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Introduction: Serological surveys of the prevalence of SARS-CoV-2 are instrumental to understanding the course of the COVID-19 epidemic. We evaluate the seroprevalence of SARS-CoV-2 among young adult Finnish females residing in 25 communities all over Finland from 2020 until 2022., Methods: Between 1st March 2020 and 30th June 2022, 3589 blood samples were collected from 3583 women born in 1992-95 when aged 25 or 28 years old attending the follow-up of an ongoing population-based trial of cervical screening strategies. The crude and population standardized SARS-CoV-2 seroprevalence was measured using nucleocapsid (induced by infection) and spike wild-type (WT) protein (induced both by infection and by vaccination) antigens over time and stratified by place of residence (inside or outside the Helsinki metropolitan region)., Results: During 2020 (before vaccinations), spike-WT and nucleocapsid IgG antibodies followed each other closely, at very low levels (<5%). Spike-WT seropositivity increased rapidly concomitant with mass vaccinations in 2021 and reached 96.3% in the 2nd quartile of 2022. Antibodies to nucleocapsid IgG remained relatively infrequent throughput 2020-2021, increasing rapidly in the 1st and 2nd quartiles of 2022 (to 19.7% and 56.6% respectively). The nucleocapsid IgG seropositivity increased more profoundly in participants residing in the Helsinki metropolitan region (4.5%, 8.4% and 43.9% in 2020, 2021 and 2022 respectively) compared to those residing in communities outside the capital region (4.5%, 4.3% and 34.7%)., Conclusions: Low SARS-CoV-2 infection-related seroprevalence during 2020-2021 suggest a comparatively successful infection control. Antibodies to the SARS-CoV-2 WT spike protein became extremely common among young women by the end of 2021, in line with the high uptake of SARS-CoV-2 vaccination. Finally, the rapid increase of seroprevalences to the SARS-CoV-2 nucleocapsid protein during the first and second quartile of 2022, imply a high incidence of infections with SARS-CoV-2 variants able to escape vaccine-induced protection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gray et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Patella alta is a clinical condition where the patella is positioned too proximal in relation to the femoral trochlea. Such an abnormality may cause patellar instability and predispose to recurrent patellofemoral dislocations and patellofemoral pain. There are no conclusive guidelines for determining a threshold for too high positioned patella, as several different methods have been described to measure patellar height. As a surgical solution, distalising tibial tubercle osteotomy has been described to correct excessive patellar height. In the early phase of the distalising tibial tubercle osteotomy postoperative protocol, weightbearing and knee flexion are limited with a brace commonly for 4-8 weeks to avoid potential implant failure leading to displacement of the osteotomy or non-union. The potential risks for adverse effects associated with the limitation rehabilitation protocol include a delay in regaining knee range of motion, stiffness and muscle weakness. As a result, recovery from surgery is delayed and may lead to additional procedures and long-term morbidity in knee function. This is a prospective, randomised, controlled, single-blinded, single centre trial comparing a novel accelerated rehabilitation protocol with the traditional, motion restricting rehabilitation protocol. All skeletally mature patients aged 35 years and younger, referred to as the distalising tibial tubercle osteotomy procedure group, are eligible for inclusion in the study. Patients will be randomised to either the fast rehabilitation group or the traditional rehabilitation group. Patients with patellar instability will be additionally treated with medial patellofemoral ligament reconstruction. The hypothesis of the trial is that the novel accelerated rehabilitation protocol will lead to faster recovery and improved functional outcome at 6, 12 and 24 weeks compared with the conservative rehabilitation protocol. A secondary hypothesis is that the complication rate will be similar in both groups. The study will document short-term recovery and the planned follow-up will be 3 years. After the 1-year follow-up, the trial results will be disseminated in a major peer-reviewed orthopaedic publication. Protocol version 3.6, date 28/11/2023., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Rahnel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cephalometric analysis is critically important and common procedure prior to orthodontic treatment and orthognathic surgery. Recently, deep learning approaches have been proposed for automatic 3D cephalometric analysis based on landmarking from CBCT scans. However, these approaches have relied on uniform datasets from a single center or imaging device but without considering patient ethnicity. In addition, previous works have considered a limited number of clinically relevant cephalometric landmarks and the approaches were computationally infeasible, both impairing integration into clinical workflow. Here our aim is to analyze the clinical applicability of a light-weight deep learning neural network for fast localization of 46 clinically significant cephalometric landmarks with multi-center, multi-ethnic, and multi-device data consisting of 309 CBCT scans from Finnish and Thai patients. The localization performance of our approach resulted in the mean distance of 1.99 ± 1.55 mm for the Finnish cohort and 1.96 ± 1.25 mm for the Thai cohort. This performance turned out to be clinically significant i.e., ≤ 2 mm with 61.7% and 64.3% of the landmarks with Finnish and Thai cohorts, respectively. Furthermore, the estimated landmarks were used to measure cephalometric characteristics successfully i.e., with ≤ 2 mm or ≤ 2° error, on 85.9% of the Finnish and 74.4% of the Thai cases. Between the two patient cohorts, 33 of the landmarks and all cephalometric characteristics had no statistically significant difference (p < 0.05) measured by the Mann-Whitney U test with Benjamini-Hochberg correction. Moreover, our method is found to be computationally light, i.e., providing the predictions with the mean duration of 0.77 s and 2.27 s with single machine GPU and CPU computing, respectively. Our findings advocate for the inclusion of this method into clinical settings based on its technical feasibility and robustness across varied clinical datasets., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sahlsten et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Traumatic brain injury (TBI) can cause neuronal damage and cerebrovascular dysfunction, leading to acute brain dysfunction and considerable physical and mental impairment long after initial injury. Our goal was to assess the impact of pediatric TBI (pTBI) on military service, completed by 65-70% of men in Finland., Methods: We conducted a retrospective register-based nationwide cohort study. All patients aged 0 to 17 years at the time of TBI, between 1998 and 2018, were included. Operatively and conservatively treated patients with pTBI were analyzed separately. The reference group was comprised of individuals with upper and lower extremity fractures. Information on length of service time, service completion, fitness for service class, and cognitive performance in a basic cognitive test (b-test) was gathered from the Finnish Military Records for both groups. Linear and logistic regression with 95% CI were used in comparisons., Results: Our study group comprised 12 281 patients with pTBI and 20 338 reference group patients who participated in conscription. A total of 8 507 (66.5%) men in the pTBI group and 14 953 (71.2%) men in the reference group completed military service during the follow-up period. Men in the reference group were more likely to complete military service (OR 1.26, CI 1.18-1.34). A total of 31 (23.3%) men with operatively treated pTBI completed the military service. Men with conservatively treated pTBI had a much higher service rate (OR 7.20, CI 4.73-11.1). In the pTBI group, men (OR 1.26, CI 1.18-1.34) and women (OR 2.05, CI 1.27-3.36) were more likely to interrupt military service than the reference group. The PTBI group scored 0.15 points (CI 0.10-0.20) less than the reference group in cognitive b-test., Conclusions: PTBI groups had slightly shorter military service periods and higher interruption rate than our reference-group. There were only minor differences between groups in cognitive b-test., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Möttönen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The estimations of the economic burden of glaucoma have focused on comparing different treatment modalities; hence, the total direct and indirect costs of glaucoma at population level are not well known., Objective: To estimate the direct and indirect costs of glaucoma and its treatment in Finland., Methods: Economic and glaucoma data were collected from the cross-sectional nationwide Health 2000 health examination survey linked to multiple national registers, which allowed a 13-year follow-up between 1999-2011 among survey participants. Direct costs covered eye- and non-eye-related hospitalizations and outpatient visits, outpatient health care services, and travel costs among participants aged 30 years or older, adjusted for age and sex. Indirect costs covered premature retirement and productivity losses among participants aged 30-64 years. Glaucoma patients (n = 192) were compared with non-glaucomatous population (n = 6,952)., Results: The annual additional total direct costs were EUR 2,660/glaucoma patient, EUR 1,769/glaucoma patient with medication, and EUR 3,979/operated glaucoma patient compared with persons without glaucoma. The respective additional total indirect costs were EUR 4,288, EUR 3,246, and EUR 12,902 per year. In total, the additional annual direct and indirect expenditures associated with glaucoma in Finland were EUR 202 million (0.86% of total expenditures of health care) and EUR 71 million (0.03% of the Finnish gross domestic product) arising mainly from non-eye-related hospitalizations and productivity losses, respectively., Conclusion: Glaucoma is associated with an increased health care consumption mainly due to non-eye-related health care, which can be explained by the vision loss as well as increased number of co-morbidities among glaucoma patients. Therefore, glaucoma constitutes a major economic burden for the health care system and society, highlighting the importance of early glaucoma interventions. The difference in direct and indirect costs between glaucoma treatment groups is explained by the uneven distribution of co-morbidities., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Purola et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: To study the probability of seeking/undergoing aesthetic dental treatment (ADT) and compare self-perception of orofacial appearance (OA) based on sex, age, and monthly income; and to estimate the impact of OA on life satisfaction (LS) among Finnish and Brazilian adults, considering the indirect effect of receiving ADT and the moderating effects of those sociodemographic variables., Methods: This was an online cross-sectional study. Orofacial Esthetic Scale (OES), Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) and Satisfaction with Life Scale (SWLS) were used. Probability of seeking/receiving ADT was calculated using logistic regression and odds ratio (OR). OA scores were compared according to sociodemographic characteristics (ANOVA, α = 5%). Structural equations models estimated the impact of OA on LS., Results: 3,614 Finns [75.1% female, 32.0 (SD = 11.6) years] and 3,979 Brazilians [69.9% female, 33.0 (SD = 11.3) years] participated in the study. Women were more likely to receive ADT than men in both countries (OR>1.3). However, no statistically or practical significant differences were observed in OA between sexes (p>0.05 or p<0.05, ηp2 = 0.00-0.02). In Finland, demand for ADT (OR = 0.9-1.0) and OA scores (p>0.05) were the same among different ages and monthly income. In Brazil, younger individuals (OR>1.6) and those with higher monthly income (OR>2.7) were more likely to receive ADT, while those with lower income had a greater psychosocial impact of OA (p<0.05; ηp2>0.07). Individuals who were more satisfied with their own OA and had less psychosocial impact from OA had higher levels of LS (β = 0.31-0.34; p<0.01; explained variance: 9.8-13.1%)., Conclusion: Demand for ADT is influenced by sociodemographic and cultural factors. Greater societal pressure on physical appearance is observed among women in Western countries. In countries with high socioeconomic inequalities, consumerism and social prestige are involved in this demand. Self-perception of orofacial appearance plays a significant role in individuals' subjective well-being. Therefore, the planning of aesthetic treatments in the orofacial region should consider the patient's perceptions and social context., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Campos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Body composition can be measured by several methods, each with specific benefits and disadvantages. Bioelectric impedance offers a favorable balance between accuracy, cost and ease of measurement in a range of settings. In this method, bioelectric measurements are converted to body composition measurements by prediction equations specific to age, population and bioimpedance device. Few prediction equations exist for populations in low-resource settings. We formed a prediction equation for total body water in Malawian adolescents using deuterium dilution as reference., Methods: We studied 86 boys and 92 girls participating in the 11-14-year follow-up of the Lungwena Antenatal Intervention Study, a randomized trial of presumptive infection treatment among pregnant women. We measured body composition by Seca m515 bioimpedance analyser. Participants ingested a weight-standardized dose of deuterium oxide, after which we collected saliva at baseline, at 3 and 4 h post-ingestion, measured deuterium concentration using Fourier-transform infrared spectroscopy and calculated total body water. We formed predictive equations for total body water using anthropometrics plus resistance and reactance at a range of frequencies, applying multiple regression and repeated cross-validation in model building and in prediction error estimation., Results: The best predictive model for percentage total body water (TBW %) was 100*(1.11373 + 0.0037049*height (cm)2/resistance(Ω) at 50 kHz- 0.25778*height(m)- 0.01812*BMI(kg/m2)- 0.02614*female sex). Calculation of absolute TBW (kg) by multiplying TBW (%) with body weight had better predictive power than a model directly constructed to predict absolute total body water (kg). This model explained 96.4% of variance in TBW (kg) and had a mean prediction error of 0.691 kg. Mean bias was 0.01 kg (95% limits of agreement -1.34, 1.36) for boys and -0.01 kg (1.41, 1.38) for girls., Conclusions: Our equation provides an accurate, cost-effective and participant-friendly body composition prediction method among adolescents in clinic-based field studies in rural Africa, where electricity is available., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Näsänen-Gilmore et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The capacity of cells to process information is currently used to design cell-based tools for ecological, industrial, and biomedical applications such as detecting dangerous chemicals or for bioremediation. In most applications, individual cells are used as the information processing unit. However, single cell engineering is limited by the necessary molecular complexity and the accompanying metabolic burden of synthetic circuits. To overcome these limitations, synthetic biologists have begun engineering multicellular systems that combine cells with designed subfunctions. To further advance information processing in synthetic multicellular systems, we introduce the application of reservoir computing. Reservoir computers (RCs) approximate a temporal signal processing task via a fixed-rule dynamic network (the reservoir) with a regression-based readout. Importantly, RCs eliminate the need of network rewiring, as different tasks can be approximated with the same reservoir. Previous work has already demonstrated the capacity of single cells, as well as populations of neurons, to act as reservoirs. In this work, we extend reservoir computing in multicellular populations with the widespread mechanism of diffusion-based cell-to-cell signaling. As a proof-of-concept, we simulated a reservoir made of a 3D community of cells communicating via diffusible molecules and used it to approximate a range of binary signal processing tasks, focusing on two benchmark functions-computing median and parity functions from binary input signals. We demonstrate that a diffusion-based multicellular reservoir is a feasible synthetic framework for performing complex temporal computing tasks that provides a computational advantage over single cell reservoirs. We also identified a number of biological properties that can affect the computational performance of these processing systems., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nikolić et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Purpose: Non-operative treatment is the most common treatment option for older patients with distal radius fracture (DRF). Traditionally, wrists have been placed in volar-flexion and ulnar deviation position (VFUDC). In recent years, there has been a trend towards using a functional position cast (FC). However, long-term results for these different casting positions are lacking., Patients and Methods: This randomized, controlled, prospective study evaluates the functional results and costs of the 2 casting positions in patients 65 and older with DRF. Primary end point in this study was Patient-Reported Wrist Evaluation (PRWE) at 24 months, and secondary end points were cost-effectiveness of treatment, health-related quality of life measurement (15D), short version of Disabilities of arm, shoulder and hand score (QuickDASH), and VAS at 24 months. The trial was registered in ClinicalTrials.gov (NCT02894983, https://clinicaltrials.gov/ct2/show/NCT02894983)., Results: We enrolled 105 patients, of which 81 (77%) continued until 24-month follow-up. 8 patients (18%) were operated in the VFUDC group and 4 (11%) in the FC group. Patients in the VFUDC group also received more frequent physical therapy. The difference in PRWE score between the VFUDC and FC groups at 24 months was -4.31. The difference in the cost of treatment per patient was €590. Both findings favored FC., Interpretation: We found a slight, but consistent difference in the functional results between groups. These results suggest that VFUDC is not superior to FC when treating Colles' type DRF. Cost analysis revealed overall costs in the VFUDC group are nearly double those in the FC group, mostly due to more physical therapy, additional visits to hospital, and additional examinations. Therefore, we recommend FC in older patients with Colles' type DRF., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ax et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Care for head and neck cancers is complex in particular for the rare ones. Knowledge is limited and histological heterogeneity adds complexity to the rarity. There is a wide consensus that to support clinical research on rare cancer, clinical registries should be developed within networks specializing in rare cancers. In the EU, a unique opportunity is provided by the European Reference Networks (ERN). The ERN EURACAN is dedicated to rare adults solid cancers, here we present the protocol of the EURACAN registry on rare head and neck cancers (ClinicalTrials.gov Identifier: NCT05483374)., Study Design: Registry-based cohort study including only people with rare head and neck cancers., Objectives: to help describe the natural history of rare head and neck cancers;to evaluate factors that influence prognosis;to assess treatment effectiveness;to measure indicators of quality of care., Methods: Settings and participants It is an hospital based registry established in hospitals with expertise in head and neck cancers. Only adult patients with epithelial tumours of nasopharynx; nasal cavity and paranasal sinuses; salivary gland cancer in large and small salivary glands; and middle ear will be included in the registry. This registry won't select a sample of patients. Each patient in the facility who meets the above mentioned inclusion criteria will be followed prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for the patient follow-up. Variables Data will be collected on patient characteristics (eg. patient demographics, lifestyle, medical history, health status); exposure data (eg. disease, procedures, treatments of interest) and outcomes (e.g. survival, progression, progression-free survival, etc.). In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will be also collected. Statistical methods The data analyses will include descriptive statistics showing patterns of patients' and cancers' variables and indicators describing the quality of care. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause specific mortality will be used to determine independent predictors of overall survival, recurrence etc. Variables to include in the multivariable regression model will be selected based on the results of univariable analysis. The role of confounding or effect modifiers will be evaluated using stratified analysis or sensitivity analysis. To assess treatment effectiveness, multivariable models with propensity score adjustment and progression-free survival will be performed. Adequate statistical (eg. marginal structural model) methods will be used if time-varying treatments/confounders and confounding by indication (selective prescribing) will be present., Results: The registry initiated recruiting in May 2022. The estimated completion date is December 2030 upon agreement on the achievement of all the registry objectives. As of October 2022, the registry is recruiting. There will be a risk of limited representativeness due to the hospital-based nature of the registry and to the fact that hospital contributing to the registry are expert centres for these rare cancers. Clinical Follow-up could also be an issue but active search of the life status of the patients will be guaranteed., Competing Interests: Paolo Bossi was part of the Advisory board or conference honoraria for: Merck, Sanofi-Regeneron, Merck Sharp & Dohme, Sun Pharma, Angelini, Bristol-Myers Squibb, Nestlè Christoph Benedikt Westphalen received honoraria from Bayer, Celgene, Ipsen, F. Hoffmann-La Roche Ltd, Servier, and Taiho, served in a consulting/advisory role for BMS, Celgene, Merck, Shire/Baxalta, Rafael Pharmaceuticals, RedHill BioPharma, and F. Hoffmann-La Roche Ltd, has received travel/accommodation expenses from Bayer, Celgene, RedHill BioPharma, F. Hoffmann-La Roche Ltd, Servier, and Taiho and has received research funding from F. Hoffmann-La Roche Ltd. Lisa Licitra participated to clinical studies that received research funding intended directly to Fondazione IRCCS Istituto Nazionale dei Tumori from Astrazeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis, Debiopharm International SA, Hoffmann – La Roche ltd, IRX Therapeutics, Medpace, Merck-Serono, MSD, Novartis, Pfizer, Roche, Buran. Also, she declares that she recived occasional payment for her participation as a speaker at conferences/congresses or as a scientific consultant for advisory boards from Astrazeneca, Bayer, MSD, Merck-Serono, AccMed, Neutron Therapeutics, Inc All the other authors declare that they have no competing interests. I confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Trama et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Pharmacovigilance reports have suggested that certain commonly used medications may trigger autoimmune diseases (ADs) and immune-mediated inflammatory diseases (IMIDs). We systematically reviewed the literature to evaluate whether psychiatric medication use is associated with ADs and IMIDs., Methods: The protocol was registered in PROSPERO (CRD42022296524) before the start of the study. We searched Medline Ovid and Scopus up to November 28th, 2021, for comparative studies, with any psychiatric medication as exposure and ADs and IMIDs as outcomes. Meta-analysis was performed using DerSimonian-Laird random-effects modeling. The PRISMA 2020 guidelines were followed in reporting. Study-level risk of bias was assessed using the Newcastle-Ottawa Scale, and the overall certainty of evidence using GRADE., Results: There were 7,265 citations from which 31 studies were eligible, all from high-income countries, covering 15 distinct immune diseases. The evidence for the association between selective serotonin reuptake inhibitor (SSRI) use and higher risk of microscopic colitis (meta-OR 2.60, 95% CI 1.05-6.39, I2 97.5%, 6 studies) was of low certainty. A subgroup analysis by the histological type of microscopic colitis showed a statistically significant association only with lymphocytic colitis (meta-OR 2.88, 95% CI 2.60-3.18, I2 00.00%, three studies). In two case-control studies, SSRI use had no significant association with psoriasis (meta-OR 0.80, 95% CI 0.58-1.10, I2 82.4%). The risk of acute pancreatitis was slightly increased with exposure to SSRIs (meta-OR 1.13, 95% CI 1.01-1.26, I2 00.0%), as was the risk of bullous pemphigoid after exposure to antipsychotics (meta-OR 1.79, 95% CI 1.17-2.73, I2 0%)., Conclusions: We reviewed the literature on whether psychiatric medications associate with the risk of ADs and IMIDs and concluded that, despite several signals, the credibility of evidence remains low at best. Prospective cohort studies would be needed as the next step to confirm the suggestions of increased risk., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Larivuo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Androgen deprivation therapy is the cornerstone treatment of advanced prostate cancer. Eventually prostate cancer cells overcome androgen deprivation therapy, giving rise to castration resistant prostate cancer (CRPC) characterized by increased androgen receptor (AR) activity. Understanding the cellular mechanisms leading to CRPC is needed for development of novel treatments. We used long-term cell cultures to model CRPC; a testosterone-dependent cell line (VCaP-T) and cell line adapted to grow in low testosterone (VCaP-CT). These were used to uncover persistent and adaptive responses to testosterone level. RNA was sequenced to study AR-regulated genes. Expression level changed due to testosterone depletion in 418 genes in VCaP-T (AR-associated genes). To evaluate significance for CRPC growth, we compared which of them were adaptive i.e., restored expression level in VCaP-CT. Adaptive genes were enriched to steroid metabolism, immune response and lipid metabolism. The Cancer Genome Atlas Prostate Adenocarcinoma data were used to assess the association with cancer aggressiveness and progression-free survival. Expressions of 47 AR-associated or association gaining genes were statistically significant markers for progression-free survival. These included genes related to immune response, adhesion and transport. Taken together, we identified and clinically validated multiple genes being linked with progression of prostate cancer and propose several novel risk genes. Possible use as biomarkers or therapeutic targets should be studied further., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Teemu J. Murtola has received lecture fees from Novartis, Janssen, Ferring, Sanofi and Bayer, and is a paid consultant for Novartis, Sanofi and Janssen. Teuvo L. J. Tammela is a paid consultant for Astellas, GSK, Pfizer, Orion Pharma and Amgen. The remaining authors declare no competing interests., (Copyright: © 2023 Nätkin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Celiac disease has an increasing incidence worldwide and is treated with lifelong adherence to a gluten-free diet. We aimed to describe gluten-free diet adherence rates in children with screening-identified celiac disease, determine adherence-related factors, and compare adherence to food records in a multinational prospective birth cohort study., Methods: Children in The Environmental Determinants of Diabetes in the Young study with celiac disease were included. Subjects had at least annual measurement of adherence (parent-report) and completed 3-day food records. Descriptive statistics, t-tests, Kruskal-Wallis tests and multivariable logistic and linear regression were employed., Results: Two hundred ninety (73%) and 199 (67%) of subjects were always adherent to a gluten-free diet at 2 and 5 years post celiac disease diagnosis respectively. The percentage of children with variable adherence increased from 1% at 2 years to 15% at 5 years. Children with a first-degree relative with celiac disease were more likely to be adherent to the gluten-free diet. Gluten intake on food records could not differentiate adherent from nonadherent subjects. Adherent children from the United States had more gluten intake based on food records than European children (P < .001 and P = .007 at 2 and 5 years respectively)., Conclusion: Approximately three-quarters of children with screening-identified celiac disease remain strictly adherent to a gluten-free diet over time. There are no identifiable features associated with adherence aside from having a first-degree relative with celiac disease. Despite good parent-reported adherence, children from the United States have more gluten intake when assessed by food records. Studies on markers of gluten-free diet adherence, sources of gluten exposure (particularly in the United States), and effects of adherence on mucosal healing are needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mehta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: 1. to elaborate a general model of physical appearance taking into account body image (BI) and orofacial appearance (OA) components; and 2. to evaluate the impact of BI and OA on life satisfaction among Brazilian adults., Methods: This is a cross-sectional observational study. The cognitive, behavioral, affective, and satisfaction/dissatisfaction aspects of BI, the satisfaction and psychosocial impact of OA, and life satisfaction were evaluated by self-reported psychometric scales. Principal Component Analysis and Parallel Analysis were performed. Structural equation models were elaborated to estimate the impact of BI and OA on life satisfaction. The fit of the models was verified and the significance of the path estimates (β) was evaluated using z-tests (α = 5%)., Results: A total of 1,940 individuals participated in the study (age: mean = 24.8, standard deviation = 5.7 years; females = 70.1%). In the male sample, three physical appearance factors were retained (OA, cognitive and behavioral components of BI, and affective and satisfaction/dissatisfaction components of BI). In the female sample, two factors were retained (OA and all components of BI). All factors had significant impact on life satisfaction (β = |0.26|-|0.48|, p&lt;0.001) in both samples. Individuals dissatisfied with BI and OA had lower levels of life satisfaction. For men, the affective and satisfaction components of BI had a greater impact on life satisfaction (β = 0.48, p&lt;0.001) than the other factors (β =] -0.30;-0.25[, p&lt;0.001). For women, both BI and OA had a similar impact (BI: β = -0.30, p&lt;0.001; OA: β = -0.32, p&lt;0.001)., Conclusion: BI and OA formed distinct clusters in the physical appearance evaluation. Physical appearance was perceived differently by men and women, fostering discussion about the sociocultural construction of the body. BI and OA had a significant impact on life satisfaction and should be considered in assessment and treatment protocols., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Campos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: To review the diagnostic accuracy of contrast-enhanced computed tomography (CT) in differentiating abscesses from cellulitis in patients with neck infections, using surgical findings as the reference standard., Materials and Methods: Previous studies in the last 32 years were searched from PubMed and Embase. Because of partial verification bias (only positive abscess findings are usually verified surgically), sensitivity and specificity estimates are unreliable, and we focused on positive predictive value (PPV). For all studies, PPV was calculated as the proportion of true positives out of all positives on imaging. To estimate pooled PPV, we used both the median with an interquartile range and a model-based estimate. For narrative purposes, we reviewed the utility of common morphological CT criteria for abscesses, such as central hypodensity, the size of the collection, bulging, rim enhancement, and presence of air, as well as sensitivity and specificity values reported by the original reports., Results: 23 studies were found reporting 1453 patients, 14 studies in children (771 patients), two in adults (137 patients), and seven including all ages (545 patients). PPV ranged from 0.67 to 0.97 in individual studies, had a median of 0.84 (0.79-0.87), and a model-based pooled estimate of 0.83 (95% confidence interval 0.80-0.85). Most morphological CT criteria had considerable overlap between abscesses and cellulitis., Conclusions: The pooled estimate of PPV is 0.83 for diagnosing neck abscesses with CT. False positives may be due to limited soft tissue contrast resolution. Overall, none of the morphological criteria seem to be highly accurate for differentiation between abscess and cellulitis., Competing Interests: The authors have declared that no competing interests exist.

Dislocation is one of the most common complications after primary total hip arthroplasty (THA). Several patient-related risk factors for dislocation have been reported in the previous literature, but only few prediction models for dislocation have been made. Our aim was to build a prediction model for an early (within the first 2 years) revision for dislocation after primary THA using two different statistical methods. The study data constituted of 37 pre- or perioperative variables and postoperative follow-up data of 16 454 primary THAs performed at our institution in 2008-2021. Model I was a traditional logistic regression model and Model II was based on the elastic net method that utilizes machine learning. The models' overall performance was measured using the pseudo R2 values. The discrimination of the models was measured using C-index in Model I and Area Under the Curve (AUC) in Model II. Calibration curves were made for both models. At 2 years postoperatively, 95 hips (0.6% prevalence) had been revised for dislocation. The pseudo R2 values were 0.04 in Model I and 0.02 in Model II indicating low predictive capability in both models. The C-index in Model I was 0.67 and the AUC in Model II was 0.73 indicating modest discrimination. The prediction of an early revision for dislocation after primary THA is difficult even in a large cohort of patients with detailed data available because of the reasonably low prevalence and multifactorial nature of dislocation. Therefore, the risk of dislocation should be kept in mind in every primary THA, whether the patient has predisposing factors for dislocation or not. Further, when conducting a prediction model, sophisticated methods that utilize machine learning may not necessarily offer significant advantage over traditional statistical methods in clinical setup., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: OP, MK, AR, OL, PN: None. AE: Zimmer Biomet, paid lectures; Depuy Synthes and Zimmer Biomet, institutional research support (not related to current study) This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: Growth failure is common in radiotherapy-treated long-term survivors of pediatric brain tumors, but studies on longitudinal growth in this patient group are lacking. Here, the aim was to assess the changes in growth patterns before and after brain tumor diagnosis, the adult height, and the risk factors for compromised growth. The incidence and treatment practices of growth hormone deficiency were analyzed., Methods: A cohort of 73 survivors of childhood brain tumor (median age 27.2 years, range 16.2 to 43.8 years) was studied after a median follow-up period of 20.4 years from diagnosis (IQR 14.9 to 22.9 years). Patients were treated in five university hospitals in Finland between 1970 and 2008. Growth curves, final height, and patient- and disease-related risk factors for compromised growth during different growth periods were analyzed. Laboratory analyses for IGF-1 and IGFBP-3 were performed at the follow-up., Results: Growth failure was evident at diagnosis, with a mean height decline of -0.6 SDS (standard deviation score) from birth (95% CI -1.15 to -0.05). Mean height SDS decline after the diagnosis was -1.09 SDS (95%CI -1.51 to -0.66). At follow-up, 37% of the study subjects (27/73) had true short stature (height < -2 SDS). The mean height deficit corrected for target height was -1.9 SDS (95% CI -1.45 to -2.40). Growth failure was associated with the age at diagnosis, corticosteroid dose, radiotherapy modality and mean dose of irradiation in the thalamic area. Low IGF-1 level (below -2.0 SDS) was found in 32% (23/72), and untreated growth hormone deficiency in 40% (29/72) of the subjects., Conclusion: Longitudinal growth impairment was common in radiotherapy-treated survivors of childhood brain tumor, resulting in compromised adult height. Loss of growth potential was evident already at diagnosis and further accelerated by the treatments. At young adulthood, unrecognized growth hormone deficiency was common., Competing Interests: The authors have declared that no competing interests exist.

Background: The incidences of spine fractures and fusion surgeries have increased. A few studies have reported an increased rate of caesarean sections (CS) in women who have undergone spine surgery but have not reported on the health of neonates., Objective: We report the incidence of spine fractures, spine fracture surgeries and fusion surgery for other reasons and the effect of these injuries and procedures on later pregnancy outcomes in Finland., Methods: Data on all fertile-aged women (1998-2018) who had undergone spine fracture or spine fusion surgery were retrieved from the Care Register for Healthcare and combined with data from the National Medical Birth Register. Women with spine fracture or spine surgery before pregnancy were compared with women without previous spine fracture or surgery. We calculated incidences of spine fracture, spine fracture surgery and fusion surgery for other reasons with 95% confidence intervals (CI). We used multivariable logistic regression to evaluate CS and neonatal health. Results are reported as adjusted odds ratios (AOR)., Results: The main finding of our study was the increasing incidence (156%) of spine fusion surgeries for other reasons in fertile-aged women. A total CS rate (including elective and unplanned CS) in the spine fracture group was 19.7% (AOR 1.26, CI 1.17-1.34), in fusion surgery for other reasons group 25.3% (AOR 1.37, CI 1.30-1.49) and 15.9% in the control group. The rate for neonates requiring intensive care in the spine fracture group was 12.2% (AOR 1.18, CI 1.08-1.29), in fusion surgery for other reasons group 13.6% (AOR 1.12, CI 1.02-1.23) and 10.0% in the control group., Conclusions: The incidence of fusion surgery for other reasons increased during our study period. The rate of CS was higher in women with preceding spine fracture or fusion surgery. Our results suggest that vaginal delivery after fractures of the spine is both possible and safe for mother and neonate., Competing Interests: The authors have declared that no competing interests exist.

Objective: Deep brain stimulation (DBS) is an effective treatment for motor symptoms of advanced Parkinson's disease (PD). Currently, DBS programming outcome is based on a clinical assessment. In an optimal situation, an objectively measurable feature would assist the operator to select the appropriate settings for DBS. Surface electromyographic (EMG) measurements have been used to characterise the motor symptoms of PD with good results; with proper methodology, these measurements could be used as an aid to program DBS., Methods: Muscle activation measurements were performed for 13 patients who had advanced PD and were treated with DBS. The DBS pulse voltage, frequency, and width were changed during the measurements. The measured EMG signals were analysed with parameters that characterise the EMG signal morphology, and the results were compared to the clinical outcome of the adjustment., Results: The EMG signal correlation dimension, recurrence rate, and kurtosis changed significantly when the DBS settings were changed. DBS adjustment affected the signal recurrence rate the most. Relative to the optimal settings, increased recurrence rates (median ± IQR) 1.1 ± 0.5 (-0.3 V), 1.3 ± 1.1 (+0.3 V), 1.7 ± 0.4 (-30 Hz), 1.7 ± 0.8 (+30 Hz), 2.0 ± 1.7 (+30 μs), and 1.5 ± 1.1 (DBS off) were observed. With optimal stimulation settings, the patients' Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) score decreased by 35% on average compared to turning the device off. However, the changes in UPRDS-III arm tremor and rigidity scores did not differ significantly in any settings compared to the optimal stimulation settings., Conclusion: Adjustment of DBS treatment alters the muscle activation patterns in PD patients. The changes in the muscle activation patterns can be observed with EMG, and the parameters calculated from the signals differ between optimal and non-optimal settings of DBS. This provides a possibility for using the EMG-based measurement to aid the clinicians to adjust the DBS., Competing Interests: The authors have read the journal’s policy and have the following competing interests: Verneri Ruonala is an inventor in the patent applications PCT/FI2019/050163 and WO2020174122A1. Saara M. Rissanen and Pasi A. Karjalainen are inventors in the patent applications EP18159445.8, PCT/EP2019/055002, PCT/FI2019/050163, WO2020174122A1, and WO2019166557A1; they are also co-funders of the company Adamant Health Ltd., which develops software for surface electromyography analysis. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: In humans, the nc886 locus is a polymorphically imprinted metastable epiallele. Periconceptional conditions have an effect on the methylation status of nc886, and further, this methylation status is associated with health outcomes in later life, in line with the Developmental Origins of Health and Disease (DOHaD) hypothesis. Animal models would offer opportunities to study the associations between periconceptional conditions, nc886 methylation status and metabolic phenotypes further. Thus, we set out to investigate the methylation pattern of the nc886 locus in non-human mammals., Data: We obtained DNA methylation data from the data repository GEO for mammals, whose nc886 gene included all three major parts of nc886 and had sequency similarity of over 80% with the human nc886. Our final sample set consisted of DNA methylation data from humans, chimpanzees, bonobos, gorillas, orangutangs, baboons, macaques, vervets, marmosets and guinea pigs., Results: In human data sets the methylation pattern of nc886 locus followed the expected bimodal distribution, indicative of polymorphic imprinting. In great apes, we identified a unimodal DNA methylation pattern with 50% methylation level in all individuals and in all subspecies. In Old World monkeys, the between individual variation was greater and methylation on average was close to 60%. In guinea pigs the region around the nc886 homologue was non-methylated. Results obtained from the sequence comparison of the CTCF binding sites flanking the nc886 gene support the results on the DNA methylation data., Conclusions: Our results indicate that unlike in humans, nc886 is not a polymorphically imprinted metastable epiallele in non-human primates or in guinea pigs, thus implying that animal models are not applicable for nc886 research. The obtained data suggests that the nc886 region may be classically imprinted in great apes, and potentially also in Old World monkeys, but not in guinea pigs., Competing Interests: The authors have declared that no competing interests exist.

Purpose of the Study: School absenteeism and school dropout jeopardize the future health and wellbeing of students. Reports on the participation of school health care in absenteeism reduction are infrequent, although physical and mental health problems are the most common causes of school absenteeism. Our aim was to explore what reasons different professionals working in schools recognize for absenteeism and which factors either promote or inhibit the inclusion of school health care in absenteeism reduction., Materials and Methods: Data for this qualitative study was gathered from ten focus groups conducted in two municipalities in southern Finland. The groups included (vice) principals, special education/resource/subject teachers, guidance counselors, school social workers, school psychologists, school nurses, school doctors, and social workers working in child protective services. Data analysis was predominantly inductive but the categorization of our results was based on existing literature., Results: Study participants identified student-, family-, and school-related reasons for absenteeism but societal reasons went unmentioned. A number of reasons promoting the inclusion of school health care in absenteeism reduction arose, such as expertise in health-related issues and the confidentiality associated with health care. Inclusion of school health care was hindered by differences in work culture and differing perceptions regarding the aims of school health care., Conclusion: Professionals working in schools were knowledgeable about the different causes of school absenteeism. Clarifying both the aims of school health care and the work culture of different professionals could facilitate the inclusion of school health care in absenteeism reduction., Competing Interests: The authors have declared that no competing interests exist.

Introductions: The rate of acute hand trauma visits to emergency departments (ED) and surgeries decreased during the COVID-19 lockdown. Our aim was to analyze the influence of national lockdown during the first wave and the regional restrictions during the second wave on the rate of visits to the ED and urgent hand surgeries in Finland., Methods: Material for this retrospective study was gathered from three Finnish hospitals All ED visits and urgent or emergency surgeries from January 2017 to December 2020 were included. Incidences per 100 000 persons with 95% confidence intervals (CI) were calculated and compared by incidence rate ratios (IRR)., Results: The incidence of hand injury was lower after the beginning of the lockdown in March 2020 (IRR 0.70 CI 0.63-0.78). After lockdown ended in May, the monthly incidences of ED visits returned to the reference level. During the lockdown, the incidence of fractures and dislocations was 42% lower in March (IRR 0.58 CI 0.50-0.68) and 33% lower in April 2020 (IRR 0.67 CI 0.57-0.80). The incidence of fracture repair surgeries was 43% lower in March 2020 (IRR 0.57 CI 0.35-0.93) and 41% lower in July 2020 (IRR 0.59 CI 0.36-0.98). Incidence of replantation was 49% higher in March 2020 (IRR 1.49 CI 0.53-4.20) and 200% higher in July 2020 (IRR 3.00 CI 0.68-13.2) but these increases had high uncertainty., Conclusions: The rate of ED visits due to hand injuries decreased while the rate of emergency hand operations remained unchanged during the national COVID-19 lockdown in spring. After the lockdown, the incidences returned to reference level and were unaffected by regional restrictions during the second wave of pandemic., Competing Interests: The authors have declared that no competing interests exist.

Objective: Growth-based determination of pubertal onset timing would be cheap and practical. We aimed to determine this timing based on pubertal growth markers. Secondary aims were to estimate the differences in growth between cohorts and identify the role of overweight in onset timing., Design: This multicohort study includes data from three Finnish cohorts-the Type 1 Diabetes Prediction and Prevention (DIPP, N = 2,825) Study, the Special Turku Coronary Risk Factor Intervention Project (STRIP, N = 711), and the Boy cohort (N = 66). Children were monitored for growth and Tanner staging (except in DIPP)., Methods: The growth data were analyzed using a Super-Imposition by Translation And Rotation growth curve model, and pubertal onset analyses were run using a time-to-pubertal onset model., Results: The time-to-pubertal onset model used age at peak height velocity (aPHV), peak height velocity (PHV), and overweight status as covariates, with interaction between aPHV and overweight status for girls, and succeeded in determining the onset timing. Cross-validation showed a good agreement (71.0% for girls, 77.0% for boys) between the observed and predicted onset timings. Children in STRIP were taller overall (girls: 1.7 [95% CI: 0.9, 2.5] cm, boys: 1.0 [0.3, 2.2] cm) and had higher PHV values (girls: 0.13 [0.02, 0.25] cm/year, boys: 0.35 [0.21, 0.49] cm/year) than those in DIPP. Boys in the Boy cohort were taller (2.3 [0.3, 4.2] cm) compared with DIPP. Overweight girls showed pubertal onset at 1.0 [0.7, 1.4] year earlier compared with other girls. In boys, there was no such difference., Conclusions: The novel modeling approach provides an opportunity to evaluate the Tanner breast/genital stage-based pubertal onset timing in cohort studies including longitudinal data on growth but lacking pubertal follow-up., Competing Interests: The authors have declared that no competing interests exist.

Background: SARS-CoV-2 diagnosis relies on the performance of nasopharyngeal swabs. Alternative sample sites have been assessed but the heterogeneity of the studies have made comparing different sites difficult., Objectives: Our aim was to compare the performance of four different sampling sites for SARS-CoV-2 samples with nasopharynx being the benchmark., Study Design: COVID-19 positive patients were recruited prospectively, and samples were collected and analysed for SARS-CoV-2 with RT-PCR from all four anatomical sites in 43 patients, who provided written informed consent., Results: All anterior nasal and saliva samples were positive, while two oropharyngeal samples were negative. There was no significant difference in the cycle threshold values of nasopharyngeal and anterior nasal samples while saliva and oropharynx had higher cycle threshold values., Conclusions: Anterior nasal swab performs as good as nasopharynx swab with saliva also finding all the positives but with higher cycle threshold values. Thus, we can conclude that anterior nasal swabs can be used for SARS-CoV-2 detection instead of nasopharyngeal swabs if the situation would require so., Competing Interests: The authors have declared that no competing interests exist.

Background: Commensal coagulase negative Staphylococcus lugdunensis may cause severe bacteremia (SLB) and complications. Treatment of SLB is not fully established and we wanted to evaluate if infectious diseases specialist consultation (IDSC) would improve management and prognosis., Methods: Multicenter retrospective study of SLB patients followed for 1 year. Patients were stratified according to bedside (formal), telephone (informal) or lack of IDSC within 7 days of SLB diagnosis., Results: Altogether, 104 SLB patients were identified: 24% received formal bedside and 52% informal telephone IDSC whereas 24% were managed without any IDSC. No differences in demographics, underlying conditions or severity of illness were observed between the groups. Patients with bedside IDSC, compared to telephone IDSC or lack of IDSC, had transthoracic echocardiography more often performed (odds ratio [OR] 4.00; 95% confidence interval [CI] 1.31-12.2; p = 0.012) and (OR 16.0; 95% CI, 4.00-63.9; P<0.001). Bedside IDSC was associated with more deep infections diagnosed compared to telephone IDSC (OR, 7.44; 95% CI, 2.58-21.4; p<0.001) or lack of IDSC (OR, 9.56; 95% CI, 2.43-37.7; p = 0.001). The overall mortality was 7%, 10% and 17% at 28 days, 90 days and 1 year, respectively. Considering all prognostic parameters, patients with IDSC, compared to lack of IDSC, had lower 90 days and 1 year mortality (OR, 0.11; 95% CI, 0.02-0.51; p = 0.005) and (OR, 0.22; 95% CI, 0.07-0.67; p = 0.007)., Conclusion: IDSC may improve management and outcome of Staphylococcus lugdunensis bacteremia., Competing Interests: The authors have declared that no competing interests exist.

Background: A concern has been that health care reorganizations during the first COVID-19 wave have led to delays in elective surgeries, resulting in increased complications and even mortality. This multicenter study examined the changes in waiting times of elective surgeries during the COVID-19 pandemic in Finland., Methods: Data on elective surgery were gathered from three Finnish public hospitals for years 2017-2020. Surgery incidence and waiting times were examined and the year 2020 was compared to the reference years 2017-2019. The mean annual, monthly, and weekly waiting times were calculated with 95% confidence intervals (CI). The most common diagnosis groups were examined separately., Findings: A total of 88 693 surgeries were included during the study period. The mean waiting time in 2020 was 92.6 (CI 91.5-93.8) days, whereas the mean waiting time in the reference years was 85.8 (CI 85.1-86.5) days, resulting in an average 8% increase in waiting times in 2020. Elective procedure incidence decreased rapidly in the onset of the first COVID-19 wave in March 2020 but recovered in May and June, after which the surgery incidence was 22% higher than in the reference years and remained at this level until the end of the year. In May 2020 and thereafter until November, waiting times were longer with monthly increases varying between 7% and 34%. In gastrointestinal and genitourinary diseases and neoplasms, waiting times were longer in 2020. In cardiovascular and musculoskeletal diseases, waiting times were shorter in 2020., Conclusion: The health care reorganizations due to the pandemic have increased elective surgery waiting times by as much as one-third, even though the elective surgery rate increased by one-fifth after the lockdown., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: Compared to in-hospital births, the long-term outcome of children born out-of-hospital, planned or unplanned, is poorly studied. This study aimed to examine mortality and morbidity by seven years of age in children born out-of-hospital compared to those born in-hospital., Methods: This study was registered retrospectively and included 790 136 children born in Finland between 1996 and 2013. The study population was divided into three groups according to birth site: in-hospital (n = 788 622), planned out-of-hospital (n = 176), and unplanned out-of-hospital (n = 1338). Data regarding deaths, hospital visits, reimbursement of medical expenses, and disability allowances was collected up to seven years of age or by the year-end of 2018. The association between birth site and childhood morbidity was determined using multivariable-adjusted Cox hazard regression analysis., Results: No deaths were reported during the first seven years after birth in the children born out-of-hospital. The percentage of children with hospital visits due to infection by seven years of age was lower in those born planned out-of-hospital and in the combined planned out-of-hospital and unplanned out-of-hospital group compared to those born in-hospital. Furthermore, the percentage of children with hospital visits and who received disability allowances due to neurological or mental disorders was higher among those born unplanned out-of-hospital and out-of-hospital in total when compared to those born in-hospital. In the multivariable-adjusted Cox proportional hazard regression analysis, the hazard ratio for hospital visits due to asthma and/or allergic diseases (HR 0.84; 95% CI 0.72-0.98) was lower in children born out-of-hospital when compared to those born in-hospital. A similar decreased risk was found due to infections (HR 0.76; 95% CI 0.68-0.84). However, the risk for neurological or mental health disorders was similar between the children born in-hospital and out-of-hospital., Conclusions: Morbidity related to asthma or allergic diseases and infections by seven years of age appeared to be lower in children born out-of-hospital. Birth out-of-hospital seemed to not be associated with increased risk for neurological morbidity nor early childhood mortality. Our study groups were small and heterogeneous and because of this the results need to be interpreted with caution., Competing Interests: The authors have declared that no competing interests exist.

Gastroenteropancreatic neuroendocrine neoplasms grade 3 (GEP-NENs G3) are rare tumors. These highly aggressive neoplasms are traditionally treated with platinum-based chemotherapy in combination with etoposide. Immune checkpoint proteins such as programmed cell death ligand (PD-L1) may have a role in different cancers allowing them escape the immune system and hence, progress. We aimed to investigate the immunohistochemical expression of PD-L1 in GEP-NEN G3 and evaluate its correlation to clinical parameters. In a cohort of 136 patients, 14 (10%) expressed PD-L1 immunoreactivity; four (3%) patients in the tumor cells and 10 (7%) had immunoreactive immune cells. PD-L1 expression did not correlate to clinical parameters, progression-free survival or overall survival. We conclude that PD-L1 expression is present only in a subset of GEP-NEN G3 patients. Further studies are needed to fully understand the role of PD-L1 in patients with GEP-NEN G3, including the future possibility for treatment with immune checkpoint inhibitors., Competing Interests: The authors have declared that no competing interests exist.

Background and Aim: Bereavement affects the health of the bereaved both emotionally and physically. Bereavement resulting from alcohol-related death of the previous generation (parents-first generation) may increase the risk of alcohol abuse and consequently alcohol-related mortality as well as all-cause mortality in the next generation (offspring-second generation). Furthermore, these associations can be bi-directional. However, there is no conclusive evidence of these effects, and studies exploring these intergenerational effects are rare. This study investigates these associations., Methods: A longitudinal data were constructed by linking participants from the Adolescent Health and Lifestyle Surveys (AHLS) from 1979 to 1997 with census and registry-based data from Statistics Finland containing the socioeconomic status of the survey participants and their parents (N = 78610) to investigate these associations. Multivariate Cox proportional hazards models were used to calculate hazard ratios with 95% confidence intervals to determine the effect of bereavement with alcohol-related mortality and all-cause mortality., Results: The findings suggest that bereavement following the death of an offspring increases the risk of both alcohol-related and all-cause mortality among both parents. The magnitude of the risk of mortality following the death of an offspring is higher for mothers than for fathers. There were no clear associations of a parent's death with an offspring's alcohol-related or all-cause mortality. However, generally, a father's death seems to be protective of the risk of mortality among the offspring while a mother's alcohol-related death slightly increased the risk of alcohol-related mortality among their offspring., Conclusions: These findings emphasise the role of bereavement, particularly resulting from the death of an offspring, on alcohol-related and all-cause mortality and therefore inequalities in mortality. Furthermore, the findings highlighting the need for alcohol abuse intervention and emotional support for bereaved persons following the death of an offspring., Competing Interests: The authors have declared that no competing interests exist.

Circulating tumor DNA (ctDNA) is released from cancer cells and oncogenic mutations in ctDNA can be measured from plasma samples. Droplet digital PCR (ddPCR) is a sensitive and specific method for the detection of mutations in ctDNA. We analyzed serial plasma samples (n = 80) from ten metastatic colorectal cancer (mCRC) patients with a known KRAS mutation in their primary tumor. The patients were undergoing oncological treatment with bevacizumab in combination with alternating capecitabine and oxaliplatin or irinotecan. Baseline ddPCR KRAS mutation allele frequency (MAF) values ranged from 0% to 63%. The first radiologic response evaluation criteria in solid tumors (RECIST) evaluation was performed 45-63 days after the initiation of treatment, and by this time three patients had an undetectable level of KRAS mutation, one had a MAF value of 0.5%, and one had a MAF value of 3% that had been reduced by 95% from the baseline value. In three of these patients the RECIST assessment was stable disease and in two partial response. In seven patients, ddPCR MAF values increased before radiological disease progression or death, while one patient remained disease-free with an undetectable KRAS mutation level. Next, we analyzed all available plasma samples with the Idylla ctKRAS system (n = 60), and found that the overall degree of agreement between ddPCR and Idylla was almost perfect (kappa value = 0.860). We used next-generation sequencing (NGS) to detect treatment-induced mutations in the last serial plasma sample of each patient, but were unable to find any new mutations when compared to the primary tumor. This study shows that ddPCR and Idylla are equally efficient for the detection of KRAS mutations in the liquid biopsies from mCRC patients and that ctDNA may indicate the disappearance of treatment responsive KRAS positive mCRC clones and serve as an early sign of disease progression., Competing Interests: PO is an oncologist and employee of Tampere and Helsinki University Hospitals and the PI of the investigator initiated AXOAXI clinical trial, which was supported by an unrestricted grant from Roche Finland. The remaining authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products to declare.

The World Health Organization declared the COVID-19 epidemic a public health emergency of international concern on March 11th, 2020, and the pandemic is rapidly spreading worldwide. COVID-19 is caused by a novel coronavirus SARS-CoV-2, which enters human target cells via angiotensin converting enzyme 2 (ACE2). We used a number of bioinformatics tools to computationally characterize ACE2 by determining its cell-specific expression in trachea, lung, and small intestine, derive its putative functions, and predict transcriptional regulation. The small intestine expressed higher levels of ACE2 mRNA than any other organ. By immunohistochemistry, duodenum, kidney and testis showed strong signals, whereas the signal was weak in the respiratory tract. Single cell RNA-Seq data from trachea indicated positive signals along the respiratory tract in key protective cell types including club, goblet, proliferating, and ciliary epithelial cells; while in lung the ratio of ACE2-expressing cells was low in all cell types (<2.6%), but was highest in vascular endothelial and goblet cells. Gene ontology analysis suggested that, besides its classical role in the renin-angiotensin system, ACE2 may be functionally associated with angiogenesis/blood vessel morphogenesis. Using a novel tool for the prediction of transcription factor binding sites we identified several putative binding sites within two tissue-specific promoters of the ACE2 gene as well as a new putative short form of ACE2. These include several interferon-stimulated response elements sites for STAT1, IRF8, and IRF9. Our results also confirmed that age and gender play no significant role in the regulation of ACE2 mRNA expression in the lung., Competing Interests: The authors have declared that no competing interests exist.

Theoretical and empirical considerations suggest that individual differences in infant visual attention correlate with variations in cognitive skills later in childhood. Here we tested this hypothesis in infants from rural Malawi (n = 198-377, depending on analysis), who were assessed with eye tracking tests of visual orienting, anticipatory looks, and attention to faces at 9 months, and more conventional tests of cognitive control (A-not-B), motor, language, and socioemotional development at 18 months. The results showed no associations between measures of infant attention at 9 months and cognitive skills at 18 months, either in analyses linking infant visual orienting with broad cognitive outcomes or analyses linking specific constructs between the two time points (i.e., switching of anticipatory looks and manual reaching responses), as correlations varied between -0.08 and 0.14. Measures of physical growth, and family socioeconomic characteristics were also not correlated with cognitive outcomes at 18 months in the current sample (correlations between -0.10 and 0.19). The results do not support the use of the current tests of infant visual attention as a predictive tool for 18-month-old infants' cognitive skills in the Malawian setting. The results are discussed in light of the potential limitations of the employed infant tests as well as potentially unique characteristics of early cognitive development in low-resource settings., Competing Interests: The authors have declared that no competing interests exist.

Whether the subtype of atrial fibrillation affects outcomes after transcatheter aortic valve replacement for aortic stenosis is unclear. The nationwide FinnValve registry included 2130 patients who underwent primary after transcatheter aortic valve replacement for aortic stenosis during 2008-2017. Altogether, 281 (13.2%) patients had pre-existing paroxysmal atrial fibrillation, 651 (30.6%) had pre-existing non-paroxysmal atrial fibrillation and 160 (7.5%) were diagnosed with new-onset atrial fibrillation during the index hospitalization. The median follow-up was 2.4 (interquartile range: 1.6-3.8) years. Paroxysmal atrial fibrillation did not affect 30-day or overall mortality (p-values >0.05). Non-paroxysmal atrial fibrillation demonstrated an increased risk of overall mortality (hazard ratio: 1.61, 95% confidence interval: 1.35-1.92; p<0.001), but not 30-day mortality (p = 0.084). New-onset atrial fibrillation demonstrated significantly increased 30-day mortality (hazard ratio: 2.76, 95% confidence interval: 1.25-6.09; p = 0.010) and overall mortality (hazard ratio: 1.68, 95% confidence interval: 1.29-2.19; p<0.001). The incidence of early or late stroke did not differ between atrial fibrillation subtypes (p-values >0.05). In conclusion, non-paroxysmal atrial fibrillation and new-onset atrial fibrillation are associated with increased mortality after transcatheter aortic valve replacement for aortic stenosis, whereas paroxysmal atrial fibrillation has no effect on mortality. These findings suggest that non-paroxysmal atrial fibrillation rather than paroxysmal atrial fibrillation may be associated with structural cardiac damage which is of prognostic significance in patients with aortic stenosis undergoing transcatheter aortic valve replacement., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Mikko Savontaus is proctor for Medtronic and Dr. Mika Laine is proctor for Boston Scientific. The other coauthors do not have any conflict of interest related to this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The inflammatory biomarkers, YKL-40 and interleukin-6 (IL-6), are elevated in patients with metastatic colorectal cancer. We examined their associations with relapse-free survival and overall survival in combination with serum C-reactive protein (CRP), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) in patients with colorectal liver metastases., Methods: Altogether 441 consecutive patients undergoing liver resection at Helsinki University Hospital between 1998 and 2013 were included in the study. Pre- and postoperative YKL-40 and IL-6 were determined from serum samples with commercially available enzyme-linked immunosorbent assay (ELISA) kits, and CRP, CEA, and CA19-9 by routine methods. Associations between these biomarkers and relapse-free and overall survival were examined using Cox regression analysis., Results: Patients with 2-5 elevated biomarkers were at an increased risk of relapse compared to those with 0-1 elevated biomarkers, preoperatively (HR 1.37, 95% CI 1.1-1.72) or postoperatively (HR 1.54, 95% CI 1.23-1.92). Patients with 2-5 elevated biomarkers were also at an increased risk of death compared to those with 0-1 elevated biomarkers, preoperatively (HR 1.76, 95% CI 1.39-2.24) or postoperatively (HR 1.83, 95% CI 1.44-2.33)., Conclusion: The results suggest that a protein panel of the inflammatory biomarkers YKL-40, IL-6, and CRP, and the cancer biomarkers CEA and CA19-9 might identify patients that benefit from more aggressive treatment and surveillance, although the additional value of IL-6 and CRP in this aspect is limited., Competing Interests: The authors have declared that no competing interests exist.

The increasing denormalization of smoking by tobacco control policies and a normative smoke-free climate may shift power towards adolescent non-smokers. It is unclear, however, how common stigmatization of smokers is among adolescents or how stigmatization relates to the denormalization of smoking in their school and social environment. This paper aims to measure (1) whether stigmatization among European adolescents varies according to smoking status and socioeconomic position (SES), and (2) whether stigmatization is greater in school environments in which smoking is denormalized (i.e. those with low smoking rates and strong school tobacco policies). Data on 12,991 adolescents were collected in 55 schools in seven European countries (SILNE R-survey, 2016/17). We applied Stuber's adapted scale of perceived stereotyping and discrimination towards smokers to smoking status and five variables indicating a power shift towards non-smokers: the school's tobacco control policy (STP) score, the percentage of adolescents in the school who smoke, parents' level of education, students' academic performance, and the percentage of their friends who smoke. Multilevel regressions were applied to the global score for perceived stigmatization. Discrimination against smokers and stereotyping of smokers were frequently reported. Smokers reported less 'perceived stigmatization of smoking' than non-smokers (Beta = -0.146, p < 0.001). High-SES students reported stereotyping and discrimination more frequently than lower-SES students. The perception of stigmatization was lower among students whose academic performance was poor (Beta = -0.070, p < 0.001) and among those who had friends who smoked (Beta = -0.141, p < 0.001). Stigmatization was lower in schools with greater exposure to smoking and was not associated with the school's STP score. Perceived stigmatization of smoking is common among European adolescents. Smokers themselves, however, perceive stigmatization less often than non-smokers. Strong school tobacco policies do not increase stigmatization, but a social environment that is permissive of smoking decreases perceived stigmatization., Competing Interests: The authors report no conflict of interest in relation to this study.

Background: Distal radius fractures are common fractures and the cornerstone of treatment remains immobilization of the wrist in a cast. At present, there is a scarcity of studies that compare different cast immobilization methods. The objective of the study was therefore to compare volar-flexion and ulnar deviation cast to functional cast position in the treatment of dorsally displaced distal radius fracture among elderly patients., Methods and Findings: We performed a pragmatic, randomized, controlled trial in three emergency centers in Finland. After closed reduction of the fracture, the wrist was placed in either volar-flexion and ulnar deviation cast or functional cast position. The follow-up was 12 months. The primary outcome was patient-rated wrist evaluation (PRWE) score at 12 months. The secondary outcomes were Quick-DASH score, grip strength, health-related quality of life (15D), and pain catastrophizing scale. The number of complications was also recorded. In total, 105 participants were included in the study. Of these, 88% were female and the mean age was 73.5 (range 65-94) years. In the primary analysis, the mean difference in patient-rated wrist evaluation measure between groups was -4.9 (95% CI: -13.1.- 3.4., p = .24) in favor of the functional cast position. Operative treatment due to loss of reduction of fracture was performed for four patients (8%) in the FC group and for seven patients (13%) in the volar-flexion and ulnar deviation cast group (OR: 0.63, 95% CI: 0.16-2.1)., Conclusion: In this study, the data were consistent with a wide range of treatment effects when comparing two different cast positions in the treatment of distal radius fracture among elderly patients at 12-month follow-up. However, the functional cast is more likely to be superior when compared to volar-flexion and ulnar deviation cast., Trial Registration: ClinicalTrials.gov identifier: NCT02894983 Accessible: https://clinicaltrials.gov/ct2/show/NCT02894983., Competing Interests: The authors have declared that no competing interests exist.

Obesity is a constantly increasing health problem worldwide. It is associated with a systemic low-grade inflammation, which contributes to the development of metabolic disorders and comorbidities such as type 2 diabetes. Diet has an important role in the prevention of obesity and its adverse health effects; as a part of healthy diet, polyphenol-rich berries, such as lingonberry (Vaccinium vitis-idaea L.) have been proposed to have health-promoting effects. In the present study, we investigated the effects of lingonberry supplementation on high-fat diet induced metabolic and inflammatory changes in a mouse model of obesity. Thirty male C57BL/6N mice were divided into three groups (n = 10/group) to receive low-fat (LF), high-fat (HF) and lingonberry-supplemented high-fat (HF+LGB) diet for six weeks. Low-fat and high-fat diet contained 10% and 46% of energy from fat, respectively. Lingonberry supplementation prevented the high-fat diet induced adverse changes in blood cholesterol and glucose levels and had a moderate effect on the weight and visceral fat gain, which were 26% and 25% lower, respectively, in the lingonberry group than in the high-fat diet control group. Interestingly, lingonberry supplementation also restrained the high-fat diet induced increases in the circulating levels of the proinflammatory adipocytokine leptin (by 36%) and the inflammatory acute phase reactant serum amyloid A (SAA; by 85%). Similar beneficial effects were discovered in the hepatic expression of the inflammatory factors CXCL-14, S100A10 and SAA by lingonberry supplementation. In conclusion, the present results indicate that lingonberry supplementation significantly prevents high-fat diet induced metabolic and inflammatory changes in a murine model of obesity. The results encourage evaluation of lingonberries as a part of healthy diet against obesity and its comorbidities., Competing Interests: RR is an employee of Kiantama Ltd; she confirms, that her position has not altered her adherence to the PLOS ONE policies. She and the other authors declare no other competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To assess the frequency and perinatal outcomes of gestational diabetes mellitus (GDM) defined by the criteria according to the International Association of Diabetes in Pregnancy Study Group (IADPSG) and the National Institute for Health and Care Excellence (NICE) diagnostic criteria for GDM., Design: A retrospective cohort study., Setting: Six secondary and tertiary delivery hospitals in Finland in 2009., Population: Pregnant women (N = 4,033) and their offspring., Methods: We used data on comprehensive screening of pregnant women with a 2-h 75-g oral glucose tolerance test (OGTT), performed between gestational weeks 24 and 40. OGTT glucose concentrations were used to identify women who fulfilled IADPSG and NICE criteria. While cut-offs according to Finnish national criteria partly overlapped with both criteria, a subgroup of IADPSG- or NICE-positive GDM women remained undiagnosed by Finnish criteria and hence non-treated. They were analysed as subgroups and compared to controls who were negative with all cut-offs., Main Outcome Measures: GDM prevalence, birth weight SD score (BWSDS), large for gestational age (LGA) and caesarean section (CS) rates., Results: Among the 4,033 women screened for GDM, 1,249 (31.0%) and 529 (13.1%) had GDM according to the IADPSG and NICE criteria, respectively. The LGA rate was similar in both groups. Regardless of the diagnostic criteria, women with GDM had a higher risk of induced delivery and CSs than controls. In IADPSG-positive non-treated women, offspring's BWSDS and CS rate were higher than in controls., Conclusions: GDM prevalence was 2.4-fold higher according to the IADPSG compared with the NICE criteria but the LGA rate did not differ. BWSDS and CS rate were increased already with mild untreated hyperglycaemia., Competing Interests: The authors have declared that no competing interests exist.

Recent studies have shown increased concentration of fetal hemoglobin (HbF) in pre-eclamptic women. Plasma hemopexin (Hpx) and alpha-1-microglobulin (A1M) are hemoglobin scavenger proteins that protect against toxic effects of free heme released in the hemoglobin degradation process. We used an enzyme-linked immunosorbent assay to analyze maternal plasma Hpx and A1M concentrations at 12-14, 18-20 and 26-28 weeks of gestation in three groups: 1) 51 women with a low risk for pre-eclampsia (LRW), 2) 49 women with a high risk for pre-eclampsia (PE) who did not develop PE (HRW) and 3) 42 women with a high risk for PE who developed PE (HRPE). The study had three aims: 1) to investigate whether longitudinal differences exist between study groups, 2) to examine if Hpx and A1M concentrations develop differently in pre-eclamptic women with small for gestational age (SGA) fetuses vs. pre-eclamptic women with appropriate for gestational age fetuses, and 3) to examine if longitudinal Hpx and A1M profiles differ by PE subtype (early-onset vs. late-onset and severe vs. non-severe PE). Repeated measures analysis of variance was used to analyze differences in Hpx and A1M concentrations between the groups. We found that the differences in longitudinal plasma Hpx and A1M concentrations in HRW compared to HRPE and to LRW may be associated with reduced risk of PE regardless of clinical risk factors. In women who developed PE, a high A1M concentration from midgestation to late second trimester was associated with SGA. There were no differences in longitudinal Hpx and A1M concentrations from first to late second trimester in high-risk women who developed early-onset or. late-onset PE or in women who developed severe or. non-severe PE., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: SRH and BÅ holds patent related to diagnosis and treatment of PE and are cofounders of A1M Pharma and Preelumina Diagnostics (www.a1m.se). The pre-existing intellectual properties involve four patents owned by A1M Pharma; 1) HbF and A1M as early stage markers for preeclampsia-1550535 2) Medical use of A1M-2638915 3) Diagnosis and treatment of preeclampsia-201500335 4) Biomarkers for preeclampsia-PA 2015 70146. We confirm that this does not alter our adherence to all PLOS ONE policies on sharing data and materials.

Markers in monocytes, precursors of macrophages, which are related to CAD, are largely unknown. Therefore, we aimed to identify genes in monocytes predictive of a new ischemic event in patients with CAD and/or discriminate between stable CAD and acute coronary syndrome. We included 66 patients with stable CAD, of which 24 developed a new ischemic event, and 19 patients with ACS. Circulating CD14+ monocytes were isolated with magnetic beads. RNA sequencing analysis in monocytes of patients with (n = 13) versus without (n = 11) ischemic event at follow-up and in patients with ACS (n = 12) was validated with qPCR (n = 85). MT-COI, STRN and COX10 predicted new ischemic events in CAD patients (power for separation at 1% error rate of 0.97, 0.90 and 0.77 respectively). Low MT-COI and high STRN were also related to shorter time between blood sampling and event. COX10 and ZNF484 together with MT-COI, STRN and WNK1 separated ACS completely from stable CAD patients. RNA expressions in monocytes of MT-COI, COX10, STRN, WNK1 and ZNF484 were independent of cholesterol lowering and antiplatelet treatment. They were independent of troponin T, a marker of myocardial injury. But, COX10 and ZNF484 in human plaques correlated to plaque markers of M1 macrophage polarization, reflecting vascular injury. Expression of MT-COI, COX10, STRN and WNK1, but not that of ZNF484, PBMCs paired with that in monocytes. The prospective study of relation of MT-COI, COX10, STRN, WNK1 and ZNF484 with unstable CAD is warranted., Competing Interests: We have the following interests: Bernward Klocke is employed by Intrexon Bioinformatics Germany which was hired by KU Leuven to deliver service in modeling. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

In contrast to earlier studies which have used modelling to perform cost-effectiveness analysis, this study links data from a randomised controlled trial with register data from nationwide registries to reveal new evidence on costs, effectiveness, and cost-effectiveness of organised mass prostate-cancer screening based on prostate-specific antigen (PSA) testing. Cost-effectiveness analyses were conducted with individual-level data on health-care costs from comprehensive registers and register data on real-world effectiveness from the two arms of the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC), following 80,149 men from 1996 through 2015. The study examines cost-effectiveness in terms of overall mortality and, in addition, in terms of diagnosed men's mortality from prostate cancer and mortality with but not from prostate cancer. Neither arm of the FinRSPC was clearly more cost-effective in analysis in terms of overall mortality. Organised screening in the FinRSPC could be considered cost-effective in terms of deaths from prostate cancer: averting just over one death per 1000 men screened. However, even with an estimated incremental cost-effectiveness ratio of below 20,000€ per death avoided, this result should not be considered in isolation. This is because mass screening in this trial also resulted in increases in death with, but not from, prostate cancer: with over five additional deaths per 1000 men screened. Analysis of real-world data from the FinRSPC reveals new evidence of the comparative effectiveness of PSA-based screening after 20 years of follow-up, suggesting the possibility of higher mortality, as well as higher healthcare costs, for screening-arm men who have been diagnosed with prostate cancer but who do not die from it. These findings should be corroborated or contradicted by similar analyses using data from other trials, in order to reveal if more diagnosed men have also died in the screening arms of other trials of mass screening for prostate cancer., Competing Interests: PK has taken part in a conference with support from Amgen. Fimlab Laboratories provided support in the form of a salary for PK, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. TT has acted as a consultant for Orion Pharma, Bayer AG, and Ferring and received research funding from Medivation, Pfizer, and Lidds AB. KT has taken part in a conference with support from Astellas and received research funding from Medivation, Astellas, and Pfizer. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

We examined the effect of liquorice ingestion on haemodynamic responses to exogenous nitric oxide donor (nitroglycerin) and β2-adrenoceptor agonist (salbutamol), and 11β-hydroxysteroid dehydrogenase activity, in 21 volunteers and 21 reference subjects. Haemodynamic data was captured before and after sublingual nitroglycerin (0.25 mg) and inhaled salbutamol (400 μg) during orthostatic challenge utilising radial pulse wave analysis and whole-body impedance cardiography. The recordings were performed at baseline and following two weeks of liquorice intake (290-370 mg/d glycyrrhizin). Urinary cortisone and cortisol metabolites were examined. Liquorice intake elevated aortic systolic and diastolic blood pressure and systemic vascular resistance when compared with the reference group. Following research drug administration the liquorice-induced increase in systemic vascular resistance was observed in the presence of nitroglycerin (p<0.05) but no longer in the presence of salbutamol. Liquorice ingestion decreased cardiac chronotropic response to upright posture (p = 0.032) in unadjusted analysis, but when adjusted for age and sex the difference in the upright change in heart rate was no longer significant. The urinary cortisone to cortisol metabolite ratio decreased from 0.70 to 0.31 (p<0.001) after liquorice intake indicating significant inhibition of the 11β-hydroxysteroid dehydrogenase type 2. In the reference group the haemodynamic variables remained virtually unchanged. These results suggest that liquorice exposure impaired vasodilatation in vivo that was induced by exogenous nitric oxide donor but not that induced by β2-adrenoceptor stimulation. Trial registration: EU Clinical Trials Register 2006-002065-39 ClinicalTrials.gov NCT01742702., Competing Interests: The authors have declared that no competing interests exist.

This article proposes the coupling of the recombinant protein avidin to the polysaccharide gellan gum to create a modular hydrogel substrate for 3D cell culture and tissue engineering. Avidin is capable of binding biotin, and thus biotinylated compounds can be tethered to the polymer network to improve cell response. The avidin is successfully conjugated to gellan gum and remains functional as shown with fluorescence titration and electrophoresis (SDS-PAGE). Self-standing hydrogels were formed using bioamines and calcium chloride, yielding long-term stability and adequate stiffness for 3D cell culture, as confirmed with compression testing. Human fibroblasts were successfully cultured within the hydrogel treated with biotinylated RGD or biotinylated fibronectin. Moreover, human bone marrow stromal cells were cultured with hydrogel treated with biotinylated RGD over 3 weeks. We demonstrate a modular and inexpensive hydrogel scaffold for cell encapsulation that can be equipped with any desired biotinylated cell ligand to accommodate a wide range of cell types., Competing Interests: The authors have declared that no competing interests exist.

Background: Positive mindset (PM) is an important domain of health-related quality of life in Singapore, a multi-ethnic urban city state in Southeast Asia. We therefore developed and calibrated a novel item bank to measure and improve PM., Methods: We developed an initial candidate pool of 48 items from focus groups, in-depth interviews and existing instruments locally developed and validated for use in Singapore. We administered all items in English to a multi-stage sample stratified for age and gender, of subjects with and without medical conditions recruited from the community and a hospital, and calibrated their responses using Samejima's Graded Response Model. We evaluated a final 36-item bank with respect to Item Response Theory (IRT) model assumptions, model fit, differential item functioning (DIF), concurrent and known-groups validity., Results: Among 493 participants (49.3% male, 41.6% above 50 years old, 33% Chinese, Malay and Indian), bifactor model analyses supported unidimensionality: explained common variance of the general factor was 0.86 and omega hierarchical was 0.97. Local independence was deemed acceptable: the average absolute residual correlations were <0.06 and 3.3% of the total item-pair residuals were flagged for local dependence. The overall model fit was adequate and provided good coverage of the PM construct (theta range: -3.6 to +2.4). Five items exhibited DIF with respect to ethnicity and gender, but were retained without modification of scores because they measured important aspects of PM. Scores correlated in the hypothesized direction with a self-reported measure of global health (Spearman's rho = -0.28, p<0.001) and discriminated between groups of participants with and without a self-reported diagnosis of a mood disorder (p = 0.007) adjusting for age, gender, ethnicity, education and marital status., Conclusion: The 36-item PM item bank demonstrated satisfactory psychometric properties for the English-speaking Singaporean population. IRT model assumptions were sufficiently met and scores showed concurrent and known-groups validity. Future studies to evaluate the validity of PM scores when items are administered adaptively are needed., Competing Interests: The authors have declared that no competing interests exist.

Cancer antigen 15-3 (CA15-3) is widely utilized for monitoring metastatic breast cancer (BC). However, its utility for early detection of breast cancer is severely limited due to poor clinical sensitivity and specificity. The glycosylation of CA15-3 is known to be affected by BC, and therefore it might offer a way to construct CA15-3 glycovariant assays with improved cancer specificity. To this end, we performed lectin-based glycoprofiling of BC-associated CA15-3. CA15-3 expressed by a BC cell line was immobilized on microtitration wells using an anti-CA15-3 antibody. The glycosylation of the immobilized CA15-3 was then detected by using lectins coated onto europium (III)-doped nanoparticles (Eu+3-NPs) and measuring the time-resolved fluorescence of Eu. Out of multiple lectin-Eu+3-NP preparations, wheat germ agglutinin (WGA) and macrophage galactose-type lectin (MGL) -Eu3+-NPs bound to the BC cell line-dericed CA15-3 glycovariants (CA15-3Lectin). To evaluate the clinical performance of these two lectin-based assays, plasma samples from metastatic BC patients (n = 53) and healthy age-matched women (n = 20).Plasma CA15-3Lectin measurements better distinguished metastatic BC patients from healthy controls than the conventional CA15-3 immunoassay. At 90% specificity, the clinical sensitivity of the assays was 66.0, 67.9 and 81.1% for the conventional CA15-3, CA15-3MGL and CA15-3WGA assays, respectively. Baseline CA15-3MGL and CA15-3WGA were correlated to conventional baseline CA15-3 levels (r = 0.68, p<0.001, r = 0.90, p>0.001, respectively). However, very low baseline CA15-3MGL levels ≤ 5 U/mL were common in this metastatic breast cancer patient population.In conclusion, the new CA15-3Lectin concept could considerably improve the clinical sensitivity of BC detection compared to the conventional CA15-3 immunoassays and should be validated further on a larger series of subjects with different cancer subtypes and stages., Competing Interests: KP and KG have a patent application (Application WO-2018011474-A1 related to this work "Lectin based diagnostics of cancers." This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The efficacy and safety of antibiotic treatment for uncomplicated acute appendicitis has been established at long-term follow-up with the majority of recurrences shown to occur within the first year. Overall costs of antibiotics are significantly lower compared with appendectomy at short-term follow-up, but long-term durability of these cost savings is unclear. The study objective was to compare the long-term overall costs of antibiotic therapy versus appendectomy in the treatment of uncomplicated acute appendicitis in the APPAC (APPendicitis ACuta) trial at 5 years., Methods and Findings: This multicentre, non-inferiority randomized clinical trial randomly assigned 530 adult patients with CT-confirmed uncomplicated acute appendicitis to appendectomy or antibiotic treatment at six Finnish hospitals. All major costs during the 5-year follow-up were recorded, whether generated by the initial visit and subsequent treatment or possible recurrent appendicitis. Between November 2009 and June 2012, 273 patients were randomized to appendectomy and 257 to antibiotics. The overall costs of appendectomy were 1.4 times higher (p<0.001) (€5716; 95% CI: €5510 to €5925) compared with antibiotic therapy (€4171; 95% CI: €3879 to €4463) resulting in cost savings of €1545 per patient (95% CI: €1193 to €1899; p<0.001) in the antibiotic group. At 5 years, the majority (61%, n = 156) of antibiotic group patients did not undergo appendectomy., Conclusions: At 5-year follow-up antibiotic treatment resulted in significantly lower overall costs compared with appendectomy. As the majority of appendicitis recurrences occur within the first year after the initial antibiotic treatment, these results suggest that treating uncomplicated acute appendicitis with antibiotics instead of appendectomy results in lower overall costs even at longer-term follow-up., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: P.S. has received personal fees for lectures from Merck, Lilly, and Orion Pharma. All other authors have declared that no competing interests exist.

Objective: The use of brain-computer interface in neurofeedback therapy for attention deficit hyperactivity disorder (ADHD) is a relatively new approach. We conducted a randomized controlled trial (RCT) to determine whether an 8-week brain computer interface (BCI)-based attention training program improved inattentive symptoms in children with ADHD compared to a waitlist-control group, and the effects of a subsequent 12-week lower-intensity training., Study Design: We randomized 172 children aged 6-12 attending an outpatient child psychiatry clinic diagnosed with inattentive or combined subtypes of ADHD and not receiving concurrent pharmacotherapy or behavioral intervention to either the intervention or waitlist-control group. Intervention involved 3 sessions of BCI-based training for 8 weeks, followed by 3 training sessions per month over the subsequent 12 weeks. The waitlist-control group received similar 20-week intervention after a wait-time of 8 weeks., Results: The participants' mean age was 8.6 years (SD = 1.51), with 147 males (85.5%) and 25 females (14.5%). Modified intention to treat analyzes conducted on 163 participants with at least one follow-up rating showed that at 8 weeks, clinician-rated inattentive symptoms on the ADHD-Rating Scale (ADHD-RS) was reduced by 3.5 (SD 3.97) in the intervention group compared to 1.9 (SD 4.42) in the waitlist-control group (between-group difference of 1.6; 95% CI 0.3 to 2.9 p = 0.0177). At the end of the full 20-week treatment, the mean reduction (pre-post BCI) of the pooled group was 3.2 (95% CI 2.4 to 4.1)., Conclusion: The results suggest that the BCI-based attention training program can improve ADHD symptoms after a minimum of 24 sessions and maintenance training may sustain this improvement. This intervention may be an option for treating milder cases or as an adjunctive treatment., Competing Interests: The authors have declared that no competing interests exist.

Aim: Intermittent preventive treatment in pregnancy (IPTp) with azithromycin and monthly sulfadoxine-pyrimethamine increased the mean child weight, mid-upper arm and head circumference at four weeks of age in a rural low-income setting. Now we assess for how long these gains were sustained during 0-5 years of age., Methods: We enrolled 1320 pregnant Malawian women in a randomized trial and treated them with two doses of sulfadoxine-pyrimethamine (control) or monthly sulfadoxine-pyrimethamine as IPTp against malaria, or monthly sulfadoxine-pyrimethamine and two doses of azithromycin (AZI-SP) as IPTp against malaria and reproductive tract infections. Child weight, mid-upper arm circumference, head circumference and weight-for-height Z-score were recorded at one, six, 12, 24, 36, 48, and 60 months., Results: Throughout follow-up, the mean child weight was approximately 100 g higher (difference in means 0.12 kg, 95% CI 0.04-0.20, P = 0.003 at one month; 0.19 kg, 95% CI 0.05-0.33, P = 0.007, at six months), mean head circumference 2 mm larger (0.3 cm, 95% CI 0.1 to 0.5, P = 0.004 at one month) and the cumulative incidence of underweight by five years of age was lower (hazard ratio 0.74, 95% CI 0.60 to 0.90, P = 0.002) in the AZI-SP group than in the control group. The 2 mm difference in the mean mid-upper arm circumference at one month (0.2 cm, 95% CI 0.0 to 0.3, P = 0.007) disappeared after three years of age. There was no difference in mean weight-for-height Z-score at any time point., Conclusion: In Malawi, IPTp with azithromycin and monthly sulfadoxine-pyrimethamine has a modest, 3-5-year positive impact on child weight, mid-upper arm circumference and head circumference, but not on weight-for-height Z-score., Competing Interests: LH reports a grant from Office of Health, Infectious Diseases, and Nutrition, Bureau for Global Health, United States Agency for International Development (USAID), through the Food and Nutrition Technical Assistance III Project (FANTA), managed by FHI 360, during the conduct of the study. Other authors declare no competing interests. Azithromycin and its placebo used in the study were provided free of charge by Pfizer Inc (New York), which had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Both maternal HIV infection and antiretroviral therapy are associated with adverse birth outcomes. The role of antenatal nutrient supplements with regard to adverse birth outcomes in HIV infected women exposed to antiretroviral therapy is not well known. We assessed the association between HIV and birth outcomes and explored whether antenatal lipid-based nutrient supplements (LNS) modulated this association., Methods: We analysed a nested cohort of pregnant Malawian women who received daily LNS, multiple micronutrients (MMN) or iron and folic acid (IFA). Birth weight, length-for-age z-score (LAZ) and weight-for-age z-score (WAZ) were analysed as continuous outcomes and proportion of stunting and small-for-gestational age (SGA) as dichotomous outcomes., Results: 134 HIV infected (46 LNS, 39 MMN, 49 IFA) and 833 HIV uninfected (271 LNS, 287 MMN, 275 IFA) women were included. Maternal HIV infection was associated with a lower mean birth weight (-129g (-209, -48), P = 0.002); LAZ (-0.34 (-0.54, -0.13), P = 0.002) and WAZ (-0.21 (-0.40, -0.02), P = 0.041) and a higher risk of stunting (RR (95% confidence interval), 1.87 (1.24, 2.83), P = 0.003) and SGA (1.66 (1.21, 2.26), P = 0.001) in the newborn. If the women received LNS, HIV was not associated with LAZ (mean difference (95%); -0.02 (-0.35, 0.31), P = 0.918) or newborn stunting (RR (95% CI), 0.84 (0.34, 2.03), P = 0.691). However HIV tended to be associated with LAZ if the women received MMN (-0.42 (-0.80, -0.03), P = 0.053); and was significantly associated with LAZ if the women received IFA (-0.52 (-0.89, -0.14), P = 0.021) and with newborn stunting if they received MMN (2.40 (1.15, 4.98), P = 0.029) or IFA (2.40 (1.26, 4.59), P = 0.024)., Conclusions: Further research to investigate the impact of LNS on various aspects of foetal growth in HIV infected women is warranted., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Long-term side effects of the treatments are common in survivors of irradiated pediatric brain tumors. Ionizing radiation in combination with surgery and chemotherapy during childhood may reduce vertebral height and bone mineral density (BMD), and cause growth failure. The aim of this study was to evaluate the late consequences of tumor treatments on vertebrae in survivors of childhood brain tumors., Methods: 72 adult survivors (mean age 27.8 years, standard deviation 6.7) of irradiated childhood brain tumor were studied by spinal magnetic resonance imaging (MRI) for vertebral abnormalities from the national cohort of Finland. Patients were treated in five university hospitals in Finland between the years 1970 and 2008. Subject height and weight were measured and body mass index (BMI) was calculated. The morphology and height/depth ratio of the vertebrae in the middle of the kyphotic thoracic curvature (Th8) and lumbar lordosis (L3) were examined. Vertebrae were analyzed by Genant's semiquantative (SQ) method and spinal deformity index (SDI) was calculated. BMD was measured by using dual X-ray absorptiometry., Results: 4.2% (3/72) of the patients had undiagnosed asymptomatic vertebral fracture and 5.6% (4/72) of patients had radiation-induced decreased vertebral body height. Male patients had flatter vertebrae compared with females. Patient age at the time of irradiation, BMI and irradiation area correlated to vertebral morphology differentially in males and females. BMD had no association with the vertebral shape. Patients who had received craniospinal irradiation were shorter than the general population., Conclusion: Childhood brain tumor survivors had a high number of vertebral abnormalities in young adulthood. Irradiation was associated with abnormal vertebral morphology and compromised final height. Male gender may predispose vertebrae to the side effects of irradiation., Competing Interests: The authors have declared that no competing interests exist.