Search

Aleksi Hamina,1,* Ingvild Odsbu,2,* Petter Christian Borchgrevink,3,4 Li-Chia Chen,5 Thomas Clausen,1 Ketil Arne Espnes,6,7 Kine Gjesdal,8,9 Marte Handal,1,10 Sirpa Hartikainen,11 Vidar Hjellvik,10 Marianne Therese Smogeli Holter,12 Trond Høibø,13 Geana Paula Kurita,14– 16 Harald Christian Langaas,7 Torgeir Gilje Lid,8,9 Torunn Hatlen Nøst,3,17 Per Sjøgren,15 Svetlana Skurtveit1,2 On behalf of the POINT study group1Norwegian Centre for Addiction Research (SERAF), Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 2Department of Mental Disorders, Division of Mental and Physical Health, the Norwegian Institute of Public Health, Oslo, Norway; 3Department of Pain and Complex Disorders, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 4Institute of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; 5Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK; 6Department of Clinical Pharmacology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 7Regional Medicines Information and Pharmacovigilance Centre (RELIS), Department of Clinical Pharmacology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 8Faculty of Health Sciences, University of Stavanger, Stavanger, Norway; 9Center for Alcohol and Drug Research (KORFOR), Stavanger University Hospital, Stavanger, Norway; 10Department of Chronic Diseases, Division of Mental and Physical Health, the Norwegian Institute of Public Health, Oslo, Norway; 11School of Pharmacy, University of Eastern Finland, Kuopio, Finland; 12Department of Psychology, Faculty of Social Sciences, University of Oslo, Oslo, Norway; 13Research Unit for General Practice, NORCE Norwegian Research Centre, Bergen, Norway; 14Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 15Department of Oncology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; 16Department of Anaesthesiology, Pain and Respiratory Support, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; 17Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway*These authors contributed equally to this workCorrespondence: Ingvild Odsbu, Department of Mental Disorders, Division of Mental and Physical Health, Norwegian Institute of Public Health, PO Box 222 Skøyen, Oslo, 0213, Norway, Tel +47 41454379, Email ingvild.odsbu@fhi.noAim: The POINT project aims to provide evidence to optimise chronic pain management, prevent adverse consequences of opioids, and improve chronic pain patients’ pain relief, functional capacity, and quality of life. We describe the outline of the project and its work packages. More specifically, we describe a cohort of persons with chronic pain and a cohort of long-term opioid users identified from a national registry linkage.Data Sources: The project utilises data from nationwide healthcare and population registers in Norway. Using the Norwegian Prescription Database, we identified a cohort of persons who have been dispensed drugs reimbursed for chronic pain and a cohort of persons who used opioids long term from 2010 to 2019. Data from the Norwegian Registry for Primary Health Care and the Norwegian Patient Registry (2008– 2019), Cancer Registry (1990– 2018) Cause of Death Registry (2010– 2019) and demographic and socioeconomic registers from Statistics Norway (2010– 2019) were linked to the cohorts.Study Population: There were 568,869 participants with chronic pain. Sixty-three percent of the cohort was women, and the mean age was 57.1 years. There were 336,712 long-term opioid users (58.6% women; 60.9 years). In chronic pain and long-term opioid user cohorts, the most frequent musculoskeletal diagnosis was back pain diagnosed in primary care (27.6% and 30.7%). Psychiatric diagnoses were also common.Main Variables: Upcoming studies will utilise psychiatric and somatic diagnoses from the patient registers, drug use from the prescription register, causes of death, demographics, and socioeconomic status (eg, education, income, workability, immigrant status) as exposures or outcomes.Conclusion and Future Plans: The two cohorts have numerous pain-related diagnoses, especially in the musculoskeletal system, and noticeably frequent somatic and psychiatric morbidity. The POINT project also includes later work packages that explore prescriber and patient perspectives around safe and effective treatment of chronic pain.Keywords: opioids, chronic pain, healthcare registers

This column presents preliminary findings of an intervention to support shared decision making in psychopharmacology consultation. The waiting area in an urban psychiatric medication clinic was transformed into a peer-run Decision Support Center featuring a user-friendly, Internet-based software program with which clients could create a one-page computer-generated report for use in the medication consultation. The Decision Support Center was used 662 times by 189 unique users from a young-adult and general adult case management team from October 2006 to September 2007. All clients had severe mental disorders. Only ten clients refused to use the intervention at some point during the pilot study. Focus groups with medical staff (N=4), clients (N=16), case managers (N=14), and peer-specialist staff (N=3) reported that the intervention helped to create efficiencies in the consultation and empower clients to become more involved in treatment-related decision making. A randomized controlled trial is currently in process. [ABSTRACT FROM AUTHOR]

Objective: To determine whether previous intravitreal injections are an independent risk factor for posterior capsular rupture (PCR) during cataract surgery after adjusting for known risk factors., Design: Single-centre medical records analysis of a population-based cohort at a university-based referral centre. A retrospective cohort study has been conducted with inclusion of cataract surgeries done from January 1, 2005 to December 31, 2020 at the Department of Ophthalmology, Medical University of Graz, Austria., Participants: All consecutive cataract surgeries done in patients of at least 18 years of age from January 1, 2005 to December 31, 2020 have been included., Methods: Association between previous intravitreal injections and PCR rates has been analysed through univariable and multivariable generalized estimating equations (GEE). Other investigated risk factors were age, combined surgery, pseudoexfoliation, surgeon's experience, and type of cataract surgery., Results: A statistically significant higher rate of posterior capsular rupture during cataract surgery has been found in patients with previous intravitreal therapy compared with patients with no history of intravitreal therapy (OR 1.27, 95% CI 1.10-1.46, p = 0.008). However, after adjusting for confounding risk factors, no statistically significant effect was seen (OR 1.04, 95% CI 0.89-1.21, p = 0.664)., Conclusion: We found no association between history of intravitreal injections and PCR during cataract surgery after adjusting for known risk factors. Further studies upon interactions between history of intravitreal injections and known risk factors for PCR, especially pseudoexfoliation, are needed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patient activation is an emerging field in healthcare research concerning knowledge, skills, and confidence of patients in managing their health. This is particularly important for patients with chronic diseases, who often require more complex care management and self-care skills. However, due to temporary or longer-lasting visual impairments, certain patient groups cannot answer a questionnaire independently. The main objective is to investigate the psychometric properties of the German Patient Activation Measure® (PAM) survey in an everyday clinical setting where it has to be read aloud., Methods: Outpatients with macular edema participated in this questionnaire-based cross-sectional study. The study assessed patient activation by the PAM® survey, self-rated health, self-efficacy, quality of life, and general mood. Interviewers read questionnaires aloud to patients. Psychometric properties of the PAM® survey were investigated by item response theory (IRT), Cronbach's α and trait-trait correlations., Results: The analysis included N = 554 patients. Median age was 69 (IQR 62.0-76.0) years and mean overall activation score 74.1 (SD 13.7). All items showed ceiling effects. Empirical reliability from the IRT model and Cronbach's α were 0.75. The PAM® survey showed a Spearman correlation of 0.54 with self-efficacy, 0.51 with quality of life and 0.34 with general mood., Conclusion: The read-aloud PAM® survey has been shown to provide to adequate measurement precision and convergent validity to be used as a screening tool in an everyday clinical setting. Objective assessment in an interview setting with the PAM® survey is possible. PAM® items are good in distinguishing lower to middle activated patients, but not patients with high activation. Further, issues with structural validity need more investigation., (© 2024. The Author(s).)

Objectives: This study compared aesthetic outcome, psychosexual distress, and treatment satisfaction between women receiving surgical treatment or medical treatment with imiquimod for vulvar high-grade squamous intraepithelial lesion., Materials and Methods: This is an extended analysis of the multicenter, randomized noninferiority trial "topical imiquimod versus surgery for vulvar intraepithelial neoplasia." Patients were randomized to primary topical treatment or surgery and stratified by unifocal or multifocal disease. Digital photos of vulvar appearance were subsequently assessed for aesthetic outcome by 3 investigators blinded to group allocation. Psychosexual distress and treatment satisfaction were assessed with the Cervical Dysplasia Distress Questionnaire, the Sexual Activity Questionnaire, and the Client Satisfaction Questionnaire at baseline and follow-up., Results: One hundred ten patients aged between 19 and 82 years were enrolled. Per-protocol analysis showed complete clinical response in 80% (37/46) using imiquimod, compared with 79% (41/52) after one surgical intervention. Photodocumentation at baseline and 6-month follow-up was available for 84 of these patients (44 imiquimod, 40 surgery). Blinded reviewer assessments of lesion size and lesion severity showed improvement from baseline to follow-up, with no differences between treatment groups. Sexual pleasure, discomfort, and distress remained stable from baseline to follow-up in both groups., Conclusions: Good aesthetic outcome of vulvar high-grade squamous intraepithelial lesion treatment can be achieved with imiquimod and surgery, consisting of ablation or local excision. Treatment satisfaction and stable psychosexual health may not be dependent on chosen treatment modality, but rather on counseling in accordance with patients' preferences., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2023, ASCCP.)

Background: The aim of this study was to investigate whether time of birth, unit volume, and staff seniority impact the incidence of maternal complications in deliveries ≥34 + 0 gestational weeks., Methods: We conducted a population-based cross-sectional study of 87 065 deliveries occurring between 2004 and 2015 in ten public hospitals in Styria, Austria. A composite adverse maternal outcome measure of uterine atony, postpartum hysterectomy, postpartum bleeding, impaired wound healing, postpartum infections requiring antibiotic treatment, sepsis, or maternal death was used to compare outcomes by time of birth, unit volume, and staff seniority. Based on delivery data, generalized estimating equations (GEEs) were used to calculate the risk of maternal adverse outcomes., Results: Maternal adverse events occurred in 1.33% of deliveries. Incidence of maternal adverse events was highest for units with >1000 deliveries (adjusted OR 1.40; CI 95%: 1.16-1.69) and higher for perinatal centers (adjusted OR 1.35; CI 95%: 1.15-1.57) compared with reference units (500-1000 deliveries/year). Delivery during the daytime compared with the afternoon and nighttime did not affect the incidence of maternal complications (P = 0.765 and P = 0.136, respectively). Compared with resident-guided deliveries, the odds ratio for an adverse event was the same when a consultant attended the delivery (adjusted OR 1.13; CI 95%: 0.98-1.30) but lower in deliveries managed by midwives only (adjusted OR 0.21; CI 95%: 0.07-0.64)., Conclusion: Procedures performed during the night shift were not associated with increased complication rates. Delivery volume and high-volume centers were associated with the highest risk of maternal complications, and units with 500-1000 deliveries per year were the lowest. With increasing odds of pregnancy risks, these results change, and delivering in a high-volume center becomes at least as safe as delivering in a smaller unit., (© 2022 The Authors. Birth published by Wiley Periodicals LLC.)

Objective: Reproducibility problems are a known limitation of radiomics. The segmentation of the target lesion plays a critical role in texture analysis variability. This study's aim was to compare the interobserver reliability of manual 2D vs. 3D lung lesion segmentation with and without pre-definition of the volume using a threshold of - 50 HU., Methods: Seventy-five patients with histopathologically proven lung lesions (15 patients each with adenocarcinoma, squamous cell carcinoma, small cell lung cancer, carcinoid, and organizing pneumonia) who underwent an unenhanced CT scan of the chest were included. Three radiologists independently segmented each lesion manually in 3D and 2D with and without pre-segmentation volume definition by a HU threshold, and shape parameters and original, Laplacian of Gaussian-filtered, and wavelet-based texture features were derived. To assess interobserver reliability and identify the most robust texture features, intraclass correlation coefficients (ICCs) for different segmentation settings were calculated., Results: Shape parameters had high reliability (64-79% had excellent and good ICCs). Texture features had weak reliability levels, with the highest ICCs (38% excellent or good) found for original features in 3D segmentation without the use of a HU threshold. A small proportion (4.3-11.5%) of texture features had excellent or good ICC values at all segmentation settings., Conclusion: Interobserver reliability of texture features from CT scans of a heterogeneous collection of manually segmented lung lesions was low with a small proportion of features demonstrating high reliability independent of the segmentation settings. These results indicate a limited applicability of texture analysis and the need to define robust texture features in patients with lung lesions., Key Points: • Our study showed a low reproducibility of texture features when 3 radiologists independently segmented lung lesions in CT images, which highlights a serious limitation of texture analysis. • Interobserver reliability of texture features was low regardless of whether the lesion was segmented in 2D and 3D with or without a HU threshold. • In contrast to texture features, shape parameters showed a high interobserver reliability when lesions were segmented in 2D vs. 3D with and without a HU threshold of - 50., (© 2023. The Author(s).)

Since Croatia joined the European Union, majority of the studies on Croatian emigrants have predominantly addressed the reasons for migration and their future predictions. The primary purpose of this study was to investigate the relationship between the sense of coherence, health behavior, acculturation, adaptation, perceived health, and quality of life (QoL) in first-generation Croatian migrants living in Austria and Ireland. Our study is the first study that addresses the perceived health and QoL of Croatian migrants since the last emigration wave in 2013. An online survey was conducted in Austria (n = 112) and Ireland (n = 116) using standardized questionnaires. Multiple linear regression analyses were conducted for emigrated Croats to identify the predictors of perceived health and QoL. The analyses revealed that the sense of coherence and psychological adaptation were the strongest predictors of perceived health and QoL in Austria and Ireland. Furthermore, in the environmental domain of QoL, a higher education, higher net income, life in Austria rather than Ireland, better health behavior, higher sense of coherence, and better psychological and sociocultural adaptation explained 55.9% of the variance. Health policies and programs should use the salutogenic model to improve the health-related quality of life and psychological adaptation of Croatian migrants., Competing Interests: The authors declare no conflict of interest.

Fibromyalgia-syndrome (FMS) is a complex disease characterized by chronic widespread pain and additional symptoms including depression, cognitive dysfunction ("fibro-fog") and maldigestion. Our research team examined whether FMS-related pain parameters assessed by quantitative sensory testing (QST) and psychological disturbances are accompanied by alterations of the fecal microbiome. We recruited 25 patients with FMS and 26 age- and sex-matched healthy controls. Medical background, food habits, psychopathology and quality of life were assessed through questionnaires. Stool samples were analyzed by 16S rRNA gene amplification and sequencing. QST was performed according to the protocol of the German Network for Neuropathic Pain. QST showed that both lemniscal and spinothalamic afferent pathways are altered in FMS patients relative to healthy controls and that peripheral as well as central pain sensitization processes are manifest. Psychometric assessment revealed enhanced scores of depression, anxiety and stress. In contrast, neither the composition nor the alpha- and beta-diversity of the fecal microbiome was changed in FMS patients. FMS patients segregate from healthy controls in various parameters of QST and psychopathology, but not in terms of composition and diversity of the fecal microbiome. Despite consideration of several confounding factors, we conclude that the contribution of the gut microbiome to the pathophysiology of FMS is limited., Competing Interests: The authors have declared that no competing interests exist.

(1) Background : Vitamin K (VK) is a fat-soluble compound with a common chemical structure, a 2-methyl-1,4-naphthoquinone ring, and a variable aliphatic side-chain. VK is involved in the synthesis of blood-clotting proteins, bone stability, anti-oxidative, and immune inflammatory-modulatory functions. Vitamin K also activates protein S, which acts as an antioxidant and anti-inflammatory. The fact that cytokine overproduction, oxidative stress, and disturbed microcirculation by thrombogenicity play a central role in severe COVID-19 prompted us to analyze this vitamin. (2) Methods : We analyzed by a validated liquid-chromatography tandem mass-spectrometry method serum vitamin K1, MK4, MK7, and VK epoxide levels in 104 healthy controls, 77 patients with non-COVID-19 pneumonia, and 135 hospitalized COVID-19 patients with potentially fatal outcomes admitted to our University Hospital between April and November 2020. We included the quotient between VK and triglyceride (TG, nmol/mmol/L) values in the analyses with respect to the TG transporter function for all VK subtypes. Additionally, we assessed anthropometric, routine laboratory, and clinical data from the laboratory and hospital information systems. (3) Results : The COVID-19 patients had significantly lower MK7 levels than non-COVID-19 pneumonia patients and healthy controls. COVID-19 and non-COVID-19 pneumonia patients had significantly lower vitamin K1 and significantly higher MK4 compared to healthy controls, but did not differ significantly from each other. Between COVID-19 non-survivors ( n = 30) and survivors ( n = 105) no significant differences were seen in all vitamin K subtypes, despite the fact that non-survivors had higher peak concentrations of IL-6, CRP, d-dimer, and higher oxygen needs, respectively. (4) Conclusions : The present data identified significantly decreased vitamin K1, K2 (MK7), and increased MK4 levels in patients with COVID-19 compared to healthy controls. Vitamin K2 (MK7) was lowest in COVID-19 patients irrespective of potentially fatal courses, indicating consumption of this VK subtype by COVID-19 immanent effects, most probably inflammatory and oxidative stress factors.

Background: The optimal management of vulvar high-grade squamous intraepithelial lesions (vHSILs) is challenging. Surgery is the standard treatment, but recurrences are observed in half of patients. Medical treatment with imiquimod is an effective alternative, but the two modalities have not been compared in a randomised trial. The aim of this study was to compare the clinical effectiveness, histological response, human papillomavirus (HPV) clearance, acceptance, and psychosexual morbidity of primary imiquimod treatment versus surgical treatment in women with vHSIL., Methods: This study was a multicentre, randomised, phase 3, non-inferiority clinical trial done by the Austrian Gynaecological Oncology group at six hospitals in Austria. We recruited female patients aged 18-90 years with histologically confirmed vHSIL with visible unifocal or multifocal lesions. Main exclusion criteria were clinical suspicion of invasion, a history of vulvar cancer or severe inflammatory dermatosis of the vulva, and any active treatment for vHSIL within the previous 3 months. Women with known immunodeficiency, who were pregnant, or who were lactating were excluded. Patients were randomly assigned (1:1) by block randomisation to imiquimod or surgery, and stratified by unifocal or multifocal disease. Treatment with imiquimod was self-administered in a slowly escalating dosage scheme up to three times per week for a period of 4-6 months. Surgery consisted of excision or ablation. Patients were assessed with vulvoscopy, vulvar biopsy, HPV tests, and patient-reported outcomes at baseline and after 6 months and 12 months. The primary endpoint was complete clinical response (CCR) at 6 months after local imiquimod treatment or one surgical intervention. Primary analysis was per protocol with a non-inferiority margin of 20%. This trial is registered at ClinicalTrials.gov, NCT01861535., Findings: 110 patients with vHSIL (78% with unifocal vHSIL and 22% with multifocal vHSIL) were randomly assigned between June 7, 2013, and Jan 8, 2020. Clinical response to treatment could be assessed in 107 patients (54 in the imiquimod group and 53 in the surgery group), and 98 patients (46 in the imiquimod group and 52 in the surgery group) completed the study per protocol. 37 (80%) of 46 patients using imiquimod had CCR, compared with 41 (79%) of 52 patients after one surgical intervention, showing non-inferiority of the new treatment (difference in proportion -0·016, 95% CI -0·15 to -0·18; p=0·0056). Invasive disease was found in five patients at primary or secondary surgery, but not in patients with per-protocol imiquimod treatment. There was no significant difference in HPV clearance, adverse events, and treatment satisfaction between study groups., Interpretation: Imiquimod is a safe, effective, and well accepted alternative to surgery for women with vHSIL and can be considered as first-line treatment., Funding: Austrian Science Fund and Austrian Gynaecological Oncology group., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The study goal was to evaluate the distances from the radial (RN), the musculocutaneous (MN) and axillary nerves (AN) and the medial neurovascular bundle of the upper arm to a minimally invasive applied plate and to define its relation to the RN during different degrees of malrotation during MIPO. The sample involved ten upper extremities. Application of a PHILOS plate was performed through a Delta-split. Intervals between the AN, MN, RN and the medial vascular bundle were defined at various positions. The humeral shaft was artificially fractured at a height of about the mean of the plate. The distal fragment was brought into 15° and 30° internal (IR) as well as external rotation (ER) and here, the plate's relation to the RN was evaluated. The medial neurovascular bundle intersected the plate at its distal part in two specimens. Regarding the distances from the RN to the plate during different rotation positions the distances became significantly longer during ER, respectively shorter during IR. The medial neurovascular bundle and the RN were identified as the main structures at risk. Care must be taken during distal screw placement and malrotation exceeding 15° must be avoided during MIPO., (© 2022. The Author(s).)

(1) Background : An inefficient immune response accompanied by an overwhelming inflammatory reaction is involved in severe courses of COVID-19. Kynurenine (KYN) has important immune-modulatory functions and may contribute to a failure in controlling SARS-CoV-2. The present study aims to explore biomarkers that hint at a fatal outcome of COVID-19 early on. (2) Methods : We established a cohort of 148 hospitalized COVID-19 patients for this study. Thirty-one patients died due to a severe COVID-19 course, and 117 recovered within 90 days. We built a biobank by collecting left-over material from these patients whenever blood arrived at the central laboratory of our University hospital for analysis of routine markers. The scientific laboratory analysis comprised KYN, Tryptophan (TRP), KYN/TRP ratio, ferritin, interleukin-6 (IL-6), C-reactive protein (CRP), creatinine, N-terminal pro-natriuretic peptide (NTproBNP), troponin T (TnT), fibrinogen, D-Dimer, prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin (AT), protein C, protein S, factor XIII, lupus aPTT, angiotensin-2, vitamin D metabolites, and telomeres in all COVID-19 patients. Basic clinical characteristics and anteceding diseases including cardiovascular, oncologic, renal, hypertension, pulmonary, metabolic (diabetes, obesity) were recorded in a database together with the laboratory data. (3) Results : At the time of diagnosis of SARS-CoV-2 infection those patients who deceased within 90 days afterwards due to COVID-19, had a significantly higher age, higher KYN, KYN/TRP ratio, ferritin, creatinine, and NTproBNP values than SARS-CoV-2 patients who survived COVID-19 along the same time span. In a Kaplan-Meier analysis the variables age, KYN, ferritin, D-Dimer, TnT, NTproBNP, and creatinine showed a significant influence on survival time. Gender, however, showed no influence. In a combined Cox regression analysis KYN had the highest hazard ratio (1.188, 95% CI: 1.071-1.319) followed by age (1.041, 95% CI: 1.011-1.073). In a ROC analysis, KYN values above the cut off limit of 4.82 nmol/l (as specified by Youden index) had a sensitivity of 82% (95% CI: 66-95%) and a specificity of 72% (95% CI: 65-82%) to predict COVID-19 related death within 90 days observation time. (4) Conclusions : Kynurenine is a promising blood biomarker to predict an increased risk of mortality in SARS-CoV-2 infected people already at the time of the first positive SARS-CoV-2 verification detected in these persons.

Background: The aim of this study was to investigate proximal humerus plating regarding drill depth and over penetration of the glenohumeral joint and to find a relation between these findings and different areas of bone mineral density (BMD) in the humeral head., Material & Methods: The study sample involved 45 upper extremities from human adult cadavers. Two different plates (HOFER; PHILOS) were applied to the proximal humerus. Each hole was drilled until the respective participant thought to have placed the drill bit subchondral. Next, penetration of the far cortex was conducted to determine the residual bone stock. Additionally, the point of screw penetration of the far cortex was identified for each hole of the plates and allocated to five regions with different bone mineral density as described by Tingart et al., Results: The screw penetration rate and the residual bone stock were compared within the 5 BMD regions. A significantly thicker residual bone stock was found at the central region (SD ± 13.1 mm) than in the anterior region (SD ± 9.5 mm) and in the posterior region (SD ± 8.5 mm). The anterior region revealed a significantly higher penetration rate than the posterior region (p = 0.01) and the central region (p = 0.03)., Conclusion: The anterior region of the humeral head was associated with a higher over penetration rate of the far cortex into the glenohumeral joint and a decreased bone stock after subchondral drilling representing a reduced bone mineral density (BMD)., Level of Evidence: Cadaver Study., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

(1) Background: Vitamin D, a well-established regulator of calcium and phosphate metabolism, also has immune-modulatory functions. An uncontrolled immune response and cytokine storm are tightly linked to fatal courses of COVID-19. The present retrospective study aimed to inves-tigate vitamin D status markers and vitamin D degradation products in a mixed cohort of 148 hospitalized COVID-19 patients with various clinical courses of COVID-19. (2) Methods: The serum concentrations of 25(OH)D 3 , 25(OH)D 2 , 24,25(OH) 2 D 3 , and 25,26(OH) 2 D 3 were determined by a validated liquid-chromatography tandem mass-spectrometry method in leftover serum samples from 148 COVID-19 patients that were admitted to the University Hospital of the Medical Uni-versity of Graz between April and November 2020. Anthropometric and clinical data, as well as outcomes were obtained from the laboratory and hospital information systems. (3) Results: From the 148 patients, 34 (23%) died within 30 days after admission. The frequency of fatal outcomes did not differ between males and females. Non-survivors were significantly older than survivors, had higher peak concentrations of IL-6 and CRP, and required mechanical ventilation more frequently. The serum concentrations of all vitamin D metabolites and the vitamin D metabolite ratio (VMR) did not differ significantly between survivors and non-survivors. Additionally, the need for res-piratory support was unrelated to the serum concentrations of 25(OH)D vitamin D and the two vitamin D catabolites, as well as the VMR. (4) Conclusion: The present results do not support a relevant role of vitamin D for the course and outcome of COVID-19.

Purpose: To compare performance data of adolescents collected with five different bicycle spiroergometry protocols and to assess the necessity for establishing standard values for each protocol., Methods: One-hundred-twenty adolescents completed two bicycle spiroergometries within 14 days. One of the two tests was performed based on our institutional weight-adapted protocol (P0). The other test was performed based on one out of four exercise protocols widely used for children and adolescents (P1, 2, 3 or 4) with 30 persons each. The two tests were performed in a random order. Routine parameters of cardiopulmonary exercise tests (CPET) such as VO 2 peak, maximum power, O 2 pulse, OUES, VE/VCO 2 slope as well as ventilatory and lactate thresholds were investigated. Agreement between protocols was evaluated by Bland-Altman analysis, coefficients of variation (CV) and intra-class correlation coefficients (ICC)., Results: None of the CPET parameters were significantly different between P0 and P1, 2, 3 or 4. For most of the parameters, low biases between P0 and P1-P4 were found and 95% confidence intervalls were narrow. CV and ICC values largely corresponded to well-defined analytical goals (CV < 10% and ICC > 0.9). Only maximal power (Pmax) showed differences in size and drift of the bias depending on the length of the step duration of the protocols., Conclusion: Comparability between examination protocols has been shown for CPET parameters independent on step duration. Protocol-dependent standard values do not appear to be necessary. Only Pmax is dependent on the step duration, but in most cases, this has no significant influence on the fitness assessment.

Nicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs), which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes is unknown. ChIs represent less than 1% of the accumbens neuronal population and are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine-seeking behavior. Using chemogenetics in transgenic rats expressing Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bidirectionally manipulated before cue-induced reinstatement. Following nicotine self-administration and extinction, ChIs were activated or inhibited before a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via AMPA/NMDA (A/N) ratios. Chemogenetic inhibition of ChIs inhibited cued nicotine seeking and resulted in decreased A/N, relative to control animals, whereas activation of ChIs was unaltered, demonstrating that ChI inhibition may modulate plasticity underlying cue-induced nicotine seeking. These results demonstrate that ChI neurons play an important role in mediating cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore., (Copyright © 2021 Leyrer-Jackson et al.)

Background: Multipotent mesenchymal stromal/stem cell (MSC) therapy is under investigation in promising (pre-)clinical trials for wound healing, which is crucial for survival; however, the optimal cell dosage remains unknown. The aim was to investigate the efficacy of different low-to-high MSC dosages incorporated in a biodegradable collagen-based dermal regeneration template (DRT) Integra®., Methods: We conducted a porcine study (N = 8 Yorkshire pigs) and seeded between 200 and 2,000,000 cells/cm 2 of umbilical cord mesenchymal stromal/stem cells on the DRT and grafted it onto full-thickness burn excised wounds. On day 28, comparisons were made between the different low-to-high cell dose groups, the acellular control, a burn wound, and healthy skin., Result: We found that the low dose range between 200 and 40,000 cells/cm 2 regenerates the full-thickness burn excised wounds most efficaciously, followed by the middle dose range of 200,000-400,000 cells/cm 2 and a high dose of 2,000,000 cells/cm 2 . The low dose of 40,000 cells/cm 2 accelerated reepithelialization, reduced scarring, regenerated epidermal thickness superiorly, enhanced neovascularization, reduced fibrosis, and reduced type 1 and type 2 macrophages compared to other cell dosages and the acellular control., Conclusion: This regenerative cell therapy study using MSCs shows efficacy toward a low dose, which changes the paradigm that more cells lead to better wound healing outcome.

Background: Nanoparticles, which are exposed to biological fluids are rapidly interacting with proteins and other biomolecules forming a corona. In addition to dimension, charge and material the distinct protein corona influences the interplay of nanoparticles with tissue barriers. In this study we were focused on the impact of in situ formed human plasma protein corona on the transfer of 80 nm polystyrene nanoparticles (PS-particles) across the human placenta. To study materno-to fetal PS transfer we used the human ex vivo placental perfusion approach, which represents an intact and physiological tissue barrier. To analyze the protein corona of PS particles we performed shotgun proteomics of isolated nanoparticles before and after tissue exposure., Results: Human plasma incubated with PS-particles of 80 nm and subsequent formed protein corona enhanced the transfer across the human placenta compared to PS-corona formed by bovine serum albumin and dextran which served as a control. Quantitative and qualitative changes of plasma proteins determined the changes in PS transfer across the barrier. Based on the analysis of the PS-proteome two candidate proteins, namely human albumin and immunoglobulin G were tested if these proteins may account for the enhanced PS-transfer across the placenta. Interestingly, the protein corona formed by human albumin significantly induced the transfer of PS-particles across the tissue compared to the formed IgG-corona., Conclusion: In total we demonstrate the PS corona dynamically and significantly evolves upon crossing the human placenta. Thus, the initial composition of PS particles in the maternal circulation is not predictive for their transfer characteristics and performance once beyond the barrier of the placenta. The precise mechanism of these effects remains to be elucidated but highlights the importance of using well designed biological models when testing nanoparticles for biomedical applications.

Background: B-lines as typical artefacts of lung ultrasound are considered as surrogate measurement for extravascular lung water. However, B-lines develop in the sub-pleural space and do not allow assessment of the whole lung. Here, we present data from the first observational multi-centre study focusing on the correlation between a B-lines score and extravascular lung water in critically ill patients suffering from a variety of diseases., Patients and Methods: In 184 adult patients, 443 measurements were obtained. B-lines were counted and expressed in a score which was compared to extravascular lung water, measured by single-indicator transpulmonary thermodilution. Appropriate correlation coefficients were calculated and receiver operating characteristics (ROC-) curves were plotted., Results: Overall, B-lines score was correlated with body weight-indexed extravascular lung water characterized by r = .59. The subgroup analysis revealed a correlation coefficient in patients without an infection of r = .44, in those with a pulmonary infection of r = .75 and in those with an abdominal infection of r = .23, respectively. Using ROC-analysis the sensitivity and specificity of B-lines for detecting an increased extravascular lung water (>10 mL/kg) was 63% and 79%, respectively. In patients with a P/F ratio <200 mm Hg, sensitivity and specificity to predict an increased extravascular lung water was 71% and 93%, respectively., Conclusions: Assessment of B-lines does not accurately reflect actual extravascular lung water. In presence of an impaired oxygenation, B-lines may reliably indicate increased extravascular lung water as cause of the oxygenation disorders., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: A reduced availability of resources has hampered the implementation of family work in psychosis. Web-based support programs have the potential to increase access to high-quality, standardized resources. This pilot study tested the Norwegian version of the Relatives Education and Coping Toolkit (REACT), a web-based United Kingdom National Health Service program in combination with phone-based support by trained family therapists., Objective: We investigated how the program was perceived by its users and identified the facilitators and barriers to its clinical implementation., Methods: Relatives of people with psychosis were offered access to REACT and to weekly family therapist support (with 1 of 2 trained family therapists) for 26 weeks. Level of distress and level of expressed emotion data were collected at baseline and after 26 weeks using the Family Questionnaire and the Relatives Stress Scale. Both family therapists and a subset of the relatives were interviewed about their experiences after completing the program., Results: During the program, relatives (n=19) had a median of 8 (range 4-11) consultations with the family therapists. Postintervention, there was a significant reduction in stress and in expressed emotions in the relatives of people with psychosis. Interviews with the relatives (n=7) and the family therapists (n=2) indicated the following themes as important-the intervention turned knowledge into action; the intervention strengthened the feeling of being involved and taken seriously by the health services; and management support and the ability for self-referral were important, while lack of reimbursement and clinician resistance to technology were barriers to implementation., Conclusions: The service was found to offer a valued clinical benefit; however, strategies that aim to engage clinicians and increase organizational support toward new technology need to be developed., (©Kristin Lie Romm, Liv Nilsen, Kristine Gjermundsen, Marit Holter, Anne Fjell, Ingrid Melle, Arne Repål, Fiona Lobban. Originally published in JMIR Mental Health (http://mental.jmir.org), 28.07.2020.)

Background : Besides anemia, iron deficiency may cause more subtle symptoms, including the restless legs syndrome (RLS), the chronic fatigue syndrome (CFS) or sleeping disorders. Objective : The aim of this pre-planned secondary analysis of the IronWoMan randomized controlled trial (RCT) was to compare the frequency and severity of symptoms associated with iron deficiency before and after (intravenous or oral) iron supplementation in iron deficient blood donors., Methods/design: Prospective, randomized, controlled, single-centre trial. (ClinicalTrials.gov: NCT01787526)., Setting: Tertiary care center in Graz, Austria., Participants: 176 (138 female and 38 male) whole-blood and platelet apheresis donors aged ≥ 18 and ≤ 65 years with iron deficiency (ferritin ≤ 30ng/mL at the time of blood donation)., Interventions: Intravenous iron (1 g ferric carboxymaltose, n = 86) or oral iron supplementation (10 g iron fumarate, 100 capsules, n = 90)., Measurements: Clinical symptoms were evaluated by a survey before iron therapy (visit 0, V0) and after 8-12 weeks (visit 1, V1), including questions about symptoms of restless legs syndrome (RLS), chronic fatigue syndrome (CFS), sleeping disorders, quality of life and symptoms like headaches, dyspnoea, dizziness, palpitations, pica and trophic changes in fingernails or hair., Results: We found a significant improvement in the severity of symptoms for RLS, fatigue and sleep quality ( p < 0.001). Furthermore, a significant decrease in headaches, dyspnoea, dizziness and palpitations was reported ( p < 0.05). There was no difference between the type of iron supplementation (intravenous versus oral) and clinical outcome data., Conclusion: Iron supplementation in iron-deficient blood donors may be an effective strategy to improve symptoms related to iron deficiency and the wellbeing of blood donors.

Introduction: Frequent blood donation often leads to iron deficiency and even anemia but appropriate strategies for detection and prevention are currently not mandatory. At the Medical University of Graz, we conducted a single-center prospective clinical trial to compare oral and IV iron supplementation in iron deficient blood donors including Austrian regular whole blood and platelet apheresis donors. We aimed to determine the difference of transferrin saturation between the treatment groups 8-12 weeks iron administration besides other parameters of iron status and blood count., Methods: 176 healthy male and female blood donors with iron deficiency (ferritin ≤30 ng/mL) were randomized to either a single dose of IV ferric carboxymaltose (1000 mg, n = 86) or oral iron (II)fumarate (100 tablets of 100 mg [10 per week], n = 90)., Results: Between 2014 and 2016, 172 donors (137 women) completed the study; 4 in the oral group were lost to follow-up. At follow-up, median (IQR) transferrin saturation and ferritin were significantly higher in the intravenous group (27 [23-35]%, vs 21.0 [16-32]%; p < 0.001 and 105 [75-145] ng/mL vs 25 [17-34] ng/mL; p < 0.001, respectively) while median (IQR) hemoglobin levels were comparable (IV, 13.6 [13.0-14.4] g/dL vs oral, 13.6 [13.0-14.2] g/dL). The frequency of adverse effects was comparable (38% in both groups) and no serious adverse events occurred., Conclusions: A single dose of 1000 mg of intravenous iron is highly effective to counteract iatrogenic iron deficiency in blood donors. Oral iron appears to be an acceptable alternative. The assessment of body iron stores should play a key role in maintaining blood donors' health. This trial was registered at www.clinicaltrials.gov as NCT01787526 on February 8, 2013 and at www.clinicaltrialsregister.eu (EudraCT identifier: 2013-000327-14) on September 24, 2013., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: New technologies, like socially assistive robots (SARs), may have the potential to support caregivers at home. Still, the evidence for people with dementia in home care is unclear because a lot of studies are performed in a laboratory or institutional setting, and mainly use robots in prototype stages., Objective: This study aims to explore the effects of the refined, commercially-available, humanoid SAR Pepper combined with a tablet PC-based dementia training program (Coach Pepper) versus an exclusively tablet PC-based dementia training program on psychosocial and physical outcomes of people with dementia living at home, including caregivers and dementia trainers. We hypothesize that Coach Pepper has a more positive effect on the primary outcome motivation (stable or decreased apathy) of people with dementia., Methods: A mixed methods study will be performed, including a randomized controlled, parallel, 2-arm study with a complementary qualitative part. This sample includes 40 PWD living at home and 40 relatives, each complemented with five professional caregivers and dementia trainers. The intervention group will receive Coach Pepper (a SAR connected with a tablet PC-based dementia training program), and the control group will receive exclusively tablet PC-based training without the SAR. The duration of the intervention will be three weeks per household. Data will be collected at baseline and during and after the intervention by standardized questionnaires, sensor data of the robot, and tablet PC, as well as semistructured interviews, focus groups, and observation., Results: To date, no results are available for this study protocol. The study intervention started in May 2019 and will end in Spring 2020., Conclusions: The intervention of this study can be seen as a nonpharmacological intervention, including cognitive and physical training by a robot. This study will help to further refine SAR for the specific needs of people with dementia living at home., International Registered Report Identifier (irrid): DERR1-10.2196/14927., (©Sandra Schüssler, Julia Zuschnegg, Lucas Paletta, Maria Fellner, Gerald Lodron, Josef Steiner, Sandra Pansy-Resch, Lara Lammer, Dimitrios Prodromou, Sebastian Brunsch, Magdalena Holter, Lorenzo Carnevale, Silvia Russegger. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 27.01.2020.)

The present study was a 4-week randomized trial to assess the efficacy and safety of sitagliptin, a dipeptidyl-peptidase-4 inhibitor, in persistent or recurring type 2 diabetes after Roux-en-Y gastric bypass surgery (RYGB). Participants (n = 32) completed a mixed meal test (MMT) and self-monitoring of plasma glucose (SMPG) before and 4 weeks after randomization to either sitagliptin 100 mg daily or placebo daily. Questionnaires were administered to assess gastrointestinal discomfort. Outcome variables were glucose, active glucagon-like peptide-1 and β-cell function during the MMT, and glucose levels during SMPG. Age (56.3 ± 8.2 years), body mass index (34.4 ± 6.7 kg/m 2 ), glycated haemoglobin (7.21 ± 0.77%), diabetes duration (12.9 ± 10.0 years), years since RYGB (5.6 ± 3.3 years) and β-cell function did not differ between the placebo and sitagliptin groups at pre-intervention. Sitagliptin was well tolerated, decreased postprandial glucose levels during the MMT (from 8.31 ± 1.92 mmol/L to 7.67 ± 1.59 mmol/L, P = 0.03) and mean SMPG levels, but had no effect on β-cell function. In patients with diabetes and mild hyperglycemia after RYGB, a short course of sitagliptin provided a small but significant glucose-lowering effect, with no identified improvement in β-cell function., (© 2017 John Wiley & Sons Ltd.)

The RAS/MAPK signaling pathway is one of the most investigated pathways, owing to its established role in numerous cellular processes and implication in cancer. Germline mutations in genes encoding members of the RAS/MAPK pathway also cause severe developmental syndromes collectively known as RASopathies. These syndromes share overlapping characteristics, including craniofacial dysmorphology, cardiac malformations, cutaneous abnormalities and developmental delay. Cardio-facio-cutaneous syndrome (CFC) is a rare RASopathy associated with mutations in BRAF , KRAS , MEK1 ( MAP2K1 ) and MEK2 ( MAP2K2 ). MEK1 and MEK2 mutations are found in ∼25% of the CFC patients and the MEK1 Y130C substitution is the most common one. However, little is known about the origins and mechanisms responsible for the development of CFC. To our knowledge, no mouse model carrying RASopathy-linked Mek1 or Mek2 gene mutations has been reported. To investigate the molecular and developmental consequences of the Mek1 Y130C mutation, we generated a mouse line carrying this mutation. Analysis of mice from a Mek1 allelic series revealed that the Mek1 Y130C allele expresses both wild-type and Y130C mutant forms of MEK1. However, despite reduced levels of MEK1 protein and the lower abundance of MEK1 Y130C protein than wild type, Mek1 Y130C mutants showed increased ERK (MAPK) protein activation in response to growth factors, supporting a role for MEK1 Y130C in hyperactivation of the RAS/MAPK pathway, leading to CFC. Mek1 Y130C mutant mice exhibited pulmonary artery stenosis, cranial dysmorphia and neurological anomalies, including increased numbers of GFAP + astrocytes and Olig2 + oligodendrocytes in regions of the cerebral cortex. These data indicate that the Mek1 Y130C mutation recapitulates major aspects of CFC, providing a new animal model to investigate the physiopathology of this RASopathy. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Colorectal cancer (CRC) is the third most common cause of cancer related death worldwide. Furthermore, with more than 1.2 million cases registered per year, it constitutes the third most frequent diagnosed cancer entity worldwide. Deregulation of protein synthesis has received considerable attention as a major step in cancer development and progression. Eukaryotic translation initiation factors (eIFs) are involved in the regulation of protein synthesis and are functionally linked to the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. The identification of factors accounting for colorectal carcinoma (CRC) development is a major gap in the field. Besides the importance of eIF3 subunits and the eIF4 complex, eIF1, eIF5 and eIF6 were found to be altered in primary and metastatic CRC. We observed significant difference in the expression profile between low and high grade CRC. eIF1, eIF5 and eIF6 are involved in translational control in CRC. Our findings also indicate a probable clinical impact when separating them into low and high grade colon and rectum carcinoma. eIF and mTOR expression were analysed on protein and mRNA level in primary low and high grade colon carcinoma (CC) and rectum carcinoma (RC) samples in comparison to non-neoplastic tissue without any disease-related pathology. To assess the therapeutic potential of targeting eIF1, eIF5 and eIF6 siRNA knockdown in HCT116 and HT29 cells was performed. We evaluated the eIF knockdown efficacy on protein and mRNA level and investigated proliferation, apoptosis, invasion, as well as colony forming and polysome associated fractions. These results indicate that eIFs, in particular eIF1, eIF5 and eIF6 play a major role in translational control in colon and rectum cancer., Competing Interests: CONFLICTS OF INTEREST The authors disclose no conflicts of interest.