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Background/Aim. Four-dimensional (4D) computed tomography (CT) simulation is a useful tool for motion assessment in lung cancer radiotherapy. Conventional three-dimensional (3D) free-breathing (FB) simulation is static, with limited motion information on respiratory movements that can produce inaccuracies in the delineation process and radiotherapy planning. The aim of this study was to compare clinically significant differences between the target volumes defined on 3D CT vs. 4D CT simulation and the potential impact on the planning target volume (PTV), bearing in mind that a reduced PTV with precise coverage of the primary tumor is extremely important. In addition, quantification of movements of the primary tumor (gross tumor volume ? GTV) was performed during 4D CT simulation on three axes: Z-superoinferior (SI), X-mediolateral (ML), and Y-anteroposterior (AP). Methods. This retrospective study evaluated 20 lung cancer patients who underwent CT simulation for radical radiotherapy treatment. FB 3D CT and 4D CT simulations were acquired for each patient in accordance with our institutional protocol. A volumetric comparison of radiation volumes defined on 3D CT vs. 4D CT simulation was done on the following: GTV 3D vs. internal GTV (IGTV) 4D and PTV 3D vs. internal PTV (IPTV) 4D. The comparison of GTV movement in the FB phase GTV (GTV FB), phase 0 (GTV 0), phase 50 (GTV 50), and phase maximum intensity projection (GTV MIP) was made with GTV FB as the basic value. The evaluation was made on all three axes. Results. The comparison of volumetric values between GTV 3D vs. IGTV 4D was 63.15 cm3 vs. 85.51 cm3 (p < 0.001), respectively. IGTV 4D was significantly larger than GTV 3D (p < 0.001). The mean value of equivalent spherical diameter (ESD) for PTV 3D vs. IPTV 4D was 8.44 cm vs. 7.82 cm (p < 0.001), respectively, and the mean value volume PTV 3D vs. IPTV 4D was 352.70 cm3 vs. 272.78 cm3 (p < 0.001), respectively. PTV 3D was significantly larger than IPTV 4D (p < 0.001). A statistically significant difference (p < 0.05) was identified in the deviation related to the Z-axis between the upper and lower lobe. Conclusion. 4D CT simulation-based delineation can reduce PTV compared to 3D simulation-based radiation therapy; therefore, it is a prerequisite for high-quality and precise radiation therapy treatment.

Objectives: 7% of proximal femoral fractures occur in patients admitted to hospital for unrelated medical and surgical presentations. This comparative study will assess morbidity and mortality in patients sustaining proximal femoral fractures both as inpatients and in the community. Methods: Retrospective review of patients admitted to a regional specialist hip unit with fracture of the proximal femur sustained both from the community and other inpatient settings. Patient demographics, risk factors and outcomes were recorded and analysed – with focus on 30-day and 1-year mortality. Results: 3445 patients were admitted over a 10-year period, 292 of which sustained proximal femoral fractures as an inpatient. 30-day and 1-year mortality was 23.7% and 47.9% respectively in the inpatient group, compared to 6.9% and 22.4% respectively in the community group. Mean time from presentation to operating room was 27.8 hours for the inpatient group, compared to 25.2 hours for the community group. Conclusion: Inpatients who sustain a proximal femoral fracture have significantly higher 30-day and 1-year mortality rates when compared to patients in the community sustaining the same injury. There is also a noted delay to theatre in this patient group.

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347, Funder: Flemish Society for Critical Care Nurses, Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score < 19, ICU stay > 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat.

In adult organisms, deregulation of the sonic hedgehog (SHH) signaling pathway is significantly correlated with different malignancies. Currently, data associating genetic polymorphisms in the SHH pathway with melanoma are scarce and largely unknown. The objective of our study was to elucidate an association between gene polymorphisms in the SHH pathway and prognosis of melanoma skin cancer patients. The current study investigated the association of PTCH1 (rs357564), SMO (rs2228617) and GLI1 (rs2228224, rs2228226), polymorphisms with melanoma predisposition and prognosis. Single-nucleotide polymorphisms were assessed by TaqMan SNP Genotyping Assays. The study involved 93 melanoma patients and 97 individuals in the control group. Melanoma patients with the variant mutant genotype GG of GLI1 rs2228226 polymorphism had poorer overall survival and recurrence-free survival (P = 0.0001 and P = 0.037, respectively). The multivariate analysis revealed that disease progression [hazard ratio (HR) = 14.434, P = 0.0001] and the GLI1 rs2228226 polymorphism (HR = 4.161, P = 0.006) persisted as independent prognostic factors. Mutated allele carriers (combined heterozygous and mutated genotypes) for GLI1 rs2228224 G and GLI1 rs2228226 G allele significantly increased melanoma risk [odds ratio (OR) = 2.261, P = 0.007; OR = 2.176, P = 0.010]. Our study demonstrated that genetic variants in GLI1, downstream member of the HH signaling pathway, are the risk factors for melanoma susceptibility and it can be a novel marker for melanoma prognosis. As a crucial SHH signaling member, GLI1 can also be regarded as a novel drug target for anti-cancer treatment in melanoma.

Naming of nouns and verbs can be selectively impaired in neurological disorders, but the specificity of the neural and cognitive correlates of such dissociation remains unclear. Functional imaging and stroke research sought to identify cortical regions selectively recruited for nouns versus verbs, yet findings are inconsistent. The present study investigated this issue in neurodegenerative diseases known to selectively affect different brain networks, thus providing new critical evidence of network specificity. We examined naming performances on nouns and verbs in 146 patients with different neurodegenerative syndromes (Primary Progressive Aphasia - PPA, Alzheimer's disease - AD, and behavioral variant Frontotemporal Dementia - FTD) and 30 healthy adults. We then correlated naming scores with MRI-derived cortical thickness values as well as with performances in semantic and syntactic tasks, across all subjects. Results indicated that patients with the semantic variant PPA named significantly fewer nouns than verbs. Instead, nonfluent/agrammatic PPA patients named fewer verbs than nouns. Across all subjects, performance on nouns (adjusted for verbs) specifically correlated with cortical atrophy in left anterior temporal regions, and performance on verbs (adjusted for nouns) with atrophy in left inferior and middle frontal, inferior parietal and posterior temporal regions. Furthermore, lower lexical-semantic abilities correlated with deficits in naming both nouns and verbs, while lower syntactic abilities only correlated with naming verbs. Our results show that different neural and cognitive mechanisms underlie naming of specific grammatical categories in neurodegenerative diseases. Importantly, our findings showed that verb processing depends on a widespread perisylvian networks, suggesting that some regions might be involved in processing different types of action knowledge. These findings have important implications for early differential diagnosis of neurodegenerative disorders.

Introduction Women with previous gestational diabetes (pGD) are at higher risk of prediabetes (PD) after delivery. The aim of this study was to determine the prevalence of and predictors for PD among women with pGD. Methods The study included 186 women with pGD treated by lifestyle modification. After delivery, the women were divided into group A (n = 80) with PD and group B (n = 106) with normal glucose tolerance (NGT), defined by the results of the 2-h oral glucose tolerance test at 4–12 weeks after delivery. We recorded age, body mass index (BMI) at conception and after delivery, fasting glucose (FG), glycated hemoglobin (HbA1c), total cholesterol (TC), triglycerides (Tg), low density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c) and the Tg/HDL-c ratio measured in the third trimester of pregnancy. Results Of the 186 women with pGD enrolled in the study, 43% showed prediabetes at 4–12 weeks after delivery, with 13.9% of these women showing impaired FG (IFG), 12.9% showing impaired glucose tolerance (IGT) and 16.2% with IFG/IGT. The groups differed in terms of age and BMI at conception and after delivery. In the third trimester of pregnancy, HbA1c was higher in women in group A than in those in group B (mean ± standard deviation: 5.6 ± 0.4 vs. 5.2 ± 0.3%; p

Dysregulation of glutamatergic neural circuits has been implicated in a cycle of toxicity, believed among the neurobiological underpinning of Alzheimer’s disease. Previously, we reported preclinical evidence that the glutamate modulator riluzole, which is FDA approved for the treatment of amyotrophic lateral sclerosis, has potential benefits on cognition, structural and molecular markers of ageing and Alzheimer’s disease. The objective of this study was to evaluate in a pilot clinical trial, using neuroimaging biomarkers, the potential efficacy and safety of riluzole in patients with Alzheimer’s disease as compared to placebo. A 6-month phase 2 double-blind, randomized, placebo-controlled study was conducted at two sites. Participants consisted of males and females, 50 to 95 years of age, with a clinical diagnosis of probable Alzheimer’s disease, and Mini-Mental State Examination between 19 and 27. Ninety-four participants were screened, 50 participants who met inclusion criteria were randomly assigned to receive 50 mg riluzole (n = 26) or placebo (n = 24) twice a day. Twenty-two riluzole-treated and 20 placebo participants completed the study. Primary end points were baseline to 6 months changes in (i) cerebral glucose metabolism as measured with fluorodeoxyglucose-PET in prespecified regions of interest (hippocampus, posterior cingulate, precuneus, lateral temporal, inferior parietal, frontal); and (ii) changes in posterior cingulate levels of the neuronal viability marker N-acetylaspartate as measured with in vivo proton magnetic resonance spectroscopy. Secondary outcome measures were neuropsychological testing for correlation with neuroimaging biomarkers and in vivo measures of glutamate in posterior cingulate measured with magnetic resonance spectroscopy as a potential marker of target engagement. Measures of cerebral glucose metabolism, a well-established Alzheimer’s disease biomarker and predictor of disease progression, declined significantly less in several prespecified regions of interest with the most robust effect in posterior cingulate, and effects in precuneus, lateral temporal, right hippocampus and frontal cortex in riluzole-treated participants in comparison to the placebo group. No group effect was found in measures of N-acetylaspartate levels. A positive correlation was observed between cognitive measures and regional cerebral glucose metabolism. A group × visit interaction was observed in glutamate levels in posterior cingulate, potentially suggesting engagement of glutamatergic system by riluzole. In vivo glutamate levels positively correlated with cognitive performance. These findings support our main primary hypothesis that cerebral glucose metabolism would be better preserved in the riluzole-treated group than in the placebo group and provide a rationale for more powered, longer duration studies of riluzole as a potential intervention for Alzheimer’s disease.

Soluble urokinase plasminogen activator receptor (suPAR) is intensively studied as a biomarker of inflammation and disease outcome in various diseases. In rheumatoid arthritis (RA), suPAR have shown an association with inflammation and swollen joints, but data on suPAR in relation to early disease course and disease progression are lacking. This study investigates the potential of suPAR to predict or reflect disease outcome in early RA. Serum suPAR was measured by enzyme-linked immunosorbent assay at disease onset and after 3 and 36 months in 252 patients from a Swedish prospective observational early RA cohort. Levels and changes of suPAR were analyzed in relation to the 28-joint disease activity score (DAS28) and joint damage according to the Larsen score at inclusion and during follow-up. 100 healthy blood donors served as controls. Circulating levels of suPAR were higher in RA patients at all time points as compared to healthy controls. Baseline suPAR was significantly associated with baseline disease activity whereas suPAR levels at 36 months were associated with joint damage at 36 months. No predictive value of suPAR levels or changes in suPAR levels over time were found. In conclusion, suPAR levels associate with disease activity in early untreated RA and reflects joint damage at later stages. Increased suPAR in established RA could indicate patients in need of frequent monitoring of joint status, irrespective of disease activity. In the view of suPAR as a rapidly emerging biomarker, it is important to be aware of its ability to reflect both inflammation and subsequent damage. (Translational Research 2021; 232:142-149) Funding Agencies|Swedish Society of Medicine; Reinhold Sund foundation; King Gustaf V 80-year foundation; Swedish Rheumatism association; Ostergotland county council

Introduction: Sentinel lymph node biopsy (SLNB) is a standard procedure at the Oncology Institute of Vojvodina since 1999 and during this period we have done more than 1700 biopsies. The aim of this study was to present our results in SLNB in breast cancer surgery. Materials and methods: This retrospective study was performed at the Department for Surgical Oncology at the Vojvodina Institute of Oncology in the period from January 1999 to December 2019. The study included 1762 patients who had undergone SLNB. The mean duration of the follow-up period was 121.89 months. All patients were women with clinically T1-2N0-1M0 breast cancer. Preoperatively, all patients were administered dual contrast media, radiotracer, and blue dye. Results: The majority of tumors were T1c (955 (54.18%). The mean number of extirpated sentinel lymph nodes (SLN) in both groups was 1.84. In 199 (36.72%) patients SLN was the only metastatic lymph node in the axilla. Micro metastases were found in 113 (21.03%) patients. The overall diagnostic accuracy of SLNB was 96%. Conclusion: Axillary SLN can serve as a reliable predictor of negativity of other ipsilateral axillary nodes. Micro metastases in the SLN are not an indication for complete axillary lymph node dissection.

The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); the Sicilian Government, AIRE ONLUS Ragusa, AVIS Ragusa, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), and Statistics Netherlands (the Netherlands); Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barcelona), Spain; Swedish Cancer Society, Swedish Scientific Council, and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (C864/A14136 to EPIC-Norfolk; C8221/A19170, C570/A16491 and C8221/ A290170 to EPIC-Oxford), Medical Research Council (MR/ N003284/1 and MC-UU_12015/1 to EPIC-Norfolk, MR/ M012190/1 to EPIC-Oxford (UK). The funding sources had no influence on the design of the study; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication.Support for this study was also provided by the COST Action CA17118 supported by COST (European Cooperation in Science and Technology, www.cost.eu) to DJH., Experimental evidence has implicated genotoxic Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF) in the development of colorectal cancer (CRC). However, evidence from epidemiological studies is sparse. We therefore assessed the association of serological markers of E. coli and ETBF exposure with odds of developing CRC in the European Prospective Investigation into Nutrition and Cancer (EPIC) study. Serum samples of incident CRC cases and matched controls (n = 442 pairs) were analyzed for immunoglobulin (Ig) A and G antibody responses to seven E. coli proteins and two isoforms of the ETBF toxin via multiplex serology. Multivariable-adjusted conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of sero-positivity to E. coli and ETBF with CRC. The IgA-positivity of any of the tested E. coli antigens was associated with higher odds of developing CRC (OR: 1.42; 95% CI: 1.05–1.91). Dual-positivity for both IgA and IgG to E. coli and ETBF was associated with >1.7-fold higher odds of developing CRC, with a significant association only for IgG (OR: 1.75; 95% CI: 1.04, 2.94). This association was more pronounced when restricted to the proximal colon cancers (OR: 2.62; 95% CI: 1.09, 6.29) compared to those of the distal colon (OR: 1.24; 95% CI: 0.51, 3.00) (pheterogeneity = 0.095). Sero-positivity to E. coli and ETBF was associated with CRC development, suggesting that co-infection of these bacterial species may contribute to colorectal carcinogenesis. These findings warrant further exploration in larger prospective studies and within different population groups., European Commission (DG-SANCO), International Agency for Research on Cancer, Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany), Hellenic Health Foundation (Greece), Sicilian Government, AIRE ONLUS Ragusa, AVIS Ragusa, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), and Statistics Netherlands (the Netherlands), Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway), Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barcelona), Spain, Swedish Cancer Society, Swedish Scientific Council, and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (C864/A14136 to EPIC-Norfolk; C8221/A19170, C570/A16491 and C8221/ A290170 to EPIC-Oxford), Medical Research Council (MR/ N003284/1 and MC-UU_12015/1 to EPIC-Norfolk, MR/ M012190/1 to EPIC-Oxford (UK), COST Action CA17118 supported by COST (European Cooperation in Science and Technology)

Background:The relationship between different surrogates of insulin resistance and left ventricular geometry in obese children is still unclear.Objective:We sought to explore the relationship between commonly used measures of insulin sensitivity/resistance (homeostatic model assessment index, serum uric acid, and triglycerides to high-density lipoprotein cholesterol ratio) and left ventricular geometry in normotensive obese children.Methods:In this cross-sectional study, 32 normotensive obese children were examined. Transthoracic echocardiography was used to measure left ventricular mass index and relative wall thickness. Homeostasis model assessment index, serum uric acid level, and a ratio of triglycerides to high-density lipoprotein cholesterol were used as markers of the insulin resistance. Simple and partial correlation analyses (to control for the effects of body mass index) were conducted to explore relationship between studied variables and left ventricular mass index or relative wall thickness as outcome variables.Results:We found positive correlations between homeostasis model assessment index and relative wall thickness (r = 0.47, p = 0.03) which remained significant after controlling for the effect of body mass index, z-score (r = 0.48, p = 0.03). The cutoff level of homeostasis model assessment index with the optimum sensitivity (Sn) and specificity (Sp) derived from the receiver operating characteristic (ROC) curves for predicting concentric remodelling was ≥5.51 with Sn = 83.33 and Sp = 68.75.Conclusion:There is a positive relationship between homeostasis model assessment index and relative wall thickness of obese normotensive children which may help to distinguish at risk obese normotensive children for the development of concentric left ventricular remodelling.

Purpose: To evaluate the significance of risk factors and analyze their interrelationship in developing age-related macular degeneration (AMD). Materials and design: This is a multicenter, cross-sectional study conducted in eight ophthalmology centers in Europe. The STARS (Simplified Thea AMD Risk-Assessment Scale) questionnaire was used to assess 12 risk factors grouped in four major categories. We used Welch’s t-test/ F ratios to determine statistically significant changes. The principal component analysis was done to investigate the association between risk factors. Results: There were 3297 participants included in our data analysis. Nineteen percent of patients had a high risk of developing AMD, whilst 45.92% and 34.85% had moderate and small risk, respectively. Atherosclerosis appeared as the most relevant risk indicator for AMD development (Cohen’s d = 0.861). Tukey’s post hoc analysis of the smoking variable showed that ex-smokers ( p Conclusion: Risk factors evaluated in our study should be considered for the development of AMD.

We evaluated the diagnostic accuracy of the controlled attenuation parameter (CAP) and liver stiffness measurements (LSM) measured with either an M or XL probe against liver biopsy (LB) in patients with non-alcoholic fatty liver disease (NAFLD). This study was a cross-sectional prospective study that included 179 NAFLD patients. With a cutoff value for CAP >= 345, we can exclude significant steatosis in 87% (79.4%-92.5%) of our population. With respect to the LSM, the highest accuracy was obtained for F >= F3 (area under the receiver operating characteristic curve [AUROC] = 0.98) and F = F4 (AUROC = 0.98). In a multivariable linear regression model, significant predictors influencing LSM were fibrosis stage (beta = 2.6, p < 0.001) as a positive predictor and lobular inflammation (beta = -0.68, p = 0.04) as a negative predictor, without significant influence after adjustment for CAP and probe type. We found that CAP is a satisfactory method for excluding advanced steatosis, while LSM is a good non-invasive marker for the exclusion of fibrosis.

Platelet glycoprotein IIb/IIIa inhibitors (GPIs) have been part of the adjuvant treatment of acute coronary syndrome for years. However, real-life data regarding the efficacy and safety of GPIs under the current indications are lacking in the setting of potent platelet inhibition. The objectives were to assess the efficacy and safety of abciximab versus tirofiban in patients with ST-elevation acute myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) and pretreated with ticagrelor, and to identify independent predictor factors of efficacy, bleeding and platelet drop. Three hundred sixty-two patients were divided by GPI administered. Clinical, laboratory, angiographic and outcome characteristics were compared. The primary objective was a composite efficacy endpoint (death from any cause, nonfatal myocardial infarction and nonfatal stroke) at 30 days. The secondary objectives were its individual components, safety (bleeding) and the impact on platelet count during hospital stay. The composite efficacy endpoint was similar in the abciximab and tirofiban groups (6.1% vs 7.3%

There are currently two treatments available for patients with chronic limb threatening ischaemia (CLTI): open surgical bypass (OSB) and percutaneous transluminal angioplasty with/without stenting (PTA/S). The aim of this study was to compare short and long term outcomes between PTA/S and OSB in CLTI patients with long (GLASS grade III and IV) femoropopliteal disease.This was a two centre retrospective study including all consecutive patients with CLTI undergoing first time lower extremity intervention at two distinct vascular surgical centres. Between 1 January 2012 and 1 January 2018, 1 545 CLTI consecutive limbs were treated for femoropopliteal GLASS grade III and IV lesions at two vascular surgical centres. Using covariables from baseline and angiographic characteristics, a propensity score was calculated for each limb. Thus, comparable patient cohorts (235 in PTA/S and 235 in OSB group) were identified for further analysis. The primary outcomes were freedom from re-intervention in the treated extremity and major amputation. Secondary outcomes were all hospital complications among the two patient groups.Total overall complication rates were significantly higher in the OSB group (20.42% vs. 5.96%, p .001), especially wound infection/seroma rate that required prolonged hospitalisation and further treatment (7.65% vs. 0%, p .001). After the median follow up of 61 months, re-intervention rates were significantly higher in the PTA/S group (log rank test, 44.68% vs. 29.79%, p = .002), but there was no significant difference in terms of major amputation rates between the two group of patients (log rank test, PTA/S 27.23% vs. OSB 22.13%, p = .17).Bypass surgery seems to be superior to PTA/S for GLASS grade III and IV femoropopliteal lesions in patients with CLTI in terms of long term re-intervention rates, but with considerably higher rates of post-operative complications. A larger cohort of patients in currently ongoing randomised trials, as well as prospective cohort studies are necessary to confirm these findings.

Spontaneous rupture of the spleen (SRS) is a rare clinical entity with a potentially poor medical outcome. In most cases, SRS is caused by neoplastic disorder. Acute promyelocytic leukaemia is a rare but important cause of SRS that physicians are required to assess for. We present a 28-year-old woman with APL and COVID-19 pneumonia, who successfully underwent embolisation of the splenic artery for spontaneously occurring splenic rupture during induction chemotherapy. After the intervention the patient completed induction chemotherapy and achieved complete remission. Our case demonstrates that emergent transcatheter arterial embolisation can be lifesaving even in the unfavourable condition of a patient with severe immune deficiency.

Introduction Sentinel node biopsy is a procedure used for axillary nodal staging in breast cancer surgery. The process uses radioactive 99mTc isotope for mapping the sentinel node(s) and all the staff involved in the procedure is potentially exposed to ionizing radiation. The colloid for radiolabelling (antimone-sulphide) with 99mTc isotope (half-life 6 h) is injected into the patient breast. The injection has activity of 18.5 MBq. The surgeon removes the primary tumor and detects active lymph nodes with gamma detection unit. The tumor as well as the active nodal tissue is transferred to pathologist for the definitive findings. The aim of the study was to measure dose equivalents to extremities and whole body for all staff and suggest practice improvement in order to minimize exposure risk. Materials and methods The measurements of the following operational quantities were performed: Hp(10) personal dose equivalent to whole body and Hp(0.07) to extremities for staff as well as ambiental dose for operating theatre and during injection. Hp(0.07) were measured at surgeon’s finger by ring thermoluminescent dosimeter (TLD) type MTS-N, and reader RADOS RE2000. Surgeon and nurse were wearing TLD personal dosimeter at the chest level. Anesthesiologist and anesthetist were wearing electronic personal dosimeters, while pathologist was wearing ring TLD while manipulating tissue samples. Electronic dosimeters used were manufactured by Polimaster, type PM1610. All TLD and electronic dosimeters data were reported, including background radiation. Background radiation was also monitored separately. Personal TLDs are standard for this type of personal monitoring, provided by accredited laboratory. Measurements of ambiental dose in workplaces of other staff involved around the patient was performed before the surgery took place, by calibrated survey meters manufactured by Atomtex, type 1667. The study involved two surgeons and one pathologist, two anesthesiologists and three anesthetists during two months period. Results and discussion The doses received by all staff are evaluated using passive and active personal dosimeters and ambiental dose monitors and practice was improved based on results collected. Average annual whole body dose for all staff involved in the procedure was less than 0.8 mSv. Extremity dose equivalents to surgeon and pathologist were far below the limits set for professionally exposed (surgeon) and for public (pathologist). Conclusions Although has proven to be very safe for all staff, additional measures for radiation protection, in accordance to ALARA principle (As Low As Reasonably Achievable) should be conducted. The recommendations for practice improvement with respect to radiation protection were issued.

Introduction: Secondary breast reconstruction is a multifactorial decision. It is based on the need for neoadjuvant/adjuvant treatment, lifestyle and expected cosmetic outcome of the patient. The aim of this study was to show early complications related with secondary breast reconstruction using latissimus dorsi myocutaneous flap and silicone breast implants. Material and methods: This retrospective study was made with 24 patients who were treated at the Institute for Oncology Vojvodina in the period from 2007 to 2013. At all patients we underwent secondary breast reconstruction using pedicle latissimus dorsi myocutaneous flap (LDMF) and silicone breast implant. Results: Almost at all patients we identified prolonged seroma formation like complication related to donor site (21/24 (87.5%)). Radiotherapy and chemotherapy after first operation have statistical significance on complications after LDMF. Smoking and obesity have no influence on complications. Conclusion: Breast reconstruction using LDMF is related with small number of early postoperative complications and gives acceptable aesthetic results.

Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To provide additional clinical evidence in regulatory submissions for a modified-release (MR) once-daily (QD) tofacitinib formulation, we compared real-world adherence and effectiveness between patients initiating the MR QD formulation and patients initiating an immediate-release (IR) twice-daily (BID) formulation. Methods Two noninterventional cohort studies were conducted. First, adherence and two effectiveness proxies were compared between patients with RA who newly initiated tofacitinib MR 11 mg QD or IR 5 mg BID in the IBM® MarketScan® Commercial and Medicare Supplemental US insurance claims databases (March 2016–October 2018). Second, using data collected in the Corrona US RA Registry (February 2016–August 2019), two Clinical Disease Activity Index (CDAI)-based measures of effectiveness were compared between tofacitinib MR 11 mg QD and IR 5 mg BID, and against noninferiority criteria derived from placebo-controlled clinical trials of the tofacitinib IR formulation. Multiple sensitivity analyses of the registry data were conducted to reassure regulators of consistent results across different assumptions. Results In each study, approximately two-thirds of patients initiated the MR formulation. In the claims database study, improved adherence and at least comparable effectiveness were observed with tofacitinib MR vs IR over 12 months, particularly in patients without prior advanced therapy. In the registry study, the noninferiority of tofacitinib MR vs IR was demonstrated for both CDAI outcomes at ~6 months; this finding was robust across multiple sensitivity analyses. Conclusion These results demonstrate the value of real-world evidence from complementary data sources in understanding the impact of medication adherence with a QD formulation in clinical practice. These analyses were suitable for regulatory consideration as an important component of evidence for the comparability of tofacitinib MR 11 mg QD vs IR 5 mg BID in patients with RA. Trial Registration Claims database study: ClinicalTrials.gov identifier NCT04018001, retrospectively registered July 12, 2019. Corrona US RA Registry study: ClinicalTrials.gov identifier NCT04267380, retrospectively registered February 12, 2020. Electronic supplementary material The online version of this article (10.1007/s12325-020-01501-z) contains supplementary material, which is available to authorized users.

Nonalcoholic fatty liver disease (NAFLD) is a serious condition that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD is associated with metabolic syndrome (MetS) and all of its components. According to data, around 25-30% of population has NAFLD. Giving the growing incidence of MetS, obesity and diabetes mellitus type 2, NAFLD related terminal-stage liver disease is becoming prevailing indication for liver transplantation. In order to prevent terminal stage of this disease, it is crucial to determine those that are in risk group, to modify their risk factors and monitor their potential progression. In the absence of other causes of chronic liver disease, the prime diagnosis of NAFLD in daily clinical practice includes anamnesis, laboratory results (increased levels of aminotransferases and gammaglutamil transferases) and imaging methods. The biggest challenge with NAFLD patients is to differentiate simple steatosis from nonalcoholic steatohepatitis, and detection of fibrosis, that is the main driver in NAFLD progression. The gold standard for NAFLD diagnosis still remains the liver biopsy (LB). However, in recent years many noninvasive methods were invented, such as transient elastography (TE). TE (FibroScan®, Echosens, Paris, France) is used for diagnosis of pathological differences of liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). Investigations in the last years have confirmed that elastographic parameters of steatsis (CAP) and fibrosis (LSM) are reliable biomarkers to non-invasively assess liver steatosis and fibrosis respectively in NAFLD patients. A quick, straightforward and non-invasive method for NAFLD screening in patients with MetS components is TE-CAP. Once diagnosed, the next step is to determine the presence of fibrosis by LSM which should point out high risk patients. Those patients should be referred to hepatologists. LB may be avoided in a substantial number of patients if TE with CAP is used for screening.

Introduction Aneurysmal subarachnoid hemorrhage is a type of spontaneous hemorrhagic stroke, which is caused by a ruptured cerebral aneurysm. Cerebral vasospasm (CVS) is the most grievous complication of subarachnoid hemorrhage (SAH). The aim of this study was to examine the risk factors that influence the onset of CVS that develops after endovascular coil embolization of a ruptured aneurysm. Materials and methods The study was designed as a cross-sectional study. The patients included in the study were 18 or more years of age, admitted within a period of 24 h of symptom onset, diagnosed and treated at a university medical center in Serbia during a 5-year period. Results Our study showed that the maximum recorded international normalized ratio (INR) values in patients who were not receiving anticoagulant therapy and the maximum recorded white blood cells (WBCs) were strongly associated with cerebrovascular spasm, increasing its chances 4.4 and 8.4 times with an increase of each integer of the INR value and 1,000 WBCs, respectively. Conclusions SAH after the rupture of cerebral aneurysms creates an endocranial inflammatory state whose intensity is probably directly related to the occurrence of vasospasm and its adverse consequences.

Progression to exudative 'wet' age-related macular degeneration (exAMD) is a major cause of visual deterioration. In patients diagnosed with exAMD in one eye, we introduce an artificial intelligence (AI) system to predict progression to exAMD in the second eye. By combining models based on three-dimensional (3D) optical coherence tomography images and corresponding automatic tissue maps, our system predicts conversion to exAMD within a clinically actionable 6-month time window, achieving a per-volumetric-scan sensitivity of 80% at 55% specificity, and 34% sensitivity at 90% specificity. This level of performance corresponds to true positives in 78% and 41% of individual eyes, and false positives in 56% and 17% of individual eyes at the high sensitivity and high specificity points, respectively. Moreover, we show that automatic tissue segmentation can identify anatomical changes before conversion and high-risk subgroups. This AI system overcomes substantial interobserver variability in expert predictions, performing better than five out of six experts, and demonstrates the potential of using AI to predict disease progression.

Interleukin-33 (IL-33) regulates innate and acquired immune response to pathogens, self-antigens and tumors. IL-33 effects on tumors depend on the dose and mode of administration along with the type of malignancy. We studied the effects of IL-33 on the development of primary and metastatic melanoma induced by B16-F1 cell line in C57BL/6 mice. Intraperitoneally applied IL-33 restricts primary tumor growth. When administered intranasally 3 days prior to the intravenous injection of the tumor cells, IL-33 promoted growth of B16-F1 melanoma metastases, while B16-F10 gave massive metastases independently of IL-33. To mimic natural dissemination, we next used a limited number (5 × 104) of B16-F1 cells intravenously followed by application of IL-33 intraperitoneally. IL-33 increased the size of metastases (10.96 ± 3.96 mm2) when compared to the control group (0.86 ± 0.39 mm2), without changing incidence and number of metastases. IL-33 increased expression of ST2 on both tumor and immune cells in metastases. Also, IL-33 enhanced eosinophils and anti-tumor NK cells in the lung. The striking finding was reduced cytotoxicity of CD8+ T cells derived from metastatic lung of IL-33 injected mice. IL-33 reduced the percentage of TNF-α+ and IFN-γ+ CD8+ T cells while increasing the frequency of CD8+ T cells that express inhibitory molecules (PD-1, KLRG-1 and CTLA-4). There was a significant accumulation of CD11b+Gr-1+ myeloid suppressor cells and FoxP3+, IL-10+ and CTLA-4+ regulatory T cells in the metastatic lung of IL-33 injected mice. The relevance of IL-33 for melanoma metastases was also documented in a significantly increased level of serum IL-33 in stage III melanoma patients.

Acupuncture is a complementary and nonpharmacological intervention that can be effective for the management of chronic pain in addition to or instead of medication. Various animal models for neuropathic pain, inflammatory pain, cancer-related pain, and visceral pain already exist in acupuncture research. We used a newly validated human pain model and examined whether acupuncture can influence experimentally induced dental pain. For this study, we compared the impact of manual acupuncture (real acupuncture), manual stimulation of a needle inserted at nonacupuncture points (sham acupuncture) and no acupuncture on experimentally induced dental pain in 35 healthy men who were randomized to different sequences of all 3 interventions in a within-subject design. BORG CR10 pain ratings and autonomic responses (electrodermal activity and heart rate variability) were investigated. An initial mixed model with repeated measures included preintervention pain ratings and the trial sequence as covariates. The results showed that acupuncture was effective in reducing pain intensity when compared to no acupuncture (β = -.708, P = .002), corresponding to a medium Cohen's d effect size of .56. The comparison to the sham acupuncture revealed no statistically significant difference. No differences in autonomic responses between real and sham acupuncture were found during the intervention procedures. PERSPECTIVE: This study established a dental pain model for acupuncture research and provided evidence that experimentally induced dental pain can be influenced by either real acupuncture or manual stimulation of needles at nonacupuncture points. The data do not support that acupoint specificity is a significant factor in reducing experimental pain.

Introduction We evaluated the effectiveness of long-term continuous subcutaneous insulin infusion (CSII) compared with multiple daily insulin (MDI) injections for glycaemic control and variability, hypoglycaemic episodes and maternal/neonatal outcomes in pregnant women with pre-existing type 1 diabetes (pT1D). Methods Our observational cohort study included 128 consecutive pregnant women with pT1D, who were treated from 1 January 2010 to 31 December 2017. Of 128 participants, 48 were on CSII and 80 were on MDI. Glycaemic control was determined by glycated haemoglobin (HbA1c) (captured in preconception and each trimester of pregnancy). Glucose variability (GV) was expressed as the coefficient of variation (CV) [calculated from self-monitoring of blood glucose (SMBG) values], and hypoglycaemia was defined as glucose values < 3.9 mmol/l. The data on maternal and neonatal outcomes were collected from obstetrical records. Results Duration of the treatment was 8.8 ± 5.3 years in the CSII and 12.6 ± 8.0 years in the MDI group. The CSII lowered HbA1c in preconception (7.1 ± 0.1 vs. 7.9 ± 0.2%, p = 0.03) and the first (6.9 ± 0.1 vs. 7.7 ± 0.2%, p = 0.02), second (6.6 ± 0.1 vs. 7.2 ± 0.1%, p = 0.003) and third (6.5 ± 0.1 vs. 6.8 ± 0.1%, p = 0.02) trimesters significantly better than MDI. Significantly lower CV was observed only for fasting glycaemia in the first trimester (17.1 vs 28.4%, p

Galectin-3 (Gal-3) has diverse roles in inflammatory and autoimmune diseases. There is evidence that Gal-3 plays a role in both type 1 and type 2 diabetes. While the role of Gal-3 expression in immune cells invading the pancreatic islets in the experimental model of type 1 diabetes mellitus has been already studied, the importance of the overexpression of Gal-3 in the target β cells is not defined. Therefore, we used multiple low doses of streptozotocin (MLD–STZ)–induced diabetes in C57Bl/6 mice to analyze the effect of transgenic (TG) overexpression of Gal-3 in β cells. Our results demonstrated that the overexpression of Gal-3 protected β cells from apoptosis and attenuated MLD–STZ–induced hyperglycemia, glycosuria, and ketonuria. The cellular analysis of pancreata and draining lymph nodes showed that Gal-3 overexpression significantly decreased the number of pro-inflammatory cells without affecting the presence of T-regulatory cells. As the application of exogenous interleukin 33 (IL-33) given from the beginning of MLD–STZ diabetes induction attenuates the development of disease, by increasing the presence of regulatory FoxP3+ST2+cells, we evaluated the potential synergistic effect of the exogenous IL-33 and TG overexpression of Gal-3 in β cells at the later stage of diabetogenesis. The addition of IL-33 potentiated the survival of β cells and attenuated diabetes even when administered later, after the onset of hyperglycemia (12–18 days), suggesting that protection from apoptosis and immunoregulation by IL-33 may attenuate type 1 diabetes.

Autism spectrum disorders (ASD) are neurodevelopmental disorders with an estimated heritability of >60%. Family-based genetic studies of ASD have generally focused on multiple small kindreds, searching for de novo variants of major effect. We hypothesised that molecular genetic analysis of large multiplex families would enable the identification of variants of milder effect. We studied a large multigenerational family of European ancestry with multiple family members affected with ASD or the broader autism phenotype (BAP). We identified a rare heterozygous variant in the gene encoding 1,4-alpha-glucan branching enzyme 1 (GBE1) that was present in seven of seven individuals with ASD, nine of ten individuals with the BAP and none of four tested unaffected individuals. We genotyped a community-acquired cohort of 389 individuals with ASD and identified three additional probands. Cascade analysis demonstrated the variant was present in eleven of thirteen individuals with familial ASD/BAP and neither of the two tested unaffected individuals in these three families, also of European ancestry. The variant was not enriched in the combined UK10K ASD cohorts of European ancestry but heterozygous GBE1 deletion was overrepresented in large ASD cohorts, collectively suggesting an association between GBE1 and ASD.

Pathogenic heterozygous variants in HMBS encoding the enzyme hydroxymethylbilane synthase (HMBS), also known as porphobilinogen deaminase, cause acute intermittent porphyria (AIP). Biallelic variants in HMBS have been reported in a small number of children with severe progressive neurological disease and in three adult siblings with a more slowly, progressive neurological disease and distinct leukoencephalopathy. We report three further adult individuals who share a distinct pattern of white matter abnormality on brain MRI in association with biallelic variants in HMBS, two individuals with homozygous variants, and one with compound-heterozygous variants. We present their clinical and radiological features and compare these with the three adult siblings previously described with leukoencephalopathy and biallelic HMBS variants. All six affected individuals presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. This recognizable pattern of MRI abnormalities is seen in all six adults described here. Biallelic variants in HMBS cause a phenotype that is distinct from AIP. It is not known whether AIP treatments benefit individuals with HMBS-related leukoencephalopathy. One individual reported here had improved neurological function for 12 months following liver transplantation followed by decline and progression of disease.

The combination of primary and secondary prevention has already influenced the colposcopic practice by reduction in HPV (human papillomavirus) vaccine-type HSIL (HIGH-GRADE SIL), colposcopy referral numbers, colposcopic positive predictive value (PPV) for CIN2+, and by modification of referral pattern, colposcopic performance, and procedures. Different strategies, both isolated and combined, have been proposed in order to maintain the diagnostic accuracy of colposcopy: patient risk stratification based on immediate or future risk of CIN3+ or on HPV genotyping after a positive screening test. Data are needed to support alternative colposcopic strategies based on vaccination status and on the application of artificial intelligence where the patient’s risk stratification is implicit in precision medicine which involves the transition from an operator-dependent morphology-based to a less-operator dependent, more biomolecular management. The patient’s risk stratification based on any combination of “history” and “test results” to decrease colposcopy workload further reduce colposcopic and histologic morphological approaches, while adding genotyping to the risk stratification paradigm means less cytologic morphologic diagnosis. In Italy, there is a strong colposcopic tradition and there is currently no immediate need to reduce the number of colposcopies. Instead, there is a need for more accredited colposcopists to maintain the diagnostic accuracy of colposcopy in the vaccination era.

BACKGROUND The influence of concomitant brain pathologies on the progression rate in PSP is unclear. OBJECTIVES To analyze the frequency and severity of copathologies and their impact on the progression in PSP. METHODS We analyzed clinic-pathological features of 101 PSP patients. Diagnoses and stages of copathologies were established according to standardized criteria, including Alzheimer's disease-related pathology, argyrophilic grains, Lewy-related pathology, transactive response DNA-binding protein 43 pathology, fused in sarcoma pathology, cerebral amyloid angiopathy, and small vessel disease. Demographic data and major clinical milestones (frequency and latency to onset) were extracted from patients' files. RESULTS Only 8% of 101 patients presented with pure PSP pathology without any copathology. Alzheimer's disease-related pathology was the most frequent (84%), followed by argyrophilic grains (58%), both occurring as single copathology or in combination with other proteinopathies or cerebrovascular disease. Lewy-related and transactive response DNA-binding protein 43 copathology occurred rarely (8% and 6%, respectively). Fused in sarcoma-positive cases were not found. While being common, copathology was mostly mild in severity, with the exception of frequently widespread argyrophilic grains. Small vessel disease was also frequent (65%). Cerebral amyloid angiopathy occurred only in the presence of Alzheimer's disease-related changes (25%). The copathologies did not have major impact on prevalence and time frame of major disease milestones. CONCLUSIONS In PSP, concomitant neurodegenerative proteinopathies or cerebrovascular diseases are frequent, but generally mild in severity. Our data confirmed that four repeat tau is still the most relevant target for PSP, whereas the impact of copathologies on progression rate appears to be of less importance. This is relevant information for the development of disease-modifying therapies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Introduction: The ?gold standard? for patients with locally advanced rectal cancer is neoadjuvant chemoradiotherapy followed by surgery. Aim: Evaluation of local recurrence after surgery for locally advanced rectal cancer. Methods and patients: Retrospective study included 189 patients, who were operated at Oncology Institute of Vojvodina from January 1st 2012 until December 31st 2017. Patients were divided into two groups. In the first group 73 patients who received chemoradiotherapy were included, while 116 patients without neoadjuvant treatment were in the second group. All patients were diagnosed with locally advanced rectal cancer. The existence of operable metastases in the liver and/or lungs did not exclude patients from the study. Patients who had undergone resection of the rectum by Miles, Hartmann or local tumor excision were excluded from the study. Results: The median follow-up period was 48 months (range 13-84). In total, 23 (12.2%) patients developed local recurrence. In the chemoradiotherapy group, 15.1% (11 of 73 patients) had a local recurrence, as compared with 10.3% (12 of 116 patients) in the group without neoadjuvant treatment. In both groups, there were no correlation between rate of local recurrence with other clinical and pathological parameters such as gender, tumor location, T and N stage, histological differentiation, or lymphovascular and perineural invasion (p>0.05). We confirmed significant association between circumferential resection margin with local recurrence in patients who were treated by preoperative chemoradiation (p=0.014). Conclusion: This study has not shown reduced risk of local recurrence after neoadjuvant therapy most likely due to small number of patients. Despite our results, neoadjuvant treatment followed by surgery remains the best treatment protocol for patients with locally advanced rectal cancer.

Background/Aim. Adverse pregnancy outcomes such as preeclampsia (PE), placental abruption (PA), fetal intrauterine growth restriction (IUGR) and stillbirth could be recognized by prenatal screening. The objective of this study was to predict IUGR by using first-trimester extremely low pregnancy-associated plasma protein-A (PAPP-A), extremely low free beta-human chorionic gonadotropin (free ?hCG) levels, and extremely high Pulsatility-index (PI) of uterine arteries, as single and combined predictors for IUGR development. Methods. This was a prospective first-trimester study analyzing singleton pregnancies at 11?13+6 weeks? gestation who underwent routine first-trimester screening at the Department of High Risk Pregnancy of the Clinic for Gynecology and Obstetrics ?Narodni front?, University of Belgrade, Serbia. First-trimester screening for PAPP-A, free ?hCG, and PI was performed in nulliparous, normotensive women with extremely low PAPP-A (PAPP-A ? 0.52 unit multiple of median ? MoM) and/or extremely low free ?hCG (free ?hCG ? 0.56 MoM) and/or extremely high PI (PI ? 2.52). Results. Of 85 pregnant women included in the final analysis, 14 (16.5%) developed IUGR. PAPP-A ? 0.52 MoM and PI ? 2.52, as single categorical variables, found to be with high predictable values for IUGR development (odds ratio ? OR = 3.064, 95% confidence interval ? CI= 0.634-14.810, p = 0.046, and OR = 2.129, 95% CI = 0.449?10.713, p = 0.021, respectively). Furthermore, the receiver operating characteristic (ROC curve identified PAPP-A and PI as continuous variables to be significant predictors of IUGR (area under curve ? AUC = 0.671, 95% CI = 0.521?0.820, p = 0.045, and AUC = 0.744, 95% CI = 0.587?0.902, p = 0.004, respectively). Conclusion. The present study suggests that the first trimester extremely low PAPP-A and increased Doppler-PI levels are single predictors of IUGR. Described model could be used in a routine daily clinical practice in resource limited settings where other parameters are not available for the prediction of IUGR development.

Background Ulcerative colitis (UC) is a chronic disease characterized by inflammation of intestinal epithelium, primarily of the colon. An increasing prevalence of metabolic syndrome (MetS) in patients with UC has been documented recently. Still, there is no evidence that MetS alters the course of the UC. Aim To test the influence of the MetS on the severity of UC and the local and systemic immune status. Methods Eighty nine patients with de novo histologically confirmed UC were divided in two groups, according to ATP III criteria: Group without MetS (no MetS) and group with MetS. Results Clinically and histologically milder disease with higher serum level of immunosuppressive cytokine interleukin-10 (IL-10) and fecal content of Galectin-3 (Gal-3) was observed in subjects with UC and MetS, compared to subjects suffering from UC only. This was accompanied with predomination of IL-10 over pro-inflammatory cytokines tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interleukin-17 (IL-17) in the sera as well as Gal-3 over TNF-α and IL-17 in feces of UC patients with MetS. Further, the patients with both conditions (UC and MetS) had higher percentage of IL-10 producing and Gal-3 expressing innate and acquired immune cells in lamina propria. Conclusion Local dominance of Gal-3 and IL-10 over pro-inflammatory mediators in patients with MetS may present a mechanism for limiting the inflammatory process and subsequent tissue damage in UC.

To investigate the natural history of optic disc pit maculopathy and explore the associations between demographic, anatomic, and functional characteristics.Retrospective, comparative case series.This was a single-center medical record review of previously untreated optic disc pit maculopathy. Baseline data of visual function, demographics, and pit physiognomy were collected, and further subgroup analysis was undertaken on patients with long-term follow-up, according to whether they were monitored or received surgical intervention. LogMAR visual acuity was the primary outcome measure, and anatomic characteristics were reported where available.Eighty-seven patients were identified with a new presentation of optic disc pit maculopathy. No demographic or pit features were correlated with vision at baseline. In 51 patients with available optical coherence tomography data, only the presence of subretinal fluid at baseline was associated with poorer visual acuity (P.001). Fifty-two patients who were monitored without treatment had available long-term follow-up data. The mean change in visual acuity in this group was 0.01, with 77% maintaining visual acuity ≤0.30. Twenty-seven patients underwent surgery and showed significant postoperative improvement in vision (P.001), with 59% achieving an acuity ≤0.30. Duration of postoperative follow-up was associated with better visual acuity (P = .007).Many patients with optic disc pit maculopathy maintain good long-term visual acuity and may demonstrate resolution of subretinal fluid in the absence of surgical intervention. There may be evidence to support delaying surgical treatment until visual deterioration is observed because of the potential stability or spontaneous improvement of the condition, the high rate of reoperation, and the long-term positive outcomes of deferred intervention.

Summary Background Tofacitinib is an oral Janus kinase (JAK) inhibitor used for the treatment of rheumatoid arthritis. We assessed the efficacy and safety of tofacitinib after methotrexate withdrawal in patients who achieved low disease activity (LDA) with tofacitinib in combination with methotrexate. Methods ORAL Shift was a phase 3b/4 non-inferiority trial in patients aged at least 18 years with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate done in 109 centres across 16 countries. After 24 weeks of open-label tofacitinib modified-release 11 mg once daily plus methotrexate, patients who achieved LDA (clinical disease activity index [CDAI] ≤10) were randomly assigned 1:1 via an automated web-based response system to receive tofacitinib plus placebo (tofacitinib monotherapy; ie, masked methotrexate withdrawal) or continue tofacitinib plus methotrexate for 24 weeks in a double-blind manner. The primary endpoint was the least squares mean change from week 24 to week 48 in disease activity score in 28 joints with four variables, including erythrocyte sedimentation rate (DAS28-4[ESR]). The primary analysis was done in all patients who received at least one dose of study treatment in both phases, and safety was assessed in all patients who received at least one dose of study treatment since enrolment. Non-inferiority of tofacitinib monotherapy versus tofacitinib plus methotrexate was declared if the upper bound of the 95% CI for the difference in change in DAS28-4(ESR) between treatment groups was less than 0·6. Safety was assessed in both phases. The trial is registered with ClinicalTrials.gov , NCT02831855 , and is complete. Findings Between Sept 1, 2016, and Nov 1, 2017, 694 patients were enrolled in the open-label phase and 623 received study treatment for 24 weeks. 533 achieved CDAI-defined LDA and were randomly assigned into the double-blind phase (267 in the tofacitinib monotherapy group and 266 in the tofacitinib plus methotrexate group). Three participants in the monotherapy group did not start treatment so were not included in the primary analysis. Non-inferiority was demonstrated (difference 0·30 [95% CI 0·12–0·48]). 107 (41%) of 264 patients in the tofacitinib monotherapy group and 109 (41%) of 266 in the tofacitinib plus methotrexate group had adverse events; five patients from each group discontinued because of adverse events; two patients died in the tofacitinib plus methotrexate group. No new safety findings were reported up to 48 weeks. Interpretation Patients with rheumatoid arthritis who achieve LDA with a combination of tofacitinib plus methotrexate may consider withdrawing methotrexate without significant worsening of disease activity or unexpected safety issues. Funding Pfizer.

Introduction Still little is known about factors, influencing the organ uptake of somatostatin receptor (SSTR)-targeting radiopharmaceuticals. The aim of this study was to assess the influence of gender on [68Ga]Ga-DOTANOC uptake. Further on, we assessed other factors such as diabetes, proton pump inhibitors (PPIs) and oral antidiabetics (OADs). Methods In 118 studies of patients with a [68Ga]Ga-DOTANOC PET/CT (m = 60, f = 58; mean age: 61 ± 15 yrs) SUVmax and SUVmean of the stomach, liver, spleen, kidneys, adrenal glands, and pancreas were assessed. Patients with history of splenectomy and significant tumor burden were excluded. Additionally, clinical information (gender, diabetes, age, pre-medications such as PPIs, OADs and somatostatin analogues (SSAs), were collected. Results [68Ga]Ga-DOTANOC uptake proved to be significantly lower in female patients compared to males for the SUVmax of the stomach (7.1, 9.1; P = 0.04), liver (8.3, 9.4; P = 0.0007), adrenal glands (15.9, 19.9; P = 0.05) kidneys (20.3, 18.9; P = 0.05) and the SUVmean of the pancreatic tail (2.9, 3.2; P = 0.03) and the kidneys (11.8, 10.6, P = 0.004). Additionally, patients with diabetes and below the age of 50 yrs. showed significantly higher SUVmax and SUVmean values of the stomach (diabetes: 9.1, 7.8; P = 0.01 and 6.0, 5.3; P = 0.004; age: 6.3, 8.3; P = 0.01 and 4.4, 5.5; P = 0.03). In contrast, intake of PPIs only affected the SUVmean of the liver (11.0, 9.0; P = 0.005), whereas OADs caused higher SUVmax values in the stomach (10.0, 7.8; P = 0.02), spleen (42.5, 32.6; P = 0.0005) adrenal glands (25.0, 16.9; P = 0.0003) and also higher SUVmean in the spleen (26.1, 21.4; P = 0.002) and adrenal glands (14.8, 12.4; P = 0.02). Conclusion Factors such as gender, diabetes and age influence [68Ga]Ga-DOTANOC uptake, whereas ongoing medications such as PPIs and OADs exerted less influence.

Immunotherapy of B-cell malignancies with bispecific antibodies is an emerging treatment option. However, not all patients benefit from these therapies, presumably due to pretreatment regimens. Therefore, we determined the effect of different treatment lines on the activity of T cells and their responsiveness to AFM11. AFM11 is a tetravalent, bispecific CD19/CD3 immunoengager based on Affimed's ROCK platform, currently being investigated in phase I clinical trials for non-Hodgkin lymphoma and acute lymphoblastic leukemia. T cells from B-cell lymphoma patients treated with either rituximab+bendamustine (R-Benda), rituximab+CHOP (R-CHOP), or with high-dose BEAM chemotherapy (HD-BEAM) and autologous HSCT were compared with T cells from healthy donors. Overall, in these patients, T-cell numbers were significantly reduced. To determine whether distinct chemotherapy affects AFM11 efficacy, functional T-cell assays were performed. It is interesting to note that, only in assays that combine target cell lysis, cytokine production and proliferation over 4 days at an effector to target ratio of up to 1:25 significant differences could be detected between the different treatment groups: T cells after R-CHOP showed only modest decrease in their functionality when compared with healthy controls, whereas R-Benda and HD-BEAM had a profound effect on AFM11-induced T-cell cytotoxicity. In conclusion, T cells from lymphoma patients are reduced in number and have functional defects following treatment with certain chemotherapy regimens, also reducing AFM11 efficacy. Importantly, AFM11 was still able to trigger B-cell-directed T-cell immunity in all treatment groups.

Intracranial aneurisms are ongoing problem for neurosurgeons and especially for interventional neuroradiologists due to its morbidity and mortality. The method of choice for treatment of the unruptured and ruptured intracranial aneurysms is endovascular coiling on account of its minimal invasiveness and high effectiveness. The aim of our study was to evaluate the safety and successfulness of endovascular coiling procedure in unruptured and ruptured intracranial aneurysms. Our study was designed as case series and consisted of patients older than 18 years, who underwent endovascular coiling of unruptured and ruptured intracranial aneurysms and follow-up examination 6 months after the interventional procedure. The procedures were performed from December 2010 to December 2016, by experienced interventional neuroradilogists (more than 400 performed embolizations each) at the Department for Interventional Neuroradiology, Clinical Center Kragujevac, Serbia. There were 681 patients (average age 47.5 ± 11.2 years) treated with endovascular coiling, out of them 324 (234 females, 90 males) had unruptured intracranial aneurysm and 357 (138 females, 219 males) had ruptured intracranial aneurysm. In our series, total complication rate was 11.71 %. Analysis of the results after first endovascular procedure has shown that complete aneurysm occlusion was accomplished in 546 patients (80.3%), near-complete in 81 patients (11.8%), and incomplete in 54 patients (7.9 %). Our results were satisfying regarding the procedure’s success, safety, outcomes and study material. However, further technical development of the materials and constant training of the interventional radiologists, are a necessity in order to improve treatment outcomes and patients’ benefit.

Diabetes mellitus (DM) with its micro- and macrocomplications is the leading global epidemic of the 21st century. The aim of the research is to determine possible changes in the complete blood count (CBC) parameters depending on glycemic controlin patients with Type 2 diabetes mellitus (T2DM).The study included a total of 178 patients with T2DM, both gender over the age of 40 years, from the Health Care Center »Dr Milorad Mika Pavlović« Indjija, Serbia. To notice the possible correlation between the CBC parameters and glucose control in T2DM, the subjects were divided in two groups with HbA1c ≤ 7% and with HbA1c7%. We analysed CBC parameters, parameters of glycoregulation, lipid status using standard biochemical methods, performed anthropometric measurements and collected patients data by questionnaire and electronic patient card.There was statistical difference between HbA1c groups for PMDW (p=0.045), HDL (p=0.0067). Using univariate linear regression it is shown that PCT was correlated with WBC (p=0.0005), neutrophils (p=0.046), monocytes (p=0.003); MPM was associated with MPV (p=0.0005); MPC (p=0.0005), PDW (P=0.0005), GLU0 (p=0.034), HDL-C (p=0.005); PMDW was correlated with HbA1c% (p=0.049), GLU0 (p=0.013), HDL-C (p=0.001), BW (p=0.043) in all patients.Based on our study results it may be concluded that some of the parameters of CBC could be useful tool in following glycemic control of diabetics.Diabetes mellitus (DM) sa mikro i makrokomplikacijama je vodeća globalna epidemija 21. veka. Cilj istraživanja je da se utvrde eventualne promene parametara kompletne krvne slike (KKS) u zavisnosti od glikoregulacije kod pacijenata sa šećernom bolesti tip 2 (DM tip 2).Istraživanjem je obuhvaćeno ukupno 178 pacijenata sa DM tip 2, oba pola, starijih od 40 godina, iz Doma zdravlja »Dr Milorad Mika Pavlović«; Inđija, Srbija. Da bi se utvrdila moguća povezanost između parametara KKS i glikoregulacije u T2DM, ispitanici su podeljeni u dve grupe, sa HbA1c ≤ 7% i sa vrednostima HbA1c7%. Analizirani su parametri KKS, parametri glikoregulacije, lipidni status korišćenjem standardnih biohemijskih postupaka, a vršena su i antropometrijska merenja. Podaci od pacijenata prikupljeni su putem upitnika i elektronskog kartona pacijenta.Utvrđena je statistički značajna razlika između grupa za PMDW (p=0,045), HDL-C (p=0,0067). Kod svih pacijenata (univarijabilna linearna regresija) rezultati su pokazali daje PCT povezan sa leukocitima (p=0,0005), neutrofilima (p=0,046), monocitima (p=0,003); MPM je u korelaciji sa MPV (p=0,0005); MPC (p=0,0005), PDW (p=0,0005), GLU0 (p=0,034), HDL-C (p=0,005); PMDW je u korelaciji sa HbA1c% (p=0,049), GLU0 (p=0,013), HDL-C (p=0,001), telesnom masom (p=0,043).Na osnovu dobijenih rezultata našeg istraživanja može se zaključiti da postoji povezanost između pojedinih hematoloških parametara i glikoregulacije kod pacijenata sa dijabetesom.

Tumor-derived exosomes can modulate the cancer microenvironment and induce metastatic spread. Exosomes may carry enzymes for leukotriene (LT) biosynthesis, but the role of exosomal LTs has not been studied in cancer. We isolated exosomes and malignant cells from pleura exudates from 14 patients with non-small cell lung cancer. Lipidomic profiles, migration and apoptosis were determined. Both exosomes and primary cancer cells contained γ-glutamyl transpeptidase 1 (GGT-1) and avidly transformed exogenous LTC4 to pro-tumorigenic LTD4, for the cells to levels 100-fold above their endogenous CysLT production. This suggests that cancer cells promote their own survival via LTD4 if supplied with LTC4, which in the exudates was produced by monocytic cells. Furthermore, exosomes promoted migration of cancer cells, which was counteracted by the CysLT1 antagonist montelukast. Montelukast also induced apoptosis of cancer cells, and this was partially inhibited by exosomes. Our results demonstrate how cancer cells and exosomes, together with monocytic cells in lung cancer tissue, can produce high amounts of LTD4, to stimulate cancer cell migration and survival. This suggests that part of the pro-metastatic effect of exosomes is mediated by the leukotriene machinery, further supporting the use of CysLT1 antagonists for lung cancer therapy.

Background: Pneumonia is the leading cause of death among children, thus, a correct early diagnosis would be ideal. The imagistic diagnosis still uses chest X-ray (CXR), but lung ultrasound (LUS) proves to be reliable for pneumonia diagnosis. The aim of our study was to evaluate the sensitivity and specificity of LUS compared to CXR in consolidated pneumonia. Methods: Children with clinical suspicion of bacterial pneumonia were screened by LUS for pneumonia, followed by CXR. The agreement relation between LUS and CXR regarding the detection of consolidation was evaluated by Cohen’s kappa test. Results: A total of 128 patients with clinical suspicion of pneumonia were evaluated, 74 of them were confirmed by imagery and biological inflammatory markers. The highest frequency of pneumonia was in the 0–3 years age group (37.83%). Statistical estimation of the agreement between LUS and CXR in detection of the consolidation found an almost perfect agreement, with a Cohen’s kappa coefficient of K = 0.89 ± 0.04 SD, p = 0.000. Sensitivity of LUS was superior to CXR in detection of consolidations. Conclusion: Lung ultrasound is a reliable method for the detection of pneumonia consolidation in hospitalized children, with sensitivity and specificity superior to CXR. LUS should be used for rapid and safe evaluation of child pneumonia.

Semantic representations are processed along a posterior-to-anterior gradient reflecting a shift from perceptual (e.g., it has eight legs) to conceptual (e.g., venomous spiders are rare) information. One critical region is the anterior temporal lobe (ATL): patients with semantic variant primary progressive aphasia (svPPA), a clinical syndrome associated with ATL neurodegeneration, manifest a deep loss of semantic knowledge. We test the hypothesis that svPPA patients perform semantic tasks by over-recruiting areas implicated in perceptual processing. We compared MEG recordings of svPPA patients and healthy controls during a categorization task. While behavioral performance did not differ, svPPA patients showed indications of greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. These findings suggest a pervasive reorganization of brain networks in response to ATL neurodegeneration: the loss of this critical hub leads to a dysregulated (semantic) control system, and defective semantic representations are seemingly compensated via enhanced perceptual processing.

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes.

Describe PSP Study Group, the ProPSP Study Group, and the Movement Disorder Society–Endorsed PSP Study Group., [Background] The Progressive Supranuclear Palsy Rating Scale is a prospectively validated physician-rated measure of disease severity for progressive supranuclear palsy. We hypothesized that, according to experts' opinion, individual scores of items would differ in relevance for patients' quality of life, functionality in daily living, and mortality. Thus, changes in the score may not equate to clinically meaningful changes in the patient's status., [Objective] The aim of this work was to establish a condensed modified version of the scale focusing on meaningful disease milestones., [Methods] Sixteen movement disorders experts evaluated each scale item for its capacity to capture disease milestones (0 = no, 1 = moderate, 2 = severe milestone). Items not capturing severe milestones were eliminated. Remaining items were recalibrated in proportion to milestone severity by collapsing across response categories that yielded identical milestone severity grades. Items with low sensitivity to change were eliminated, based on power calculations using longitudinal 12-month follow-up data from 86 patients with possible or probable progressive supranuclear palsy., [Results] The modified scale retained 14 items (yielding 0–2 points each). The items were rated as functionally relevant to disease milestones with comparable severity. The modified scale was sensitive to change over 6 and 12 months and of similar power for clinical trials of disease-modifying therapy as the original scale (achieving 80% power for two-sample t test to detect a 50% slowing with n = 41 and 25% slowing with n = 159 at 12 months)., [Conclusions] The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine. © 2021 International Parkinson and Movement Disorder Society., This work was supported by the Munich Cluster for Systems Neurology (Synergy), the Volkswagen Stiftung, the Lower Saxony Ministry for Science, the Niedersächsisches Vorab, and the Petermax-Müller Foundation (Etiology and Therapy of Synucleinopathies and Tauopathies). This project was also supported by the German Center for Neurodegenerative Diseases e.V. (DZNE), German PSP Gesellschaft, and the International Parkinson & Movement Disorder Society.

Funding Acknowledgements Type of funding sources: None. Background The workflow and reperfusion time in STEMI patients are associated with morbidity-mortality. COVID19 lockdown restrictions could impact on routine prehospital management of STEMI. Methods and purpose Retrospective study comparing patients treated for STEMI during the period of lockdown in Spain (03/15/2020 to 05/31/2020) and patients with STEMI treated in the same period of the previous year (2019). The aim is to present our experience comparing the two periods attending to the prehospital flow of patients, the reperfusion strategy of choice, the prehospital complications and the "patient delay time" for reperfusion. Results We included 73 patients from the pre-COVID period and 67 patients from the lockdown. Baseline characteristics are shown in table 1. During the lockdown, there was a significant increase in the number of patients who activated the emergency medical system (emergency number 112) bypassing an outpatient medical center. In addition and possibly due to patients’ preference for keeping social distance, there was an increase in the number of self-referred patients to the emergency department (ED), decreasing number of patients attended by ambulance system (table 1). There were no significant differences neither in the choice of reperfusion strategy nor in the occurrence of complications (image 1). The mean time from symptom onset to first medical contact (patient delay time) was not significantly prolonged (table 1). Conclusion During COVID-19 lockdown, the flow of STEMI patients to the ED was modified because of patients preferences. It did not mean longer times to first medical attention or increase in the number of complications. Table 1Pre-Covid (n = 73)Lockdown COVID-19 (n = 67)p valueSex male; n (%) /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-536869121 1107305727 33554432 0 415 0;} @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:swiss; mso-font-pitch:variable; mso-font-signature:-469750017 -1073732485 9 0 511 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin-top:0cm; margin-right:0cm; margin-bottom:8.0pt; margin-left:0cm; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:Calibri; mso-fareast-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; 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Image 1

Funding Acknowledgements Type of funding sources: None. Introduction Controversy remains about the best strategy for STEMI reperfusion during the COVID-19 pandemic. There are no uniform criteria in this setting and it has been proposed that fibrinolysis may be the strategy of choice during lockdown. The aim is to present our experience and safety in maintaining the guidelines based STEMI reperfusion strategy. Methods and purpose Retrospective study comparing patients treated for STEMI during the period of lockdown in Spain (03/15/2020 to 05/31/2020) and patients with STEMI treated in the same period of the previous year (2019). Result We included 73 patients from the pre-COVID period versus 67 patients from the lockdown. Baseline characteristics are showed in table 1. There were no significant differences neither in the choice of reperfusion strategy (fibrinolysis or primary percutaneous coronary intervention) nor in the occurrence of complications. Independently of the reperfusion strategy, there was not a significant increase on reperfusion times (table 1). There were no significant differences in complications during admission. In our experience, PPCI achieved similar in-hospital and 30-day mortality, as compared with fibrinolysis during the COVID-19 lockdown (Image 1). There was not any case of SARS-CoV2 infection among cath lab staff. Conclusions To use conventional guidelines based reperfusion strategy of STEMI patients is a safe and effective strategy during the COVID-19 lockdown. Table 1Pre-Covid (n = 73)Lockdown COVID-19 (n = 67)p valueSex male; n (%)55 (75,3)49 (73,1)0,76Age yr66 +/- 1365 +/- 150,92Hypertension; n (%)40 (54,8)42 (62,7)0,34Diabetes; n (%)24 (32,9)10 (14,9)0,013*Hypercholesterolemia; n (%)39 (53,4)33 (49,2)0,62Smoker; n (%)26 (35,6)25 (37,3)0,83Previous MI; n (%)12 (16,4)9 (13,4)0,62Reperfusion strategy, n (%)Fibrinolysis5 (6,8) /* Font Definitions */ @font-face {font-family:Calibri; panose-1:2 15 5 2 2 2 4 3 2 4; mso-font-charset:0; mso-generic-font-family:swiss; mso-font-pitch:variable; mso-font-signature:-469750017 -1073732485 9 0 511 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin-top:0cm; margin-right:0cm; margin-bottom:8.0pt; margin-left:0cm; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:Calibri; mso-fareast-theme-font:minor-latin; 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Image 1

The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada; PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPICNorfolk, MR/M012190/1 to EPIC-Oxford) (UK). We thank the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, and the National Institute for Public Health and the Environment (RIVM)-Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC Study., For information on how to submit an application for gaining access to EPIC data and/or biospecimens, please follow the instructions at http://epic.iarc.fr/ access/index.php., Informed consent was given by all study participants, and ethical approval for the entire EPIC cohort was obtained from the Institutional Review Board of the International Agency for Research on Cancer in Lyon, France, under protocol numbers SC/24/4 and SC/24/6, as well as from local ethics committees in the participating countries., The authors thank the EPIC participants and staff for their valuable contribution to this research and Bertrand Hemon (International Agency for Research on Cancer) for managing the data for the EPIC project., Background Trans fatty acids (TFAs) have been hypothesised to influence breast cancer risk. However, relatively few prospective studies have examined this relationship, and well-powered analyses according to hormone receptor-defined molecular subtypes, menopausal status, and body size have rarely been conducted. Methods In the European Prospective Investigation into Cancer and Nutrition (EPIC), we investigated the associations between dietary intakes of TFAs (industrial trans fatty acids [ITFAs] and ruminant trans fatty acids [RTFAs]) and breast cancer risk among 318,607 women. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for other breast cancer risk factors. Results After a median follow-up of 8.1 years, 13,241 breast cancer cases occurred. In the multivariable-adjusted model, higher total ITFA intake was associated with elevated breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). A similar positive association was found between intake of elaidic acid, the predominant ITFA, and breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). Intake of total RTFAs was also associated with higher breast cancer risk (HR for highest vs lowest quintile, 1.09, 95% CI 1.01-1.17; P trend = 0.015). For individual RTFAs, we found positive associations with breast cancer risk for dietary intakes of two strongly correlated fatty acids (Spearman correlation r = 0.77), conjugated linoleic acid (HR for highest vs lowest quintile, 1.11, 95% CI 1.03-1.20; P trend = 0.001) and palmitelaidic acid (HR for highest vs lowest quintile, 1.08, 95% CI 1.01-1.16; P trend = 0.028). Similar associations were found for total ITFAs and RTFAs with breast cancer risk according to menopausal status, body mass index, and breast cancer subtypes. Conclusions These results support the hypothesis that higher dietary intakes of ITFAs, in particular elaidic acid, are associated with elevated breast cancer risk. Due to the high correlation between conjugated linoleic acid and palmitelaidic acid, we were unable to disentangle the positive associations found for these fatty acids with breast cancer risk. Further mechanistic studies are needed to identify biological pathways that may underlie these associations., European Commission European Commission Joint Research Centre, International Agency for Research on Cancer, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, German Cancer Research Center (DKFZ) (Germany), Federal Ministry of Education & Research (BMBF), Deutsches Krebsforschungszentrum (Germany), Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro (AIRC), Consiglio Nazionale delle Ricerche (CNR), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund International (WCRF), Instituto de Salud Carlos III PI13/00061 PI13/01162, Junta de Andalucia, Catalan Institute of Oncology (Spain), Swedish Cancer Society Swedish Research Council, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C570/A16491 C8221/A19170, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) 1000143 MR/M012190/1, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, National Institute for Public Health and the Environment (RIVM)-Bilthoven, the Netherlands, Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain), Regional Government of Navarra (Spain), ERC-2009-AdG 232997

Background: Anemia is present in almost 5% of adults worldwide and accompanies clinical findings in many diseases. Diseases of the gastrointestinal (GI) tract and liver are a common cause of anemia, so patients with anemia are often referred to a gastroenterologist. Summary: Anemia could be caused by various factors such as chronic bleeding, malabsorption, or chronic inflammation. In clinical practice, iron deficiency anemia and the combined forms of anemia due to different pathophysiological mechanisms are most common. Esophagogastroduodenoscopy, colonoscopy, and the small intestine examinations in specific situations play a crucial role in diagnosing anemia. In anemic, GI asymptomatic patients, there are recommendations for bidirectional endoscopy. Although GI malignancies are the most common cause of chronic bleeding, all conditions leading to blood loss, malabsorption, and chronic inflammation should be considered. From a gastroenterologist’s perspective, the clinical spectrum of anemia is vast because many different digestive tract diseases lead to bleeding. Key Messages: The gastroenterological approach in solving anemia’s problem requires an optimal strategy, consideration of the accompanying clinical signs, and the fastest possible diagnosis. Although patients with symptoms of anemia are often referred to gastroenterologists, the diagnostic approach requires further improvement in everyday clinical practice.