Background and purpose Although a tourniquet may reduce bleeding during total knee replacement (TKA), and thereby possibly improve fixation, it might also cause complications. Migration as measured by radiostereometric analysis (RSA) can predict future loosening. We investigated whether the use of a tourniquet influences prosthesis fixation measured with RSA. This has not been investigated previously to our knowledge. less thanbrgreater than less thanbrgreater thanMethods 50 patients with osteoarthritis of the knee were randomized to cemented TKA with or without tourniquet. RSA was performed postoperatively and at 6 months, 1 year, and 2 years. Pain during hospital stay was registered with a visual analog scale (VAS) and morphine consumption was measured. Overt bleeding and blood transfusions were registered, and total bleeding was estimated by the hemoglobin dilution method. Range of motion was measured up to 2 years. less thanbrgreater than less thanbrgreater thanResults RSA maximal total point motion (MTPM) differed by 0.01 mm (95% CI-0.13 to 0.15). Patients in the tourniquet group had less overt bleeding (317 mL vs. 615 mL), but the total bleeding estimated by hemoglobin dilution at day 4 was only slightly less (1,184 mL vs. 1,236 mL) with a mean difference of -54 mL (95% CI-256 to 152). Pain VAS measurements were lower in the non-tourniquet group (p = 0.01). There was no significant difference in morphine consumption. Range of motion was 11 more in the non-tourniquet group (p = 0.001 at 2 years). less thanbrgreater than less thanbrgreater thanInterpretation Tourniquet use did not improve fixation but it may cause more postoperative pain and less range of motion.

Background and purpose - Aseptic loosening is a main cause of late revision in total knee replacement (TKR). Teriparatide, a recombinant parathyroid hormone (PTH), stimulates osteoblasts and has been suggested to improve cancellous bone healing in humans. This might also be relevant for prosthesis fixation. We used radiostereometric analysis (RSA) to investigate whether teriparatide influences prosthesis fixation. Early migration as measured by RSA can predict future loosening. Patients and methods - In a randomized controlled trial with blind evaluation, 50 patients with osteoarthritis of the knee were allocated to a teriparatide treatment group (Forsteo, 20 mu g daily for 2 months postoperatively) or to an untreated control group. RSA was performed postoperatively and at 6 months, 12 months, and 24 months. The primary effect variable was maximal total point motion (MTPM) from 12 to 24 months. Results - Median maximal total point motion from 12 to 24 months was similar in the 2 groups (teriparatide: 0.14 mm, 10% and 90% percentiles: 0.08 and 0.24; control: 0.13 mm, 10% and 90% percentiles: 0.09 and 0.21). [Authors: this is perhaps better than using "10th" and "90th", which looks ugly in print. /language editor] The 95% confidence interval for the difference between group means was -0.03 to 0.04 mm, indicating that no difference occurred. Interpretation - We found no effect of teriparatide on migration in total knee replacement. Other trials using the same dosing have suggested a positive effect of teriparatide on human cancellous fracture healing. Thus, the lack of effect on migration may have been due to something other than the dose. In a similar study in this issue of Acta Orthopaedica, we found that migration could be reduced with denosumab (Ledin etal. 2017). The difference in response between the anabolic substance teriparatide and the antiresorptive denosumab suggests that resorption has a more important role during the postoperative course than any deficit in bone formation.

Background and purpose - Aseptic loosening is a main cause of late revision in total knee replacement (TKR). Migration of implants as measured by radiostereometric analysis (RSA) can predict future loosening. This migration is associated with bone resorption. Denosumab is a human monoclonal antibody that binds to receptors on osteoclast precursors and osteoclasts. This prevents osteoclast formation, resulting in less bone resorption in cortical and trabecular bone. We investigated whether denosumab can reduce migration of TKR, as measured with RSA. Patients and methods - In this 2-center, randomized, double-blind placebo-controlled trial, 50 patients with osteoarthritis of the knee were treated with an injection of either denosumab (60 mg) or placebo 1 day after knee replacement surgery and again after 6 months. RSA was performed postoperatively and after 6, 12, and 24 months. The primary effect variable was RSA maximal total point motion (MTPM) after 12 months. We also measured other RSA variables and the knee osteoarthritis outcome score (KOOS). Results - The primary effect variable, MTPM after 12 months, showed that migration in the denosumab group was statistically significantly less than in the controls. Denosumab MTPM 12 months was reduced by one-third (denosumab: median 0.24 mm, 10% and 90% percentiles: 0.15 and 0.41; placebo: median 0.36 mm, 10% and 90% percentiles: 0.20 and 0.62). The secondary MTPM variables (6 and 24 months) also showed a statistically significant reduction in migration. There was no significant difference in MTPM for the period 12-24 months. KOOS sub-variables were similiar between denosumab and placebo after 12 and 24 months. Interpretation - Denosumab reduces early migration in total knee replacement, as in previous trials using bisphosphonates. As migration is related to the risk of late loosening, denosumab may be beneficial for long-term results.

Introduction In Sweden, roughly 3000 patients are reoperated each year due to pain and loss of function related to a loosened hip or knee prosthesis. These reoperations are strenuous for the patient, technically demanding and costly for the healthcare system. Any such reoperation that can be prevented would be of great benefit. Bisphosphonates are drugs that inhibit osteoclast function. Several clinical trials suggest that bisphosphonates lead to improved implant fixation and one small study even indicates better functional outcome. Furthermore, in epidemiological studies, bisphosphonates have been shown to decrease the rate of revision for aseptic loosening by half. Thus, there are several indirect indications that bisphosphonates could improve patient-reported outcome, but no firm evidence. Methods and analysis This is a pragmatic randomised, placebo-controlled, double-blinded, academic clinical trial of a single postoperative dose of zoledronic acid, in patients younger than 80 years undergoing primary total hip or knee replacement for osteoarthritis. Participants will be recruited from two orthopaedic departments. All surgeries will be performed, and study drugs given at Motala Hospital, Sweden. The primary endpoint is to investigate between-group differences in the Hip dysfunction and Osteoarthritis Outcome Score and the Knee injury and Osteoarthritis Outcome Score at 3-year follow-up. Secondary outcomes will be investigated at 1 year, 3 years and 6 years, and stratified for hip and knee implants. These secondary endpoints are supportive, exploratory or explanatory. A total of 1000 patients will be included in the study. Ethics and dissemination The study has been approved by the Regional Ethical Review Board in Linkoping (DNR 2015/286-31). The study will be reported in accordance with the Consolidated Standards of Reporting Trials statement for pharmacological trials. The results will be submitted for publication in peer-reviewed academic journals and disseminated to patient organisations and the media.

Catalysts and electmcatalysts are crucial for energy production and storage. To develop cost-efficient systems taking advantage of functionalized surfaces, the catalysts can be synthesized as nanomaterials or thin films. In this work, cobalt thin films were deposited on low-alloyed steel using magnetron sputtering. The films are uniform with a smooth surface and a thickness of similar to 400 nm. The films were electrochemically oxidized via anodization to a mix of cobalt oxides, one of them being Co3O4, at room temperature in an alkaline solution. The electrocatalytic performances of the anodized films were evaluated in 1 M KOH electrolyte saturated with oxygen. Cathodic currents in -0.5 mA/cm(2) range, corresponding to oxygen reduction reaction (ORR) activity, were measured with cyclic voltammetry. The catalytic activity of the films was evaluated as a function of time. The anodized Co coating exhibited three times higher activity than the steel substrate. The kinetics for the ORR were evaluated through Tafel plots and a slope of 226 mV/decade was found. Post-ORR characterization of the films revealed hexagonal plate-like oxide particles on the surface. After 50 cyclic voltammograms, the film was further oxidized, indicating that the ORR activity also affects the overall surface state of the film. This study demonstrates that thin films, after electrochemical modification, can be electrocatalysts for the oxygen reduction reaction and potentially used for applications in energy production and storage.

Corrosion resistance and catalytic activity toward the oxygen reduction reaction (ORR) in an alkaline environment are two key properties for water recombination applications. In this work, CoCrFexNi (0 <= x <= 0.7) thin films were deposited by magnetron sputtering on polished steel substrates. The native passive layer was 2-4 nm thick and coherent to the columnar grains determined by transmission electron microscopy. The effect of Fe on the corrosion properties in 0.1 M NaCl and 1 M KOH and the catalytic activity of the films toward ORR were investigated. Electrochemical impedance spectroscopy and potentiodynamic polarization measurements indicate that CoCrFe0.7Ni and CoCrFe0.3Ni have the highest corrosion resistance of the studied films in NaCl and KOH, respectively. The high corrosion resistance of the CoCrFe0.7Ni film in NaCl was attributed to the smaller overall grain size, which leads to a more homogeneous film with a stronger passive layer. For CoCrFe0.3Ni in KOH, it was attributed to a lower Fe dissolution into the electrolyte and the build-up of a thick and protective hydroxide layer. Scanning Kelvin probe force microscopy showed no potential differences globally in any of the films, but locally, a potential gradient between the top of the columns and grain boundaries was observed. Corrosion of the films was likely initiated at the top of the columns where the potential was lowest. It was concluded that Fe is essential for the electrochemical activation of the surfaces and the catalytic activity toward ORR in an alkaline medium. The highest catalytic activity was recorded for high Fe-content films (x >= 0.5) and was attributed to the formation of platelet-like oxide particles on the film surface upon anodization. The study showed that the combination of corrosion resistance and catalytic activity toward ORR is possible for CoCrFexNi, making this material system a suitable candidate for water recombination in an alkaline environment.

(CoCrFeNi)_1−xMo_x thin films with various Mo content (0–10 at.%) were grown by magnetron sputtering on a stainless steel substrate. The films with 0–2 at.% presented two crystal structures: one FCC phase and one sigma phase, while films with higher Mo content only had the FCC structure. All films have a (111) texture and follow the topography of the substrate. The corrosion resistance of the films was evaluated in 0.05 M H₂SO₄ at room temperature and at 80 °C. It was observed that the corrosion current densities considerably decreased for Mo > 2 at%, and that the current densities were higher at the elevated temperature. Scanning Kelvin Probe Force Microscopy showed a large potential difference between the main FCC phase and sigma phase for the Mo0–2 films. This would suggest that preferential dissolution of the FCC phase occurs over the sigma and reduces the corrosion resistance. Such preferential dissolution does not occur for the higher Mo content films with only the FCC phase. The high corrosion resistance was also attributed to the inhibition of Fe and Cr dissolution by Mo and the stabilisation of the Cr enriched oxide by incorporating Mo oxides into the passive film, identified by X-ray photoelectron spectroscopy. The low corrosion current densities (below 1 µA/cm²) make these thin films possible candidates for protective coatings of bipolar plates in PEM fuel cells.

Ensembles of neural networks have shown to give better predictive performance and more reliable uncertainty estimates than individual networks. Additionally, ensembles allow the uncertainty to be decomposed into aleatoric (data) and epistemic (model) components, giving a more complete picture of the predictive uncertainty. Ensemble distillation is the process of compressing an ensemble into a single model, often resulting in a leaner model that still outperforms the individual ensemble members. Unfortunately, standard distillation erases the natural uncertainty decomposition of the ensemble. We present a general framework for distilling both regression and classification ensembles in a way that preserves the decomposition. We demonstrate the desired behaviour of our framework and show that its predictive performance is on par with standard distillation.

Labelling of data for supervised learning canbe costly and time-consuming and the riskof incorporating label noise in large data setsis imminent. When training a flexible discriminative model using a strictly proper loss,such noise will inevitably shift the solution towards the conditional distribution over noisylabels. Nevertheless, while deep neural networks have proven capable of fitting randomlabels, regularisation and the use of robustloss functions empirically mitigate the effectsof label noise. However, such observationsconcern robustness in accuracy, which is insufficient if reliable uncertainty quantificationis critical. We demonstrate this by analysingthe properties of the conditional distributionover noisy labels for an input-dependent noisemodel. In addition, we evaluate the set ofrobust loss functions characterised by noiseinsensitive, asymptotic risk minimisers. Wefind that strictly proper and robust loss functions both offer asymptotic robustness in accuracy, but neither guarantee that the finalmodel is calibrated. Moreover, even with robust loss functions, overfitting is an issue inpractice. With these results, we aim to explain observed robustness of common training practices, such as early stopping, to labelnoise. In addition, we aim to encourage thedevelopment of new noise-robust algorithmsthat not only preserve accuracy but that alsoensure reliability. 

Annotating data for supervised learning can be costly. When the annotation budget is limited, active learning can be used to select and annotate those observations that are likely to give the most gain in model performance. We propose an active learning algorithm that, in addition to selecting which observation to annotate, selects the precision of the annotation that is acquired. Assuming that annotations with low precision are cheaper to obtain, this allows the model to explore a larger part of the input space, with the same annotation budget. We build our acquisition function on the previously proposed BALD objective for Gaussian Processes, and empirically demonstrate the gains of being able to adjust the annotation precision in the active learning loop.

Noise-contrastive estimation (NCE) is a popular method for estimating unnormalised probabilistic models, such as energy-based models, which are effective for modelling complex data distributions. Unlike classical maximum likelihood (ML) estimation that relies on importance sampling (resulting in ML-IS) or MCMC (resulting in contrastive divergence, CD), NCE uses a proxy criterion to avoid the need for evaluating an often intractable normalisation constant. Despite apparent conceptual differences, we show that two NCE criteria, ranking NCE (RNCE) and conditional NCE (CNCE), can be viewed as ML estimation methods. Specifically, RNCE is equivalent to ML estimation combined with conditional importance sampling, and both RNCE and CNCE are special cases of CD. These findings bridge the gap between the two method classes and allow us to apply techniques from the ML-IS and CD literature to NCE, offering several advantageous extensions.

The demand for steel components with tailored properties is constantly growing. To obtain a specific variation of microstructures and mechanical properties along the component it must undergo a controllable cooling. One way to control the cooling rates along the component is by using different simultaneous water jet impingements on a hot austenitized surface. This can be done by a newly developed test rig for water Impinging Jet Quenching Technique (IJQT). This work discusses the effect of IJQT on mechanical properties and fracture behavior of 15 mm steel plates containing 0.27 and 0.38 mass-% carbon. The samples were cooled in a specifically designed setup of the technique to obtain simultaneous water and air cooling resulting in diverse microstructures. The mechanical property gradients of both steels were analyzed through hardness measurements and tensile tests. The fracture surfaces and the near fracture regions were observed using scanning electron microscope and light optical microscope respectively. The results from tensile tests showed that the larger part of the sample with higher carbon content was fully hardened, however smoothly transitioning to a more ductile region. The sample with lower carbon content combined various degrees of hardening and transitioned from higher to lower ultimate tensile strength values. Fracture behavior of higher carbon steel was predominantly brittle transitioning to a ductile, while the lower carbon steel had a small region showing brittle fracture transitioning to a larger region of predominant ductile fracture behavior.

Soil-working tools in agriculture are made of boron-containing steels with high wear resistance and hardenability. Nevertheless, these tools are subject to high impacts, abrasive wear, and fatigue and are therefore prone to failure. To combine varying levels of properties within one component in as-quenched condition can be beneficial for such products. To obtain this property variation, a component must undergo a complex and controllable cooling. Therefore, the aim of this work is to obtain a microstructure gradient along two 15 mm-thick steel plates in a newly developed test rig by water jet impingement technique to confirm its controllability and flexibility. Furthermore, a quenching simulation model is created for hardness prediction using phase transformation data from a machine learning tool. Microstructure variation is observed using light optical microscopy and the electron backscatter diffraction technique. Mechanical properties are studied through tensile tests and hardness measurements and are also compared with simulation results. The 0.27 mass% C steel sample is obtained in almost fully martensitic state transitioning to a softer ferritic/bainitic condition, while the 0.38 mass% C steel sample results predominantly into a fully hardened martensitic state and slightly shows ferritic and bainitic features along the sample. The quenching simulation model shows promising hardness prediction for both steels. A newly developed impinging jet quenching technique is used for differential quenching of 15 mm-thick boron steel sheets with the aim of obtaining microstructure and property gradients along their lengths. As a result, combinations of differential hardness profiles along with varying hardening degrees are produced and metallurgically characterized through microstructure observations and mechanical tests.

Hardening of carbon steel products by austenitization and immersion in a quenching medium is a widely used heat treatment to obtain a hard and strong martensitic structure. To avoid the undesired consequences, such as residual stresses or insufficient hardening depth, the cooling rates must be accurately measured and controlled. This can be achieved using the impinging water jet quenching technique. The aim of this work is to perform hardening of four low-alloyed 70 mm cylindrical carbon steel bars, using impinging water jet quenching technique with different jet flow rates, and to analyze its effect on thermal evolution and residual stresses. The temperature evolution during quenching experiments is recorded and used as input to a comprehensive quenching model to predict phase transformations, final hardness, and residual stresses of cylindrical bars. All four quenching experiments result in a fully hardened martensitic state. Furthermore, a decrease in jets' flow rate, within a certain interval, results in different thermal histories and in lower compressive residual stresses on the surface. The results from quenching simulations show promising hardness, microstructure, and residual stress predictions that are validated by hardness measurements, optical microscopy, and residual stress analysis using X-Ray diffraction method. Four 70 mm cylindrical steel bars are martensite hardened with different water jet flow rates using impinging jet quenching technique. A finite element method (FEM) quenching model is created to simulate phase transformations and predict the resulting microstructure, hardness, and residual stresses. The model is metallurgically validated through hardness measurements, microstructure observations, and residual stress measurements using X-ray diffraction technique.image (c) 2024 WILEY-VCH GmbH

Background Various frequencies of adverse motor outcomes (cerebral palsy and hemiplegia) after paediatric ischaemic stroke have been reported. Few reports on the risks of adverse motor outcomes in nationwide cohorts and contributing risk factors are available. Objectives To assess risk of adverse motor outcome and potential risk factors thereof after paediatric ischaemic stroke in a nationwide cohort. Methods This nationwide matched cohort study identified 877 children <18 years of age diagnosed with ischaemic stroke through the Swedish national health registers from 1997 to 2016. These children, exposed to ischaemic stroke, alive 1 week after stroke, were matched for age, sex and county of residence with 10 unexposed children. Using Cox regression, we estimated the risk of adverse motor outcomes in children with stroke compared to that in unexposed children. Logistic regression was applied to compare the characteristics of children with and without adverse motor outcomes after stroke. Results Out of the 877 children with ischaemic stroke, 280 (31.9%) suffered adverse motor outcomes compared with 21 (0.2%) of the 8770 unexposed: adjusted hazard ratio (aHR) 167.78 (95% confidence interval (CI) 107.58, 261.66). There were no differences between risk estimates of adverse motor outcome according to age at stroke: perinatal stroke (aHR 124.11, 95% CI 30.45, 505.84) and childhood stroke (aHR 182.37, 95% CI 113.65, 292.64). An association between adverse motor outcome and childhood stroke aOR 1.56 (95% CI 1.05, 2.31) was found when analysing only children with ischaemic stroke. No associations were found between adverse motor outcome and sex, gestational age or parental age at birth. Conclusions The risk of adverse motor outcome is substantial after paediatric ischaemic stroke, especially childhood stroke, confirming results of previous smaller studies. This study found no associations between sex, gestational age or parental age and adverse motor outcome after paediatric ischaemic stroke.

Background: Early intervention after perinatal brain insults requires early detection of infants with cerebral palsy (CP). General Movements Assessments (GMA) in the fidgety movement period has a high predictive value for CP. Aim: To investigate the NeuroMotionTM apps usability regarding film quality and user experience and to assess the inter-rater reliability of GMA in a neonatal risk group. Methods: GMA, inter-rater reliability and film quality was assessed in a cohort consisting of 37 infants enrolled in a multicentre study of GMA as part of the Swedish neonatal follow-up program for high-risk infants. Some of these infants were filmed twice. For evaluation of user experience 95 parents of 52 infants were addressed with a web-based questionnaire. A GMA expert assessed film quality and performed GMA and three on-site assessors, individually performed GMA. Inter-rater reliability was computed using Krippendorffs alpha (k-alpha). Results: In all, 45 films showed good or excellent quality. The response rate of the questionnaire survey was 40% and revealed predominantly positive perceptions of the NeuroMotionTM app. GMA in 36 infants resulted in substantial agreement (k-alpha = 0.72, 95%CI = 0.3-1.0) between the three on-site assessors consensus and the GMA expert. Inter-rater reliability for GMA between the on-site assessors was moderate (k-alpha = 0.48, 0.18-0.74). Conclusion: The NeuroMotionTM app produces good technical quality films and the app user experience was overall positive. High agreement was observed between the on-site assessors and the GMA expert. The study design is feasible for more extensive GMA studies in cohorts of infants at risk of CP. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

There is growing evidence of the positive effects of constraint-induced movement therapy (CIMT) for infants at high risk of unilateral cerebral palsy (UCP) when provided by parents with in-person coaching/supervision from occupational therapists during home visits. The aim of this study is to investigate whether Baby-mCIMT (modifiedCIMT) can be as effective if parents are coached/supervised remotely. In this case-control study, we recruited 20 infants and re-used 18 controls, 4-8-month-old infants in both groups at high risk of UCP. The same protocol regarding inclusion criteria, data collection, and training volume was used in both groups. The training was conducted for two 6-week periods, separated by a 6-week break, consisting of daily 30 min sessions conducted by parents, supported by therapist coaching once a week. The primary outcome was measured using the Hand Assessment for Infants (HAI). There was no difference in the change of HAI units (p = 0.803) or that of the affected-hand raw score (p = 0.942) between the two groups. The remote coaching method was well received by parents. In conclusion, this demonstrates that remote coaching/supervision is as effective as the in-person approach, requiring less time and effort for both families and healthcare providers.

Background/Objectives: Recent guidelines on early intervention in children at high risk of cerebral palsy (CP) recommend parental involvement and family-centered home-based interventions with parents as primary trainers. Therapist coaching by home visitation is resource demanding, and telerehabilitation is a viable option for remote intervention and coaching. This study aims to describe parents' experiences of engaging in Baby-mCIMT coached remotely. Their infants are at high risk of unilateral cerebral palsy and the parents have been the primary trainers in regard to home-based intervention, optimizing the use of the affected hand. Methods: A qualitative approach involving semi-structured interviews with eight parents was employed. Data were analyzed using qualitative content analysis. Results: The overarching theme "Parents in the driver's seat-learning through remote coaching to create conditions to enhance the child's motor skills" describes parents' experiences as primary training providers. The following three underlying categories with subcategories were identified: (1) Baby-mCIMT coached remotely in an everyday context-practical and technical prerequisites; (2) the child's response and the therapists' coaching supports active parental learning; (3) capability and sense of control-strengthening and demanding aspects. Conclusions: Our findings revealed that Baby-mCIMT coached remotely empowered the parents as primary trainers, which provided them with opportunities for understanding and learning about their child and their development. The findings underscore the importance of responsive professional guidance and a strong therapist-parent relationship to succeed with the Baby-mCIMT program coached remotely and to manage the digital coaching format.

While the management of pregnant patients with systemic lupus erythematosus (SLE) has improved over the last decades, the risk of maternal, foetal, and neonatal complications is still substantial. We evaluated the occurrence of adverse pregnancy outcomes (APO) occurring in 2002-2018 among patients with SLE from the catchment area of the Department of Rheumatology in Lund, Sweden. Longitudinal clinical and laboratory data were collected and analysed. Results were stratified according to the sequence of conception. We investigated a total of 59 pregnancies in 28 patients. Prior lupus nephritis was the clinical feature that, in a multivariable regression analysis, displayed the strongest association with APO overall (OR 6.0,p= 0.02). SLE combined with antiphospholipid syndrome (APS) was associated with the risk of miscarriage (OR 3.3,p= 0.04). The positivity of multiple antiphospholipid antibodies (aPL) was associated with APO overall (OR 3.3,p= 0.05). IgG anti-cardiolipin during pregnancy resulted in a higher risk of preterm delivery (OR 6.8,p= 0.03). Hypocomplementaemia was associated with several APO, but only in the first pregnancies. We conclude that, despite the close follow-up provided, a majority of pregnancies resulted in >= 1 APO, but a few of them were severe. Our study confirms the importance of previous lupus nephritis as a main risk factor for APO in patients with SLE.

The complement system constitutes a crucial part of the innate immunity, mediating opsonization, lysis, inflammation, and elimination of potential pathogens. In general, there is an increased activity of the complement system during pregnancy, which is essential for maintaining the hosts defense and fetal survival. Unbalanced or excessive activation of the complement system in the placenta is associated with pregnancy complications, such as miscarriage, preeclampsia, and premature birth. Nonetheless, the actual clinical value of monitoring the activation of the complement system during pregnancy remains to be investigated. Unfortunately, normal reference values specifically for pregnant women are missing, and for umbilical cord blood (UCB), data on complement protein levels are scarce. Herein, complement protein analyses (C1q, C3, C4, C3d levels, and C3d/C3 ratio) were performed in plasma samples from 100 healthy, non-medicated and non-smoking pregnant women, collected during different trimesters and at the time of delivery. In addition, UCB was collected at all deliveries. Maternal plasma C1q and C3d/C3 ratio showed the highest mean values during the first trimester, whereas C3, C4, and C3d had rising values until delivery. We observed low levels of C1q and C4 as well as increased C3d and C3d/C3 ratio, particularly during the first trimester, as a sign of complement activation in some women. However, the reference limits of complement analyses applied for the general population appeared appropriate for the majority of the samples. As expected, the mean complement concentrations in UCB were much lower than in maternal plasma, due to the immature complement system in neonates.

Although several biomarkers are available to monitor the acute phase response, the short pentraxin C-reactive protein (CRP) is dominating in clinical practice. The long pentraxin 3 (PTX3) is structurally and functionally related to CRP, but not liver-derived. In addition, increased levels of PTX3 have been linked to preeclampsia. Reference intervals are usually based on healthy blood donors. Several physiological and immunological alterations occur during normal pregnancy with subsequent potential effects on blood analytes. Hence, this study aims to determine pregnancy-specific reference intervals for CRP and PTX3. Longitudinal clinical data and blood plasma samples from the 1(st), 2(nd) and 3(rd) trimester of 100 healthy, non-medicating, females aged 18-40 at the time-point of conception were available to us. High-sensitivity CRP measurements were performed by turbidimetry and enzyme-linked immunosorbent assay (ELISA) was used to quantify PTX3. CRP and PTX3 levels followed each other during the first two trimesters and both increased during the third trimester. CRP showed a median of 4.12 mg/L in the third trimester, and were significantly higher compared to the first (median 2.39 mg/L, p < 0.0001) and the second (median 2.44 mg/L, p=0.0006) trimesters. In the third trimester PTX3 levels reached a median of 7.70 mu g/L, and were significantly higher compared to the first (median 3.33 mu g/L, p < 0.0001) and the second (median 3.70 mu g/L, p < 0.0001) trimesters. Plasma albumin was inversely correlated with CRP (rho=-0.27, p < 0.0001), but not with PTX3. In conclusion, it is important to consider pregnancy-specific reference values as elevations of CRP and PTX3 during the later phase may occur in absence of infection.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer and its incidence is increasing. Preoperative diagnosis is warranted in order to avoid two-stage procedures that are associated with additional costs and higher radioactive iodine remnant uptake. In the setting of thyroid cancer, somatic BRAF V600E-mutations are highly specific for PTC and can be analyzed in aspirates from fine-needle aspiration cytology (FNAC). The gold standard to perform FNAC is ultrasound guidance. Here, we analyze whether adding BRAF V600E-mutation analysis could be of value in palpation-guided FNACs. A total of 430 consecutive patients were included. Ultrasound-guided FNACs were performed in 251 patients and 179 patients underwent palpation-guided FNACs. BRAF V600E-mutation analysis was performed using two methods, an allele-specific polymerase chain reaction (PCR) analyzed by capillary gel electrophoresis (PCR/Qiaxcel), and a droplet digital PCR (ddPCR) assay. A total of 80 patients underwent surgery, and histology revealed 25 patients to have PTC. Of the 25 PTCs, 23 (92%) showed a BRAF V600E-mutation. Both mutation analysis methods (PCR/Qiaxcel and ddPCR) produced concordant results. In the ultrasound-guided group, the preoperative diagnostic sensitivity of FNAC using the Bethesda classification alone was very high and additional BRAF V600E-mutation analysis added little to the preoperative diagnostic sensitivity. By contrast, in the palpation-guided group, by adding BRAF V600E-mutation analysis, eight instead of four patients were diagnosed of having PTC. This increase in the diagnostic sensitivity was statistically significant (p < 0.05). The costs per sample were as low as 62 USD (PCR/Qiaxcel and ddPCR) and 35 USD (PCR/Qiaxcel only). Ultrasound-guided FNAC should be aimed for when dealing with thyroid nodules. However, if palpation-guided FNAC cannot be avoided or may be required due to resource utilization, adding BRAF V600E-mutation analysis using the methods described in this study might significantly increase the proportion of preoperatively diagnosed PTCs. The additional costs can be considered very reasonable.

PurposeHemithyroidectomies are mainly performed for two indications, either therapeutically to relieve compression symptoms or diagnostically for suspicious nodule(s). In case of the latter, one could consider the approach to be rather extensive since the majority of patients have no symptoms and will have benign disease. The aim of this study is to investigate the complication rates of diagnostic hemithyroidectomy and to compare it with the complication rates of compressive symptoms hemithyroidectomy.MethodsData from patients who had undergone hemithyroidectomy either for compression symptoms or for excluding malignancy were extracted from a well-established Scandinavian quality register (SQRTPA). The following complications were analyzed: bleedings, wound infections, and paresis of the recurrent laryngeal nerve (RLN). Risk factors for these complications were examined by univariable and multivariable logistic regression.ResultsA total of 9677 patients were included, 3871 (40%) underwent surgery to exclude malignancy and 5806 (60%) due to compression symptoms. In the multivariable analysis, the totally excised thyroid weight was an independent risk factor for bleeding. Permanent (6-12 months after the operation) RLN paresis were less common in the excluding malignancy group (p = 0.03).ConclusionA range of factors interfere and contribute to bleeding, wound infections, and RLN paresis after hemithyroidectomy. In this observational study based on a Scandinavian quality register, the indication "excluding malignancy" for hemithyroidectomy is associated with less permanent RLN paresis than the indication "compression symptoms." Thus, patients undergoing diagnostic hemithyroidectomy can be reassured that this procedure is a safe surgical procedure and does not entail an unjustified risk.

The aim was to explore patients' early experiences of symptoms after hemithyroidectomy and how these symptoms influenced their daily lives. An inductive explorative qualitative research design was performed. Sixteen patients from two hospitals were interviewed between two-three weeks after the surgery. All the patients experienced compression symptoms before the surgery. The study was analyzed with conventional manifest content analysis. The inductive analysis yielded two main categories and one subcategory. The two main categories were: Early postoperative symptoms that caused disadvantage in daily life and Early postoperative symptoms and coping strategies. The subcategory was: Early postoperative experiences of concerns about the future. Key points: 1. Patients experienced early postoperative symptoms that affected their lives in multiple levels, making them develop coping strategies and awaking concerns about remaining symptoms in the future. 2. The effect of hemithyroidectomy influenced patients' daily life in the early postoperative phase considerably. 3. The study shows that tailored preoperative patient information is important. The findings may guide professionals to tailored preoperative information to optimize the care for this patient group.

Aim The purpose of this study was to explore the utility of two single-item self-report (SR) questions to assess physical inactivity in patients with heart failure (HF). Methods and results This is a cross-sectional study using data from 106 patients with HF equipped with accelerometers for 1 week each. Two SR items relating to physical activity were also collected. Correlations between accelerometer activity counts and the SR items were analysed. Patients were classified as physically active or inactive on the basis of accelerometer counts, and the SR items were used to try to predict that classification. Finally, patients were classified as having high self-reported physical activity or low self-reported physical activity, on the basis of the SR items, and the resulting groups were analysed for differences in actual physical activity. There were significant but weak correlations between the SR items and accelerometer counts: rho = 0.24, P = 0.016 for SR1 and rho = 0.21, P = 0.033 for SR2. Using SR items to predict whether a patient was physically active or inactive produced an area under the curve of 0.62 for SR1, with a specificity of 92% and a sensitivity of 30%. When dividing patients into groups on the basis of SR1, there was a significant difference of 1583 steps per day, or 49% more steps in the high self-reported physical activity group (P < 0.001). Conclusions There might be utility in the single SR question for high-specificity screening of large populations to identify physically inactive patients in order to assign therapeutic interventions efficiently where resources are limited.

BackgroundPhysical inactivity and a sedentary lifestyle are common among people with heart failure (HF), which may lead to worse prognosis. On an already existing mHealth platform, we developed a novel tool called the Activity coach, aimed at increasing physical activity. The aim of this study was to evaluate the usability of the Activity coach and assess feasibility of outcome measures for a future efficacy trial.MethodsA mixed-methods design was used to collect data. People with a HF diagnosis were recruited to use the Activity coach for four weeks. The Activity coach educates the user about physical activity, provides means of registering daily physical activity and helps the user to set goals for the next week. The usability was assessed by analysing system user logs for adherence, reported technical issues and by interviews about user experiences. Outcome measures assessed for feasibility were objective physical activity as measured by an accelerometer, and subjective goal attainment. Progression criteria for the usability assessment and for the proposed outcomes, were described prospectively.ResultsTen people with HF were recruited, aged 56 to 78 with median age 72. Data from nine of the ten study participants were included in the analyses. Usability: The Activity coach was used 61% of the time and during the first week two study participants called to seek technical support. The Activity coach was found to be intuitive and easy to use by all study participants. An increased motivation to be more physically active was reported by six of the nine study participants. However, in spite of feeling motivated, four reported that their habits or behaviours had not been affected by the Activity coach. Feasibility: Data was successfully stored in the deployed hardware as intended and the accelerometers were used enough, for the data to be analysable. One finding was that the subjective outcome goal attainment, was challenging to collect. A proposed mitigator for this is to use pre-defined goals in future studies, as opposed to having the study participants be completely free to formulate the goals themselves.ConclusionsIt was confirmed that the Activity coach was easy to use. Furthermore, it might stimulate increased physical activity in a population of people with HF, who are physically inactive. The outcomes investigated seem feasible to include in a future efficacy trial.Trial registrationClinicalTrials.gov identifier: NCT05235763. Date of first registration: 11/02/2022.

The K(V)7.4 and K(V)7.5 subtypes of voltage -gated potassium channels play a role in important physiological processes such as sound amplification in the cochlea and adjusting vascular smooth muscle tone. Therefore, the mechanisms that regulate K(V)7.4 and K(V)7.5 channel function are of interest. Here, we study the effect of polyunsaturated fatty acids (PUFAs) on human K(V)7.4 and KV7.5 channels expressed in Xenopus oocytes. We report that PUFAs facilitate activation of hK(V)7.5 by shifting the V50 of the conductance versus voltage (G(V)) curve toward more negative voltages. This response depends on the head group charge, as an uncharged PUFA analogue has no effect and a positively charged PUFA analogue induces positive V-50 shifts. In contrast, PUFAs inhibit activation of hK(V)7.4 by shifting V-50 toward more positive voltages. No effect on V-50 of hK(V)7.4 is observed by an uncharged or a positively charged PUFA analogue. Thus, the hK(V)7.5 channels response to PUFAs is analogous to the one previously observed in hK(V)7.1-7.3 channels, whereas the hK(V)7.4 channel response is opposite, revealing subtype-specific responses to PUFAs. We identify a unique inner PUFA interaction site in the voltage-sensing domain of hKV7.4 underlying the PUFA response, revealing an unconventional mechanism of modulation of hK(V)7.4 by PUFAs.

Background and PurposeCannabidiol (CBD) is used clinically as an anticonvulsant. Its precise mechanism of action has remained unclear. CBD was recently demonstrated to enhance the activity of the neuronal K(V)7.2/7.3 channel, which may be one important contributor to CBD anticonvulsant effect. Curiously, CBD inhibits the closely related cardiac K(V)7.1/KCNE1 channel. Whether and how CBD affects other K(V)7 subtypes remains uninvestigated and the CBD interaction sites mediating these diverse effects remain unknown. Experimental ApproachHere, we used electrophysiology, molecular dynamics simulations, molecular docking and site-directed mutagenesis to address these questions. Key ResultsWe found that CBD modulates the activity of all human K(V)7 subtypes and that the effects are subtype dependent. CBD enhanced the activity of K(V)7.2-7.5 subtypes, seen as a V-50 shift towards more negative voltages or increased maximum conductance. In contrast, CBD inhibited the K(V)7.1 and K(V)7.1/KCNE1 channels, seen as a V-50 shift towards more positive voltages and reduced conductance. In K(V)7.2 and K(V)7.4, we propose a CBD interaction site at the subunit interface in the pore domain that overlaps with the interaction site of other compounds, notably the anticonvulsant retigabine. However, CBD relies on other residues for its effects than the conserved tryptophan that is critical for retigabine effects. We propose a similar, though not identical CBD site in K(V)7.1, with a non-conserved phenylalanine being important. Conclusions and ImplicationsWe identify novel targets of CBD, contributing to a better understanding of CBD clinical effects and provide mechanistic insights into how CBD modulates different K(V)7 subtypes.

The amyloid beta (A beta) peptide has a central role in Alzheimer's disease (AD) pathology. The peptide length can vary between 37 and 49 amino acids, with A beta 1-42 being considered the most disease-related length. However, A beta 1-40 is also found in A beta plaques and has shown to form intertwined fibrils with A beta 1-42. The peptides have previously also shown to form different fibril conformations, proposed to be related to disease phenotype. To conduct more representative in vitro experiments, it is vital to uncover the impact of different fibril conformations on neurons. Hence, we fibrillized different A beta 1-40:42 ratios in concentrations of 100:0, 90:10, 75:25, 50:50, 25:75, 10:90 and 0:100 for either 24 h (early fibrils) or 7 days (aged fibrils). These were then characterized based on fibril width, LCO-staining and antibody-staining. We further challenged differentiated neuronal-like SH-SY5Y human cells with the different fibrils and measured A beta content, cytotoxicity and autophagy function at three different time-points: 3, 24, and 72 h. Our results revealed that both A beta 1-40:42 ratio and fibril maturation affect conformation of fibrils. We further show the impact of these conformation changes on the affinity to commonly used A beta antibodies, primarily affecting A beta 1-40 rich aggregates. In addition, we demonstrate uptake of the aggregates by neuronally differentiated human cells, where aggregates with higher A beta 1-42 ratios generally caused higher cellular levels of A beta. These differences in A beta abundance did not cause changes in cytotoxicity nor in autophagy activation. Our results show the importance to consider conformational differences of A beta fibrils, as this can have fundamental impact on A beta antibody detection. Overall, these insights underline the need for further exploration of the impact of conformationally different fibrils and the need to reliably produce disease relevant A beta aggregates.image

Alzheimer's disease (AD) progression is closely linked to the propagation of pathological Amyloid beta (A beta), a process increasingly understood to involve extracellular vesicles (EVs), namely exosomes. The specifics of A beta packaging into exosomes remain elusive, although evidence suggests an ESCRT (Endosomal Sorting Complex Required for Transport)-independent origin to be responsible in spreading of AD pathogenesis. Intriguingly, PrPC, known to influence exosome abundance and bind oligomeric A beta (oA beta), can be released in exosomes via both ESCRT-dependent and ESCRT-independent pathways, raising questions about its role in oA beta trafficking. Thus, we quantified A beta levels within EVs, cell medium, and intracellularly, alongside exosome biogenesis-related proteins, following deletion or overexpression of PrPC. The same parameters were also evaluated in the presence of specific exosome inhibitors, namely Manumycin A and GW4869. Our results revealed that deletion of PrPC increases intracellular A beta accumulation and amplifies EV abundance, alongside significant changes in cellular levels of exosome biogenesis-related proteins Vps25, Chmp2a, and Rab31. In contrast, cellular expression of PrPC did not alter exosomal A beta levels. This highlights PrPC's influence on exosome biogenesis, albeit not in direct A beta packaging. Additionally, our data confirm the ESCRT-independent exosome release of A beta and we show a direct reduction in Chmp2a levels upon oA beta challenge. Furthermore, inhibition of opposite exosome biogenesis pathway resulted in opposite cellular PrPC levels. In conclusion, our findings highlight the intricate relationship between PrPC, exosome biogenesis, and A beta release. Specifically, they underscore PrPC's critical role in modulating exosome-associated proteins, EV abundance, and cellular A beta levels, thereby reinforcing its involvement in AD pathogenesis.Graphical abstractThere are two main exosome biogenesis pathways: ESCRT dependent and ESCRT independent. In this study, we explored the effect of the cellular prion protein (PrPC) on the release of Amyloid beta via exosomes. Our findings demonstrate that Amyloid beta mainly is released via an ESCRT-independent pathway, independent of PrPC. However, lack of PrPC resulted in upregulation of the ESCRT-dependent proteins Tsg101 and VPS25, a decrease in Chmp2a, and an overall increase in extracellular vesicles. Lack of PrPC also caused an accumulation of cellular, but not exosomal, Amyloid beta.

Background: Lifelong vitamin and mineral supplementation is recommended after bariatric surgery to prevent nutritional deficiencies, but it is not clear to which extent patients adhere to the recommended medication. The aim of this study was to assess adherence to supplementation. Additionally, we assessed predictors of low adherence and biochemical deficiencies.Methods: 263 adults were followed two years post bariatric surgery (89.4 % Roux-en-Y gastric bypass, 10.6 % sleeve gastrectomy) regarding adherence to calcium-vitamin D, vitamin B12 and iron. Pharmacy refill data was used to objectively capture adherence-rate. Predictors of low adherence were assessed via questionnaires and medical records. Blood sampling was performed preoperatively, and 1-and 2-years post-surgery.Results: About 60 % of the study participants had high adherence-rate (>= 80 %) two years post-surgery, but a significant proportion had discontinued the intended lifelong supplementation: 15 % for calcium-vitamin D and 12 % for B12. Biochemical deficiencies were uncommon two years after surgery, both in adherent and non -persistent subjects, except for a 10 % prevalence of anemia. Younger age, experience of side effects, mental health problems and no regular use of medication before surgery, were factors associated with low adherence.Conclusion: Substantial variation existed in adherence to supplementation regimens after bariatric surgery during the first two years after bariatric surgery, but biochemical deficiencies were rare. The results indicate need for tailored follow-up and strategies to support long-term persistence.

IntroductionPoor adherence to recommended vitamin and mineral supplementation after bariatric surgery is common and challenging for healthcare professionals to identify. There are several questionnaires for self-reporting of adherence to chronic medication, but none has so far been evaluated for assessment of adherence to vitamin and mineral supplementation after bariatric surgery. The aim of this study was to assess the accuracy of the 5-item Medication Adherence Report Scale (MARS-5) in measuring adherence to vitamin and mineral supplementation post bariatric surgery (gastric bypass or sleeve gastrectomy).MethodThe psychometric properties of MARS-5 for vitamin and mineral supplementation were validated in two cohorts: one at 1 year post bariatric surgery (n = 120) and the other at 2 years post-surgery (n = 211). MARS-5 was compared to pharmacy refill data for vitamin B12 and combined calcium/vitamin D as reference.ResultsCorrelation analyses demonstrated that the MARS-5 had acceptable validity compared to objectively measured adherence rates from pharmacy refill data (calculated as continuous, multiple-interval measures of medication availability/gaps-coefficient ranged from 0.49 to 0.54). Internal reliability (Cronbach's alpha) was high: 0.81 and 0.95, respectively. There was a clear ceiling effect where one out of three had a maximum score on MARS-5.ConclusionMARS-5 demonstrated acceptable psychometric properties for assessment of adherence to vitamin and mineral supplementation post bariatric surgery.

Objective This trial evaluated a smartphone applications effectiveness in improving adherence to vitamin and mineral supplementation postoperatively. Methods This study was a randomized controlled trial comprising 140 patients undergoing bariatric surgery (gastric bypass or sleeve gastrectomy). Participants were randomized 1:1 to the 12-week intervention, using the smartphone application PromMera, or to standard care. The primary end point was adherence to vitamin and mineral supplementation. Results Initiation rate and overall adherence to supplementation were high in both groups. Change in objectively measured adherence rate from before the intervention to 1 year post surgery, measured with pharmacy refill data, did not differ between groups for vitamin B-12 (-9.6% [SD = 27%] vs. -9.3% [SD = 30%]; p = 0.48) or calcium/vitamin D (-12.3% [SD = 29%] vs. -11.5% [SD = 32%]; p = 0.44). A modest effect on the secondary end point (subjectively measured adherence, using the Medication Adherence Report Scale-5) was seen immediately after the intervention (intervention group 0.00 [SD = 1.3] vs. control group -1.2 [SD = 3.5]; p = 0.021), but this effect did not persist 1 year post surgery. No differences were detected in the prevalence of biochemical deficiencies. Conclusions The use of the smartphone application PromMera did not obtain a lasting improvement in adherence to vitamin and mineral supplementation 1 year post bariatric surgery.