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Abstract As other crises before, the COVID-19 pandemic put established discursive routines at stake. By framing the pandemic as a crisis, an immediate search for adequate counter-measures started to define proper means of mitigation and protection for the population. In the early stages of COVID-19, when little reliable information on the virus and its transmission behaviour was available, an intense use of metaphor to explain and govern the crisis had to be expected. Beside its well-known impact on (geo-)politics, a thorough analysis especially of the use of spatial metaphors to reason about the crises is still missing. In our approach, we rely on the foundational work of Lakoff and Johnson (1980) on image schemata, and prior work on spatial metaphors as part of argumentation patterns from cultural geography (Schlottmann, 2008). After a thorough analysis of prominent examples according to the argumentation scheme of Toulmin (1976 [1958]), we explored examples from the pre-existing corpus on COVID-19, deliberately compiled by DWDS for analysis of language patterns used throughout the pandemic. In a subsequent filter-refinement approach building on methods from cognitive linguistics and utilising a chunk of the same corpus, we were able to obtain and discuss results on the variety of spatial metaphors used at that time.

Background: Red blood cell (RBC) transfusions play an important role in supportive care in children and neonates with cancer. However, in current clinical practice, evidence-based recommendations are lacking on when to administer prophylactic RBC transfusions. To address this gap, a clinical practice guideline (CPG) was developed to systematically review the available evidence and provide recommendations for clinicians. Methods: A systematic literature review in three databases was conducted. The GRADE methodology was used to assess, extract, and summarize the evidence. A multidisciplinary panel of 21 professionals was assembled to ensure comprehensive expertise. If there was insufficient evidence in children with cancer, additional evidence was gathered in general pediatric or adult oncology guidelines, or the panel utilized shared expert opinion to develop a comprehensive CPG. Multiple in-person meetings were conducted to discuss evidence, complete evidence-to-decision frameworks, and formulate recommendations. Results: Four studies including 203 children with all types of cancer, met the inclusion criteria. The expert panel assessed all evidence and translated it into recommendations. In total, 47 recommendations were formulated regarding RBC transfusions in children and neonates with cancer. For instance, specific thresholds for prophylactic RBC transfusions were recommended for children and neonates with cancer who have sepsis, are on ECMO, or are undergoing radiotherapy. Conclusion: This clinical practice guideline presents evidence-based recommendations regarding RBC transfusions in children and neonates with cancer. By providing these recommendations, we aim to guide clinicians and contribute to improving outcomes for children and neonates with cancer. [ABSTRACT FROM AUTHOR]

Background: Conventional advice to reduce the risk of breast cancer-related lymphedema (BCLE) suggests avoidance of daily-living risks, and limited research has investigated these risks. Objective: This study aimed to examine the occurrence, patterns, and effects of daily-living risks on BCLE. Methods: A cross-sectional design was used to collect data from 567 patients at a metropolitan cancer center in the United States. The Lymphedema Risk-Reduction Behavior Checklist was used to assess the occurrence of 11 daily-living risks. Descriptive, regression, and factor analyses were performed. Results: Significant odds of BCLE were associated with infection (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.95–3.42), cuts/scratches (OR 2.65, 95% CI 1.97–3.56), sunburn (OR 1.89, 95% CI 1.39–3.56), oil splash or steam burns (OR 2.08, 95% CI 1.53–3.83), and insect bites (OR 1.59, 95% CI 1.18–2.13). The daily-living risks were clustered into factors related to skin trauma and carrying objects. Skin trauma risk was significantly associated with BCLE (B = 0.539, z = 3.926, OR 1.714, 95% CI 1.312–2.250; p < 0.001). Having three, four, or five skin trauma risks significantly increased the odds of BCLE to 4.31, 5.14, and 6.94 times, respectively. The risk of carrying objects had no significant or incremental effects on BCLE. Conclusion: Complete avoidance of daily-living risks is challenging given 52.73% of patients incurred more than five daily-living risks. Our study findings underscore the importance of 'what to do' strategies to minimize infection and skin trauma. [ABSTRACT FROM AUTHOR]

Oral mucosal melanomas (OMMs) are aggressive neoplasms commonly found in dogs but rare in humans. Utilizing whole exome sequencing (WES), which focuses on protein-coding regions to reveal mutation profiles, we conducted a comparative analysis of canine OMM and human melanomas. This study involved DNA extraction, exome enrichment, and sequencing from three canine OMM cell lines (CMGD-2, CMGD-5, TLM-1), five canine OMM frozen samples, a human OMM cell line (MEMO), and a human commercial skin melanoma cell line (SK-MEL-28). The sequencing and subsequent analysis of FASTQ files yielded final variant files, leading to the identification of mutations. Our findings revealed a total of 500 mutated genes in canine OMM, including significant ones such as EP300, FAT4, JAK3, LRP1B, NCOR1, and NOTCH1. Notably, 82 shared mutations were identified between human melanomas and canine OMM genomes. These mutations were categorized based on the gene functions. The identification of these mutations provides critical insights that can pave the way for the development of novel therapeutic strategies for both canine and human OMM, offering hope for more effective treatments in the future. [ABSTRACT FROM AUTHOR]

Astrocytes are the most abundant cell type in the mammalian brain and provide structural and metabolic support to neurons, regulate synapses and become reactive after injury and disease. However, a small subset of astrocytes settles in specialized areas of the adult brain where these astrocytes instead actively generate differentiated neuronal and glial progeny and are therefore referred to as neural stem cells1–3. Common parenchymal astrocytes and quiescent neural stem cells share similar transcriptomes despite their very distinct functions4–6. Thus, how stem cell activity is molecularly encoded remains unknown. Here we examine the transcriptome, chromatin accessibility and methylome of neural stem cells and their progeny, and of astrocytes from the striatum and cortex in the healthy and ischaemic adult mouse brain. We identify distinct methylation profiles associated with either astrocyte or stem cell function. Stem cell function is mediated by methylation of astrocyte genes and demethylation of stem cell genes that are expressed later. Ischaemic injury to the brain induces gain of stemness in striatal astrocytes7. We show that this response involves reprogramming the astrocyte methylome to a stem cell methylome and is absent if the de novo methyltransferase DNMT3A is missing. Overall, we unveil DNA methylation as a promising target for regenerative medicine.Single-cell analysis of the transcriptome, chromatin accessibility and methylome of adult neural stem cells and astrocytes demonstrates that stemness is driven by methylation profiles distinct from those of astrocytes. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOSSMARCB1-, which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOSSMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOSSmarcb1-. In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOSSMARCB1- within the TME. Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous and aggressive type of T-cell lymphoma. Here, the authors perform single-cell analyses of human and murine PTCL-NOS tumors, and identify a subtype defined by the loss of SMARCB1 that could be targeted with HDAC-inhibitor combination therapies. [ABSTRACT FROM AUTHOR]

In Chile most of the walnut orchards are located in semiarid areas prone to saline conditions. Therefore, mitigating salinity stress is a relevant issue for farmers, especially for 'Chandler', the most sensitive planted variety. The aim of this study was to evaluate the effect of an extract of Ascophyllum nodosum (ANE; Acadian Organic®), applied through drip irrigation, on the vegetative and productive response of 'Chandler' walnut orchard affected by salinity (soil EC 1.8 dS m-1; irrigation water 2.0 dS m-1), effects on physical and biological soil properties. A dose of 4 L ha-1 ANE was applied monthly during two seasons (2021-2022 and 2022-2023) from the beginning of shoot growth until one month before harvest (24 L ha-1 per season), compared to unamended control. ANE applications promoted good conditions for tree development, greater shoot thickness, higher SPAD index measurements and better vegetative expression, represented by the NDVI spectral index. Consequently, a greater proportion of kernel filling and sizes was found in the ANE treatment (kernel size >32 mm, first season: 54% ANE vs 45% control; second season: 26% ANE vs 6% control). The stress mitigation of ANE promoted a positive cumulative effect after 1 season, with early vegetative development in the second season and significantly greater fruit size and yield efficiency. In addition, ANE application significantly improved physical and biological soil properties, possibly increased soil microbial activity, stimulated organic matter accumulation, improved the soil aggregate stability, and increased soil macroporosity at greater depths. The latter is relevant for salt management since a more stable soil porous system favors adequate water distribution in the soil profile under irrigation cycles, improving the displacement of salts and, consequently, reducing salinity stress. [ABSTRACT FROM AUTHOR]

Purpose: Numerous studies investigated generic psychosocial outcomes in survivors of childhood cancer (CCS). The present study aimed to describe survivor-specific psychosocial consequences in CCS, and to identify socio-demographic and medical associated factors. Methods: CCS from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort (diagnosed 1963–2001) part 2 (age ≥ 18 years, diagnosed < 18 years, ≥ 5 years since diagnosis) completed the Benefit & Burden Scale (BBSC) and the Impact of Cancer–Childhood Cancer (IOC-CS). Items were scored on a 5-point Likert scale (range 1–5). We examined outcomes with descriptive statistics, and socio-demographic and medical associated factors with regression analyses, corrected for multiple testing (p < 0.004). Results: CCS, N = 1713, age mean (M) 36 years, 49% female, ≥ 15 years since diagnosis, participated. On average, CCS reported 'somewhat' Benefit (M = 2.9), and 'not at all' to 'a little' Burden (M = 1.5) of childhood cancer. Average scores on IOC-CS' positive impact scales ranged from 2.5 (Personal Growth) to 4.1 (Socializing), and on the negative impact scales from 1.4 (Financial Problems) to 2.4 (Thinking/Memory). Apart from cognitive problems, CCS reported challenges as worries about relationship status, fertility, and how cancer had affected siblings. Female sex was associated with more Personal Growth, and more negative impact. CCS more highly educated, partnered, and employed had higher positive and lower negative impact. CCS older at diagnosis reported more positive impact. CNS tumor survivors and those who had head/cranium radiotherapy had higher negative impact. CNS tumor survivors reported less positive impact. Conclusion and implications: The majority of CCS reported positive impact of cancer while most CCS reported little negative impact. While this may indicate resiliency in most CCS, health care providers should be aware that they can also experience survivor-specific challenges that warrant monitoring/screening, information provision and psychosocial support. [ABSTRACT FROM AUTHOR]

Purpose: Vitamin C deficiency is associated with excess mortality in kidney transplant recipients (KTR). We aim to evaluate plasma vitamin C status at different post-transplantation moments and assess the main characteristics associated with vitamin C deficiency in KTR. Methods: Plasma vitamin C was assessed in 598 KTR at 3-, 6-, 12-, 24-, and 60-months post-transplantation, 374 late KTR with a functioning graft ≥ 1 year, and 395 potential donors. Vitamin C deficiency was defined as plasma vitamin C ≤ 28 µmol/L. Diet was assessed by a 177-item food frequency questionnaire. Data on vitamin C-containing supplements use were extracted from patient records and verified with the patients. Results: Vitamin C deficiency ranged from 46% (6-months post-transplantation) to 30% (≥ 1 year post-transplantation). At all time points, KTR had lower plasma vitamin C than potential donors (30–41 µmol/L vs 58 µmol/L). In cross-sectional analyses of the 953 KTR at their first visit ≥ 12 months after transplantation (55 ± 14 years, 62% male, eGFR 55 ± 19 mL/min/1.73 m2), the characteristics with the strongest association with vitamin C deficiency were diabetes and smoking (OR 2.67 [95% CI 1.84–3.87] and OR 1.84 [95% CI 1.16–2.91], respectively). Dietary vitamin C intake and vitamin C supplementation were associated with lower odds (OR per 100 mg/day 0.38, 95% CI 0.24–0.61 and OR 0.21, 95% CI 0.09–0.44, respectively). Conclusion: Vitamin C deficiency is frequent among KTR regardless of the time after transplantation, especially among those with diabetes and active smokers. The prevalence of vitamin C deficiency was lower among KTR with higher vitamin C intake, both dietary and supplemented. Further research is warranted to assess whether correcting this modifiable risk factor could improve survival in KTR. [ABSTRACT FROM AUTHOR]

Online platforms have broadened the opportunities of people to interact with nature through community/citizen science, especially in urban areas. However, there is a lack of comprehensive understanding of the social and environmental factors that influence nature interactions in cities. Here, we aim to identify the social and environmental predictors that impact nature interactions, by combining citizen science data with environmental and demographic data in New York City. We applied generalized linear models to identify which of 12 social and environmental factors influence nature interactions in public parks (n = 355) in the Borough of Queens, New York, New York (USA) in two scenarios, small-medium sized parks only (n = 355) and all parks (n = 359). We used iNaturalist records, including the number of users (Observers), Observations, Observed Biodiversity, and a calculated interaction effect (number of users × observations, Interaction), as metrics of nature interactions. For small-medium parks, all nature interactions were significantly influenced by park area, canopy cover, percent population with blood pressure and asthma conditions, noise, and summer mean temperature. Observers and Interaction were positively associated with median income. Observers, Observations, and Interaction were predicted by percent water cover, impervious cover, distance to public transportation, and ethnic diversity. In the analysis that included all parks, the results were similar with minor differences. This study demonstrates a holistic approach to a very specific type of human-nature interaction newly made available with technological advances, seen through an interdisciplinary lens and will help inform planners, residents, and city government on creating more interactive and socio-environmentally beneficial urban green spaces. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) survivors are at risk for developing subsequent neoplasms, but there is limited information on long-term risks and risk factors for both subsequent malignant neoplasms (SMNs) and subsequent non-malignant neoplasms (SNMNs). We analyzed long-term risk and risk factors for SMNs and SNMNs among 3291 5-year ALL survivors from the Dutch Childhood Cancer Survivor Study-LATER cohort (1963–2014). We calculated standardized incidence ratios (SIRs) and cumulative incidences and used multivariable Cox proportional hazard regression analyses for analyzing risk factors. A total of 97 survivors developed SMNs and 266 SNMNs. The 30-year cumulative incidence was 4.1% (95%CI: 3.5–5.3) for SMNs and 10.4%(95%CI: 8.9–12.1) for SNMNs. Risk of SMNs was elevated compared to the general population (SIR: 2.6, 95%CI: 2.1–3.1). Survivors treated with hematopoietic stem cell transplantation (HSCT) with total body irradiation (TBI) (HR:4.2, 95%CI: 2.3–7.9), and without TBI (HR:4.0,95%CI: 1.2–13.7) showed increased SMN risk versus non-transplanted survivors. Cranial radiotherapy (CRT) was also a risk factor for SMNs (HR:2.1, 95%CI: 1.4–4.0). In conclusion, childhood ALL survivors have an increased SMN risk, especially after HSCT and CRT. A key finding is that even HSCT-treated survivors without TBI treatment showed an increased SMN risk, possibly due to accompanied chemotherapy treatment. This emphasizes the need for careful follow-up of HSCT and/or CRT-treated survivors. [ABSTRACT FROM AUTHOR]

Copyright of Die Unfallchirurgie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Die Dermatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Individuals suffering from depression exhibit a higher rate of unintended pregnancies, which are associated with negative outcomes for both parents and children. Often, unintended pregnancies result from contraceptive mistakes. Here, we examine the relationship between depression and the consistency of contraceptive behavior, testing ambivalence as a possible mediator. The analyses were based on cross-sectional data from the second and third waves of the German Relationship and Family Panel Pairfam. A German-speaking sample without children (N = 190; 117 female, 73 male), who reported not attempting to conceive or become pregnant during the last 12 months, was analyzed in comparison with a propensity score matched sample. Ambivalence was operationalized as the difference between the ideal and realistic number of children in wave 2. Data from wave 3 were used to assess contraceptive behavior. Depressed mood in wave 2 and consistency of contraceptive behavior in wave 3 were negatively correlated. After including ambivalence in wave 2 as a mediator in the model, the direct path between depressed mood and consistency of contraceptive behavior remained significant, with no significant mediation found. For men only, we observed a significant negative association of ambivalence with the consistency of contraceptive behavior in the last 3 months. No significant relationship was found between depressed mood and ambivalence. We conclude that future research aiming to better understand the consistency of contraceptive behavior should incorporate measures of ambivalence. [ABSTRACT FROM AUTHOR]

Purpose: In current clinical practice, recommendations regarding restrictions in daily life for children with cancer are often lacking or not evidence-based. Critically reviewing the evidence and formulating recommendations are therefore of great importance as social restrictions (e.g., swimming, school attendance, sports) can impair the quality of life of these children severely. Therefore, our aim was to develop a clinical practice guideline for clinicians, children, and their parents regarding social restrictions in children with cancer. Methods: A comprehensive multidisciplinary panel was assembled, comprising 21 professionals and patient representatives. A systematic literature review was performed, including dual appraisal of all citations. The GRADE methodology was used to extract, summarize, and assess the evidence. Multiple in-person meetings were held to rank outcomes, discuss evidence, complete evidence-to-decision frameworks, and formulate recommendations. Final recommendations were unanimously supported by all panel members. Results: Six studies, including 758 children, formed the evidence base for the recommendations. Given the scarcity of the available evidence and various designs of studies in children with cancer, additional evidence was extracted from adult oncology guidelines, and shared expert opinions were utilized. In total, 14 recommendations were formulated of which multiple result in changes in current policy and standard of practice in the Netherlands. Topics covered in this guideline are swimming, having pets, visiting the zoo or farm, performing sports or high-velocity events, attending school or kindergarten, and use of public transport. This guideline is not intended to provide recommendations for patients after end of treatment, for palliative care settings, or for children undergoing a stem cell transplantation. Conclusions: In this clinical practice guideline, we provide recommendations regarding restrictions in daily life in children with cancer. These include evidence-based recommendations and, in the absence of sufficient evidence, recommendations based on expert evidence. With these recommendations, we provide guidance for clinicians, children, and parents and contribute to improving quality of life for children with cancer. [ABSTRACT FROM AUTHOR]

Creatine is a natural nitrogenous organic acid that is integral to energy metabolism and crucial for proper cell functioning. The kidneys are involved in the first step of creatine production. With kidney transplantation being the gold-standard treatment for end-stage kidney disease, kidney transplant recipients (KTR) may be at risk of impaired creatine synthesis. We aimed to compare creatine homeostasis between KTR and controls. Plasma and urine concentrations of arginine, glycine, guanidinoacetate, creatine and creatinine were measured in 553 KTR and 168 healthy controls. Creatine intake was assessed using food frequency questionnaires. Iothalamate-measured GFR data were available in subsets of 157 KTR and 167 controls. KTR and controls had comparable body weight, height and creatine intake (all P > 0.05). However, the total creatine pool was 14% lower in KTR as compared to controls (651 ± 178 vs. 753 ± 239 mmol, P < 0.001). The endogenous creatine synthesis rate was 22% lower in KTR as compared to controls (7.8 ± 3.0 vs. 10.0 ± 4.1 mmol per day, P < 0.001). Despite lower GFR, the plasma guanidinoacetate and creatine concentrations were 21% and 41% lower in KTR as compared to controls (both P < 0.001). Urinary excretion of guanidinoacetate and creatine were 66% and 59% lower in KTR as compared to controls (both P < 0.001). In KTR, but not in controls, a higher measured GFR was associated with a higher endogenous creatine synthesis rate (std. beta: 0.21, 95% CI: 0.08; 0.33; P = 0.002), as well as a higher total creatine pool (std. beta: 0.22, 95% CI: 0.11; 0.33; P < 0.001). These associations were fully mediated (93% and 95%; P < 0.001) by urinary guanidinoacetate excretion which is consistent with production of the creatine precursor guanidinoacetate as rate-limiting factor. Our findings highlight that KTR have a disturbed creatine homeostasis as compared to controls. Given the direct relationship of measured GFR with endogenous creatine synthesis rate and the total creatine pool, creatine supplementation might be beneficial in KTR with low kidney function. Trial registration ID: NCT02811835. Trial registration URL: https://clinicaltrials.gov/ct2/show/NCT02811835. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this work is to evaluate secukinumab vs. placebo in a challenging-to-treat and smaller US patient subpopulation of the international FUTURE 2–5 studies in patients with psoriatic arthritis (PsA). Methods: Data were pooled from US patients enrolled in the phase 3 FUTURE 2–5 studies (NCT01752634, NCT01989468, NCT02294227, and NCT02404350). Patients received secukinumab 300 or 150 mg with subcutaneous loading dose, secukinumab 150 mg without subcutaneous loading dose, or placebo. Categorical efficacy and health-related quality-of-life (QoL) outcomes and safety were evaluated at week 16. Subgroup analyses were performed based on tumor necrosis factor inhibitor (TNFi) status and body mass index (BMI). For hypothesis generation, odds ratios (ORs) for American College of Rheumatology (ACR) 20/50/70 and Psoriasis Area and Severity Index (PASI) 75/90/100 responses by treatment were estimated using logistic regression without adjustment for multiple comparisons. Results: Of 2148 international patients originally randomized, 279 US patients were included in this pooled analysis. Mean BMI was > 30 kg/m2 and 55.2% had prior TNFi treatment. ORs for ACR20/50/70 significantly favored patients receiving secukinumab 300 mg and 150 mg with loading dose vs. placebo (P < 0.05), but not those receiving secukinumab 150 mg without loading dose vs. placebo. For PASI75, ORs favored all secukinumab groups over placebo (P < 0.05); for PASI90 and PASI100, only the secukinumab 300-mg group was significantly favored over placebo (P < 0.05). Conclusions: In this challenging sub-population of US patients with PsA, secukinumab provided rapid improvements in disease activity and QoL. Patients with PsA and active psoriasis might benefit more from secukinumab 300 mg than 150 mg. [ABSTRACT FROM AUTHOR]

The accuracy of hourly global horizontal irradiance forecasts provided by the ICON (Icosahedral Nonhydrostatic Weather and Climate Model), GFS (Global Forecast System), and MeteoFrance Global models for Moscow, Russia, over a 36-h forecast horizon, is analyzed. The study investigates the suitability of these freely available global Numerical Weather Prediction (NWP) models for predicting the output of PV power plants, considering the standards of the Russian wholesale electricity and capacity market. The study conducts a comparative assessment of the forecasts from the mentioned models. A notable conclusion drawn from the study is the superior performance of all the NWP models over the naive 36-h persistence forecast, as indicated by the root mean square error, mean absolute error and mean bias error metrics. The overall findings suggest a higher accuracy of hourly global horizontal irradiance forecasts from the ICON model compared to the others under the investigated conditions. [ABSTRACT FROM AUTHOR]

A large proportion of human proteins contain post-translational modifications that cannot be synthesized by prokaryotes. Thus, mammalian expression systems are often employed to characterize structure/function relationships using NMR spectroscopy. Here we define the selective isotope labeling of secreted, post-translationally modified proteins using human embryonic kidney (HEK)293 cells. We determined that alpha-[15N]- atoms from 10 amino acids experience minimal metabolic scrambling (C, F, H, K, M, N, R, T, W, Y). Two more interconvert to each other (G, S). Six others experience significant scrambling (A, D, E, I, L, V). We also demonstrate that tuning culture conditions suppressed V and I scrambling. These results define expectations for 15N-labeling in HEK293 cells. [ABSTRACT FROM AUTHOR]

Purpose: Long-term follow-up (LTFU) care for childhood cancer survivors (CCSs) is essential to improve and maintain their quality of life. The Survivorship Passport (SurPass) is a digital tool which can aid in the delivery of adequate LTFU care. During the European PanCareSurPass (PCSP) project, the SurPass v2.0 will be implemented and evaluated at six LTFU care clinics in Austria, Belgium, Germany, Italy, Lithuania and Spain. We aimed to identify barriers and facilitators to the implementation of the SurPass v2.0 with regard to the care process as well as ethical, legal, social and economical aspects. Methods: An online, semi-structured survey was distributed to 75 stakeholders (LTFU care providers, LTFU care program managers and CCSs) affiliated with one of the six centres. Barriers and facilitators identified in four centres or more were defined as main contextual factors influencing implementation of SurPass v2.0. Results: Fifty-four barriers and 50 facilitators were identified. Among the main barriers were a lack of time and (financial) resources, gaps in knowledge concerning ethical and legal issues and a potential increase in health-related anxiety in CCSs upon receiving a SurPass. Main facilitators included institutions' access to electronic medical records, as well as previous experience with SurPass or similar tools. Conclusions: We provided an overview of contextual factors that may influence SurPass implementation. Solutions should be found to overcome barriers and ensure effective implementation of SurPass v2.0 into routine clinical care. Implications for Cancer Survivors: These findings will be used to inform on an implementation strategy tailored for the six centres. [ABSTRACT FROM AUTHOR]

Impaired respiratory variation of right atrial pressure (RAP) in severe pulmonary hypertension (PH) suggests difficulty tolerating increased preload during inspiration. Our study explores whether this impairment links to specific factors: right ventricular (RV) diastolic function, elevated RV afterload, systolic RV function, or RV-pulmonary arterial (PA) coupling. We retrospectively evaluated respiratory RAP variation in all participants enrolled in the EXERTION study. Impaired respiratory variation was defined as end-expiratory RAP − end-inspiratory RAP ≤ 2 mm Hg. RV function and afterload were evaluated using conductance catheterization. Impaired diastolic RV function was defined as end-diastolic elastance (Eed) ≥ median (0.19 mm Hg/mL). Seventy-five patients were included; PH was diagnosed in 57 patients and invasively excluded in 18 patients. Of the 75 patients, 31 (41%) had impaired RAP variation, which was linked with impaired RV systolic function and RV-PA coupling and increased tricuspid regurgitation and Eed as compared to patients with preserved RAP variation. In backward regression, RAP variation associated only with Eed. RAP variation but not simple RAP identified impaired diastolic RV function (area under the receiver operating characteristic curve [95% confidence interval]: 0.712 [0.592, 0.832] and 0.496 [0.358, 0.634], respectively). During exercise, patients with impaired RAP variation experienced greater RV dilatation and reduced diastolic reserve and cardiac output/index compared with patients with preserved RAP variation. Preserved RAP variation was associated with a better prognosis than impaired RAP variation based on the 2022 European Society of Cardiology/European Respiratory Society risk score (chi-square P = 0.025) and survival free from clinical worsening (91% vs 71% at 1 year and 79% vs 50% at 2 years [log-rank P = 0.020]; hazard ratio: 0.397 [95% confidence interval: 0.178, 0.884]). Subgroup analyses in patients with group 1 and group 4 PH demonstrated consistent findings with those observed in the overall study cohort. Respiratory RAP variations reflect RV diastolic function, are independent of RV-PA coupling or tricuspid regurgitation, are associated with exercise-induced haemodynamic changes, and are prognostic in PH. Trial registration. NCT04663217. [ABSTRACT FROM AUTHOR]

This study presents a novel framework that integrates the universal jamming gripper (UG) with unmanned aerial vehicles (UAVs) to enable automated grasping with no human operator in the loop. Grounded in the principles of granular jamming, the UG exhibits remarkable adaptability and proficiency, navigating the complexities of soft aerial grasping with enhanced robustness and versatility. Central to this integration is a uniquely formulated constrained trajectory optimization using model predictive control, coupled with a robust force control strategy, increasing the level of automation and operational reliability in aerial grasping. This control structure, while simple, is a powerful tool for various applications, ranging from material handling to disaster response, and marks an advancement toward genuine autonomy in aerial manipulation tasks. The key contribution of this research is the combination of a UG with a suitable control strategy, that can be kept relatively straightforward thanks to the mechanical intelligence built into the UG. The algorithm is validated through numerical simulations and virtual experiments. [ABSTRACT FROM AUTHOR]

Age-related diseases pose great challenges to health care systems worldwide. During aging, endothelial senescence increases the risk for cardiovascular disease. Recently, it was described that Phosphatase 1 Nuclear Targeting Subunit (PNUTS) has a central role in cardiomyocyte aging and homeostasis. Here, we determine the role of PNUTS in endothelial cell aging. We confirm that PNUTS is repressed in senescent endothelial cells (ECs). Moreover, PNUTS silencing elicits several of the hallmarks of endothelial aging: senescence, reduced angiogenesis and loss of barrier function. Findings are validate in vivo using endothelial-specific inducible PNUTS-deficient mice (Cdh5-CreERT2;PNUTSfl/fl), termed PNUTSEC-KO. Two weeks after PNUTS deletion, PNUTSEC-KO mice present severe multiorgan failure and vascular leakage. Transcriptomic analysis of PNUTS-silenced HUVECs and lungs of PNUTSEC-KO mice reveal that the PNUTS-PP1 axis tightly regulates the expression of semaphorin 3B (SEMA3B). Indeed, silencing of SEMA3B completely restores barrier function after PNUTS loss-of-function. These results reveal a pivotal role for PNUTS in endothelial homeostasis through a SEMA3B downstream pathway that provides a potential target against the effects of aging in ECs. PNUTS-deficient mice exhibit multiorgan failure and vascular leakage. PNUTS regulates SEMA3B, suggesting a target for endothelial aging. [ABSTRACT FROM AUTHOR]

Granular gases demand models capable of capturing their distinct characteristics. The widely employed inelastic hard-sphere model (IHSM) introduces complexities that are compounded when incorporating realistic features like surface roughness and rotational degrees of freedom, resulting in the more intricate inelastic rough hard-sphere model (IRHSM). This paper focuses on the inelastic rough Maxwell model (IRMM), presenting a more tractable alternative to the IRHSM and enabling exact solutions. Building on the foundation of the inelastic Maxwell model (IMM) applied to granular gases, the IRMM extends the mathematical representation to encompass surface roughness and rotational degrees of freedom. The primary objective is to provide exact expressions for the Navier–Stokes–Fourier transport coefficients within the IRMM, including the shear and bulk viscosities, the thermal and diffusive heat conductivities, and the cooling-rate transport coefficient. In contrast to earlier approximations in the IRHSM, our study unveils inherent couplings, such as shear viscosity to spin viscosity and heat conductivities to counterparts associated with a torque-vorticity vector. These exact findings provide valuable insights into refining the Sonine approximation applied to the IRHSM, contributing to a deeper understanding of the transport properties in granular gases with realistic features. [ABSTRACT FROM AUTHOR]

COVID-19, caused by SARS-CoV-2, can lead to a severe inflammatory disease characterized by significant lymphopenia. However, the underlying cause for the depletion of T-cells in COVID-19 patients remains incompletely understood. In this study, we assessed the presence of different T-cell subsets in the progression of COVID-19 from mild to severe disease, with a focus on TCF1 expressing progenitor T-cells that are needed to replenish peripheral T-cells during infection. Our results showed a preferential decline in TCF1+ progenitor CD4 and CD8+ T-cells with disease severity. This decline was seen in various TCF1+ subsets including naive, memory and effector-memory cells, and surprisingly, was accompanied by a loss in cell division as seen by a marked decline in Ki67 expression. In addition, TCF1+ T-cells showed a reduction in pro-survival regulator, BcL2, and the appearance of a new population of TCF1 negative caspase-3 expressing cells in peripheral blood from patients with severe disease. The decline in TCF1+ T-cells was also seen in a subgroup of severe patients with vitamin D deficiency. Lastly, we found that sera from severe patients inhibited TCF1 transcription ex vivo which was attenuated by a blocking antibody against the cytokine, interleukin-12 (IL12). Collectively, our findings underscore the potential significance of TCF1+ progenitor T-cells in accounting for the loss of immunity in severe COVID-19 and outline an array of markers that could be used to identify disease progression. This study shows that severity of disease in COVID-19 patients is characterized by the preferential loss of TCF1+ progenitor T-cells needed to self-renew and replenish the immune system. [ABSTRACT FROM AUTHOR]

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype–phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Copyright of Monatsschrift Kinderheilkunde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: In the over-80 s, femoral bone is often osteoporotic and unlikely to be conducive to periprosthetic bone rehabitation. This observation often leads to cemented fixation for hemiarthroplasty in femoral neck fracture. Hydroxyapatite is a bioactive coating that has already demonstrated its osteoinductive properties. Our hypothesis is that hydroxyapatite enables prosthetic osseointegration in patients over 80, as well as periprosthetic cortical thickening. The objective was to evaluate the osseointegration of a hydroxyapatite-coated femoral stem in femoral neck fractures in the over-80 s, and the evaluation of the periprosthetic bone regeneration permitted by hydroxyapatite. Methods: This was a retrospective study. Osseointegration and periprosthetic bone regeneration were assessed on pre-operative, immediate post-operative and last follow-up radiographs with Engh score, O-SS score, cortical index, Canal Bone Ration (CBR) and Canal Fill Ratio (CFR). Results: One hundred and forty-six patients were included. At last follow-up, 99.3% (n = 145) of stems were osseointegrated. The mean Engh score was 19.9 [SD 3.1]. The mean O-SS score was 19.1 [SD 2.4], corresponding to very good osseointegration. The mean CBR at last follow-up was 0.48 [SD 0.07], corresponding to a non-osteoporotic femur. There was a significant difference with pre-operative CBR (p < 0,001). The pre-operative cortical index and the index at the last follow-up were significantly different for all levels of measurement (p < 0,001). The CFR at last follow-up was also significantly different with the post-operative CFR (p < 0,001). Conclusion: This study shows the value of using a hydroxyapatite-coated stem on senile, osteoporotic bone to improve cortical thickness along the entire length of femoral bone. [ABSTRACT FROM AUTHOR]

Stem cell-based therapy is a potential alternative strategy for brain repair, with neural stem cells (NSC) presenting as the most promising candidates. Obtaining sufficient quantities of NSC for clinical applications is challenging, therefore alternative cell types, such as neural crest-derived dental pulp stem cells (DPSC), may be considered. Human DPSC possess neurogenic potential, exerting positive effects in the damaged brain through paracrine effects. However, a method for conversion of DPSC into NSC has yet to be developed. Here, overexpression of octamer-binding transcription factor 4 (OCT4) in combination with neural inductive conditions was used to reprogram human DPSC along the neural lineage. The reprogrammed DPSC demonstrated a neuronal-like phenotype, with increased expression levels of neural markers, limited capacity for sphere formation, and enhanced neuronal but not glial differentiation. Transcriptomic analysis further highlighted the expression of genes associated with neural and neuronal functions. In vivo analysis using a developmental avian model showed that implanted DPSC survived in the developing central nervous system and respond to endogenous signals, displaying neuronal phenotypes. Therefore, OCT4 enhances the neural potential of DPSC, which exhibited characteristics aligning with neuronal progenitors. This method can be used to standardise DPSC neural induction and provide an alternative source of neural cell types. [ABSTRACT FROM AUTHOR]

Purpose: Insulin sensitivity (Si) and its role in glucose intolerance of acromegaly has been extensively evaluated. However, data on insulin secretion is limited. We aimed to assess stimulated insulin secretion using an intravenous glucose tolerance test (IVGTT) in active acromegaly. Methods: We performed an IVGTT in 25 patients with active acromegaly (13 normal glucose tolerance [NGT], 6 impaired glucose tolerance [IGT] and 6 diabetes mellitus [DM]) and 23 controls (8 lean NGT, 8 obese NGT and 7 obese IGT). Serum glucose and insulin were measured at 20 time points along the test to calculate Si and acute insulin response (AIRg). Medical treatment for acromegaly or diabetes was not allowed. Results: In acromegaly, patients with NGT had significantly (p for trend < 0.001) higher AIRg (3383 ± 1082 pmol*min/L) than IGT (1215 ± 1069) and DM (506 ± 600). AIRg was higher in NGT (4764 ± 1180 pmol*min/L) and IGT (3183 ± 3261) controls with obesity than NGT (p = 0.01) or IGT (p = 0.17) acromegaly. Si was not significantly lower in IGT (0.68 [0.37, 0.88] 106*L/pmol*min) and DM (0.60 [0.42, 0.84]) than in NGT (0.81 [0.58, 1.55]) patients with acromegaly. NGT (0.33 [0.30, 0.47] 106*L/pmol*min) and IGT (0.37 [0.21, 0.66]) controls with obesity had lower Si than NGT (p = 0.001) and IGT (p = 0.43) acromegaly. Conclusion: We demonstrated that low insulin secretion is the main driver behind glucose intolerance in acromegaly. Compared to NGT and IGT controls with obesity, patients with NGT or IGT acromegaly had higher Si. Together, these findings suggest that impaired insulin secretion might be a specific mechanism for glucose intolerance in acromegaly. [ABSTRACT FROM AUTHOR]

Purpose of Review: The objective of this review is to summarize the literature on the prevalence and diagnosis of obesity and its metabolic profile, including bone metabolism, focusing on the main inflammatory and turnover bone mediators that better characterize metabolically healthy obesity phenotype, and to summarize the therapeutic interventions for obesity with their effects on bone health. Recent Findings: Osteoporosis and fracture risk not only increase with age and menopause but also with metabolic diseases, such as diabetes mellitus. Thus, patients with high BMI may have a higher bone fragility and fracture risk. However, some obese individuals with healthy metabolic profiles seem to be less at risk of bone fracture. Summary: Obesity has become an alarming disease with growing prevalence and multiple metabolic comorbidities, resulting in a significant burden on healthcare and increased mortality. The imbalance between increased food ingestion and decreased energy expenditure leads to pathological adipose tissue distribution and function, with increased secretion of proinflammatory markers and harmful consequences for body tissues, including bone tissue. However, some obese individuals seem to have a healthy metabolic profile and may not develop cardiometabolic disease during their lives. This healthy metabolic profile also benefits bone turnover and is associated with lower fracture risk. [ABSTRACT FROM AUTHOR]

Background: Whether spinocerebellar ataxia 27B (SCA27B) may present as a cerebellar multiple system atrophy (MSA-C) mimic remains undetermined. Objectives: To assess the prevalence of FGF14 (GAA)≥250 expansions in patients with MSA-C, to compare SCA27B and MSA-C clinical presentation and natural history. Methods: FGF14 expansion screening combined with longitudinal deep-phenotyping in a prospective cohort of 195 patients with sporadic late-onset cerebellar ataxia. Results: After a mean disease duration of 6.4 years, 111 patients were not meeting criteria for MSA-C while 24 and 60 patients had a final diagnosis of possible and probable MSA-C, respectively. 16 patients carried an FGF14 (GAA)≥250 expansion in the group not meeting MSA-C criteria (14.4%), 3 patients in the possible MSA-C group (12.5%), but none among probable MSA-C cases. SCA27B patients were evolving more slowly than probable MSA-C patients. Conclusions: FGF14 (GAA)≥250 expansion may account for MSA look-alike cases and should be screened among slow progressors. [ABSTRACT FROM AUTHOR]

Chile, the world’s largest copper producer, generates massive amounts of mine tailings that are a source of ongoing environmental concern for local communities. The main objective of this work is to evaluate the concentration of As, Cd, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Zn and SO42− in soils, water and vegetation in the communities surrounding the Cu Ovejería mine tailings dam, in central Chile. Soils, water and plants samples were collected from the towns of Chacabuco, Huechún, Huertos Familiares, Punta Peuco and Santa Matilde, which are located at 3 to 8 km from the mine tailings site, operated by CODELCO since 1999. The results showed that the levels of metals/metalloids and SO42− in water (pH 6.7–7.9) met both WHO limits and Chilean water quality standards for multiples uses. In soil (pH 7.7–8.4), total and available concentrations of metals/metalloids did not exceed international reference values. Plants with acceptable levels of metals and S were Citrus limon, Eucalyptus, Schinus molle, Prunus persica, Medicago sativa, Citrus sinensis and Ficus carica. The only species with Fe content well above the reference value and with high concentrations of other metals (Cu, Mn, Mo and Pb) was Acacia caven. The concentrations of chemical species determined between 2015 and 2018, in different media and locations near the active Cu tailings dam Ovejeria, in central Chile, allow to conclude that in general the levels are comparable to national and international references and do not indicate contamination. [ABSTRACT FROM AUTHOR]

Abstract Alzheimer's disease (AD) is the most common form of dementia, and neuroinflammation is an important hallmark of the pathogenesis. Tumor necrosis factor (TNF) might be detrimental in AD, though the results coming from clinical trials on anti‐TNF inhibitors are inconclusive. TNFR1, one of the TNF signaling receptors, contributes to the pathogenesis of AD by mediating neuronal cell death. The blood–cerebrospinal fluid (CSF) barrier consists of a monolayer of choroid plexus epithelial (CPE) cells, and AD is associated with changes in CPE cell morphology. Here, we report that TNF is the main inflammatory upstream mediator in choroid plexus tissue in AD patients. This was confirmed in two murine AD models: transgenic APP/PS1 mice and intracerebroventricular (icv) AβO injection. TNFR1 contributes to the morphological damage of CPE cells in AD, and TNFR1 abrogation reduces brain inflammation and prevents blood–CSF barrier impairment. In APP/PS1 transgenic mice, TNFR1 deficiency ameliorated amyloidosis. Ultimately, genetic and pharmacological blockage of TNFR1 rescued from the induced cognitive impairments. Our data indicate that TNFR1 is a promising therapeutic target for AD treatment.

The Escherichia coli TetR-related transcriptional regulator RutR is involved in the coordination of pyrimidine and purine metabolism. Here we report that lysine acetylation modulates RutR function. Applying the genetic code expansion concept, we produced site-specifically lysine-acetylated RutR proteins. The crystal structure of lysine-acetylated RutR reveals how acetylation switches off RutR-DNA-binding. We apply the genetic code expansion concept in E. coli in vivo revealing the consequences of RutR acetylation on the transcriptional level. We propose a model in which RutR acetylation follows different kinetic profiles either reacting non-enzymatically with acetyl-phosphate or enzymatically catalysed by the lysine acetyltransferases PatZ/YfiQ and YiaC. The NAD+-dependent sirtuin deacetylase CobB reverses enzymatic and non-enzymatic acetylation of RutR playing a dual regulatory and detoxifying role. By detecting cellular acetyl-CoA, NAD+ and acetyl-phosphate, bacteria apply lysine acetylation of transcriptional regulators to sense the cellular metabolic state directly adjusting gene expression to changing environmental conditions. The mechanisms underlying adaptation of bacteria to changing environmental conditions remain poorly understood. Here, the authors show bacteria using lysine acetylation of transcriptional regulators to adjust gene expression to changing conditions. [ABSTRACT FROM AUTHOR]

Copyright of Die Unfallchirurgie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: Investigation of Microtubuli-associated Protein 2 (MAP2) expression and its clinical relevance in prostate cancer. Material and Methods: MAP2 expression was immunohistochemically analysed on radical prostatectomy specimens using whole block sections (n = 107) and tissue microarrays (TMA; n = 310). The staining intensity was evaluated for carcinoma, benign tissue and prostatic intraepithelial neoplasia. Expression data were correlated with clinicopathological parameters and biochemical recurrence-free survival. Additionally, MAP2 protein expression was quantitatively analysed in the serum of histologically confirmed prostate carcinoma patients and the control group using a commercial enzyme-linked immunosorbent assay. Results: MAP2 staining was significantly stronger in neoplastic tissue than in non-neoplastic prostatic glands, both in whole block sections (p < 0.01) and in TMA sections (p < 0.05). TMA data revealed significantly stronger MAP2 staining in high-grade tumors. Survival analysis showed a significant correlation between strong MAP2 staining in carcinoma and shortened biochemical recurrence-free survival after prostatectomy (p < 0.001). Multivariate Cox regression analysis confirmed MAP2 as an independent predictor for an unfavourable course. Mean MAP2 serum levels for non-PCA vs. PCA patients differed significantly (non-PCA = 164.7 pg/ml vs. PCA = 242.5 pg/ml, p < 0.001). Conclusion: The present data support MAP2 as a novel biomarker in PCA specimens. MAP2 is correlated with tumor grade and MAP2 high-expressing PCA is associated with an increased risk of biochemical recurrence after radical prostatectomy. Future studies are necessary to evaluate MAP2 as a valuable immunohistochemical biomarker in preoperative PCA diagnostic procedures, in particular with regard to treatment modalities. [ABSTRACT FROM AUTHOR]

We investigated whether urinary vascular non-inflammatory molecule-1 (vanin-1), a promising early-onset tubular injury marker, correlates with other established tubular injury markers and is associated with graft failure in kidney transplant recipients (KTR). We measured 24 h urinary vanin-1 excretion in 656 KTR (age 53 ± 13 years, 43% female, estimated glomerular filtration rate (eGFR) 53 ± 21 mL/min/1.73 m2) who had undergone kidney transplantation ≥ 1 year. The median 24 h urinary vanin-1 excretion was 145 [51–331] pmol/24 h. 24 h urinary vanin-1 excretion correlated weakly but significantly with other tubular injury markers (ρ = 0.14, p < 0.001 with urinary liver-type fatty acid binding protein, ρ = 0.13, p = 0.001 with urinary post-translationally modified fetuin-A protein, and ρ = 0.10, p = 0.011 with plasma neutrophil gelatinase-associated lipocalin) and with eGFR (ρ = − 0.13, p = 0.001). During a median follow-up of 7.4 [4.9–8.0] years, 94 (14%) KTR developed death-censored graft failure. In multivariable Cox regression analyses, 24 h urinary vanin-1 excretion was not associated with an increased risk of death-censored graft failure (adjusted hazard ratio [95% confidence interval] = 0.96 [0.86–1.07], p = 0.5). In conclusion, our findings do not support the role of urinary vanin-1 as a biomarker of graft failure after kidney transplantation. [ABSTRACT FROM AUTHOR]

Purpose: The KLIK method is a tool to systematically monitor and discuss Health Related Quality of Life (HRQOL) in clinical practice. It has been successfully used in clinical practice in The Netherlands, and has recently been implemented in survivorship care for young adult childhood cancer survivors (CCSs). This study evaluates implementation fidelity and satisfaction of CCSs and healthcare practitioners (HCPs) with the KLIK method in survivorship care. Methods: CCSs' HRQOL was monitored using the KLIK questionnaire (PedsQL generic 18–30 years). In a mixed-methods design, implementation fidelity was based on registrations, and user satisfaction was assessed with evaluation surveys (CCSs) and semi-structured interviews (CCSs, HCPs). Descriptive statistics and qualitative analysis methods were used. Results: A total of 245 CCSs were eligible for the study. Fidelity was 79.2% (194/245) for registration in the KLIK PROM portal, 89.7% (174/194) for completed KLIK questionnaires, 74.7% (130/174) for its discussion during consultation. Of the eligible CCSs, 17.6% (43/245) completed the study evaluation survey. Five CCSs and HCPs were invited for an interview and participated. CCSs (7.7/10) and HCPs (7.5/10) were satisfied with the KLIK method. Reported facilitators included increased insight into CCSs' functioning, improved preparation before, and communication during consultation, without lengthening consultation duration. Barriers included CCSs not always completing KLIK questionnaires, incomplete content of the KLIK questionnaire, and the need for customization for CCSs with cognitive disabilities. Conclusion: The KLIK method is a feasible and valuable tool to systematically monitor and discuss HRQOL in survivorship care. Integration of the KLIK method within the organization is essential, with structural support in reminding CCSs to complete questionnaires. [ABSTRACT FROM AUTHOR]

Purpose: Notch and Wnt/β-catenin signaling are responsible for regulation of intestinal stem cells (ISCs) proliferation and differentiation. The purpose of the study was to evaluate Wnt/β-catenin and Notch signaling roles in regulation of ISC differentiation following ischemia–reperfusion (IR) injury in a rat. Methods: Rats were assigned into two groups: Sham rats underwent laparotomy without vascular intervention and IR rats underwent occlusion of SMA and portal vein for 20 min followed by 48 h of reperfusion. Wnt/β-catenin and Notch-related gene expression were determined using Real-Time PCR. Enterocyte proliferation, differentiation and Wnt-related proteins were determined by immunohistochemistry. Results: IR rats demonstrated a significant decrease in β-catenin gene expression, a decrease in cyclin D1 and β-catenin positive cells in jejunum and ileum compared to Sham rats. IR rats demonstrated a significant increase in Notch-related gene expression in jejunum and ileum compared to Sham rats. The number of secretory cells was higher mainly in the jejunum and number of absorptive cells was significantly lower in jejunum and lower in ileum in IR rats compared to Sham rats. Conclusions: Intestinal stem-cell differentiation is toward secretory cells 48 h after IR injury; however, Wnt/β-catenin pathway inhibition and Notch-related gene expression stimulation suggest crosstalk between pathways. [ABSTRACT FROM AUTHOR]

Introduction: This observational study evaluated response in patients with rheumatoid arthritis (RA) who switched from an interleukin-6 receptor inhibitor (IL-6Ri) to a Janus kinase inhibitor (JAKi) and vice versa. Methods: Adult patients with RA, who initiated IL-6Ri or JAKi (following discontinuation of JAKi or IL-6Ri, respectively) during/after December 2012 and had a 6-month follow-up visit were enrolled. Clinical outcomes were evaluated at baseline and the follow-up visit. Continuous outcomes included Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire (HAQ), pain, fatigue, tender joint count, swollen joint count, Physician Global Assessment (MDGA), Patient Global Assessment (PtGA), and morning stiffness duration. Categorical outcomes included the proportion of patients achieving CDAI low disease activity (LDA), remission, and minimal clinically important differences (MCIDs) for HAQ, pain, fatigue, MDGA, and PtGA. Continuous outcomes were summarized as mean changes from baseline, and categorical outcomes as response rates. Differences in the outcome measures between groups were evaluated using linear and logistic regression models. Results: Between IL-6Ri (n = 100) and JAKi initiators (n = 129), no significant differences were noted for continuous outcomes. Within both groups, a significant proportion of patients achieved LDA, remission, and MCIDs for other measures, although the odds of achieving LDA were higher among IL-6Ri (vs. JAKi) initiators with moderate-to-severe disease (adjusted odds ratio: 3.30 [1.01, 10.78]). Conclusions: Patients with RA can achieve improvement in response when switching between IL-6Ri and JAKi. Although both therapies affect the IL-6 pathway, there are distinct mechanisms of action, which likely contribute to their clinical improvement, when reciprocally switched as follow-on treatments. [ABSTRACT FROM AUTHOR]

Introduction: To understand factors leading to biologic switches and to develop a readily usable model with data collected in clinical care at preceding visits, with the overall aim to predict the probability of switching biologic at a subsequent clinic visit in patients with rheumatoid arthritis (RA). Methods: Participants were adults with RA participating in the CorEvitas RA registry. The study matched patients who switched biologics or targeted synthetic disease-modifying anti-rheumatic drugs (tsDMARDs) with control patients who had not switched biologics/tsDMARDs; the cohort was divided into a training and test set for prediction model development and validation. Using the training set, the best subset regression, lasso, and elastic net methods were used to determine the best potential models. Area under the ROC curve (AUC) was used for the final selection of the best model, and estimated coefficients of this model were applied to the test dataset to predict switching. Results: A total of 5050 patients were included, of whom 3016 were in the training set and 2034 were in the test dataset. The average age was 59.6 years, the majority were female (3998, 79.2%), and the average duration of RA at the time of switch or control visit was 12.8 years. The final model included prior Clinical Disease Activity Index (CDAI) by category, prior patient pain measurement, change in CDAI from baseline, age group, and number of prior biologics, all of which were significantly associated with switching biologics. The AUC was 0.690 for this model with the training dataset. The model was then applied to the test data with similar performance; the AUC was 0.687. Conclusion: We have developed a simple model to determine the probability of switching biologics for RA at the following clinic visit. This model could be used in practice to provide clinicians with more information about their patient's trajectory and likelihood of switching to a new biologic. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the impact of treatment for Hodgkin lymphoma (HL) on clinical reproductive markers and pregnancy outcomes. Methods: This study was embedded within the DCOG LATER-VEVO study; a Dutch, multicenter, retrospective cohort study between 2004 and 2014. Serum anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B, antral follicle count (AFC), and self-reported (first) pregnancy outcomes were evaluated in female childhood HL survivors and controls. Results: 84 HL survivors and 798 controls were included, aged 29.6 and 32.7 years old at time of assessment. Median age at HL diagnosis was 13.4 years. Cyclophosphamide equivalent dose (CED-score) exceeded 6000 mg/m2 in 56 women and 14 survivors received pelvic irradiation. All clinical markers were significantly deteriorated in survivors (odds-ratio for low AMH (< p10) 10.1 [95% CI 4.9; 20.6]; low AFC (< p10) 4.6 [95% CI 2.1; 9.9]; elevated FSH (> 10 IU/l) 15.3 [95% CI 5.7; 41.1], low Inhibin B (< 20 ng/l) 3.6 [ 95% CI 1.7; 7.7], p < 0.001). Pregnancy outcomes were comparable between survivors and controls (± 80% live birth, ± 20% miscarriage). However, survivors were significantly younger at first pregnancy (27.0 years vs 29.0 years, P = 0.04). Adjusted odds-ratio for time to pregnancy > 12 months was 2.5 [95% CI 1.1; 5.6] in survivors, p = 0.031. Adverse outcomes were specifically present after treatment with procarbazine and higher CED-score. Conclusion: HL survivors appear to have an impaired ovarian reserve. However, chance to achieve pregnancy seems reassuring at a young age. Additional follow-up studies are needed to assess fertile life span and reproductive potential of HL survivors, in particular for current HL treatments that are hypothesized to be less gonadotoxic. [ABSTRACT FROM AUTHOR]

The treatment of burn injury patients is a unique challenge for clinicians. The extent of thermal injuries ranges from very small burns to life-threatening burn injuries. Insufficient treatment can result in a substantial impairment in the quality of life. In order to avoid such sequelae a targeted treatment must be carried out. A precise diagnosis determines the necessary treatment. Superficial second-degree burns (2a) not involving the face, hand or joints with a total body surface area smaller than 10% can usually be treated with modern wound dressings in an outpatient setting. Deep second-degree burns (2b) are an indication for debridement. In addition to the classical surgical procedures with tangential excision, enzymatic debridement can also be employed. Similarly, indeterminate burns (2a/2b) are also considered to be an indication for enzymatic debridement. Third-degree burns are treated with early debridement and skin grafting. These patients can also benefit from special dermal replacement procedures for an improvement of the functional and esthetic results. Due to the long-term visible sequelae of burns, aftercare of these patients is indicated. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations have been performed to compute the isothermal compressibility κ T of liquid propan-1-ol in the temperature range 200 ≤ T ≤ 300 K. A change in behaviour, from normal (high T) to anomalous (low T), has been identified for κ T at 210 < T < 230 K. The average number of hydrogen bonds (H–bond) per molecule turns to saturation in the same temperature interval, suggesting the formation of a relatively rigid network. Indeed, simulation results show a strong tendency to form H–bond clusters with distinct boundaries, with the average largest size and width of the size distribution growing upon decreasing temperature, in agreement with previous theoretical and experimental studies. These results also emphasise a connection between the behaviour of κ T and the formation of nanometric structures. [ABSTRACT FROM AUTHOR]

Belantamab mafodotin, a B-cell maturation antigen-targeting antibody–drug conjugate (ADC), was investigated in Japanese patients with relapsed/refractory multiple myeloma in Part 1 of the phase I DREAMM-11 study. Patients who had received ≥ 2 prior lines of therapy including a proteasome inhibitor and immunomodulatory agent were eligible. Eight patients received belantamab mafodotin monotherapy at 2.5 mg/kg (n = 4) or 3.4 mg/kg (n = 4) by intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. Primary objectives were tolerability and safety, and secondary objectives included pharmacokinetics (PK) and efficacy. The most common Grade ≥ 3 adverse event was thrombocytopenia/platelet count decreased (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]), and no dose-limiting toxicities were observed. Ocular events, including keratopathy findings, were observed in most patients (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]) and were managed with dose modifications. All resolved within the study period. Overall response rates were 50% (2/4) in the 2.5 mg/kg cohort and 25% (1/4) in the 3.4 mg/kg cohort. Although PK profiles in Japanese patients varied, individual exposures overlapped with previous results in Western populations. Belantamab mafodotin monotherapy was generally well-tolerated and demonstrated clinical activity at both doses. [ABSTRACT FROM AUTHOR]