity increase was achieved by scanning over a mobility region several percent around that of the target explosive, to separate various isobaric compounds by Gaussian deconvolution. (i) All four MS/MS channels analyzed exhibit several background peaks within the narrow mobility intervals investigated. At least one of these interferents is much stronger than the instrument background at the explosive's mobility, making DMA separation most helpful. (ii) For Nitroglycerin and PETN the combined filtering techniques have not lowered ambient chemical noise down to 0.01 ppq. (iii) Interferents are greatly reduced for TNT and RDX, resulting in minimal chemical noise: 322 blank tests for RDX yielded mean signal of 0.0012 ppq and standard deviation σ = 0.0035 ppq (mean + 3σ detection limit of 0.01 ppq).

ß8 Integrin Expression and Activation of TGF-ß by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage.

Activation of TGF-ß by dendritic cells (DCs) expressing αvß8 integrin is essential for the generation of intestinal regulatory T cells (Tregs) that in turn promote tolerance to intestinal Ags. We have recently shown that αvß8 integrin is preferentially expressed by CD103(+) DCs and confers their ability to activate TGF-ß and generate Tregs. However, how these DCs become specialized for this vital function is unknown. In this study, we show that ß8 expression is controlled by a combination of factors that include DC lineage and signals derived from the tissue microenvironment and microbiota. Specifically, our data demonstrate that TGF-ß itself, along with retinoic acid and TLR signaling, drives expression of αvß8 in DCs. However, these signals only result in high levels of ß8 expression in cells of the cDC1 lineage, CD8α(+), or CD103(+)CD11b(-) DCs, and this is associated with epigenetic changes in the Itgb8 locus. Together, these data provide a key illustrative example of how microenvironmental factors and cell lineage drive the generation of regulatory αvß8-expressing DCs specialized for activation of TGF-ß to facilitate Treg generation.

Musicogenic reflex seizures in epilepsy with glutamic acid decarbocylase antibodies.

BACKGROUND: Musicogenic reflex seizures (MRS) are a rare form of seizures described in patients with temporal lobe epilepsy (TLE), mainly of unknown etiology. Epilepsy with antibodies against glutamic acid decarboxylase (GAD-ab) is a form of autoimmune epilepsy for which no specific semiology has been described. AIM OF THE STUDY: To retrospectively review the incidence of MRS in the general epileptic population and in the series of patients with epilepsy and GAD-ab and to describe its clinical and paraclinical characteristics. METHODS: Patients recorded between January 2010 and January 2016 in the Database of Bellvitge Hospital Epilepsy Unit were reviewed. RESULTS: From a group of 1510 epileptic patients, three reported MRS (0.0019%) (two patients with epilepsy and GAD-ab and one patient with cryptogenic TLE). The incidence of MRS in patients with epilepsy and GAD-ab was 2 of 22 (9%). Both patients had a normal magnetic resonance Imaging (MRI), but FDG-PET showed medial temporal lobe hypometabolism (unilateral or bilateral) in both and also in the insula in one of them. MRS (recorded via video-EEG[electroencephalography] in one patient) arose from the right temporal lobe. CONCLUSIONS: MRS may be a distinctive seizure type in patients with epilepsy and antiGADab. Determination of GAD-ab should be carried out in all cases of MRS, even those with normal structural MRI.

A new classification system for the restoration of root filled teeth.

The aim of this report is to (i) review the current literature on the status of root filled teeth, (ii) analyse the most important factors in decision-making, (iii) discuss the current restorative concepts, and (iv) classify both the evidence and clinical practice in a way that seeks to be clear, understandable and helpful for clinicians. Restoration of root filled teeth represents a challenge for the clinician and remains a controversial subject. The guidelines describe a new classification that is drawn from evidence presented in the literature and also from clinical expertise-based reviews. It describes five categories of teeth.

Resource recovery from sulphate-rich sewage through an innovative anaerobic-based water resource recovery facility (WRRF).

This research work proposes an innovative water resource recovery facility (WRRF) for the recovery of energy, nutrients and reclaimed water from sewage, which represents a promising approach towards enhanced circular economy scenarios. To this aim, anaerobic technology, microalgae cultivation, and membrane technology were combined in a dedicated platform. The proposed platform produces a high-quality solid- and coliform-free effluent that can be directly discharged to receiving water bodies identified as sensitive areas. Specifically, the content of organic matter, nitrogen and phosphorus in the effluent was 45 mg COD·L-1, 14.9 mg N·L-1 and 0.5 mg P·L-1, respectively. Harvested solar energy and carbon dioxide biofixation in the form of microalgae biomass allowed remarkable methane yields (399 STP L CH4·kg-1 CODinf) to be achieved, equivalent to theoretical electricity productions of around 0.52 kWh per m3 of wastewater entering the WRRF. Furthermore, 26.6% of total nitrogen influent load was recovered as ammonium sulphate, while nitrogen and phosphorus were recovered in the biosolids produced (650 ± 77 mg N·L-1 and 121.0 ± 7.2 mg P·L-1).

GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS).

BACKGROUND: First Spanish trial of Ewing sarcoma (ES) including adults and children with the aim to test the efficacy of Gemcitabine and Docetaxel (G/D) in newly diagnosed high-risk (HR) patients. METHODS: This was a prospective, multicentric, non-randomised, open study for patients ⩽40 years with newly diagnosed ES. HR patients (metastatic, axial-pelvic primaries or bone marrow micrometastasis) received 2 window cycles of G/D. Patients with an objective response (OR) to G/D received 12 monthly cycles of G/D after completion of mP6. The primary end point was the OR rate to the G/D window phase and the event-free survival (EFS) and overall survival (OS) for all patients. The study is registered at ClinicalTrials.gov (identifier: NCT00006734). RESULTS: Forty-three patients were enroled, median age 17 years (range, 3-40). After a median follow-up of 43.4 months, the 5-year OS rate is 55.0% (95% CI, 41-74%) with an EFS of 50.0% (95% CI, 36-68%). The 5-year OS and EFS rates for standard risk (SR) patients was 76.0% (95% CI, 57-100%) and 71.0% (CI, 54-94%); for HR 36.0% (CI, 20-65%) and 29.0% (CI, 15-56%). Twelve of 17 (70.6%) high-risk (HR) patients showed an OR (7 PR and 5 SD) to G/D window therapy. The 5-year OS rate for patients ⩽18 years of age was 74.0% (CI, 56-97%) and 31.0% for >18 years (95% CI, 15-66%), P<0.001. Grade 4 adverse events during mP6 occurred in 28/39 of patients (72%) and did not correlate with age. Multivariate survival analyses with <18 vs ⩾18 and risk groups significant differences, P<0.00001. Using a Cox model for OS, both age and risk group were statistically significant (P=0.0011 and P=0.0065, respectively). CONCLUSIONS: Age at diagnosis is an independent prognostic factor superior to the presence of metastases with 18 years as the strongest cut-off. The mP6 regimen provided survival curves that plateau at 3 years and G/D produced significant responses in HR-ES that is worth further exploring.

Gemcitabine plus sirolimus for relapsed and progressing osteosarcoma patients after standard chemotherapy: a multicenter, single-arm phase II trial of Spanish Group for Research on Sarcoma (GEIS).

BACKGROUND: Patients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. Fas cell surface death receptor and mammalian target of rapamycin pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients. PATIENTS AND METHODS: A multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma. Osteosarcoma patients, relapsed or progressing after standard chemotherapy and unsuitable for metastasectomy received gemcitabine and rapamycin p.o. 5 mg/day except for the same day of gemcitabine administration, and the day before. The main end point was 4-month progression-free survival rate (PFSR), with the assumption that rates higher than 40% would be considered as an active regimen. Translational research aimed to correlate biomarkers with the clinical outcome. RESULTS: Thirty-five patients were enrolled and received at least one cycle. PFSR at 4 months was 44%, and after central radiologic assessment, 2 partial responses and 14 stabilizations (48.5%) were reported from 33 assessable patients. The most frequent grade 3-4 adverse events were: neutropenia (37%), thrombocytopenia (20%), anemia (23%), and fatigue (15%); however, only three patients had febrile neutropenia. Positive protein expression of RRM1 significantly correlated with worse PFS and overall survival, while positivity of P-ERK1/2 was correlated with significant better overall survival. CONCLUSION: Gemcitabine plus sirolimus exhibits satisfactory antitumor activity and safety in this osteosarcoma population, exceeding the prespecified 40% of 4-month PFSR. The significant correlation of biomarkers with clinical outcome encourages further prospective investigation.

A systems approach identifies time-dependent associations of multimorbidities with pancreatic cancer risk.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. METHODS: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases. RESULTS: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01-12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11-2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36-0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9-16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29-2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis. CONCLUSIONS: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis between MP and PDAC points to a mechanistic link between these conditions.