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Chronic, non-healing, dermal wounds form a worldwide medical problem with limited and inadequate treatment options and high societal burden and costs. With the advent of regenerative therapies exploiting extracellular matrix (ECM) components, its efficacy to augment wound healing is to be explored. This systematic review was performed to assess and compare the current therapeutic efficacy of ECM hydrogels on dermal wound healing. The electronic databases of Embase, Medline Ovid, and Cochrane Central were searched for in vivo and clinical studies on the therapeutic effect of ECM-composed hydrogels on dermal wound healing (April 13, 2021). Two reviewers selected studies independently. Studies were assessed based on ECM content, ECM hydrogel composition, additives, and wound healing outcomes, such as wound size, angiogenesis, and complications. Of the 2102 publications, 9 rodent-based studies were included while clinical studies were not published at the time of the search. Procedures to decellularize tissue or cultured cells and subsequently generate hydrogels were highly variable and in demand of standardization. ECM hydrogels with or without additives reduced wound size and also seem to enhance angiogenesis. Serious complications were not reported. To date, preclinical studies preclude to draw firm conclusions on the efficacy and working mechanism of ECM-derived hydrogels on dermal wound healing. The use of ECM hydrogels can be considered safe. Standardization of decellularization protocols and implementation of quality and cytotoxicity controls will enable obtaining a generic and comparable ECM product. Impact statementExtracellular matrix (ECM)-based hydrogels are biocompatible and harbor growth factors that can instruct tissue healing. Their application is a novelty in (pre)clinical wound healing treatment. This systematic review provides an overview of the current evidence for ECM hydrogels in enhancing wound healing and an extensive overview of the decellularization procedures used. Lastly, challenges and future directions to standardize decellularization procedures and implement quality controls are proposed.

Hutton et al. (2016) argued that computational hydrology can only be a proper science if the hydrological community makes sure that hydrological model studies are executed and presented in a reproducible manner. Hut, Drost and van de Giesen replied that to achieve this hydrologists should not “re-invent the water wheel” but rather use existing technology from other fields (such as containers and ESMValTool) and open interfaces (such as the Basic Model Interface, BMI) to do their computational science (Hut et al., 2017). With this paper and the associated release of the eWaterCycle platform and software package (available on Zenodo: https://doi.org/10.5281/zenodo.5119389, Verhoeven et al., 2022), we are putting our money where our mouth is and providing the hydrological community with a “FAIR by design” (FAIR meaning findable, accessible, interoperable, and reproducible) platform to do science. The eWaterCycle platform separates the experiments done on the model from the model code. In eWaterCycle, hydrological models are accessed through a common interface (BMI) in Python and run inside of software containers. In this way all models are accessed in a similar manner facilitating easy switching of models, model comparison and model coupling. Currently the following models and model suites are available through eWaterCycle: PCR-GLOBWB 2.0, wflow, Hype, LISFLOOD, MARRMoT, and WALRUS While these models are written in different programming languages they can all be run and interacted with from the Jupyter notebook environment within eWaterCycle. Furthermore, the pre-processing of input data for these models has been streamlined by making use of ESMValTool. Forcing for the models available in eWaterCycle from well-known datasets such as ERA5 can be generated with a single line of code. To illustrate the type of research that eWaterCycle facilitates, this paper includes five case studies: from a simple “hello world” where only a hydrograph is generated to a complex coupling of models in different languages. In this paper we stipulate the design choices made in building eWaterCycle and provide all the technical details to understand and work with the platform. For system administrators who want to install eWaterCycle on their infrastructure we offer a separate installation guide. For computational hydrologists that want to work with eWaterCycle we also provide a video explaining the platform from a user point of view (https://youtu.be/eE75dtIJ1lk, last access: 28 June 2022)​​​​​​​. With the eWaterCycle platform we are providing the hydrological community with a platform to conduct their research that is fully compatible with the principles of both Open Science and FAIR science.

Background: Many treatments aim to slow down or reverse the visible signs of skin aging and thereby improve skin quality. Measurement devices are frequently employed to measure the effects of these treatments to improve skin quality, for example, skin elasticity, color, and texture. However, it remains unknown which of these devices is most reliable and valid. Materials and methods: MEDLINE, Embase, Cochrane Central, Web of Science, and Google Scholar databases were searched. Instruments were scored on reporting construct validity by means of convergent validity, interobserver, intraobserver, and interinstrument reliability. Results: For the evaluation of skin color, 11 studies were included describing 16 measurement devices, analyzing 3172 subjects. The most reliable device for skin color assessment is the Minolta Chromameter CR-300 due to good interobserver, intraobserver, and interinstrument reliability. For skin elasticity, seven studies assessed nine types of devices analyzing 290 subjects in total. No intra and interobserver reliability was reported. Skin texture was assessed in two studies evaluating 72 subjects using three different types of measurement devices. The PRIMOS device reported excellent intra and interobserver reliability. None of the included reviewed devices could be determined to be valid based on construct validity. Conclusion: The most reliable devices to evaluate skin color and texture in ordinary skin were, respectively, the Minolta Chromameter and PRIMOS. No reliable device is available to measure skin elasticity in ordinary skin and none of the included devices could be determined to be designated as valid.

Background Many prognostic models for Hepatocellular Carcinoma (HCC) have been developed to inform patients and doctors about individual prognosis. Previous reviews of these models were qualitative and did not assess performance at external validation. We assessed the performance of prognostic models for HCC and set a benchmark for biomarker studies. Methods All externally validated models predicting survival for patients with resected HCC were systematically reviewed. After selection, we extracted descriptive statistics and aggregated c-indices using meta-analysis. Results Thirty-eight validated prognostic models were included. Models used on average 7 (IQR:4–9) prognostic factors. Tumor size, tumor number, and vascular invasion were almost always included. Alpha-fetoprotein (AFP) was commonly incorporated since 2007. Recently, the more subjective items ascites and encephalopathy have been dropped. Eight established models performed poor to moderate at external validation, with a pooled C-index below 0.7; including the Barcelona Clinic Liver Cancer (BCLC) system, the American Joint Committee on Cancer (AJCC) 7th edition, the Cancer of the Liver Italian (CLIP) Program, and the Japan Integrated Staging (JIS) score. Out of 24 prognostic models predicting OS, only 6 (25%) had good performance at external validation with pooled C-indices above 0.7; the Li-post (0.77), Li-OS (0.74), Yang-pre (0.74), Yang-post (0.76), Shanghai-score (0.70), and Wang-nomogram (0.71). Models improved over time, but overall performance and study quality remained low. Conclusions Six validated prognostic models demonstrated good performance for predicting survival after resection of HCC. These models can guide patients and doctors and are a benchmark for future models incorporating novel biomarkers.

BACKGROUND: One of the most popular short-scar rhytidectomy techniques used nowadays is the minimal access cranial suspension (MACS) lift developed by Tonnard and Vaerpele. The technique uses purse-string sutures in combination with limited skin undermining to obtain a clear vertical tissue repositioning. Since its introduction, the technique has extensively been described and used around the world by facial plastic surgeons. Now, 18 years after its introduction, a systematic review concerning the results and complications of the MACS lift is presented to establish its current position in facial rejuvenation. METHODS: The MEDLINE, Embase, Cochrane Central, and Google Scholar databases were searched for studies evaluating the MACS lift (June 10, 2020). Outcomes of interest were long-term effect, satisfaction, and complications of the MACS lifting as determined by the patient and/or surgeon. RESULTS: Six studies were included, with 739 patients treated with the MACS lift in total. No major complications were reported, four studies did report on the occurrence of minor complications. All of the six studies reported relatively high levels of satisfaction. Three studies reported a shorter procedural duration for the MACS lift compared with the conventional facelift. In three of the six included studies, the level of evidence was low. The effect on neck rejuvenation is limited. CONCLUSION: The MACS lift can be considered a minimally invasive facelift procedure with a relatively low complication rate. The procedure, often combined with additional procedures, results in evident patient and/or surgeon satisfaction. To obtain a better desired result on an aged neck area, additional procedures are warranted.

Objective: Blood pressure fluctuates during diastole to create a dicrotic wave but the mechanistic origin remains poorly understood. We sought to investigate the characteristics and determinants of diastolic pressure and flow fluctuations with a focus on stiffness gradients between the central aorta and peripheral arteries. Methods: Using applanation tonometry and duplex ultrasound, pulse waveforms were recorded on the femoral artery in 592 patients (age: 55=14years) to estimate the diastolic pressure fluctuation as a residual wave against the mono-exponential decay and the diastolic flow fluctuation as a bidirectional (forward and reverse) velocity wave. The radial, carotid, and dorsalis pedis pressures were also recorded to measure the peripheral/aortic pulse pressure (PP) and pulse wave velocity (PWV) ratios. Results: There were close resemblances between the femoral pressure and flow fluctuation waveforms. The pressure and flow fluctuations were mutually correlated in relative amplitude as indexed to the total pulse height (r=0.63), and the former temporally followed the latter. In multivariate-adjusted models, higher peripheral/aortic PP and PWV ratios were independently associated with greater pressure and flow fluctuation indices (P

Rationale: The ability of peripheral blood biomarkers to assess COPD risk and progression is unknown. Genetics and gene expression may capture important aspects of COPD-related biology that predict...

Background: Maladaptive ER stress signaling in diabetic kidney disease (DKD) is linked to increased glomerular and tubular expression of the cell death-promoting transcription factor C/EBP homologous protein (CHOP). We determined whether therapy with locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) targeting CHOP ameliorates experimental DKD. Methods: Following an in vivo dose-escalation study, we determined the efficacy of CHOPASO in the early and later stages of experimental DKD (8- or 16-week-old db/db mice, respectively) alone or in combination with an angiotensin-converting enzyme inhibitor (ACEi). Renal functional parameters and morphological analyses were used to determine the effects. Renal gene expression profiling was conducted to determine differentially regulated genes and pathways. Several human CHOP-ASOs were tested in hyperglycemia-exposed human kidney cells. Results: CHOP-ASOs efficiently reduced renal CHOP expression in diabetic mice and reduced markers of DKD at early and late stages. Early combined intervention (CHOP-ASO and ACEi) efficiently prevented interstitial damage. At the later timepoint, the combined treatment reduced indices of both glomerular and tubular damage more efficiently than either intervention alone. A significantly larger number of genes and disease pathways were affected by CHOP-ASO, including reduced Slc5a2 (sodium-glucose transport protein 2) and PROM1 (CD133). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and prevented cell death of human kidney cells in vitro Conclusions: The ASO-based approach efficiently reduced renal CHOP expression in a diabetic mouse model, providing an additional benefit to an ACEi in particular at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental DKD.

Data-based methods are capable to monitor machine components. Approaches for semi-supervised anomaly detection are trained using sensor data that describe the normal state of machine components. Thus, such approaches are interesting for industrial practice, since sensor data do not have to be labeled in a time-consuming and costly way. In this work, an ensemble approach for semi-supervised anomaly detection is used to detect anomalies. It is shown that the ensemble approach is suitable for condition monitoring of ball screws. For the evaluation of the approach, a data set of a regular test cycle of a ball screw from automotive industry is used.

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. Significance: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer. See related commentary by Letai, p. 290. This article is highlighted in the In This Issue feature, p. 275

Background: The purpose of this study is to evaluate survivorship and outcomes of high-activity patients compared to low-activity patients after total hip arthroplasty. Methods: A retrospective review identified 2002 patients (2532 hip) that underwent a primary total hip arthroplasty with vitamin E–infused highly crosslinked polyethylene liner. Patients were divided into 2 groups based on their University of California Los Angeles (UCLA) activity level: low activity (LA) (UCLA ≤5) and high activity (HA) (UCLA ≥6). Outcomes included Harris Hip Score, UCLA activity score, and reoperations. A multivariate nominal regression analysis was performed to evaluate the significance of postoperative activity level on survivorship. Results: The mean follow-up duration was 4.5 years (range, 0.3 to 9.9 years). HA group had significantly higher improvements in Harris Hip Score (HHS) (P < .001) and UCLA activity score (P < .001). Aseptic revisions were performed in 2.1% of the LA group and in 0.4% hips of the HA group (P < .001). After controlling for age, gender, preoperative pain, HHS, and body mass index, a higher postoperative activity level remained a significant factor for improved aseptic survivorship with an odds ratio of 4.9 (95% confidence interval, 1.1 to 21.2, P = .03). The all-cause 5-year survivorship was 99% for the HA group and 96% to for the LA group (P < .001). The aseptic 5-year survivorship was 99.6% for the HA group and 98% for the LA group (P < .001). Conclusions: This study found that a higher activity level after primary THA was not deleterious to survivorship at short to midterm follow-up with modern implants.

Introduction: Stereotactic ablative radiotherapy (SABR) can achieve good local control for metastatic adrenal lesions. Magnetic resonance (MR)-guidance with daily on-table plan adaptation can augment the delivery of SABR with greater dose certainty. The goal of this study was to quantify the potential clinical benefit MR-guided daily-adaptive adrenal SABR using the normal tissue complication probability (NTCP) framework. Methods: Patients treated with adrenal MR-guided SABR at a single institution were retrospectively reviewed. Lyman-Kutcher-Burman NTCP models were used to calculate the NTCP of upper abdominal organs-at-risk (OARs) at simulation and both before and after daily on-table plan adaptation. Differences in OAR NTCPs were assessed using signed-rank tests. Potential predictors of the benefits of adaptation were assessed by linear regression. Results: Fifty-two adrenal MR-guided SABR courses were analyzed. The baseline simulation plan underestimated the absolute stomach NTCP by 10.0% on average (95% confidence interval: 4.7–15.2%, p < 0.001). Daily on-table adaptation lowered absolute NTCP by 8.7% (4.2–13.2%, p < 0.001). The most significant predictor of the benefits of adaptation was lesion laterality (p = 0.018), with left-sided lesions benefitting more (13.3% [6.3–20.4%], p < 0.001) than right-sided lesions (2.1% [−1.6–5.7%], p = 0.25). Sensitivity analyses did not change the statistical significance of the findings. Conclusion: NTCP analysis revealed that patients with left adrenal tumors were more likely to benefit from MR-guided daily on-table adaptive SABR using current dose/fractionation regimens due to reductions in predicted gastric toxicity. Right-sided adrenal lesions may be considered for dose escalation due to low predicted NTCP.

This study analyzes self–other agreement in leadership communication and its relation to knowledge integration across the artistic, technical and administration areas in theaters. Results of a cros...

BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV(1) to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV(1) and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV(1) and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

Background Lipofilling has become popular as a treatment to improve aging-related skin characteristics (eg, wrinkles, pigmentation spots, pores, or rosacea). Different additives such as platelet-rich plasma (PRP) or stromal vascular fraction (SVF) have been combined with lipofilling to increase the therapeutic effect of adipose-derived stromal cells (ASCs). Objectives The aim of this study was to examine the hypothesis that mechanically isolated SVF augments the therapeutic effect of PRP-supplemented lipofilling to improve facial skin quality. Methods This prospective, double-blind, placebo-controlled, randomized trial was conducted between 2016 and 2019. In total, 28 female subjects were enrolled; 25 completed the follow-up. All patients received PRP-supplemented lipofilling with either mechanically isolated SVF or saline. SVF was isolated by fractionation of adipose tissue (tSVF). Results were evaluated by changes in skin elasticity and transepidermal water loss, changes in skin-aging-related features, ie, superficial spots, wrinkles, skin texture, pores, vascularity, and pigmentation, as well as patient satisfaction (FACE-Q), recovery, and number of complications up to 1 year postoperative. Results The addition of tSVF to PRP-supplemented lipofilling did not improve skin elasticity, transepidermal water loss, or skin-aging-related features. No improvement in patient satisfaction with overall facial appearance or facial skin quality was seen when tSVF was added to PRP-supplemented lipofilling. Conclusions In comparison to PRP-supplemented lipofilling, PRP-supplemented lipofilling combined with tSVF does not improve facial skin quality or patient satisfaction in a healthy population. PRP-supplemented lipofilling combined with tSVF can be considered a safe procedure. Level of Evidence: 2

Background Total knee arthroplasty (TKA) is a common treatment for end-stage knee osteoarthritis but is associated with increased complication rates compared with unicompartmental knee arthroplasty (UKA). UKA offers better functional outcomes but is associated with a higher risk of revision. The purpose of this study was to apply good-practice, stated-preference methods to quantify patient preferences for benefit-risk tradeoffs associated with arthroplasty treatments for end-stage knee osteoarthritis. Methods A discrete-choice experiment was developed with the following attributes: chance of complications, functional ability, awareness of the knee implant, and chance of needing another operation within 10 years. Patients included those aged 40 to 80 years with knee osteoarthritis. A pivot design filtered respondents into 1 of 2 surveys on the basis of self-reported functional ability (good compared with fair or poor) as measured by the Oxford Knee Score. Treatment-preference data were collected, and relative attribute-importance weights were estimated. Results Two hundred and fifty-eight completed survey instruments from 92 males and 164 females were analyzed, with 72 respondents in the good-function cohort and 186 in the fair/poor-function cohort. Patients placed the greatest value or relative importance on serious complications and rates of revision in both cohorts. Preference weights did not vary between cohorts for any attribute. In the good-function cohort, 42% of respondents chose TKA and 58% chose UKA. In the fair/poor-function cohort, 54% chose TKA and 46% chose UKA. Conclusions Patient preferences for various treatment attributes varied among patients in a knee osteoarthritis population. Complication and revision rates were the most important factors to patients, suggesting that physicians should focus on these areas when discussing treatments. The proportion of patients who chose UKA suggests that the current trend of increased UKA utilization is aligned with patient preferences. Clinical relevance Systematic elicitation of patient preferences for knee arthroplasty procedures, which lays out evidence-based risks and benefits of different treatments, indicates a larger subset of the knee osteoarthritis population may prefer UKA than would be suggested by the current rates of utilization of the procedure. Arthroplasty treatment should align with patient preferences and eligibility criteria to better deliver patient-centered care.

Purpose of review The trend in the perioperative management of patients having orthopedic surgery in the ambulatory setting emphasizes time-efficiency and rapid turnovers. Anesthetic techniques and management continue to evolve to increase efficiency and decrease time spent in recovery. Recent findings Minimizing time patients spend in phase 1 recovery or bypassing phase 1 altogether, known as fast-tracking, has become an important goal in containing costs in high turnover, ambulatory settings. Anesthetic techniques, particularly implementation of regional anesthesia and multimodal analgesia, have evolved to maximize efficiency. Summary Anesthetic goals in the setting of high-turnover orthopedic surgery include effective multimodal analgesia, decreasing monotherapy with opioids, and patient education. Regional anesthesia as part of a multimodal analgesic regimen is increasingly used in ambulatory surgery fast-tracking protocols.

Background Autologous lipofilling is an emerging procedure to treat and possibly reverse dermal scars and to reduce scar-related pain, but its efficacy and mechanisms are poorly understood. Objectives The aim of this study was to test the hypothesis that repeated lipografts reverse dermal scars by reinitiation of wound healing. Methods In a prospective, non-placebo-controlled clinical study, 27 adult patients with symptomatic scars were given 2 lipofilling treatments at 3-month intervals. As primary outcome, clinical effects were measured with the Patient and Observer Scar Assessment Scale (POSAS). Scar biopsies were taken before and after treatments to assess scar remodeling at a cellular level. Results Twenty patients completed the study. Patients’ scars improved after lipofilling. The total POSAS scores (combined patient and observer scores) decreased from 73.2 [14.7] points (mean [standard deviation]) pretreatment to 46.1 [14.0] and 32.3 [13.2] points after the first and second lipofilling treatment, respectively. Patient POSAS scores decreased from 37.3 [8.8] points to 27.2 [11.3] and 21.1 [11.4] points, whereas observer POSAS scores decreased from 35.9 [9.5] points to 18.9 [6.0] and 11.3 [4.5] points after the first and second treatment, respectively. After each lipofilling treatment, T lymphocytes, mast cells, and M2 macrophages had invaded scar tissue and were associated with increased vascularization. In addition, the scar-associated epidermis showed an increase in epidermal cell proliferation to levels similar to that normal in skin. Moreover, lipofilling treatment caused normalization of the extracellular matrix organization towards that of normal skin. Conclusions Autologous lipofilling improves the clinical outcome of dermal scars through the induction of a pro-regenerative immune response, increased vascularization, and epidermal proliferation and remodeling of scar tissue extracellular matrix. Level of Evidence: 4

Background This study aimed to assess the performance of the pre- and postoperative early recurrence after surgery for liver tumor (ERASL) models at external validation. Prediction of early hepatocellular carcinoma (HCC) recurrence after resection is important for individualized surgical management. Recently, the preoperative (ERASL-pre) and postoperative (ERASL-post) risk models were proposed based on patients from Hong Kong. These models showed good performance although they have not been validated to date by an independent research group. Methods This international cohort study included 279 patients from the Netherlands and 392 patients from Japan. The patients underwent first-time resection and showed a diagnosis of HCC on pathology. Performance was assessed according to discrimination (concordance [C] statistic) and calibration (correspondence between observed and predicted risk) with recalibration in a Weibull model. Results The discriminatory power of both models was lower in the Netherlands than in Japan (C statistic, 0.57 [95% confidence interval {CI} 0.52–0.62] vs 0.69 [95% CI 0.65–0.73] for the ERASL-pre model and 0.62 [95% CI 0.57–0.67] vs 0.70 [95% CI 0.66–0.74] for the ERASL-post model), whereas their prognostic profiles were similar. The predictions of the ERASL models were systematically too optimistic for both cohorts. Recalibrated ERASL models improved local applicability for both cohorts. Conclusions The discrimination of ERASL models was poorer for the Western patients than for the Japanese patients, who showed good performance. Recalibration of the models was performed, which improved the accuracy of predictions. However, in general, a model that explains the East–West difference or one tailored to Western patients still needs to be developed.

Introduction: We hypothesized that subclinical disruption in blood pressure (BP) dynamics, captured by lower complexity and higher variability, may contribute to dementia risk, above and beyond BP levels. Methods: This prospective cohort study followed 1835 older adults from 1997 to 2016, with BP complexity quantified by sample entropy and BP variability quantified by coefficient of variation using beat-to-beat BP measured at baseline. Results: Three hundred thirty-four participants developed dementia over 20 years. Reduced systolic BP (SBP) complexity was associated with a higher risk of dementia (hazard ratio [HR] comparing extreme quintiles: 1.55; 95% confidence interval [CI]: 1.09-2.20). Higher SBP variability was also associated with a higher risk of dementia (HR comparing extreme quintiles: 1.57; 95% CI: 1.11-2.22. These findings were observed after adjusting for age, sex, apolipoprotein E (APOE) genotype, mean SBP, and other confounding factors. Discussions: Our findings suggest that lower complexity and higher variability of beat-to-beat SBP are potential novel risk factors or biomarkers for dementia.

Effective clinical intervention strategies for coronavirus disease 2019 (COVID-19) are urgently needed. Although several clinical trials have evaluated use of convalescent plasma containing virus-neutralizing antibodies, levels of neutralizing antibodies are usually not assessed and the effectiveness has not been proven. We show that hamsters treated prophylactically with a 1:2560 titer of human convalescent plasma or a 1:5260 titer of monoclonal antibody were protected against weight loss, had a significant reduction of virus replication in the lungs, and showed reduced pneumonia. Interestingly, this protective effect was lost with a titer of 1:320 of convalescent plasma. These data highlight the importance of screening plasma donors for high levels of neutralizing antibodies. Our data show that prophylactic administration of high levels of neutralizing antibody, either monoclonal or from convalescent plasma, prevent severe SARS-CoV-2 pneumonia in a hamster model, and could be used as an alternative or complementary to other antiviral treatments for COVID-19.

AimsA limited number of investigations with conflicting results have described perivascular lymphocytic infiltration (PVLI) in the setting of total knee arthroplasty (TKA). The purpose of this study was to determine if PVLI found in TKAs at the time of aseptic revision surgery was associated with worse clinical outcomes and survivorship.MethodsA retrospective review was conducted on 617 patients who underwent aseptic TKA revision who had histological analysis for PVLI at the time of surgery. Clinical and radiological data were obtained pre- and postoperatively, six weeks postoperatively, and then every year thereafter.ResultsWithin this cohort, 118 patients (19.1%) were found to have PVLI on histological analysis. Re-revision was performed on 83 patients (13.4%) with no significant differences in all-cause or aseptic revisions between groups. A higher incidence of PVLI was noted in female patients (p = 0.037). There was no significant difference in improvement in the range of motion (p = 0.536), or improvement of KSC (p = 0.66), KSP (p = 0.61), or KSF (p = 0.3) clinical outcome scores between PVLI and no PVLI sub-groups. There was a higher incidence of a preoperative diagnosis of pain in the PVLI group compared with patients without PVLI (p = 0.002) present.ConclusionPVLI found on large-scale histological analysis in TKAs at aseptic revision surgery was not associated with worse clinical outcomes or rates of re-revision. Cite this article: Bone Joint J 2021;103-B(6 Supple A):145–149.

Aims The purpose is to determine the non-inferiority of a smartphone-based exercise educational care management system after primary knee arthroplasty compared with a traditional in-person physiotherapy rehabilitation model. Methods A multicentre prospective randomized controlled trial was conducted evaluating the use of a smartphone-based care management system for primary total knee arthroplasty (TKA) and partial knee arthroplasty (PKA). Patients in the control group (n = 244) received the respective institution’s standard of care with formal physiotherapy. The treatment group (n = 208) were provided a smartwatch and smartphone application. Early outcomes assessed included 90-day knee range of movement, EuroQoL five-dimension five-level score, Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR) score, 30-day single leg stance (SLS) time, Time up and Go (TUG) time, and need for manipulation under anaesthesia (MUA). Results Overall, 90-day mean flexion was not significantly different between the control (121° (SD 11.7°)) and treatment groups (121o; p = 0.559); 90-day mean SLS was 22.7 seconds (SD 9.8) in controls and 24.3 seconds (SD 20.8) in treatment (p = 0.519); 90-day mean TUG times were 10.1 seconds (SD 4.8) in control and 9.3 seconds (SD 3.3) in treatment (p = 0.139). Mean KOOS JR scores were significantly different between control group (73.6 (SD 13.4)) and treatment group (70.4 (SD 12.6); p = 0.026). MUAs were performed in nine (3.7%) patients in the control group and four (1.9%) in the treatment group (p = 0.398). Physiotherapy was performed by 230 (94.4%) of control group and 123 (59.3%) of treatment group (p < 0.001). There were no significant differences between groups in postoperative urgent care visits, or readmissions within 90 days, with significantly fewer emergency department visits in the treatment group (16 (8.2%) vs five (2.5%), p = 0.014). Conclusion The use of the smartwatch/smartphone care platform demonstrated non-inferiority of clinically significant outcomes to traditional care models, while requiring significantly less postoperative physiotherapy and fewer emergency department visits. This platform could aid in decreasing postoperative costs, while improving patient engagement and communication with the healthcare team. Cite this article: Bone Joint J 2021;103-B(6 Supple A):3–12.

OBJECTIVE: To determine the proportions of patients who (1) perceived their symptoms to be satisfactory, (2) perceived their treatment to have failed, or (3) perceived that they improved to an important degree at 3 months after arthroscopic meniscal surgery; and to determine Knee injury and Osteoarthritis Outcome Score (KOOS) subscale scores corresponding to the Patient Acceptable Symptom State (PASS), treatment failure, and the minimal important change (MIC) for improvement.DESIGN: Prospective cohort study.METHODS: Patients from the Knee Arthroscopy Cohort Southern Denmark who had arthroscopic meniscal surgery were included. The PASS, treatment failure, and MIC improvement values were calculated for the KOOS subscales with anchor-based approaches, using the adjusted predictive modeling method. Subgroup analyses were performed by stratifying by age (40 years or younger versus older than 40 years) and surgery type.RESULTS: Six hundred fourteen patients (44% female; mean ± SD age, 50 ± 13 years) were included. At 3 months after arthroscopic meniscal surgery, 45% of patients perceived their symptoms to be satisfactory, 19% perceived the treatment to have failed, and 44% to 60% perceived that they had improved to an important degree across the 5 KOOS subscales (for PASS/treatment failure, respectively: pain, 74 and 60 points; symptoms, 72 and 61 points; function in activities of daily living, 81 and 68 points; sport and recreational function, 43 and 26 points; and knee-related quality of life, 52 and 40 points; for MIC improvement: pain, 12 points; symptoms, 8 points; function in activities of daily living, 12 points; sport and recreational function, 17 points; and knee-related quality of life, 9 points). The PASS values were 6 to 17 points higher for patients 40 years or younger compared to patients older than 40 years.CONCLUSION: At 3 months after meniscal surgery, approximately half of the patients perceived their symptoms to have improved to an important degree, 4 in every 10 patients perceived their symptoms to be satisfactory, and 2 in every 10 patients perceived the treatment to have failed. J Orthop Sports Phys Ther 2021;51(6):281-288. Epub 30 Jan 2021. doi:10.2519/jospt.2021.10149.

Background Acute kidney injury (AKI) subtypes combining kidney functional parameters and injury biomarkers may have prognostic value. We aimed to determine whether neutrophil gelatinase-associated lipocalin (NGAL)/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) defined subtypes are of prognostic relevance in cardiac surgery patients. Methods We studied 198 higher-risk cardiac surgery patients. We allocated patients to four groups: Kidney Disease Improving Global Outcomes (KDIGO)-AKI-negative and NGAL/hepcidin-25 ratio-negative (no AKI), KDIGO AKI-negative and NGAL/hepcidin-25 ratio-positive (subclinical AKI), KDIGO AKI-positive and NGAL/hepcidin-25 ratio-negative (clinical AKI), KDIGO AKI-positive and NGAL/hepcidin-25 ratio-positive (combined AKI). Outcomes included in-hospital mortality (primary) and long-term mortality (secondary). Results We identified 127 (61.6%) patients with no AKI, 13 (6.6%) with subclinical, 40 (20.2%) with clinical and 18 (9.1%) with combined AKI. Subclinical AKI patients had a 23-fold greater in-hospital mortality than no AKI patients. For combined AKI vs. no AKI or clinical AKI, findings were stronger (odds ratios (ORs): 126 and 39, respectively). After adjusting for EuroScore, volume of intraoperative packed red blood cells, and aortic cross-clamp time, subclinical and combined AKI remained associated with greater in-hospital mortality than no AKI and clinical AKI (adjusted ORs: 28.118, 95% CI 1.465–539.703; 3.737, 95% CI 1.746–7.998). Cox proportional hazard models found a significant association of biomarker-informed AKI subtypes with long-term survival compared with no AKI (adjusted ORs: pooled subclinical and clinical AKI: 1.885, 95% CI 1.003–3.542; combined AKI: 1.792, 95% CI 1.367–2.350). Conclusions In the presence or absence of KDIGO clinical criteria for AKI, the urinary NGAL/hepcidin-25-ratio appears to detect prognostically relevant AKI subtypes. Trial registration number NCT00672334, clinicaltrials.gov, date of registration: 6th May 2008, https://clinicaltrials.gov/ct2/show/NCT00672334. Graphic abstract Definition of AKI subtypes: subclinical AKI (KDIGO negative AND Ratio-positive), clinical AKI (KDIGO positive AND Ratio-negative) and combined AKI (KDIGO positive AND Ratio-positive) with urinary NGAL/hepcidin-25 ratio-positive cut-off at 85% specificity for in-hospital death. AKI, acute kidney injury. AUC, area under the curve. NGAL, neutrophil gelatinase-associated lipocalin. KDIGO, Kidney Disease Improving Global Outcomes Initiative AKI definition.

OBJECTIVE: To compare overall survival of patients with a cCR undergoing active surveillance versus standard esophagectomy.SUMMARY OF BACKGROUND DATA: One-third of patients with esophageal cancer have a pathologically complete response in the resection specimen after neoadjuvant chemoradiotherapy. Active surveillance may be of benefit in patients with cCR, determined with diagnostics during response evaluations after chemoradiotherapy.METHODS: A systematic review and meta-analysis was performed comparing overall survival between patients with cCR after chemoradiotherapy undergoing active surveillance versus standard esophagectomy. Authors were contacted to supply individual patient data. Overall and progression-free survival were compared using random effects meta-analysis of randomized or propensity score matched data. Locoregional recurrence rate was assessed. The study-protocol was registered (PROSPERO: CRD42020167070).RESULTS: Seven studies were identified comprising 788 patients, of which after randomization or propensity score matching yielded 196 active surveillance and 257 standard esophagectomy patients. All authors provided individual patient data. The risk of all-cause mortality for active surveillance was 1.08 [95% confidence interval (CI): 0.62-1.87, P = 0.75] after intention-to-treat analysis and 0.93 (95% CI: 0.56-1.54, P = 0.75) after per-protocol analysis. The risk of progression or all-cause mortality for active surveillance was 1.14 (95% CI: 0.83-1.58, P = 0.36). Five-year locoregional recurrence rate during active surveillance was 40% (95% CI: 26%-59%). 95% of active surveillance patients undergoing postponed esophagectomy for locoregional recurrence had radical resection.CONCLUSIONS: Overall survival was comparable in patients with cCR after chemoradiotherapy undergoing active surveillance or standard esophagectomy. Diagnostic follow-up is mandatory in active surveillance and postponed esophagectomy should be offered to operable patients in case of locoregional recurrence.

Over one-quarter of patients would choose not to undergo standard oesophagectomy again, at least 1 year after they underwent neoadjuvant chemoradiotherapy and standard oesophagectomy. These patients had worse short- and long-term health-related quality of life (HRQoL) than patients who chose standard oesophagectomy. Considering both treatments, 5-year survival and long-term HRQoL were considered most important factors by individual patients.

BackgroundPulmonary arterial hypertension (PAH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. This study assessed the impact of RV diastolic stiffness on RA–RV interaction.MethodsPAH patients with low or high end-diastolic elastance (Eed) (n=94) were compared with controls (n=31). Treatment response was evaluated in 62 patients. RV and RA longitudinal strain, RA emptying and RV filling were determined and diastole was divided into a passive and active phase. Vena cava backflow was calculated as RA active emptying−RV active filling and RA stroke work as RA active emptying×RV end-diastolic pressure.ResultsWith increased Eed, RA and RV passive strain were reduced while active strain was preserved. In comparison to controls, patients had lower RV passive filling but higher RA active emptying and RA stroke work. RV active filling was lower in patients with high Eed, resulting in higher vena cava backflow. Upon treatment, Eed was reduced in ~50% of the patients with high Eed, which coincided with larger reductions in afterload, RV mass and vena cava backflow and greater improvements in RV active filling and stroke volume in comparison with patients in whom Eed remained high.ConclusionsIn PAH, RA function is associated with changes in RV function. Despite increased RA stroke work, severe RV diastolic stiffness is associated with reduced RV active filling and increased vena cava backflow. In 50% of patients with high baseline Eed, diastolic stiffness remained high, despite treatment. A reduction in Eed coincided with a large reduction in afterload, increased RV active filling and decreased vena cava backflow.

Apoptosis, a key mechanism of programmed cell death, is triggered by caspase-3 protein and lowering its levels with gene therapy may rescue cell death after central nervous system damage. We developed a novel, non-viral gene therapy to block caspase-3 gene expression using small interfering RNA (siRNA) delivered by polybutylcyanoacrylate nanoparticles (CaspNPs). In vitro CaspNPs significantly blocked caspase-3 protein expression in C6 cells, and when injected intraocularly in vivo, CaspNPs lowered retinal capsase-3 immunofluorescence by 57.9% in rats with optic nerve crush. Longitudinal, repeated retinal ganglion cell counts using confocal neuroimaging showed that post-traumatic cell loss after intraocular CaspNPs injection was only 36.1% versus 63.4% in lesioned controls. Because non-viral gene therapy with siRNA-nanoparticles can selectively silence caspace-3 gene expression and block apoptosis in post-mitotic neurons, siRNA delivery with nanoparticles may be promising for neuroprotection or restoration of central visual system damage and other neurological disorders. The animal study procedures were approved by the German National Act on the use of experimental animals (Ethic Committee Referat Verbraucherschutz, Veterinarangelegenheiten; Landesverwaltungsamt Sachsen-Anhalt, Halle, Germany, # IMP/G/01-1150/12 and # IMP/G/01-1469/17).

Contains fulltext : 238662.pdf (Publisher’s version ) (Closed access)

Background: Treatment of patients with pulmonary arterial hypertension (PAH) is conventionally based on functional plus invasive measurements obtained during right heart catheterization (RHC). Whether risk assessment during repeated measurements could also be performed on the basis of imaging parameters is unclear, as a direct comparison of strategies is lacking. Research Question: How does the predictive value of noninvasive parameters compare with that of invasive hemodynamic measurements 1 year after the diagnosis of idiopathic PAH? Study Design and Methods: One hundred and eighteen patients with idiopathic PAH who underwent RHC and cardiac MRI (CMR) were included in this study (median time between baseline evaluation and first parameter measures, 1.0 [0.8-1.2] years). Forty-four patients died or underwent lung transplantation. Forward Cox regression analyses were done to determine the best predictive functional, hemodynamic, and/or imaging model. Patients were classified as high risk if the event occurred < 5 years after diagnosis (n = 24), whereas patients without event were classified as low risk. Results: A prognostic model based on age, sex, and absolute values at follow-up of functional parameters (6-min walk distance) performed well (Akaike information criterion [AIC], 279; concordance, 0.67). Predictive models with only hemodynamic (right atrial pressure, mixed venous oxygen saturation; AIC, 322; concordance, 0.66) or imaging parameters (right ventricular ejection fraction; AIC, 331; concordance, 0.63) at 1 year of follow-up performed similarly. The predictive value improved when functional data were combined with either hemodynamic data (AIC, 268; concordance, 0.69) or imaging data (AIC, 273; concordance, 0.70). A model composed of functional, hemodynamic, and imaging data performed only marginally better (AIC, 266; concordance, 0.69). Finally, changes between baseline and 1-year follow-up were observed for multiple hemodynamic and CMR parameters; only a change in CMR parameters was of prognostic predictive value. Interpretation: At 1 year of follow-up, risk assessment based on CMR is at least equal to risk assessment based on RHC. In this study, only changes in CMR, but not hemodynamic parameters, were of prognostic predictive value during the first year of follow-up.

Active surveillance for patients with esophageal cancer and a clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) is being studied. Active surveillance requires accurate clinical response evaluations. 18F-FDG PET/CT might be able to detect local tumor recurrence after nCRT as soon as the esophagus recovers from radiationinduced esophagitis. The aims of this study were to assess the value of serial 18F-FDG PET/CT scans for detecting local recurrence in patients beyond 3 mo after nCRT and to determine when radiation-induced esophagitis has resolved. Methods: This retrospectivemulticenter study included patients who had cCR after nCRT, who initially declined surgery, and who subsequently underwent active surveillance. Clinical response evaluations included 18F-FDG PET/CT, endoscopic biopsies, and endoscopic ultrasound with fine-needle aspiration at regular intervals. SUVmax normalized for lean body mass (SULmax) was measured at the primary tumor site. The percentage change in SULmax (D%SULmax) between the last follow-up scan and the scan at 3 mo after nCRT was calculated. Tumor recurrence was defined as biopsy-proven vital tumor at the initial tumor site. Results: Of 41 eligible patients, 24 patients had recurrent disease at a median of 6.5 mo after nCRT and 17 patients remained cancer free during a median follow-up of 24 mo after nCRT. Five of 24 patients with tumor recurrence had sudden intense SULmax increases of greater than 180%. In 19 of 24 patients with tumor recurrence, SULmax gradually increased (median D%SULmax, 118%), whereas SULmax decreased (median D%SULmax, -12%) in patients with ongoing cCR (P , 0.001, independent-samples t test). In patients with ongoing cCR, SULmax was lowest at 11 mo after nCRT. Conclusion: Serial 18F-FDG PET/CT might be a useful tool for detecting tumor recurrence during active surveillance. In patients with ongoing cCR, the lowest SULmax was reached at 11 mo after nCRT, suggesting that radiation-induced esophagitis had mostly resolved by that time. These findings warrant further evaluation in a larger cohort.

International audience; This paper reports the results of an investigation of industrial requirements for thermodynamic and transport properties carried out during the years 2019–2020. It is a follow-up of a similar investigation performed and published 10 years ago by the Working Party (WP) of Thermodynamics and Transport Properties of European Federation of Chemical Engineering (EFCE).1 The main goal was to investigate the advances in this area over the past 10 years, to identify the limitations that still exist, and to propose future R&D directions that will address the industrial needs. An updated questionnaire, with two new categories, namely, digitalization and comparison to previous survey/changes over the past 10 years, was sent to a broad number of experts in companies with a diverse activity spectrum, in oil and gas, chemicals, pharmaceuticals/biotechnology, food, chemical/mechanical engineering, consultancy, and power generation, among others, and in software suppliers and contract research laboratories. Very comprehensive answers were received by 37 companies, mostly from Europe (operating globally), but answers were also provided by companies in the USA and Japan. The response rate was about 60%, compared to 47% in the year 2010. The paper is written in such a way that both the majority and minority points of view are presented, and although the discussion is focused on needs and challenges, the benefits of thermodynamics and success stories are also reported. The results of the survey are thematically structured and cover changes, challenges, and further needs for a number of areas of interest such as data, models, systems, properties, and computational aspects (molecular simulation, algorithms and standards, and digitalization). Education and collaboration are discussed and recommendations on the future research activities are also outlined. In addition, a few initiatives, books, and reviews published in the past decade are briefly discussed. It is a long paper and, to provide the reader with a more complete understanding of the survey, many (anonymous) quotations (indicated with “...” and italics) from the industrial colleagues who have participated in the survey are provided. To help disseminate the specific information of interest only to particular industrial sectors, the paper has been written in such a way that the individual sections can also be read independently of each other.

Self-optimizing process planning is an essential approach for finding optimum process parameters and reducing ramp-up times in machining processes. For this purpose, polishing is presented as an application example. In conventional polishing processes, the process parameters are selected according to the operator’s expertise in order to achieve a high-quality surface in the final production step. By implementing machine learning (ML) models in process planning, a correlation between process parameter and measured surface quality is generated. The application of this knowledge automates the selection of optimal process parameters in computer-aided manufacturing (CAM) and enables a continuous adaptation of the NC-code to changing process conditions. Applying the presented ML-model, the prediction accuracy of 83% will adapt the process parameters to achieve the target roughness of 0.2 μm. The sample efficiency is shown by the decrease in root mean square error from 0.1–0.28 to 0.02–0.07 μm with additional polishing iterations.

Autoantibody-associated cognitive impairment is an expanding field in geriatric psychiatry. We aim to assess the association between the presence of specific neural autoantibodies and cognitive performance in a memory clinic cohort. 154 patients with cognitive impairment were included between 2019 and 2020 presenting initially in a memory clinic. We evaluated their patient files retrospectively applying epidemiologic parameters, psychopathology, neuropsychology, intracellular and membrane-surface autoantibodies in serum and cerebrospinal fluid (CSF) and markers of neurodegeneration in CSF. In 26 of 154 patients, we searched for neural autoantibodies due to indicators for autoimmunity. In 15/26 (58%) of patients we detected serum and/or CSF autoantibodies. We identified autoantibodies against intracellular or cell-surface antigens in 7 of all 26 (27%) patients with cognitive dysfunction, although we cannot exclude patients with potential specific autoantibodies lacking autoimmune indicators. There were no significant differences between psychopathological and neuropsychological profiles in groups of patients with cognitive impairment comprising patients with autoantibodies (ABS + COG), no autoantibodies (ABS − COG), and Alzheimer’s disease (ADCOG). Concerning our CSF parameters, we detected intrathecal IgG synthesis in 14% of ABS + COG and in 13% of ABS − COG patients, whereas no intrathecal IgG synthesis was found in ADCOG patients. Furthermore, CSF Aß42 was significantly diminished in the ADCOG compared to the ABS + COG group (p p

Vaccine-induced thrombotic thrombocytopenia (VITT) is a thrombotic complication mimicking heparin induced thrombocytopenia (HIT). This very rare but severe thrombotic complication occurs post vaccination against SARS-Cov-2. Diagnosis of VITT remains challenging, but a current consensus report suggests a 10-point guideline for early detection of VITT, which should be confirmed by PF-4 immunoassays. The latter is considered to be the most reliable diagnostic test. We observed platelet aggregates and increased platelet volume in patients with VITT in routine blood smear analyses. These routine blood analytic findings may - together with the clinical presentation - support and speed up the diagnosis of VITT, and may be of particular importance in low-income countries with limited access to PF-4 immunoassays.

Purpose: To develop a high-resolution three-dimensional (3D) magnetic resonance imaging (MRI)-based treatment planning approach for uveal melanomas (UM) in proton therapy.Materials/methods: For eight patients with UM, a segmentation of the gross tumor volume (GTV) and organs-at-risk (OARs) was performed on T1- and T2-weighted 7 Tesla MRI image data to reconstruct the patient MR-eye. An extended contour was defined with a 2.5-mm isotropic margin derived from the GTV. A broad beam algorithm, which we have called pi Dose, was implemented to calculate relative proton absorbed doses to the ipsilateral OARs. Clinically favorable gazing angles of the treated eye were assessed by calculating a global weighted-sum objective function, which set penalties for OARs and extreme gazing angles. An optimizer, which we have named OPT'im-Eye-Tool, was developed to tune the parameters of the functions for sparing critical-OARs.Results: In total, 441 gazing angles were simulated for every patient. Target coverage including margins was achieved in all the cases (V-95% > 95%). Over the whole gazing angles solutions space, maximum dose (D-max) to the optic nerve and the macula, and mean doses (D-mean) to the lens, the ciliary body and the sclera were calculated. A forward optimization was applied by OPT'im-Eye-Tool in three different prioritizations: iso-weighted, optic nerve prioritized, and macula prioritized. In each, the function values were depicted in a selection tool to select the optimal gazing angle(s). For example, patient 4 had a T2 equatorial tumor. The optimization applied for the straight gazing angle resulted in objective function values of 0.46 (iso-weighted situation), 0.90 (optic nerve prioritization) and 0.08 (macula prioritization) demonstrating the impact of that angle in different clinical approaches.Conclusions: The feasibility and suitability of a 3D MRI-based treatment planning approach have been successfully tested on a cohort of eight patients diagnosed with UM. Moreover, a gaze-angle trade-off dose optimization with respect to OARs sparing has been developed. Further validation of the whole treatment process is the next step in the goal to achieve both a non-invasive and a personalized proton therapy treatment. (c) 2020 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.

Background The objective of this systematic review was to evaluate the performance of prognostic survival models for intrahepatic cholangiocarcinoma (iCCA) when validated in an external dataset. Furthermore, it sought to identify common prognostic factors across models, and assess methodological quality of the studies in which the models were developed. Methods The PRISMA guidelines were followed. External validation studies of prognostic models for patients with iCCA were searched in 5 databases. Model performance was assessed by discrimination and calibration. Results Thirteen external validation studies were identified, validating 18 different prognostic models. The Wang model was the sole model with good performance (C-index above 0.70) for overall survival. This model incorporated tumor size and number, lymph node metastasis, direct invasion into surrounding tissue, vascular invasion, Carbohydrate antigen (CA) 19-9, and carcinoembryonic antigen (CEA). Methodological quality was poor in 11/12 statistical models. The Wang model had the highest score with 13 out of 17 points. Conclusion The Wang model for prognosis after resection of iCCA has good quality and good performance at external validation, while most prognostic models for iCCA have been developed with poor methodological quality and show poor performance at external validation.

Higher customer requirements and increasing competitive pressure lead to a growing number of variants and smaller batch sizes in manufacturing. As a result, companies have to deal with challenges of small series manufacturing. A unidimensional set-up optimization cannot provide a satisfying solution. At the same time, production system-specific control algorithms are usually complex and require constant adaptation as customer requirements change continuously. To address these issues, this paper presents a hybrid genetic algorithm which allows modular sequence optimization in production scheduling. Hybrid elements are used to reach a high solution quality within a short runtime.

Das Seilschleifen gewinnt im Rückbau kerntechnischer Anlagen immer mehr an Bedeutung. Aufgrund der hohen Belastung kommt es jedoch häufig zu frühzeitigem Werkzeugversagen. Seilschleifwerkzeuge bestehen aus Schleifsegmenten, die mittels Gummierung auf dem Trägerseil fixiert werden. In diesem Beitrag wird der Einfluss des Werkzeugverbundes auf das Einsatzverhalten und die Lebensdauer untersucht. Die Verwendung von neuen Werkstoffen als Vergussmasse zeigt dabei das Potenzial einer signifikanten Lebensdauersteigerung. Wire grinding processes are frequently used in dismantling of nuclear facilities. However, the tool life is limited due to high thermal and mechanical loads. Wire grinding tools consist of grinding segments that are fixed to the carrier wire by means of rubber coating. In this article, the influence of the tool structure on the grinding behaviour and the tool life is investigated. The use of new materials shows the potential of a significant increase in tool life.

Energy efficiency is an essential factor for promoting sustainable manufacturing. Various types of energy consumption occur in modern process chains. This includes usage of electrical energy, e.g. for machine tools or air compression, but also energy consumption through use of resources (such as raw materials and supplies). In this paper, a process chain from the automotive industry is considered with the purpose of identifying energy saving potentials of various kinds. The process chain is used for the production of an axle component. In order to evaluate saving potentials, the current state of the process chain is analyzed. Then, the impact of process parameter optimization on the energy demand is examined. It was found that small energy savings through parameter optimization are possible. However, this can be problematic since process parameters are closely linked to process reliability, so energy savings might be achieved at the expense of product quality. Furthermore, it turns out that the reduction of the process energy is not sufficient for a broad energetic optimization of the process chain and base load reducing measures are required instead. Therefore, further analysis is focused on energetic effects of such measures as machine design, recycling, adjustments of process chain and product design. These were found to be an effective lever for minimizing energy demand of the process chain. A combination of feasible measures adds up to a potential energy saving of 11.5% in the investigated scenario.

Contains fulltext : 242805.pdf (Publisher’s version ) (Open Access) Background and purpose - From previous studies, we know that clinical outcomes of revision total knee arthroplasty (rTKA) differ among reasons for revision. Whether the prevalence of repeat rTKAs is different depending on the reason for index rTKA is unclear. Therefore, we (1) compared the repeat revision rates between the different reasons for index rTKA, and (2) evaluated whether the reason for repeat rTKA was the same as the reason for the index revision.Patients and methods - Patients (n = 8,978) who underwent an index rTKA between 2010 and 2018 as registered in the Dutch Arthroplasty Register were included. Reasons for revision, as reported by the surgeon, were categorized as: infection, loosening, malposition, instability, stiffness, patellar problems, and other. Competing risk analyses were performed to determine the cumulative repeat revision rates after an index rTKA for each reason for revision.Results - Overall, the cumulative repeat revision rate was 19% within 8 years after index rTKA. Patients revised for infection had the highest cumulative repeat revision rate (28%, 95% CI 25-32) within 8 years after index rTKA. The recurrence of the reason was more common than other reasons after index rTKA for infection (18%), instability (8%), stiffness (7%), and loosening (5%).Interpretation - Poorest outcomes were found for rTKA for infection: over 1 out of 4 infection rTKAs required another surgical intervention, mostly due to infection. Recurrence of other reasons for revision (instability, stiffness, and loosening) was also considerable. Our findings also emphasize the importance of a clear diagnosis before doing rTKA to avert second revision surgeries.

Objective: THBD (thrombomodulin) is part of the anticoagulant protein C-system that acts at the endothelium and is involved in anti-inflammatory and barrier-stabilizing processes. A recombinant soluble form of THBD was shown to have protective effects in different organs, but how the endogenous THBD is regulated during ischemia, particularly in the brain is not known to date. The aim of this study was to investigate the role of THBD, especially in brain endothelial cells, during ischemic stroke. Approach and Results: To induce ischemic brain damage, we occluded the middle cerebral artery of mice. We found an increased endothelial expression of Thbd in the peri-infarct area, whereas in the core of the ischemic tissue Thbd expression was decreased compared with the contralateral side. We generated a novel Cre/loxP-based mouse line that allows for the inducible deletion of Thbd specifically in brain endothelial cells, which worsened stroke outcome 48 hours after middle cerebral artery occlusion. Unexpectedly, we found no signs of increased coagulation, thrombosis, or inflammation in the brain but decreased vessel diameters and impaired angiogenesis in the peri-infarct area that led to a reduced overall vessel length 1 week after stroke induction. Conclusions: Endogenous THBD acts as a protective factor in the brain during ischemic stroke and enhances vessel diameter and proliferation. These previously unknown properties of THBD could offer new opportunities to affect vessel function after ischemia and thereby improve stroke outcome.

Background: Most implants for total knee arthroplasty (TKA) are comprised of alloys that contain nickel. Controversy exists whether metal allergies produce negative effects and affect clinical outcomes. The purpose of this study was to retrospectively review a minimum 2-year follow-up with an ion-bombarded titanium TKA implant in patients with reported metal sensitivity. Methods: A retrospective review of patients who underwent primary TKA with the ion-bombarded titanium Vanguard (Zimmer Biomet, Warsaw, IN) implant with 2-year minimum follow-up was performed from 2008 through 2017. The query revealed 346 patients (451 knees) with minimum 2-year follow-up. The mean age was 64.7 years, the mean body mass index was 35.1 kg/m2, and 95% of patients were women. Results: The mean follow-up was 4.6 years. The mean range of motion improved from 109° to 112° (P = .03), University of California Los Angeles activity scale from 4.1 to 5.1 (P < .001), Knee Society Clinical scores from 36 to 89 (P < .001), and Knee Society Functional scores from 48 to 73 (P < .001). There were 5 (1.1%) revisions: 2 infections (2-staged exchange), 1 tibial revision for aseptic loosening after a fall, and 2 bearing exchanges for instability. Other surgeries were open reduction internal fixation of periprosthetic fracture, 1 arthroscopic release of snapping popliteus, and 4 local wound incision and debridement (2 superficial infections and 2 nonhealing wounds). Manipulation under anesthesia was required in 27 (6%) patients. Conclusions: These early results are encouraging for the use of alternative metal titanium alloy implants in metal-sensitive patients undergoing primary TKA. At 4.6 years of mean follow-up, patients had substantial improvement in the range of motion and clinical outcomes with a low frequency of revision.

Delivery of breath-hold MR-guided SABR is time-consuming, and the use of real-time tumor-tracking in a sagittal plane may fail to detect out-of-plane displacements of organs-at-risk. Analysis of daily MR-scans performed pre- and post-SABR revealed frequent decreases in stomach volumes, and in the planned stomach doses.

Background Breast augmentation is one of the most commonly performed aesthetic plastic surgical procedures, with over 250,000 procedures in the United States in 2020 alone. However, the safety of breast implants should be closely researched and monitored, especially in the long term. Objectives This study was undertaken to evaluate the long-term results of round micro-textured Eurosilicone (Eurosilicone S.A.S, Apt Cedex, France) Cristalline Paragel breast implants from a single-center, single-surgeon experience regarding both patient-reported outcome measures and revisions. Methods A retrospective cohort study was undertaken of 84 patients who underwent primary breast augmentation with round micro-textured Eurosilicone Cristalline Paragel breast implants, either submuscular (dual-plane) or subglandular placed, between 2001 and 2004. All patients were contacted for informed consent, and after approval, the validated BREAST-Q questionnaire was sent and utilized to analyze patient satisfaction. In addition, objective data regarding revisions, including capsular contracture, rupture rate, pain, and/or aesthetic causes needing revision surgery, were analyzed. Results High BREAST-Q scores (67%-100% for 0-100 scale variables and 66.0%-77.3% of the patients scored “very satisfied” on categorical variables) were found without clinically significant differences between patients with dual-plane–placed implants and subglandular-placed implants. The overall revision rate was 29.8%, also with no significant differences between groups (P = 0.317). Conclusions This study showed high patient satisfaction and relatively low revision rates after 15 to 19 years of follow-up of round micro-textured Eurosilicone Cristalline Paragel breast implants. No clinically relevant significant differences were found between dual-plane and subglandular placement of the implants. Level of Evidence: 4

BACKGROUND: To investigate the association between altered sex hormone expression and long-term right ventricular (RV) adaptation and progression of right heart failure in a Dutch cohort of Pulmonary Arterial Hypertension (PAH)-patients across a wide range of ages. METHODS: In this study we included 279 PAH-patients, of which 169 females and 110 males. From 59 patients and 21 controls we collected plasma samples for sex hormone analysis. Right heart catheterization (RHC) and/or cardiac magnetic resonance (CMR) imaging was performed at baseline. For longitudinal data analysis, we selected patients that underwent a RHC and/or CMR maximally 1.5 years prior to an event (death or transplantation, N = 49). RESULTS: Dehydroepiandrosterone-sulfate (DHEA-S) levels were reduced in male and female PAHpatients compared to controls, whereas androstenedione and testosterone were only reduced in female patients. Interestingly, low DHEA-S and high testosterone levels were correlated to worse RV function in male patients only. Subsequently, we analyzed prognosis and RV adaptation in females stratified by age. Females < 45years had best prognosis in comparison to females & GE;55years and males. No differences in RV function at baseline were observed, despite higher pressure-overload in females < 45years. Longitudinal data demonstrated a clear distinction in RV adaptation. Although females < 45years had an event at a later time point, RV function was more impaired at end-stage disease. CONCLUSIONS: Sex hormones are differently associated with RV function in male and female PAHpatients. DHEA-S appeared to be lower in male and female PAH-patients. Females < 45years could persevere pressure-overload for a longer time, but had a more severe RV phenotype at end-stage disease.J Heart Lung Transplant 2022;41:445-457 (c) 2021 The Author(s). Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)