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Summary Objective To assess botulinum toxin treatment for buccinator muscle synkinesis including: how often the synkinesis was troublesome; who benefitted and how from the treatment; and what were the adverse effects, ideal dosage, and injection site. Subjects and Methods Facial palsy (FP) patients and patients with hemifacial spasms who were attending for multiple site botulinum-toxin treatment for facial sequelae were assessed for buccinator synkinesis. The study group comprises those experiencing buccinator synkinesis with associated bothering symptoms who were willing to try injection also to the buccinator muscle. Results During 9/2017–12/2019, 126 different patients with facial sequelae were treated with multiple-site botulin-toxin injections by the author. Of them, 83 (66%) received injection also for buccinator synkinesis and 66/82 (80%) wanted to continue with the buccinator injections. The most remarkable results were seen with FP patients biting the mucus membrane of their cheek: usually the biting ceased totally. Patients with powerful hemifacial cheek spasms also experienced cessation of the spasms, contrasting any previous treatments. Adverse effects were mostly mild: slight weakness of the corner of the mouth or additional leakage of saliva or liquids. Only a few patients experienced more pronounced adverse effects. The most posterior contracting part of the buccinator muscle proved to be the best site for the injection. Conclusions Buccinator synkinesis was very common and its treatment gave many patients additional relief from facial sequelae symptoms. Professionals treating patients with synkinesis and hemifacial spasms should add well-tolerated buccinator injections to their repertoire of injection sites.

Methotrexate/6-mercaptopurine maintenance therapy improves acute lymphoblastic leukemia (ALL) outcome. Cytotoxicity is mediated by DNA incorporation of thioguanine nucleotides (DNA-TG). We investigated the association of DNA-TG to relapse risk in 1 910 children and young adults with non-high risk ALL. In a cohort-stratified Cox regression analysis adjusted for sex, age, and white cell count at diagnosis, the relapse-specific hazard ratio (HRa) per 100 fmol/μg increase in weighted mean DNA-TG (wmDNA-TG) was 0.87 (95% CI 0.78-0.97; p = 0.013) in the 839 patients who were minimal residual disease (MRD) positive at end of induction therapy (EOI), whereas this was not the case in EOI MRD-negative patients (p = 0.76). Validation analysis excluding the previously published Nordic NOPHO ALL2008 pediatric cohort yielded a HRa of 0.92 (95% CI 0.82-1.03; p = 0.15) per 100 fmol/μg increase in wmDNA-TG in EOI MRD-positive patients. If also excluding the United Kingdom cohort, in which samples were taken non-randomly in selected patients, the HRa for the EOI MRD-positive patients was 0.82 (95% CI 0.68-0.99; p = 0.044) per 100 fmol/μg increase in wmDNA-TG. The importance of DNA-TG as a biomarker for maintenance therapy intensity calls for novel strategies to increase DNA-TG, although its clinical value may vary by protocol backbone.

Paediatric patients with cancer and those undergoing haematopoietic cell transplantation are at high risk of bacterial infections. The 8th European Conference on Infections in Leukaemia (ECIL-8) convened a Paediatric Group to review the literature and to formulate recommendations for the use of antibiotics according to the European Society of Clinical Microbiology and Infectious Diseases grading system. The evaluation of antibacterial prophylaxis included mortality, bloodstream infection, febrile neutropenia, emergence of resistance, and adverse effects as endpoints. Initial antibacterial therapy and antibiotic de-escalation or discontinuation focused on patients with a clinically stable condition and without previous infection or colonisation by resistant bacteria, and on patients with a clinically unstable condition or with previous infection or colonisation by resistant bacteria. The final considerations and recommendations of the ECIL-8 Paediatric Group on antibacterial prophylaxis, initial therapy, and de-escalation strategies are summarised in this Policy Review.

6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008. TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m2 for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 − 3.0 × 109/L. Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p

Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P < 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.

Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10−8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10−9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.

Publisher Copyright: © 2021 The Authors Background: In Finland, the surveillance of healthcare-associated infections (HAI) became obligatory by the renewed Communicable Diseases Act on the 1st March 2017. Aim: To introduce HAI surveillance protocol (HALT-2 by ECDC) in primary care hospitals in the largest hospital district in Finland, and to measure the burden of HAIs and antimicrobial use patterns for improvement. Methods: Two identical point prevalence surveys (PPS) were organized in autumn 2015 and in spring 2017. The infection control persons (ICP) in the hospitals were inducted to the HAI definitions and the study protocol to collect the data with questionnaires on the study days. The data were checked and analyzed by the areal infection control unit. The hospitals were provided feedback of the results and HAI prevention methods. Findings: In 2015, 2218 patients from 22 hospitals and in 2017, 2343 patients from 25 hospitals were studied. The prevalence of HAI was 11% in both surveys (ranges per hospital 4–24% and 4–31%, respectively). Of all HAIs, 37% originated from referring hospitals. Respiratory tract, urinary tract and skin were the most frequent sites of infection. One fourth of all patients received at least one systemic antimicrobial. The process showed that recognition of HAIs may be difficult for non-experienced ICPs. Conclusions: The HALT-2 protocol proved useful in introducing HAI surveillance and prevention in primary care hospitals with active patient transfer from other hospitals and relatively high prevalence of HAI and antimicrobial use. For annually repeated surveys, slightly shorter electronic questionnaires are essential.

aintenance therapy containing methotrexate and 6-mercapto-purine is essential to cure acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of thioguanine nucleotides into DNA (DNA-TG), and higher leukocyte DNA-TG is associated with increased relapse-free survival. As 6-thioguanine provides 6-fold higher cytosolic levels of thioguanine nucleotides than does 6-mercaptopurine, we added low-dose 6-thioguanine to methotrexate/6mercaptopurine maintenance therapy to explore if this combination results in significantly higher DNA-TG. The target population of the “Thiopurine Enhanced ALL Maintenance therapy” (TEAM) study was 30 patients with non-high-risk ALL, aged 1-45 years on methotrexate/6-mercaptopurine maintenance therapy receiving no other systemic chemotherapy. Incremental doses of 6-thioguanine were added to methotrexate/6-mercaptopurine maintenance therapy (starting 6-thioguanine dose: 2.5 mg/m2/day, maximum: 12.5 mg/m2/day). The primary endpoint was DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance therapy according to the TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m2/day as the maximum 6-thioguanine dose. TEAM resulted in significantly higher DNA-TG levels compared to those in both TEAM patients before their inclusion in TEAM (on average 251 fmol/mg DNA higher [95% confidence interval: 160-341; P

Purpose To explore the characteristics, medical treatments, and long-term facial palsy outcome in Ramsay Hunt syndrome. Methods Patient questionnaire including self-assessment of long-term facial palsy outcome and retrospective chart review. Initial facial palsy grade was compared to self-assessed or patient record stated palsy outcome. Occurrence of different characteristics (blisters, hearing loss, vertigo, etc.) of the syndrome were assessed. Results Altogether 120 patients were included of which 81 answered the questionnaire. All but one patient had received virus medication (aciclovir, valaciclovir), and half received simultaneous corticosteroids. If the medication was started within 72 h of Ramsay Hunt diagnosis, facial palsy recovered totally or with only slight sequelae in over 80% of the patients. Only a minority of the patients experienced varicella blisters simultaneously with facial palsy, blisters more often preceded or followed the palsy. Approximately 20% of the patients had their blisters in hidden places in the ear canal or mouth. Conclusions The long-term outcome of facial palsy in medically treated Ramsay Hunt syndrome was approaching the outcome of Bell’s palsy. It is crucial to ask and inform the patient about the blisters and look for them since, more often than not, the blisters precede or follow the palsy and can be in areas not easily seen.

Objective To study whether diets based on the Nordic food culture and dietary recommendations are related to periodontal disease development. Methods The data were based on the Health 2000 and 2011 Surveys (BRIF8901). The participants were aged 30-49 in 2000, periodontally healthy, without diabetes or rheumatoid arthritis. Analyses were made in the total study population (n = 240) and among nonsmokers (n = 193) in 2011. Periodontal condition was determined in a clinical examination, and the number of teeth with deepened (≥4 mm) periodontal pockets in 2011 was used as an outcome. The diet was measured using a validated food frequency questionnaire and the quality of the diet using the Baltic Sea Diet Score (BSDS) and the Recommended Finnish Diet Score (RFDS) in 2000. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using Poisson regression models. Results Low scores (indicating poor diet) in both the BSDS and the RFDS were associated with the development of deepened periodontal pockets. Among nonsmokers, the associations between low dietary scores and the number of teeth with deepened periodontal pockets were stronger than among the whole study population. Conclusions Among middle-aged adults, poor-quality diet appears to be associated with the development of periodontal disease.

There is limited evidence for any dietary factor, except alcohol, in breast cancer (BC) risk. Therefore, studies on a whole diet, using diet quality indices, can broaden our insight. We examined associations of the Nordic Diet (mNDI), Mediterranean diet (mMEDI) and Alternative Healthy Eating Index (mAHEI) with postmenopausal BC risk. Five Finnish cohorts were combined including 6374 postmenopausal women with dietary information. In all, 8–9 dietary components were aggregated in each index, higher total score indicating higher adherence to a healthy diet. Cox proportional hazards regression was used to estimate the combined hazard ratio (HR) and 95% confidence interval (CI) for BC risk. During an average 10-year follow-up period, 274 incident postmenopausal BC cases were diagnosed. In multivariable models, the HR for highest vs. lowest quintile of index was 0.67 (95 %CI 0.48–1.01) for mNDI, 0.88 (0.59–1.30) for mMEDI and 0.89 (0.60–1.32) for mAHEI. In this combined dataset, a borderline preventive finding of high adherence to mNDI on postmenopausal BC risk was found. Of the indices, mNDI was more based on the local food culture than the others. Although a healthy diet has beneficially been related to several chronic diseases, the link with the etiology of postmenopausal BC does not seem to be that obvious.

OBJECTIVES The aim of the study was to evaluate the neurocognitive and motor development of biliary atresia (BA) patients in childhood and adolescence and to identify risk factors for impaired outcome. METHODS We invited all BA patients between ages 1 and 20 years followed up at Helsinki University Children's Hospital in Finland between 1 January 2019 to 31 January 2020 to participate. All participants underwent age-appropriate validated neurocognitive tests. Participants between 3.0 and 16.9 years of age were assessed with the Movement Assessment Battery for children, version 2. Guardians of participants between ages 5 and 17 years filled the Five-to-Fifteen-Revised (5-15R) parental questionnaire. RESULTS The mean (±standard deviation [SD]) total intelligence quotient (IQ) of the 39 participants was 91 ± 15, lower compared with test norms (mean IQ 100 ± 15, P

Publisher Copyright: © 2021 Background: Living with an untreated cancer may alter quality of life (QoL) in the long term. Objective: To prospectively study long-term changes in general, mental, and physical QoL in a contemporary active surveillance (AS) patient cohort with low-risk prostate cancer (PCa). Design, setting, and participants: The study population consisted of patients enrolled in the PRIAS trial in Helsinki University Hospital (n = 348). The RAND-36 questionnaire was used to assess general QoL at the start of AS and at 1, 3, 5, 7, 9, and 11 years during follow-up. Patients who had undergone robot-assisted laparoscopic prostatectomy (RALP; n = 88) also received the questionnaire after treatment. Outcome measurements and statistical analysis: Changes over time were analysed using multilevel mixed-effects regression models, and reported as the mean and95% confidence interval. A rule of 0.5 × standard deviation was used to estimate changes of clinical importance. Results and limitations: Median follow-up until the end of AS or last follow-up was 7.2 (range 0.3−12.7) yr. A decrease was observed in six of eight QoL subdomains at 7 yr. However, all scores were above age-stratified reference values. There was no difference between the group who continued AS throughout the study period and the group who discontinued AS and underwent RALP. More than half of the study cohort discontinued AS (n = 198; 57%), 135 men (68%) because of events specified in the protocol and only seven (3.5%) because of anxiety. Metastatic disease developed in six patients (1.7%), and two cases (0.6%) of PCa-related death were recorded among 348 patients in more than 12 yr of overall follow-up. The lack of a randomised control population is a limitation of the study. Conclusions: Contemporary protocolised AS does not impair general QoL. Men undergoing a treatment change (RALP) did not experience a decrease in QoL before or after their treatment change. Patient summary: Active surveillance is a safe treatment option for men with low-risk prostate cancer. We show that this follow-up strategy does not cause a decline in patients’ general quality of life.

Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved. Asparaginase-associated pancreatitis (AAP) frequently affects children treated for acute lymphoblastic leukemia (ALL) causing severe acute and persisting complications. Known risk factors such as asparaginase dosing, older age and single nucleotide polymorphisms (SNPs) have insufficient odds ratios to allow personalized asparaginase therapy. In this study, we explored machine learning strategies for prediction of individual AAP risk. We integrated information on age, sex, and SNPs based on Illumina Omni2.5exome-8 arrays of patients with childhood ALL (N=1564, 244 with AAP aged 1.0 to 17.9 y) from 10 international ALL consortia into machine learning models including regression, random forest, AdaBoost and artificial neural networks. A model with only age and sex had area under the receiver operating characteristic curve (ROC-AUC) of 0.62. Inclusion of 6 pancreatitis candidate gene SNPs or 4 validated pancreatitis SNPs boosted ROC-AUC somewhat (0.67) while 30 SNPs, identified through our AAP genome-wide association study cohort, boosted performance (0.80). Most predictive features included rs10273639 (PRSS1-PRSS2), rs10436957 (CTRC), rs13228878 (PRSS1/PRSS2), rs1505495 (GALNTL6), rs4655107 (EPHB2) and age (1 to 7 y). Second AAP following asparaginase re-exposure was predicted with ROC-AUC: 0.65. The machine learning models assist individual-level risk assessment of AAP for future prevention trials, and may legitimize asparaginase re-exposure when AAP risk is predicted to be low.

Purpose To determine the long-term facial palsy outcome of Ramsay Hunt Syndrome by face-to-face grading by House–Brackmann Grading System, Facial Nerve Grading System 2.0, and Sunnybrook Facial Grading System concomitantly. To compare the applicability of the grading scales. To compare patients’ self-assessed facial palsy outcome results to gradings performed by the investigator. To compare the face-to-face assessed facial palsy outcome to the initial palsy grade. Methods Fifty-seven patients self-assessed their facial palsy outcome and came to a one-time follow-up visit. The palsy outcome was graded by one investigator using the three above-mentioned grading systems concomitantly. The median time from syndrome onset to follow-up visit was 6.6 years. Result A good long-term face-to-face assessed palsy outcome was enjoyed by 84% of the patients. Trying to assess only one House–Brackmann grade to represent the palsy outcome was impossible for most patients. Facial Nerve Grading System 2.0 worked better, but needed adjustments and certain sequelae findings needed to be neglected for it to be executable. The Sunnybrook system worked the best. Nearly 20% of the patients assessed themselves differently from the investigator: both better and worse. Conclusion The Sunnybrook scale was the most applicable system used. With antiviral medication, the outcome of facial palsy in Ramsay Hunt syndrome starts to resemble that of Bell’s palsy and emphasizes the importance of recognizing the syndrome and treating it accordingly. The results give hope to patients instead of the gloomy prospects that have stigmatized the syndrome.

Aims: The aim was to examine whether the contribution of physical work exposures to the risk of sickness absence (SA) is different between those with and without common mental disorders (CMD). Methods: We used questionnaire data on four work exposures and CMD from 6159 participants of the Helsinki Health Study cohort with 12,458 observations from three surveys (2000–2002, 2007 and 2012). We formed combination exposures for the work exposures (hazardous exposures, physical workload, computer and shift work) with CMD. Associations with SA of different length were examined with negative binomial regression models. Results: We observed stronger associations for CMD with SA than for the individual work exposures. The strength of the associations for hazardous exposures and physical workload increased with length of SA, especially when the participant also had CMD. The strongest associations for the combined exposures were observed for SA ⩾15 days, the rate ratios being 2.63 (95% CI 2.27–3.05) among those with hazardous exposure and CMD, and 3.37 (95% CI 2.93−3.88) among those with heavy physical workload and CMD. Conclusions: Employees with hazardous exposures or physical workload combined with CMD were at the highest risk of SA compared with those without these exposures or with only one exposure.

Purpose To evaluate the long-term (minimum of 2 years from the palsy onset) outcome of pediatric facial palsy by patient questionnaire and face-to-face assessment by the Sunnybrook facial grading system, House–Brackmann grading system, and Facial Nerve Grading System 2.0. To compare the outcome results of self-assessment with the face-to-face assessment. To assess the applicability of the grading scales. To assess the palsy recurrence rate (minimum of a 10-year follow-up). Methods 46 consecutive pediatric facial palsy patients: 38 (83%) answered the questionnaire and 25 (54%) attended a follow-up visit. Chart review of 43 (93%) after a minimum of 10 years for the facial palsy recurrence rate assessment. Results Of the 25 patients assessed face-to-face, 68% had totally recovered but 35% of them additionally stated subjective sequelae in a self-assessment questionnaire. Good recovery was experienced by 80% of the patients. In a 10-year follow-up, 14% had experienced palsy recurrence, only one with a known cause. Sunnybrook was easy and logical to use, whereas House–Brackmann and the Facial Nerve Grading System 2.0 were incoherent. Conclusions Facial palsy in children does not heal as well as traditionally claimed if meticulously assessed face-to-face. Patients widely suffer from subjective sequelae affecting their quality of life. Palsy recurrence was high, much higher than previously reported even considering the whole lifetime. Of these three grading systems, Sunnybrook was the most applicable.

Red blood cell transfusions are an essential part of supporting care in leukemia treatment. We examined the prevalence of iron overload and its effects on organ function and childhood growth in pediatric patients after allogeneic HSCT for acute lymphoblastic leukemia. Twenty-three patients were included (median age 12.6, range 7.5-21.4 years). Body iron load was determined using laboratory tests, hepatic and cardiac MRI, and by calculating iron received from transfusions. We performed multivariate analysis to determine association of body iron load with liver enzymes, cardiac function, insulin resistance, and growth. Median plasma ferritin was 344 (range 40-3235) ng/mL and exceeded 1000 ng/mL in three patients (13%). In MRI, 11 patients (48%) had hepatic iron overload and 1 patient (4%) myocardial iron overload. In cardiac MRI, 8 patients (35%) had significant but subclinical decrease in ejection fraction (median z-score -1.7, range -3.1-0.14), but cardiac function did not associate with iron status. Alanine transaminase associated with transfused iron per time unit (P = .001) after the median follow-up of 4.5 years. No correlation was found between iron load and growth or insulin resistance. Iron overload is common in children transplanted for ALL, but iron overload associated organ dysfunction is not present at early age. We recommend evaluation of iron load for all patients at least once during follow-up after transplantation.

Paediatric patients with cancer and those undergoing allogeneic haematopoietic cell transplantation have an increased susceptibility to invasive fungal diseases. In addition to differences in underlying conditions and comorbidities relative to adults, invasive fungal diseases in infants, children, and adolescents are unique in terms of their epidemiology, the validity of current diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of phase 3 clinical trials to provide data to guide evidence-based interventions. To re-examine the state of knowledge and to further improve invasive fungal disease diagnosis, prevention, and management, the 8th European Conference on Infections in Leukaemia (ECIL-8) reconvened a Paediatric Group to review the literature and to formulate updated recommendations according to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM) grading system, which are summarised in this Review.

Objective: To evaluate the conditions behind the symptoms in patients with suspected Lyme borreliosis (LB) who were referred to an infectious diseases clinic. Methods: In this retrospective, population-based study, we collected data from the medical records of all patients referred for infectious disease consultations in 2013 due to presumed LB from a population of 1.58 million. The patients were classified according to the certainty of LB on the basis of their symptoms, signs and laboratory results. Data on the outcomes and subsequent alternative diagnoses during the 4-year follow-up period were reviewed from all of the available patient records from public, private and occupational healthcare providers. Results: A total of 256 patients (16/100 000) were referred as a result of suspicion of LB; 30 (12%) of 256 were classified with definite, 36 (14%) with probable and 65 (25%) with possible LB. LB was unlikely in 121 (47%) patients. A novel diagnosis was discovered in the background symptoms in 73 (29%) of pa-tients. Previously diagnosed comorbidities caused at least some of the symptoms in 48 (19%) patients. Other explanations for symptoms were found in 81 (67%) of 121 of unlikely and 22 (34%) of 65 of possible LB patients. The spectrum of conditions behind the symptoms was quite broad and most often were musculoskeletal, neurological, psychological or functional disorders. Conclusions: LB was unlikely in half of the patients with presumed LB. In most cases the patients had other conditions that explained their symptoms. Elisa Kortela, Clin Microbiol Infect 2021;27:1022 (c) 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

BACKGROUND: Multiparametric magnetic resonance imaging (MRI), with or without MRI‐targeted biopsy, is an alternative test to systematic transrectal ultrasonography‐guided biopsy in men suspected of having prostate cancer. At present, evidence on which test to use is insufficient to inform detailed evidence‐based decision‐making. OBJECTIVES: To determine the diagnostic accuracy of the index tests MRI only, MRI‐targeted biopsy, the MRI pathway (MRI with or without MRI‐targeted biopsy) and systematic biopsy as compared to template‐guided biopsy as the reference standard in detecting clinically significant prostate cancer as the target condition, defined as International Society of Urological Pathology (ISUP) grade 2 or higher. Secondary target conditions were the detection of grade 1 and grade 3 or higher‐grade prostate cancer, and a potential change in the number of biopsy procedures. SEARCH METHODS: We performed a comprehensive systematic literature search up to 31 July 2018. We searched CENTRAL, MEDLINE, Embase, eight other databases and one trials register. SELECTION CRITERIA: We considered for inclusion any cross‐sectional study if it investigated one or more index tests verified by the reference standard, or if it investigated the agreement between the MRI pathway and systematic biopsy, both performed in the same men. We included only studies on men who were biopsy naïve or who previously had a negative biopsy (or a mix of both). Studies involving MRI had to report on both MRI‐positive and MRI‐negative men. All studies had to report on the primary target condition. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed the risk of bias using the QUADAS‐2 tool. To estimate test accuracy, we calculated sensitivity and specificity using the bivariate model. To estimate agreement between the MRI pathway and systematic biopsy, we synthesised detection ratios by performing random‐effects meta‐analyses. To estimate the proportions of participants with prostate cancer detected by only one of the index tests, we used random‐effects multinomial or binary logistic regression models. For the main comparisions, we assessed the certainty of evidence using GRADE. MAIN RESULTS: The test accuracy analyses included 18 studies overall. MRI compared to template‐guided biopsy: Based on a pooled sensitivity of 0.91 (95% confidence interval (CI): 0.83 to 0.95; 12 studies; low certainty of evidence) and a pooled specificity of 0.37 (95% CI: 0.29 to 0.46; 12 studies; low certainty of evidence) using a baseline prevalence of 30%, MRI may result in 273 (95% CI: 249 to 285) true positives, 441 false positives (95% CI: 378 to 497), 259 true negatives (95% CI: 203 to 322) and 27 (95% CI: 15 to 51) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations and inconsistency. MRI‐targeted biopsy compared to template‐guided biopsy: Based on a pooled sensitivity of 0.80 (95% CI: 0.69 to 0.87; 8 studies; low certainty of evidence) and a pooled specificity of 0.94 (95% CI: 0.90 to 0.97; 8 studies; low certainty of evidence) using a baseline prevalence of 30%, MRI‐targeted biopsy may result in 240 (95% CI: 207 to 261) true positives, 42 (95% CI: 21 to 70) false positives, 658 (95% CI: 630 to 679) true negatives and 60 (95% CI: 39 to 93) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations and inconsistency. The MRI pathway compared to template‐guided biopsy: Based on a pooled sensitivity of 0.72 (95% CI: 0.60 to 0.82; 8 studies; low certainty of evidence) and a pooled specificity of 0.96 (95% CI: 0.94 to 0.98; 8 studies; low certainty of evidence) using a baseline prevalence of 30%, the MRI pathway may result in 216 (95% CI: 180 to 246) true positives, 28 (95% CI: 14 to 42) false positives, 672 (95% CI: 658 to 686) true negatives and 84 (95% CI: 54 to 120) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations, inconsistency and imprecision. Systemic biopsy compared to template‐guided biopsy: Based on a pooled sensitivity of 0.63 (95% CI: 0.19 to 0.93; 4 studies; low certainty of evidence) and a pooled specificity of 1.00 (95% CI: 0.91 to 1.00; 4 studies; low certainty of evidence) using a baseline prevalence of 30%, systematic biopsy may result in 189 (95% CI: 57 to 279) true positives, 0 (95% CI: 0 to 63) false positives, 700 (95% CI: 637 to 700) true negatives and 111 (95% CI: 21 to 243) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations and inconsistency. Agreement analyses: In a mixed population of both biopsy‐naïve and prior‐negative biopsy men comparing the MRI pathway to systematic biopsy, we found a pooled detection ratio of 1.12 (95% CI: 1.02 to 1.23; 25 studies). We found pooled detection ratios of 1.44 (95% CI 1.19 to 1.75; 10 studies) in prior‐negative biopsy men and 1.05 (95% CI: 0.95 to 1.16; 20 studies) in biopsy‐naïve men. AUTHORS' CONCLUSIONS: Among the diagnostic strategies considered, the MRI pathway has the most favourable diagnostic accuracy in clinically significant prostate cancer detection. Compared to systematic biopsy, it increases the number of significant cancer detected while reducing the number of insignificant cancer diagnosed. The certainty in our findings was reduced by study limitations, specifically issues surrounding selection bias, as well as inconsistency. Based on these findings, further improvement of prostate cancer diagnostic pathways should be pursued.

Physical inactivity has been associated with both insomnia symptoms and smoking. Further, they are all independently associated with increased sickness absence (SA) from work. However, joint contribution of either physical activity (PA) with insomnia symptoms or with smoking to SA and, especially, their direct cost for the employer is poorly understood. Therefore, we aimed to examine these joint associations with short-term (

Background: Borderline ovarian tumors (BOTs) are a subgroup of ovarian malignancies with low malignant potential. Very limited earlier data are available on familial clustering of BOTs with other cancers. We aim to explore histology-specific familial associations among BOTs and associations between BOTs and any invasive cancers. Methods: On the basis of 16.1 million individuals in the Swedish Family-Cancer Database, we estimated familial risks for overall or histology-specific patients with BOT considering both BOT and any invasive cancers in first-degree relatives (parents or siblings), as well as familial risks for invasive cancers considering family history of BOTs. Results: A total of 4,199 BOT cases were found in the offspring generation; among them, 34 (0.8%) cases had first-degree relatives diagnosed with any BOT, and 2,489 (59.3%) cases with any invasive cancers. A family history of BOT was associated with risks for all BOTs (RR = 2.20, P < 0.001). Papillary BOT in first-degree relatives was associated with the increased risk of having the same type of BOT (RR = 10.10, P < 0.001). BOTs showed familial associations with some invasive cancers, most consistently with colorectal, ovarian, pancreatic, lung, and bone cancers, and with leukemia. In histologic analyses, associations of BOT with even rare cancers of the anus, thyroid, and endocrine glands were noted. Conclusions: BOTs may share susceptibility with themselves and a number of invasive cancers. Impact: These results provide insight into familial associations of BOT for the first time, which may help with the etiologic mechanism and preventive strategy of BOTs, as well as the genetic counseling for patients with BOT. Cancer Epidemiol Biomarkers Prev; 27(11); 1358–63. ©2018 AACR.

Supplemental Digital Content is Available in the Text., PURPOSE: The purpose of this study was to develop and test a new method to measure the usability of absorbent incontinence care products from the caregivers' perspective and to investigate if the method can be used to differentiate between product types in a product change. DESIGN: Process evaluation and validation study. SUBJECTS AND SETTING: Product developers and end users participated in designing the new method. Thereafter, professional caregivers acted as testers of the new method, ranking usability when performing absorbent product changes on patients in a simulated nursing home care environment, assisted by third-party research institute moderators. METHODS: Design and evaluation of a new method designed to assess the usability of body-worn absorbent incontinence care products for lay caregivers were completed. The evaluation included formative and summative evaluations of effectiveness (product fit), efficiency (time and physical workload), and satisfaction. A person-centered approach aimed at including all subjects and settings to generate a single usability score for decision making and product benchmarking. Experienced caregivers changed 4 types of products: (1) disposable body-worn pads with mesh briefs (2-piece system); (2) disposable all-in-one briefs; (3) disposable, T-shaped, and belted brief; and (4) disposable pull-up pants on simulated patients in standing or lying position. Each product change was performed by 1 unassisted experienced caregiver. The probability of success as a score for each product type was calculated across the 4 metrics and reported with 95% confidence intervals (CIs). Descriptive and inferential statistics were developed assuming a binary statistical model, using the weighted scores from each of the factors. An overall usability score was calculated. RESULTS: The method we developed discriminated between usability of different product types. The overall score for the disposable pull-up product (90%; CI: 83%-97%) was better (P < .05) than for the disposable T-shaped brief (83%; CI: 77%-89%), the disposable brief (53%; CI: 45%-61%), and the disposable body-worn pad with mesh pant (61%; CI: 56%-66%) in standing patients. For lying patients, the overall score for the disposable T-shaped brief product (81%; CI: 73%-89% was better (P < .05) than the disposable brief (65%; CI: 45%-61%) and the disposable body-worn pads with mesh brief (62%; CI: 55%-69%). Reliability was evaluated quantitatively in terms of measurement uncertainties in the results. CONCLUSION: The method we described demonstrated differentiation of usability based on product type indicating concurrent validity. Further testing in diverse real-world care environments is needed to evaluate and confirm the validity and to assess reliability of this method in the research setting.

The first US Food and Drug Administration (FDA)- and EMA-approved oncolytic virus has been available since 2015. However, there are no markers available that would predict benefit for the individual patient. During 2007–2012, we treated 290 patients with advanced chemotherapy-refractory cancers, using 10 different oncolytic adenoviruses. Treatments were given in a Finnish Medicines Agency (FIMEA)-regulated individualized patient treatment program (the Advanced Therapy Access Program [ATAP]), which required long-term follow-up of patients, which is presented here. Focusing on the longest surviving patients, some key clinical and biological features are presented as “oncograms.” Some key attributes that could be captured in the oncogram are suggested to predict treatment response and survival after oncolytic adenovirus treatment. The oncogram includes immunological laboratory parameters assessed in peripheral blood (leukocytes, neutrophil-to-lymphocyte ratio, interleukin-8 [IL-8], HMGB1, anti-viral neutralizing antibody status), features of the patient (gender, performance status), tumor features (histological tumor type, tumor load, region of metastases), and oncolytic virus-specific features (arming of the virus). The retrospective approach used here facilitates verification in a prospective controlled trial setting. To our knowledge, the oncogram is the first holistic attempt to identify the patients most likely to benefit from adenoviral oncolytic virotherapy. Keywords: oncolytic adenovirus, oncolytic virotherapy, immunotherapy, cancer, immunostimulation, anti-cancer, adenovirus, oncoimmunology, immunogram, oncogram

Transrectal prostate biopsies carry the risk of infection. By using non-selective culture plates, instead of commonly used ciprofloxacin (CIP)-containing plates, we analyzed the association between Escherichia coli CIP minimal inhibitory concentration (MIC) and post-biopsy infectious complications. A pre-biopsy rectal swab was taken from 207 consecutive men, scheduled for transrectal 12-core prostate biopsy with CIP 750 mg as the mostly used prophylaxis. CIP MIC of rectal Gram-negative bacilli was determined from a chromogenic agar. Rectal E. coli were categorized to resistant (R) and intermediate (I) isolates together (R + I, MIC 0.25 mg/l) and to sensitive (S, MIC ≤ 0.25 mg/l) using EUCAST clinical breakpoints. In addition, epidemiological cutoff (ECOFF R, MIC 0.064 mg/l) was used for categorization. Eighteen (8.7%) men showed CIP R + I E. coli by the EUCAST breakpoints and 41 (19.8%) using the ECOFF R criteria. During follow-up, 15 (7.2%) men had infectious symptoms, of which 9 (4.3%) were culture-confirmed infections. Only 4 (26.7%) of these 15 patients showed R + I E. coli in the rectal swab according to EUCAST, but 10 (66.7%) using the ECOFF cutoff. Rectal E. coli CIP R + I by the EUCAST clinical breakpoints associated with infectious complications with OR 5.7 (95% CI 1.5-21.8, P = 0.005) and ECOFF R E. coli by OR 10.7 (95% CI 3.0-37.6, P 0.001). Men carrying rectal E. coli with moderately lowered CIP susceptibility (MICECOFF 0.064 mg/l) were identified and, interestingly, they showed a high risk of developing infectious symptoms after the biopsy. This explains why some men develop infectious complications despite appropriate antibiotics before prostatic biopsies.NCT02140502.

Early identification of the potential to adopt a long-term unhealthy diet, could improve weight outcomes for patients having undergone bariatric surgery.We explored whether presurgical sociodemographic and lifestyle characteristics, together with the type of surgery, could predict 10-year changes in dietary intake after bariatric surgery.Surgical departments and primary healthcare centers, nationwide.Participants were from the Swedish Obese Subjects study, a matched (nonrandomized) prospective trial comparing bariatric surgery with standard care for obese patients. This study included the 1695 surgery patients with complete information on presurgery diet. Questionnaires were completed before and 6 months, 1-4, 6, 8, and 10 years after surgery. Analyses were conducted with linear mixed-model.Dietary changes were observed in 1561, 1298, and 1243 participants, at the 2-, 6-, and 10-year follow-ups, respectively. Sex and treatment type predicted changes in energy, carbohydrate, protein, and fiber intake over the follow-up (P.05). Furthermore, male sex, younger age, a sedentary behavior, and gastric bypass predicted increased alcohol consumption (P.001). Two important phases for intervening bariatric patients' diet were identified. The first was 6 months after surgery, when the maximal changes in diet were achieved. The second, stretched from 6 months until 4 years after surgery, during which earlier commitments to dietary changes were largely abandoned.Male sex and banding surgery in particular predicted unfavorable post-surgery changes in energy and macronutrient intake. Furthermore, gastric bypass, a younger age, and an unhealthy lifestyle presurgery, may predispose individuals to increased alcohol intake after surgery.

Aim To analyse incidence, treatment and outcomes of paediatric liver malignancies in Finland during 1987-2017. Methods Medical records and national cancer registry data of 47 children with liver malignancies were reviewed. Survival was calculated with the Kaplan-Meier method. Results During follow-up, liver malignancy incidence remained stable at 1.1:10(6). Altogether, 42 patients with hepatoblastoma (n = 24), hepatocellular carcinoma (n = 11) and undifferentiated embryonal sarcoma (n = 7) underwent surgery at median age 4.6 (interquartile range, 2.0-9.6) years and were followed up for 13 (7.0-19) years. Cumulative 5-year survival was 86% for hepatoblastoma, 41% for hepatocellular carcinoma and 67% for undifferentiated embryonal sarcoma. Five-year survival was decreased among hepatoblastoma patients aged >= 2.4 years (73% versus 100%, P = .040), with PRETreatment EXTent of disease IV (PRETEXT, 60% vs 100%, P = .004), and with recurrent disease (67% vs 88%, P = .029). Recurrent/residual disease associated with decreased 5-year survival in hepatocellular carcinoma (0% vs 83%, P = .028). Survival was similar among 19 transplanted and 23 resected patients. In total, 14 deaths occurred either for the underlying malignancy (n = 8), adverse effects of chemotherapy (n = 5) or unrelated reasons (n = 1). Conclusion Outcomes for PRETEXT I-III hepatoblastoma and un-metastasized hepatocellular carcinoma were encouraging. Adverse effects of chemotherapy significantly contributed to mortality.

Background Lyme neuroborreliosis (LNB) is often treated with intravenous ceftriaxone even if doxycycline is suggested to be noninferior to ceftriaxone. We evaluated the efficacy of oral doxycycline in comparison to ceftriaxone in the treatment of LNB. Methods Patients with neurological symptoms suggestive of LNB without other obvious reasons were recruited. The inclusion criteria were (1) production of Borrelia burgdorferi–specific antibodies in cerebrospinal fluid (CSF) or serum; (2) B. burgdorferi DNA in the CSF; or (3) an erythema migrans during the past 3 months. Participants were randomized in a 1:1 ratio to receive either oral doxycycline 100 mg twice daily for 4 weeks, or intravenous ceftriaxone 2 g daily for 3 weeks. The participants described their subjective condition with a visual analogue scale (VAS) from 0 to 10 (0 = normal; 10 = worst) before the treatment, and 4 and 12 months after the treatment. The primary outcome was the change in the VAS score at 12 months. Results Between 14 September 2012 and 28 December 2017, 210 adults with suspected LNB were assigned to receive doxycycline (n = 104) or ceftriaxone (n = 106). The per-protocol analysis comprised 82 patients with doxycycline and 84 patients with ceftriaxone. The mean change in the VAS score was −3.9 in the doxycycline group and −3.8 in the ceftriaxone group (mean difference, 0.17 [95% confidence interval, −.59 to .92], which is within the prespecified equivalence margins of −1 to 1 units). Participants in both groups improved equally. Conclusions Oral doxycycline is equally effective as intravenous ceftriaxone in the treatment of LNB. Clinical Trials Registration NCT01635530 and EudraCT 2012-000313-37.

Objective: The impact of pediatric intestinal failure (IF) on neurodevelopment beyond infancy has not been systematically studied. Our aim was to evaluate cognitive and motor impairment and to identify risk factors for adverse outcomes among children with IF. Methods: We conducted a cross-sectional single-center study at the Helsinki University Children's Hospital. Patients with IF with >60 days of parental nutrition (PN) dependency aged between 3 and 16 years (n = 40) were invited to participate. The cognitive and motor skills were evaluated using validated tests: Wechsler Preschool and Primary Scale of Intelligence, 3rd edition, Wechsler Intelligence Scale for Children, 4th edition, and Movement Assessment Battery for Children, 2nd edition. Results: All the patients attending the study tests (n = 30, males = 24) were included. Their median age, gestational age, and birth weight was 7.5 (range 3-16) years, 35 (interquartile range [IQR] 28-38) weeks and 2238 (IQR 1040-3288) grams, respectively. Median duration of PN was 13 (IQR 5-37) months and 9 patients were currently on PN. Median intelligence quotient was 78 (IQR 65-91) and 10 (35%) patients had an intelligence quotient under 70 (-2 standard deviation). Significant motor impairment was detected in 10 patients (36%) and milder difficulties in 8 (28%). Adverse cognitive outcome was associated with neonatal short bowel syndrome, number of interventions under general anesthesia, and length of inpatient status, whereas adverse motor outcome was associated with prematurity. Conclusion: Clinically significant cognitive and motor impairments are alarmingly common among neonatal patients with IF. We recommend early neurodevelopmental follow-up for all children with IF.

Objectives To evaluate the suitability, benefits, and limitations of sialendoscopy for pediatric patients. Methods We performed a retrospective analysis of all pediatric sialendoscopy patients (aged 16 years or younger) in our tertiary care institution between September 2007 and October 2018. We characterized patient data, procedure-related factors, complications, and outcomes. Results In total, 55 sialendoscopies were performed on 42 patients. Among these, 36 were diagnostic endoscopies and 19 were interventional. Five endoscopies were performed under local anesthesia. We identified 16 sialolithiasis patients, where removal of a sialolith was possible in 11 (69%) cases; one case required a second endoscopy. We removed two sialoliths under local anesthesia. Among recurrent juvenile parotitis (RJP) patients, 18/20 (90%) were symptom-free after a single sialendoscopy, and all after a second endoscopy. The median follow-up time was 70 months. We achieved a 95% success rate in sialendoscopies, with a failure-to-treat rate of 15%. The complication rate for the study cohort was 2%, with prolonged parotid swelling the only complication encountered. Conclusions Sialendoscopy represented a safe and effective method to treat pediatric patients. Local anesthesia was successful in selected cases, even for sialolith removal. Sialendoscopy had a soothing effect on RJP and the majority of sialoliths were suitable for endoscopic removal.

Peripancreatic adipose tissue (PAT) is an understudied visceral fat depot that surrounds pancreas and is in touch with spleen and liver. Recent previous studies suggest that obesity-associated PAT inflammation accelerates pancreatic neoplasia in KrasG12D mice and that PAT conditioned-medium from pre-diabetic rats (9 weeks on high-fat diet; HFD) stimulates insulin secretion, proliferation and apoptosis in INS-1 cells. In this study, we aimed to better characterize PAT functionality in the context of HFD-induced obesity. PAT is a very small depot (0,5 ±0,04 mg) with a relatively high number of small adipocytes in unchallenged mice on chow, and we found that PAT expansion is less pronounced at early stages of HFD-feeding compared to the expansion of inguinal (IWAT), gonadal (GWAT) and mesenteric adipose tissues (MWAT). After 8-weeks HFD feeding the expansion of PAT was however comparable to the other three fat depots, but still PAT was more protected against the deleterious effects of HFD on adipose tissue inflammation and insulin resistance as judged by gene expression analysis (adiponectin, insulin receptor and inflammation markers). Feeding after 16-weeks HFD reduced the glucose and lipid uptake in all fat depots however, it was less pronounced in PAT; both fatty acid and glucose oxidation rates were higher in PAT compared to IWAT, GWAT and MWAT. Moreover, we noted that PAT is the only fat depot where the tissue weight correlates positively with liver weight in HFD-induced obese mice, and surgical removal of PAT followed by 16-week-HFD-feeding was associated with increased hepatic triglyceride content and accumulation of more and larger lipid droplets. PAT did not regenerate during this 16-week HFD time course suggesting that its precursor cells reside within the depot. Taken all data together, we propose that PAT, although it is located in the visceral compartment, can be considered as a metabolically/immunologically healthy fat depot that protects against hepatic steatosis in advanced obesity. Disclosure B. Chanclón: None. P. Micallef: None. E. Banke Nordbeck: None. Y. Wu: None. B. Wilder: None. J. Kanerva: None. P. Rorsman: None. I. Wernstedt Asterholm: None.

Purpose Physical work exposures and common mental disorders (CMD) have been linked to increased risk of work disability, but their joint associations with disability retirement due to any cause, mental disorders or musculoskeletal diseases have not been examined. Methods The data for exposures and covariates were from the Finnish Helsinki Health Study occupational cohort surveys in 2000–2002, 2007 and 2012. We used 12,458 observations from 6159 employees, who were 40–60 years old at baseline. CMD were measured by the General Health Questionnaire (GHQ-12, cut-off point 3+). Four self-reported work exposures (hazardous exposures, physical workload, computer and shift work) were combined with CMD and categorized as “neither”, “work exposure only”, “CMD only”, and “both”. Associations with register-based disability retirement were assessed with Cox proportional hazards models for sample survey data adjusting for confounders over 5-year follow-up. Additionally, synergy indices were calculated for the combined effects. Results Those reporting CMD and high physical workload had a greater risk of disability retirement due to any cause (HR 4.26, 95% CI 3.60–5.03), mental disorders (HR 5.41, 95% CI 3.87–7.56), and musculoskeletal diseases (HR 4.46, 95% CI 3.49–5.71) when compared to those with neither. Synergy indices indicated that these associations were synergistic. Similar associations were observed for CMD and hazardous exposures, but not for combined exposures to CMD and computer or shift work. Conclusions Identification of mental health problems among employees in physically demanding jobs is important to support work ability and reduce the risk of premature exit from work due to disability.

Background: Melkersson-Rosenthal syndrome (MRS) is often classified under the term orofacial granulomatosis (OFG). A part of OFG patients eventually develop Crohn's disease (CD), but the relationship between MRS and CD is unknown. Goals: To evaluate the long-term outcomes of MRS patients, with specific interest in bowel-related symptoms. Study: This follow-up study consisted of adult patients with MRS - including the monosymptomatic form, cheilitis granulomatosa (CG) - who had participated in our earlier MRS study (diagnosed after 1995 in Helsinki University Hospital). A phone interview was conducted with 27 patients (77.1% of the patients from the earlier study) and included questions about orofacial symptoms, facial palsy, intestinal symptoms, concomitant illnesses, medications, possible food avoidances and family history. Stool samples were collected to measure faecal calprotectin, a surrogate marker for intestinal inflammation. Results: The median follow-up time from symptom onset was 30 years. Three (11.1%) patients had developed inflammatory bowel disease (IBD); one CG patient developed CD, and two MRS patients with facial palsy developed ulcerative colitis. In addition, several other patients reported intestinal symptoms, but the examination of faecal calprotectin did not indicate intestinal inflammation. Conclusions: There was a connection between MRS and IBD - not only CD but ulcerative colitis as well. Key message Melkersson-Rosenthal syndrome (MRS) is a chronic condition often classified as a subtype of orofacial granulomatosis. Oral manifestations are common in MRS. We found a connection between MRS and inflammatory bowel disease, not only Crohn's disease but ulcerative colitis as well.

Objectives Neuroborreliosis is a rare cause of cerebral vasculitis and stroke. The incidence of Lyme borreliosis in Finland has been increasing in the last 20 years, so we expect that Lyme neuroborreliosis–associated vasculitis can be a more common cause of stroke in the future. Materials & methods We have retrospectively identified all adult patients (>16 years old) diagnosed with borreliosis (A69.2 Lyme borreliosis), transient ischemic attack (TIA, G45), and ischemic stroke (I63) at Helsinki University Hospital during 1.1.2014–31.10.2019 at our neurological emergency department. Medical data and follow-up data were retrospectively collected from medical records. Neuroborreliosis was diagnosed according to the European Federation of Neurological Societies guidelines. Results We have identified 10 cases of neuroborreliosis–associated stroke or TIA and/or vasculitis. Vasculitis as a manifestation of borreliosis was diagnosed in six patients of 1454 (0.4%) and stroke or TIA in nine (0.6%) of all borreliosis patients at Helsinki University Hospital. Clinical outcomes for all our patients were good with a modified Rankin scale (mRS) 0–2. Conclusions Lyme neuroborreliosis–associated vasculopathy and cerebrovascular events still remain rare but should be considered especially in Lyme borreliosis endemic areas. Prognosis is good with appropriate antibiotic treatment, but additional immunosupressive treatment is sometimes needed.

Objective To examine the association between chronotype and timing of energy and macronutrient intakes in adults. Methods The study sample included 1,854 participants from the National FINRISK 2007 and FINDIET 2007 studies, aged 25 to 74 years. Diet was assessed with 48-hour dietary recalls. Chronotype was assessed with a shortened version of Horne and Ostberg's Morningness–eveningness Questionnaire. Associations between chronotype and intakes of energy and macronutrients in the morning (by 10 am) and in the evening (after 8 pm) were analyzed with linear regression and ANOVA followed by Bonferroni post hoc test. Results In the morning, evening types had lower energy and macronutrient intakes (except for sucrose of which they had a higher intake) than morning types (P

In two brothers born to consanguineous parents, we identified an unusual neurological disease that manifested with ataxia, psychomotor retardation, cerebellar and cerebral atrophy, and leukodystrophy. Via linkage analysis and exome sequencing, we identified homozygous c.2801C>T (p.(Ser934Leu)) in POLR1A (encoding RPA194, largest subunit of RNA polymerase I) and c.511C>T (p.(Arg171Trp)) in OSBPL11 (encoding oxysterol-binding protein-like protein 11). Although in silico analysis, histopathologic evidence and functional verification indicated that both variants were deleterious, segregation with the patient phenotype established that the POLR1A defect underlies the disease, as a clinically unaffected sister also was homozygous for the OSBPL11 variant. Decreased nucleolar RPA194 was observed in the skin fibroblasts of only the affected brothers, whereas intracellular cholesterol accumulation was observed in the skin biopsies of the patients and the sister homozygous for the OSBPL11 variant. Our findings provide the first report showing a complex leukodystrophy associated with POLR1A. Variants in three other RNA polymerase subunits, POLR1C, POLR3A and POLR3B, are known to cause recessive leukodystrophy similar to the disease afflicting the present family but with a later onset. Of those, POLR1C is also implicated in a mandibulofacial dysostosis syndrome without leukodystrophy as POLR1A is. This syndrome is absent in the family we present.

11524 Background: Survival for RR-ES at 5 years remains < 15%, so novel treatments are needed. Almost all Phase II trials for RR-ES use response as the primary outcome measure. It is unclear whether response is a valid surrogate for survival outcomes. Methods: Patients (pts) were eligible if they had RR-ES and were evaluable for imaging response (primary outcome) if they had measurable disease by RECIST 1.1. The randomization was initially between four chemotherapy regimens: topotecan-cyclophosphamide, irinotecan-temozolomide, gemcitabine-docetaxel (GD), high-dose ifosfamide. Response was assessed after 2, 4 (primary) and 6 cycles of therapy and was classified as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD). PFS and OS were secondary outcomes. Survival from each assessment point by response status was analyzed, by Cox models, with hazard ratios (HR) given for PR v. SD and CR+PR v. SD. Results: From 2015-19, 241 pts with response data were entered. The relationship between response status and PFS and OS is shown in the table (HR < 1.0 indicates better outcome for PR or CR+PR than SD). Both PFS and OS were similar for pts with PR or CR+PR compared to those with SD. OS was inferior for patients with PD (all p < 0.01) (PFS is by definition zero for patients with PD at that timepoint). Small numbers mean CR results are not reliable. Results were consistent across all treatments and between refractory and relapsed disease. At the first interim assessment the GD arm was dropped, with risk ratios for response compared to the other three arms (blinded as still open) of 0.3, 0.5 and 0.5. If a new outcome – disease control (CR+PR+SD) – is defined, the risk ratios are 0.7, 0.8 and 0.7; i.e. still inferior for GD, but less so. Conclusions: Response does not correlate with survival outcomes in RR-ES, so considering PR, or even CR, a success and SD a failure when evaluating treatments may be misleading. We propose PFS as a better primary outcome for future trials and it will be introduced as such in the rEECur trial. Clinical trial information: ISRCTN36453794 . [Table: see text]

11523 Background: Ewing 2008R1 (EudraCT2008-003658-13, Sponsor UKM) was conducted in 12 countries. It evaluated the effect of zolendronic acid (ZOL) maintenance therapy on event-free (EFS, primary endpoint) and overall survival (OS) from randomization in standard risk Ewing Sarcoma (EwS). Methods: Phase III, open label, prospective, multi-center, randomized controlled clinical trial. Eligible patients (pts) had localized EwS with either good histological response to induction chemotherapy and/or small tumors ( < 200ml). Pts received 6 cycles VIDE induction and 8 VAI (male) or 8 VAC consolidation (female) and were randomized to receive either 9 cycles of maintenance ZOL or no further treatment (control;ctrl). ZOL cycles started parallel to the 6th consolidation cycle. Randomization was stratified by tumor site (pelvis/no pelvis). Two-sided adaptive inverse-normal 4-stage design, changed after the 1st interim analysis via Müller-Schäfer method. Initial sample size 448 pts, type I error rate 5%, power 80%. Results: 284 pts were randomized between 2009 and 2018 (142 ZOL / 142 ctrl). With a median follow-up of 3.9 years, the primary endpoint EFS was not significantly different between the ZOL and ctrl group in the adaptive design (HR 0.74, 95% CI 0.43-1.28, intention to treat). 3-year (3y) EFS rates were 84.0% (95% CI 77.7-90.8%) for ZOL vs 81.7% (95% CI 75.2-88.8%) for ctrl. Results were similar in the per protocol collective. Cause-specific HR for local recurrence in ZOL was csHR 0.30 (95% CI 0.08 -1.09; p = 0.07), for metastatic progress/new metastases csHR 1.0 (CI 0.5-2.2), for combined relapse/progress csHR 0.3 (95% CI 0.1-1.7), for second malignancies csHR 4.0 (95% CI 0.45-36.1) compared to ctrl. The 3y OS was 92.8% (95% CI 88.4-97.5%) for ZOL and 94.6% (95% CI 90.9-98.6%) for ctrl. For ZOL the 5y OS was 87.3% (95% CI 80.7-94.5%) and 89% (95% CI 83.7-95.9%) for ctrl. Noticeable more renal, neurological and gut toxicities were observed for ZOL (p < 0.05), with severe renal toxicities occurring more often in the ZOL arm (p = 0.003). Conclusions: In patients with standard risk localized Ewing Sarcoma there is no benefit from maintenance treatment with zoledronic acid, but significant side effects were observed. Clinical trial information: NCT00987636 .

Background: Long-term sickness absence (LTSA; >10 days) creates huge economic burden for employers and societies. Lifestyle behaviours and quality of sleep may reduce the risk of LTSA, but the possible savings achieved through improving these risk factors have been poorly quantified. We aimed to provide monetary estimates for the association of risk factors with cost of LTSA. Methods: The Helsinki Health Study is a cohort of employees of the City of Helsinki, Finland (n=8960, response rate 67%). In 2007, the participants received a questionnaire that gathered information on their lifestyle and sleep. A sum of the risk factors was calculated: Participants received one point for being a smoker; heavy alcohol user (>7 portions/week for women and >14 portions/week for men); physically inactive (

Familial risk of ovarian cancer is well-established but whether ovarian cancer clusters with other cancers and the clusters differ by histology remains uncertain. Using data from the Swedish Family-Cancer Database, we explored familial associations of ovarian cancer with other cancers with a novel approach; relative risk for (histology-specific) ovarian cancer was estimated in families with patients affected by other cancers, and conversely, risks for other cancers in families with (histology-specific) ovarian cancer patients. Eight discordant cancers were associated with ovarian cancer risk, of which family history of breast cancer showed a dose-response (P-trend

Evidence on the relation between the threat of nuclear war and mental health among adolescents is conflicting. We studied 1493 adolescents in the 10th to 12th grades in school, who completed self-administered questionnaires 1–43 days before the Persian Gulf war broke out. Regression analyses controlled for several potential confounders. After this, the frequency of thinking about nuclear war and the frequency of fearing nuclear war were positively related to perceived present state anxiety among both boys and girls. Among boys, both thinking and fearing were positively related to the psychosomatic symptom score. Among girls, estimates on deaths due to nuclear war associated significantly with psychosomatic symptoms. Long-term effects of the threat of nuclear war on mental health of adolescents merit further study.

Key Clinical Message Patients with unknown clinical or radiological asymmetry in the face structures combined with atrophy and weakness of the masticatory muscles should be comprehensively examined clinically and with MRI, neurophysiological measurements, and serologically. Malignant lesions or benign idiopathic unilateral trigeminal motor neuropathy should be considered as an etiological explanation for the asymmetry.

Histological Gleason grading of prostate cancer has been through modifications and conjoined into a Grade Grouping system recently. The aim of this study was to determine whether the new Grade Grouping system predicts disease-specific and all-cause mortality after radical prostatectomy. We constructed a clinical database consisting of all consecutively radical prostatectomy treated men between 1983 and 1998 and between 2000 and 2005 at the Helsinki University Hospital and at the Turku University Hospital, respectively. Patients' all-cause and prostate cancer specific mortality information was updated in November 2015 from the Finnish Cancer Registry. Secondary therapy information was also available from the patients' records at Helsinki. Univariate and multivariate statistical analyses were performed to assess predictive significance of the Grade Grouping system. Grade Grouping associated independently with increased risk of prostate cancer specific mortality within 15 years of follow-up in a multivariable model containing age at operation, diagnostic prostate-specific antigen, pathological stage and lymph node status at operation. Additionally, the all-cause mortality-free survival time and time to secondary therapies were different between the Grade Groups, emphasized in the subanalysis of Grade Groups 1-2 versus Grade Groups 3-5. We can conclude that the new Grade Grouping system is feasible in predicting prostate cancer specific survival after radical surgical treatment. Grade Grouping offers a simpler way to interpret the predicted course of the disease to individual patients and thus may help in justifying more conservative follow-up approaches, especially in the lower Grade Group patients. (C) 2018 The Authors. Published by Elsevier Inc.

The clinical course of prostate cancer is highly variable. Current prognostic variables, stage, and Gleason score have limitations in assessing treatment regimens for individual patients, especially in the intermediate-risk group of Gleason score 7. ERG:TMPRSS2 fusion and loss of PTEN are some of the most common genetic alterations in prostate cancer. Immunohistochemistry of PTEN and ERG has generated interest as a promising method for more precise outcome prediction but requires further validation in population-based cohorts. We studied the predictive value of ERG and PTEN expression by immunohistochemistry in two large radical prostatectomy cohorts comprising 815 patients with extensive follow-up information. Clinical end points were initiation of secondary therapy, overall survival, and disease-specific survival. Predictions of clinical outcomes were also assessed according to androgen receptor (AR) activity. PTEN loss, especially in ERG-negative cancers, predicted initiation of secondary treatments and shortened disease-specific survival time, as well as stratifying Gleason score 7 patients into different prognostic groups with regard to secondary treatments and disease-specific survival. High AR immunoreactivity in ERG-negative cancers with PTEN loss predicted worse disease-specific survival. We also observed that in Gleason score 7 ERG-negative cases with PTEN loss and high AR expression have significantly shorter disease-specific survival time compared with ERG-positive cases. Our conclusion is that loss of PTEN is a strong determining factor for shorter disease-specific survival time and initiation of secondary therapies after radical prostatectomy. The predictive value of PTEN immunoreactivity is further accentuated in ERG-negative cancers with high AR expression. Negative PTEN expression, accompanied by ERG status, can be used to stratify patients with Gleason score 7 into different survival groups. Assessment of PTEN and ERG status could provide an additional tool for initial diagnostics when determining the prognosis and subsequent follow-up regimen for patients treated by radical prostatectomy.

In clinical trials with oncolytic adenoviruses, there has been no mortality associated with treatment vectors. Likewise, in the Advanced Therapy Access Program (ATAP), where 290 patients were treated with 10 different viruses, no vector-related mortality was observed. However, as the patient population who received adenovirus treatments in ATAP represented heavily pretreated patients, often with very advanced disease, some patients died relatively soon after receiving their virus treatment mandating autopsy to investigate cause of death. Eleven such autopsies were performed and confirmed disease progression as the cause of death in each case. The regulatory requirement for investigating the safety of advanced therapy medical products presented a unique opportunity to study tissue samples collected as a routine part of the autopsies. Oncolytic adenoviral DNA was recovered in a wide range of tissues, including injected and noninjected tumors and various normal tissues, demonstrating the ability of the vector to disseminate through the vascular route. Furthermore, we recovered and cultured viable virus from samples of noninjected brain metastases of an intravenously treated patient, confirming that oncolytic adenovirus can reach tumors through the intravascular route. Data presented here give mechanistic insight into mode of action and biodistribution of oncolytic adenoviruses in cancer patients.

Vitamin D has been suggested to protect against depression, but epidemiological evidence is scarce. The present study investigated the relationship of serum 25-hydroxyvitamin D (25(OH)D) with the prevalence of depressive and anxiety disorders. The study population consisted of a representative sample of Finnish men and women aged 30–79 years from the Health 2000 Survey. The sample included 5371 individuals, of which 354 were diagnosed with depressive disorder and 222 with anxiety disorder. Serum 25(OH)D concentration was determined from frozen samples. In a cross-sectional study, a total of four indicators of depression and one indicator of anxiety were used as dependent variables. Serum 25(OH)D was the risk factor of interest, and logistic models used further included sociodemographic and lifestyle variables as well as indicators of metabolic health as confounding and/or effect-modifying factors. The population attributable fraction (PAF) was estimated. Individuals with higher serum 25(OH)D concentrations showed a reduced risk of depression. The relative odds between the highest and lowest quartiles was 0·65 (95 % CI 0·46, 0·93;Pfor trend = 0·006) after adjustment for sociodemographic, lifestyle and metabolic factors. Higher serum 25(OH)D concentrations were associated with a lower prevalence of depressive disorder especially among men, younger, divorced and those who had an unhealthy lifestyle or suffered from the metabolic syndrome. The PAF was estimated to be 19 % for depression when serum 25(OH)D concentration was at least 50 nmol/l. These results support the hypothesis that higher serum 25(OH)D concentrations protect against depression even after adjustment for a large number of sociodemographic, lifestyle and metabolic factors. Large-scale prospective studies are needed to confirm this finding.

Source at https://doi.org/10.1186/s13148-018-0466-3. © The Author(s). 2018 Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients. Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1–18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data. Results: Among the 137 patients that later relapsed, patients with a CIMP− profile (n = 42) at initial diagnosis had an inferior overall survival (pOS5years 33%) compared to CIMP+ patients (n = 95, pOS5years 65%) (p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors. Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.

Ovarian cancer is a heterogeneous disease. Data regarding familial risks for specific proband, age at diagnosis and histology are limited. Such data can assist genetic counseling and help elucidate etiologic differences among various histologic types of ovarian malignancies. By using the Swedish Family-Cancer Database, we calculated relative risks (RRs) for detailed family histories using a two-way comparison, which implied e.g. estimation of RRs for overall ovarian cancer when family history was histology-specific ovarian cancer, and conversely, RRs for histology-specific ovarian cancer when family history was overall ovarian cancer. In families of only mother, only sisters or both mother and sisters diagnosed with ovarian cancer, cancer risks for ovary were 2.40, 2.59 and 10.40, respectively; and were higher for cases diagnosed before the age of 50 years. All histological types showed a familial risk in two-way analyses, except mucinous and sex cord-stromal tumors. RRs for concordant histology were found for serous (2.47), endometrioid (3.59) and mucinous ovarian cancers (6.91). Concordant familial risks were highest for mucinous cancer; for others, some discordant associations, such as endometrioid-undifferentiated (9.27) and serous-undifferentiated (4.80), showed the highest RRs. Familial risks are high for early-onset patients and for those with multiple affected relatives. Sharing of different histological types of ovarian cancer is likely an indication of the complexity of the underlying mechanisms.

Ovarian cancer is a heterogeneous disease. Data regarding familial risks for specific proband, age at diagnosis and histology are limited. Such data can assist genetic counseling and help elucidate etiologic differences among various histologic types of ovarian malignancies. By using the Swedish Family-Cancer Database, we calculated relative risks (RRs) for detailed family histories using a two-way comparison, which implied e.g. estimation of RRs for overall ovarian cancer when family history was histology-specific ovarian cancer, and conversely, RRs for histology-specific ovarian cancer when family history was overall ovarian cancer. In families of only mother, only sisters or both mother and sisters diagnosed with ovarian cancer, cancer risks for ovary were 2.40, 2.59 and 10.40, respectively; and were higher for cases diagnosed before the age of 50 years. All histological types showed a familial risk in two-way analyses, except mucinous and sex cord-stromal tumors. RRs for concordant histology were found for serous (2.47), endometrioid (3.59) and mucinous ovarian cancers (6.91). Concordant familial risks were highest for mucinous cancer; for others, some discordant associations, such as endometrioid-undifferentiated (9.27) and serous-undifferentiated (4.80), showed the highest RRs. Familial risks are high for early-onset patients and for those with multiple affected relatives. Sharing of different histological types of ovarian cancer is likely an indication of the complexity of the underlying mechanisms.