Search

Simultaneous inhibition of transforming growth factor‐β (TGF‐β) type I receptors Acvr1b and Tgfbr1 signalling has been associated with excessive skeletal muscle hypertrophy in vivo. However, it remains unclear whether the increased muscle mass in vivo is a direct result of inhibition of intracellular TGF‐β signalling or whether this is an indirect effect of an altered extracellular anabolic environment. Here, we tested whether individual or simultaneous knockdown of TGF‐β type I receptors in C2C12 myotubes was sufficient to induce muscle hypertrophy. The expression levels of TGF‐β type I receptors Acvr1b and Tgfbr1 in myotubes were knocked down individually or in combination in the absence or presence of TGF‐β1 and myostatin. Knocking down either Acvr1b or Tgfbr1 did not significantly change cell phenotype. Unexpectedly, simultaneous knockdown of both receptors reduced C2C12 myotube diameter, mRNA expression levels of Hgf, Ccn2 and Mymx with or without TGF‐β1 and myostatin administration. In spite of decreased phosphorylation of Smad2/3, phosphorylation of P70S6K was reduced. In addition, the gene expression level of β1‐syntrophin (Sntb1), which encodes a protein associated with the dystrophin−glycoprotein complex, was increased. Parallel experiments where Sntb1 gene expression was reduced showed an increase in myotube diameter and fusion of C2C12 myoblasts. Together, these results indicate that the knockdown of both TGF‐β type I receptors reduced myotube diameter. This atrophic effect was attributed to reduced protein synthesis signalling and an increased expression of β1‐syntrophin. These results have implications for our fundamental understanding of how TGF‐β signalling regulates skeletal muscle size. [ABSTRACT FROM AUTHOR]

Macrophage infiltration and accumulation in the atherosclerotic lesion are associated with plaque progression and instability. Depletion of macrophages from the lesion might provide valuable insights into plaque stabilization processes. Therefore, we assessed the effects of systemic and local macrophage depletion on atherogenesis. To deplete monocytes/macrophages we used atherosclerosis‐susceptible Apoe−/− mice, bearing a MaFIA (macrophage‐Fas‐induced‐apoptosis) suicide construct under control of the Csf1r (CD115) promotor, where selective apoptosis of Csf1r‐expressing cells was induced in a controlled manner, by administration of a drug, AP20187. Systemic induction of apoptosis resulted in a decrease in lesion macrophages and smooth‐muscle cells. Plaque size and necrotic core size remained unaffected. Two weeks after the systemic depletion of macrophages, we observed a replenishment of the myeloid compartment. Myelopoiesis was modulated resulting in an expansion of CSF1Rlo myeloid cells in the circulation and a shift from Ly6chi monocytes toward Ly6cint and Ly6clo populations in the spleen. Local apoptosis induction led to a decrease in plaque burden and macrophage content with marginal effects on the circulating myeloid cells. Local, but not systemic depletion of Csf1r+ myeloid cells resulted in decreased plaque burden. Systemic depletion led to CSF1Rlo‐monocyte expansion in blood, possibly explaining the lack of effects on plaque development. [ABSTRACT FROM AUTHOR]

Purpose: Total knee arthroplasty (TKA) is the standard treatment of end‐stage osteoarthritis. TKA is often used and, therefore, poses a healthcare and societal burden, which is likely to increase further. Headroom analyses evaluate a technology under development by making assumptions about its effectiveness. This article applies a headroom approach to forecast the potential value of innovations that improve TKA‐related care in the Netherlands in terms of cost‐effectiveness and surgeries avoided. Methods: A state‐transition model estimating lifetime direct health effects, healthcare‐ and societal costs and percentage of avoide d surgeries was developed. The model compared care as usual to five hypothetical interventions to calculate the headroom associated with (1) preventing the need for TKAs, (2) preventing the need for all TKA revisions, (3) postponing TKAs without quality‐of‐life loss, (4) preventing periprosthetic joint infections (PJIs) and (5) improving patient satisfaction. Results: Preventing the need for all TKAs amounted to €43,076 of headroom. Preventing the need for TKA revisions amounted to €2276 (5.8% of surgeries avoided), postponing TKAs by 5 years amounted to €7634 (32.4% of surgeries avoided), preventing PJIs amounted to €1187 (1.4% of surgeries avoided) and improving patient satisfaction amounted to €16,622 (0% of surgeries avoided). The headroom of each hypothetical intervention was highest in younger populations (<50 years of age). Conclusion: There is a headroom for improving TKA‐related care. Innovations to avoid or postpone TKA (i.e., joint‐preserving treatments) as well as those that improve patient satisfaction can be effective in maximizing the value for money and avoiding surgeries. Due to the decreasing average patient age, innovations to reduce revision rates and PJIs will become more valuable as these are most effective in younger patients. It is currently unclear how cost‐effectiveness considerations should be traded off against the prevention of surgery to reduce the increasing burden on the healthcare system. Level of Evidence: Level III economic evaluation/decision‐analytic model. [ABSTRACT FROM AUTHOR]

Over the last decade, the fact that novel perspectives on various aspects of soils have remained strongly controversial long after they emerged, without any kind of consensus being reached about them, raises question about the underlying reasons for this phenomenon. The on‐going debate on the usefulness of aggregates to describe the functions of soils illustrates some of the key aspects of that question. Similar debates on other soil‐related issues also appear stalled, or have been for a long time and are only now moving forward. This might suggest a fundamental aversion to change, which when it gets overcome, only does so slowly. However, at the same time, somewhat surprisingly, researchers appear willing to quickly seize opportunities provided by new idea or novel perspectives on other topics. In that context, the objective of the present article is to analyse in detail what may cause such contrasting reactions to novelty. We consider, then ultimately dismiss, explanations based on how strongly or not novel perspectives have been actively promoted, on how access to suitable technology may impede or only slow down perspective shifts and on whether a recent theory of the 'slowed canonical progress in large fields of science' applies to the relatively small soil science community. Then, taking soil aggregates as a case in point, we come to realize that it is the extent to which a novel perspective mandates an interdisciplinary approach that determines whether or not it is adopted quickly. From that standpoint, we envisage a number of practical actions that could be taken to facilitate in the future the emergence in soil science of interdisciplinary research efforts, which we argue are absolutely essential to successfully tackle the enormous complexity of soils and to come up with satisfactory answers to the daunting environmental and food security problems we currently face in their management. [ABSTRACT FROM AUTHOR]

Summary: Background and Objectives: Adoption and acceptance of digital health services (DHS) in the German population and in persons with skin diseases is unclear. Both factors were analyzed in this survey. Methods: A standardized survey with items on digital competences and attitudes, use and acceptance of DHS was applied to a representative sample of the German adult population. Bivariate and multivariate analyses were conducted. Results: Out of 2,101 participants, 29.9% reported having had skin diseases in the last 12 months. Among them, adoption and acceptance were at 43.6% and 52.3%, respectively. Both values are significantly higher compared to participants without skin diseases (29.2%; p < 0.01 and 45.5%; p < 0.01). 18.9% of participants with a skin disease used digital diagnostic support, but only 9.7% applied it for a skin disease (p < 0.01). For all participants, with and without skin disease, the DHS most commonly used were passive health monitoring (14.3%) and diagnostic support (11.5%), telemedicine was least used (4.7% video‐consultation, 2.5% store‐and‐forward). Use and acceptance were associated with young age, education, low data privacy concerns, digital confidence, having a skin disease, and high severity of skin disease. Conclusions: DHS for skin diseases are used rarely but have a high potential. [ABSTRACT FROM AUTHOR]

Copyright of Journal der Deutschen Dermatologischen Gesellschaft is the property of Wiley-Blackwell 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.)

Daily activity patterns of free‐ranging wildlife affect a wide range of ecological and physiological processes and, in turn are affected by anthropogenic disturbances to the environment. However, obtaining a continuous record of activity without disturbing wild animals is logistically challenging. We used commercially available, multi‐purpose light‐level geolocator dataloggers to continuously record light environment and time spent out of water during 5‐months (1 May to 9 September 2021) in an ectothermic freshwater turtle species, the northern map turtle (Graptemys geographica). We used these data to compare time of year and sex differences in thermoregulatory behavior in an ectothermic species in its natural habitat. We recorded >500 000 data points from 17 individual turtles (nine males and eight females). We found no differences in the mean light levels, or proportion of time spent out of the water, between males and females. However, there was a significant effect of both time of year and sex by time of year interaction in both light level, proportion of time spent dry, and number of state changes (i.e., shuttling behavior, wet to dry or dry to wet), suggesting that turtles alter their aerial basking behavior over the course of the season and that the changes in patterns of aerial basking behavior differ between the sexes throughout the year. In general, the proportion of time spent dry decreased over the active season, with an increase during the last week of June and the first week of July, while the number of state changes increased in females during late May/early June before decreasing, while males remained relatively constant. These changes may reflect the different energetic demands associated with reproduction between the two sexes. The overall downward trend in aerial basking likely reflects the role of increasing environmental temperatures, particularly water temperature, in the maintenance of body temperature in this largely aquatic species. [ABSTRACT FROM AUTHOR]

Background: Bronchoalveolar lavage (BAL) cytology results from 1 lung might not be representative of both lungs. Objectives: To determine whether the lung site sampled would influence the horse's BAL cytology profile, and if a pooled BAL sample would be superior with regard to BAL cytology diagnosis in a cohort of healthy and subclinical asthmatic warmblood horses. Animals: Fifty‐nine horses in 2021 and 70 horses in 2022, the follow‐up included 53 of the same in each year. Methods: A cross‐sectional study with follow‐up included BAL cytology samples from individual lungs and from pooled BAL samples. The BAL samples were enumerated and differential cell count were applied to categorize the horses as control or with airway inflammation (AI). Results: Bronchoalveolar lavage mast cell count was higher in left lung compared to right lung (2021; median 1.6 [range, 0.6‐3.3] vs 1.2 [0.7‐1.5] P =.009, 2022; median 3.1 [2.1‐4.2] vs 2.4 [1.7‐3.4], P <.001) and compared to pooled samples (2022; median 2.6 [1.7‐3.7], P <.001). Between year 2021 and 2022, 17 of the horses had changes in BAL cytology from control to AI or vice versa. Conclusions and Clinical Importance: Pooled BAL sample was the least reliable for detecting AI, and was not representative of the overall lung condition. [ABSTRACT FROM AUTHOR]

The article discusses the impact of dupilumab treatment on olfactory function in patients with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP). The study found that more than half of patients experienced rapid improvement in olfactory function within 28 days of treatment, with significant enhancements in smell perception. Patients who were responsive to oral corticosteroids showed better results with dupilumab treatment. The findings suggest that dupilumab could be an effective and fast-acting option for improving olfactory function in CRSwNP patients, with potential implications for treatment stratification based on corticosteroid responsiveness. [Extracted from the article]

Background and Aims: To further substantiate the role of antibody‐mediated complement activation in multifocal motor neuropathy (MMN) immunopathology, we investigated the distribution of promotor polymorphisms of genes encoding the membrane‐bound complement regulators CD46, CD55, and CD59 in patients with MMN and controls, and evaluated their association with disease course. Methods: We used Sanger sequencing to genotype five common polymorphisms in the promotor regions of CD46, CD55, and CD59 in 133 patients with MMN and 380 controls. We correlated each polymorphism to clinical parameters. Results: The genotype frequencies of rs28371582, a 21‐bp deletion in the CD55 promotor region, were altered in patients with MMN as compared to controls (p.009; Del/Del genotype 16.8% vs. 7.7%, p.005, odds ratio: 2.43 [1.27–4.58]), and patients carrying this deletion had a more favorable disease course (mean difference 0.26 Medical Research Council [MRC] points/year; 95% confidence interval [CI]: 0.040–0.490, p.019). The presence of CD59 rs141385724 was associated with less severe pre‐diagnostic disease course (mean difference 0.940 MRC point/year; 95% CI: 0.083–1.80, p.032). Interpretation: MMN susceptibility is associated with a 21‐bp deletion in the CD55 promotor region (rs2871582), which is associated with lower CD55 expression. Patients carrying this deletion may have a more favorable long‐term disease outcome. Taken together, these results point out the relevance of the pre‐C5 level of the complement cascade in the inflammatory processes underlying MMN. [ABSTRACT FROM AUTHOR]

As part of the Synergetic Utilisation of CO2$_2$ storage Coupled with geothermal EnErgy Deployment project, investigating CO2$_2$ reinjection with different seismic methods, both passive and active seismic surveys have been conducted at the geothermal power plant at Hellisheiði, Iceland. During the 2021 survey, two geophone lines recorded noise for a week. We process the passive‐source data with seismic interferometry to image the subsurface structure around the CarbFix2 reinjection reservoir. To improve image quality, we perform an illumination analysis to select only noise panels dominated by body‐wave energy. The results show that most noise panels are dominated by air‐wave energy arriving from the direction of the power plant. We use panels with a near‐vertical incidence to create a zero‐offset image and a larger selection of body‐wave‐dominated panels to create virtual common‐shot gathers. We process the gathers with a simple reflection seismology processing workflow to obtain stacked images. The zero‐offset images show a relatively lower signal‐to‐noise ratio and only horizontal reflectors. The stacked images show slightly dipping reflectors and possibly lateral amplitude variations around the expected injection region. This could indicate a region of interest for future research into the reinjection reservoir. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) has been proposed as a risk factor for exercise‐induced pulmonary haemorrhage (EIPH) due to increased pressure in the left atrium. Objective: To evaluate if AF was associated with EIPH following a standardised exercise test (SET) to fatigue. Study design: Two‐arm controlled experiment. Methods: Ten untrained Standardbred mares mean (standard deviation [SD]) age 6 (2) years performed a SET on the treadmill in sinus rhythm (SR) (SET1) and 25–44 days after induction of self‐sustained AF (SET2). AF was induced by tachypacing using a pacing device. Endoscopy, including tracheal wash and bronchoalveolar lavage (BAL), was performed 48–72 h before and 24 h after the two SETs. In addition, endoscopic grading of tracheal blood was performed 2 h after each SET. Results: After SET1, none of the horses showed blood in the trachea, and two horses showed erythrophagocytosis. Following SET2, two horses had grade 1 blood in the trachea and free erythrocytes and erythrophagocytosis in the BAL, while another two horses had erythrophagocytosis in the BAL. In SET2, the overall performance on the treadmill was decreased with a lower maximum velocity (SET1 10.3 ± 0.8 m/s vs. SET2 8.9 ± 0.9 m/s, p = 0.004), a higher heart rate (284 ± 21 vs. 221 ± 18 bpm, p = 0.003) and more abnormal QRS complexes (p < 0.001) compared with SET1. Conclusions: Two horses showed signs of EIPH, resulting in visible blood in the trachea, when exercising in AF compared with SR. However, a possible link between EIPH, pulmonary pressure and AF needs to be further elucidated. [ABSTRACT FROM AUTHOR]

Vital rates for small, non-breeding individuals are important components of population dynamics for many species, but often individuals of these sizes are difficult to locate, capture, and track. As such, biologists frequently lack reliable estimates of juvenile survival because sample sizes and recapture rates for this life stage are low. Long-lived animals often take many years to reach sexual maturity and spend much of this time in the smaller size classes, making them sensitive to changes in survival rates. We estimated the survival rates of all size classes for the northern map turtle (Graptemys geographica) using a mark-recapture dataset with >3,500 captures from 2019-2021 and 210 nests from 2018-2021. As turtle size increased, annual survival probability increased regardless of sex. Estimated annual survival probability for turtles >18 cm long (i.e., adult females >15 years) was about 0.95, over 4 times higher than turtles that were 3 cm long (i.e., hatchlings <1 year; 0.22 annual survival probability). Although we did not observe a difference in survival probability between sexes of any size class, adult females are nearly twice the size of adult males, leading to an increased annual survival probability for females of 0.95, compared to 0.80 for males. Changes in adult survival had the greatest influence on population estimates over time, with temporary decreases, such as those due to poaching or an environmental disaster, potentially leading to unrecoverable decreases in the overall population size. Our study provides detailed survival rates for all size classes in a long-lived turtle, which are necessary to assess population stability and can be used to determine the most effective conservation or management practices. [ABSTRACT FROM AUTHOR]

Actively open‐minded thinking (AOT) is a thinking style in which people engaged in judgment and decision‐making actively seek out and then evaluate information in a manner that is intentionally disconnected from their prior beliefs and motivations and in line with self‐perceptions of autonomy. Actively open‐minded thinkers have been observed to make both more accurate judgments about the magnitude of risks and more evidence‐based decisions under uncertainty in a wide range of situations such as climate change and politics. In addition, actively open‐minded thinkers functioning in domains where they lack a desired level of knowledge are open to "outsourcing" the job of critical reasoning thinking to credible experts; in other words, they are better able to gauge who is trustworthy and then rely on the insights of these trustworthy others to help them reach a conclusion. We report results from a follow‐up to research previously published in Risk Analysis that confirms these tenets in the context of COVID‐19. We then extend these results to offer a series of recommendations for strengthening the process and outcomes of risk analysis: leveraging the latent norm of autonomy and personal agency that underpins AOT, activating or engaging with approaches to reasoning—such as decision structuring—that are in line with AOT, and working upstream and downstream of risk analysis to establish AOT as a norm of its own. [ABSTRACT FROM AUTHOR]

A study conducted in Germany evaluated a teledermatology application that allows patients to submit information and images of their skin for evaluation by a dermatologist. The study found that the application was highly satisfactory, cost-effective, and efficient in providing therapy. The evaluation included analyzing data from 1232 patients and conducting surveys on patient and physician satisfaction. The majority of patients expressed satisfaction with the application, and many reported that their medical concerns were clarified without needing an in-person visit. The study concluded that the teledermatology application is suitable for a wide range of dermatological patients and can improve access to care. [Extracted from the article]

Copyright of Equine Veterinary Journal is the property of Wiley-Blackwell 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.)

Digital health interventions (DHI) potentially improve the efficiency and effectiveness of dermatological care. Currently, an overview clustering and characterizing the evidence on DHIs is missing. This systematic mapping of the literature aims to analyse published research on DHIs in dermatology to identify trends and gaps in research. For this purpose, a systematic search of the MEDLINE database was conducted in August 2022 to identify original publications on DHIs in dermatology. Data on country, targeted audience, DHI category, indication, outcome parameter and study design were extracted. Out of 12,009 records identified in MEDLINE, 403 studies were included in the final analysis. Studies on DHIs mainly performed in western countries, headed by the United States (n = 133), Germany (n = 32) and Spain (n = 23). Of all identified DHIs, 261 targeted healthcare providers (HCP), 66 clients (e.g. patients, caregivers, healthy individuals) and 67 both clients and HCPs. A majority of DHIs focussed on establishing a diagnosis (n = 254). Every other study analysed store‐and‐forward teledermatology (n = 187), followed by artificial intelligence applications for image analysis (n = 65). The most often analysed DHI category for clients was a support of health behaviour change (n = 31). Monitoring of clients was targeted by 77 studies. Skin cancer (n = 148), wounds (n = 29) and psoriasis (n = 29) were the most targeted indications by DHIs. Most studies analysed diagnostic performance (n = 166), fewer studies analysed acceptance (n = 92) and effectiveness (n = 98). Usability (n = 32) and efficiency (n = 36) were investigated only to a small extent. Studies on DHIs in dermatology have focused on teledermatology and AI applications, with an emphasis on skin cancer diagnosis. Apart from that, a range of DHIs for different user groups, purposes and indications were identified, demonstrating the broad potential for DHIs in dermatology. Further research with a wider set of outcome parameters is needed to fully understand the potential of DHIs and ensure their sustainable implementation into dermatological care. [ABSTRACT FROM AUTHOR]

Ageing is associated with a decline in autophagy and elevated reactive oxygen species (ROS), which can breach the capacity of antioxidant systems. Resulting oxidative stress can cause further cellular damage, including DNA breaks and protein misfolding. This poses a challenge for longevous organisms, including humans. In this review, we hypothesise that in the course of human evolution selective autophagy receptors (SARs) acquired the ability to sense and respond to localised oxidative stress. We posit that in the vicinity of protein aggregates and dysfunctional mitochondria oxidation of key cysteine residues in SARs induces their oligomerisation which initiates autophagy. The degradation of damaged cellular components thus could reduce ROS production and restore redox homeostasis. This evolutionarily acquired function of SARs may represent one of the biological adaptations that contributed to longer lifespan. Inversely, loss of this mechanism can lead to age‐related diseases associated with impaired autophagy and oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Dupilumab is an anti‐T2‐inflammatory biological registered for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), indicated by integrated CRS‐care pathways when optimal medico‐surgical treatment yields insufficient CRS control. This study aims to evaluate long‐term results with focus on established therapeutic efficacy while tapering dupilumab. Methods: Real‐life, prospective observational cohort study in single tertiary referral center with add‐on dupilumab as primary biological treatment in adult (≥18 years) biological‐naïve CRSwNP patients per the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS)2020‐indication with a 2‐year follow‐up. Tapering (increasing interdose interval) applied every 24 weeks, conditional to sufficient treatment response and CRS control. Results: Mean scores (s.d.) of all co‐primary outcomes improved significantly from baseline (228) to the 48 (214) and 96‐weeks (99) timepoints: Nasal Polyp Score (0–8) improved from 5,3 (1,9) to 1,4 (1,8) and 1,3 (1,7); SinoNasal Outcome Test (SNOT)‐22 (0–110) improved from 53,6 (19,6) to 20,2 (15,4) and 21,2 (15,6); Sniffin'Sticks‐12 identification test (0–12; 0–6 anosmia, 7–10 hyposmia, 11–12 normosmia) improved from 3,7 (2,4) to 7,7 (2,9) and 7,3 (3,04); Asthma Control Test (5–25; >19 indicating well‐controlled asthma) improved from 18,5 (4,8) to 21,8 (3,8) and 21,4 (3,9). Tapering was feasible in 79,5% of the patients at the 24‐weeks timepoint, and in 93,7% and 95,8% at the 48‐ and 96‐weeks timepoints, respectively. One‐way repeated‐measures ANOVA demonstrated no significant alterations of individual co‐primary outcome mean‐scores from 24 weeks onward. Conclusion: This first long‐term real‐life prospective observational cohort study shows high therapeutic efficacy of dupilumab for severe CRswNP in the first 2 years. Therapeutic efficacy is principally established within 24 weeks and endures while tapering dupilumab conditional to treatment response and CRS control. [ABSTRACT FROM AUTHOR]

Cyclic peptides are poised to target historically difficult to drug intracellular protein–protein interactions, however, their general cell impermeability poses a challenge for characterizing function. Recent advances in microfluidics have enabled permeabilization of the cytoplasmic membrane by physical cell deformation (i.e., mechanoporation), resulting in intracellular delivery of impermeable macromolecules in vector‐ and electrophoretic‐free approaches. However, the number of payloads (e.g., peptides) and/or concentrations delivered via microfluidic mechanoporation is limited by having to pre‐mix cells and payloads, a manually intensive process. In this work, we show that cells are momentarily permeable (t1/2 = 1.1–2.8 min) after microfluidic vortex shedding (μVS) and that lower molecular weight macromolecules can be cytosolically delivered upon immediate exposure after cells are processed/permeabilized. To increase the ability to screen peptides, we built a system, dispensing‐microfluidic vortex shedding (DμVS), that integrates a μVS chip with inline microplate‐based dispensing. To do so, we synced an electronic pressure regulator, flow sensor, on/off dispense valve, and an x‐y motion platform in a software‐driven feedback loop. Using this system, we were able to deliver low microliter‐scale volumes of transiently mechanoporated cells to hundreds of wells on microtiter plates in just several minutes (e.g., 96‐well plate filled in <2.5 min). We validated the delivery of an impermeable peptide directed at MDM2, a negative regulator of the tumor suppressor p53, using a click chemistry‐ and NanoBRET‐based cell permeability assay in 96‐well format, with robust delivery across the full plate. Furthermore, we demonstrated that DμVS could be used to identify functional, low micromolar, cellular activity of otherwise cell‐inactive MDM2‐binding peptides using a p53 reporter cell assay in 96‐ and 384‐well format. Overall, DμVS can be combined with downstream cell assays to investigate intracellular target engagement in a high‐throughput manner, both for improving structure–activity relationship efforts and for early proof‐of‐biology of non‐optimized peptide (or potentially other macromolecular) tools. [ABSTRACT FROM AUTHOR]

Women tend to make a decision about participation in breast cancer screening and adhere to this for future invitations. Therefore, our study aimed to provide high‐quality information on cumulative risks of false‐positive (FP) recall and screen‐detected breast cancer over multiple screening examinations. Individual Dutch screening registry data (2005‐2018) were gathered on subsequent screening examinations of 92 902 women age 49 to 51 years in 2005. Survival analyses were used to calculate cumulative risks of a FP and a true‐positive (TP) result after seven examinations. Data from 66 472 women age 58 to 59 years were used to extrapolate to 11 examinations. Participation, detection and additional FP rates were calculated for women who previously received FP results compared to women with true negative (TN) results. After 7 examinations, the cumulative risk of a TP result was 3.7% and the cumulative risk of a FP result was 9.1%. After 11 examinations, this increased to 7.1% and 13.5%, respectively. Following a FP result, participation was lower (71%‐81%) than following a TN result (>90%). In women with a FP result, more TP results (factor 1.59 [95% CI: 1.44‐1.72]), more interval cancers (factor 1.66 [95% CI: 1.41‐1.91]) and more FP results (factor 1.96 [95% CI: 1.87‐2.05]) were found than in women with TN results. In conclusion, due to a low recall rate in the Netherlands, the cumulative risk of a FP recall is relatively low, while the cumulative risk of a TP result is comparable. Breast cancer diagnoses and FP results were more common in women with FP results than in women with TN results, while participation was lower. [ABSTRACT FROM AUTHOR]

Background and purpose: Coronavirus disease 2019 (COVID‐19) affects the brain, leading to long‐term complaints. Studies combining brain abnormalities with objective and subjective consequences are lacking. Long‐term structural brain abnormalities, neurological and (neuro)psychological consequences in COVID‐19 patients admitted to the intensive care unit (ICU) or general ward were investigated. The aim was to create a multidisciplinary view on the impact of severe COVID‐19 on functioning and to compare long‐term consequences between ICU and general ward patients. Methods: This multicentre prospective cohort study assessed brain abnormalities (3 T magnetic resonance imaging), cognitive dysfunction (neuropsychological test battery), neurological symptoms, cognitive complaints, emotional distress and wellbeing (self‐report questionnaires) in ICU and general ward (non‐ICU) survivors. Results: In al, 101 ICU and 104 non‐ICU patients participated 8–10 months post‐hospital discharge. Significantly more ICU patients exhibited cerebral microbleeds (61% vs. 32%, p < 0.001) and had higher numbers of microbleeds (p < 0.001). No group differences were found in cognitive dysfunction, neurological symptoms, cognitive complaints, emotional distress or wellbeing. The number of microbleeds did not predict cognitive dysfunction. In the complete sample, cognitive screening suggested cognitive dysfunction in 41%, and standard neuropsychological testing showed cognitive dysfunction in 12%; 62% reported ≥3 cognitive complaints. Clinically relevant scores of depression, anxiety and post‐traumatic stress were found in 15%, 19% and 12%, respectively; 28% experienced insomnia and 51% severe fatigue. Conclusion: Coronavirus disease 2019 ICU survivors had a higher prevalence for microbleeds but not for cognitive dysfunction compared to general ward survivors. Self‐reported symptoms exceeded cognitive dysfunction. Cognitive complaints, neurological symptoms and severe fatigue were frequently reported in both groups, fitting the post‐COVID‐19 syndrome. [ABSTRACT FROM AUTHOR]

Scientific reasoning ability, the ability to reason critically about the quality of scientific evidence, can help laypeople use scientific evidence when making judgments and decisions. We ask whether individuals with greater scientific reasoning ability are also better calibrated with respect to their ability, comparing calibration for skill with the more widely studied calibration for knowledge. In three studies, participants (Study 1: N = 1022; Study 2: N = 101; and Study 3: N = 332) took the Scientific Reasoning Scale (SRS; Drummond & Fischhoff, 2017), comprised of 11 true–false problems, and provided confidence ratings for each problem. Overall, participants were overconfident, reporting mean confidence levels that were 22.4–25% higher than their percentages of correct answers; calibration improved with score. Study 2 found similar calibration patterns for the SRS and another skill, the Cognitive Reflection Test (CRT), measuring the ability to avoid intuitive but incorrect answers. SRS and CRT scores were both associated with success at avoiding negative decision outcomes, as measured by the Decision Outcomes Inventory; confidence on the SRS, above and beyond scores, predicted worse outcomes. Study 3 added an alternative measure of calibration, asking participants to estimate the number of items answered correctly. Participants were less overconfident by this measure. SRS scores predicted correct usage of scientific information in a drug facts box task and holding beliefs consistent with the scientific consensus on controversial issues; confidence, above and beyond SRS scores, predicted worse drug facts box performance but stronger science‐consistent beliefs. We discuss the implications of our findings for improving science‐relevant decision‐making. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether the limitations of young persons with a mild intellectual disability or borderline intellectual functioning preclude feasibility of the daily diary method. Method: For 60 consecutive days, 50 participants (Mage = 21.4, 56% male) who receive care in an ambulatory, residential, or juvenile detention setting, self‐rated both standardised and personalised diary questions through an app. Diary entries were used for feedback in treatment. Interviews were used to explore acceptability. Results: Average compliance was 70.4%, while 26% of participants dropped out. Compliance was good in ambulatory (88.9%) and residential care (75.6%), but not in the juvenile detention setting (19.4%). The content of self‐selected diary items varied widely. Participants deemed the method acceptable. Conclusions: Daily monitoring is feasible for individuals with a mild intellectual disability or borderline intellectual functioning receiving ambulatory or residential care, and can provide scientists and practitioners with important insights into day‐to‐day behavioural patterns. Lay summary Once per day for two months, young persons with a mild intellectual disability who received specialized care could complete diary questions about their daily experiences through an app on their mobile phone.Diaries consisted of eight questions that were pre‐selected by the researchers (about anxiety, negative thinking, impulsivity and sensation seeking), as well as closed‐ or open‐ended personalized questions about topics that each participant had suggested for him or herself.On average, they completed over 70% of their diary surveys and perceived increased self‐awareness, due to the daily self‐evaluations and discussing their weekly diary responses with their care professional throughout the study.The daily diary method is feasible and can provide scientists and practitioners with important insights the daily lives of young persons with a mild intellectual disability. [ABSTRACT FROM AUTHOR]

Aim: Creation of a diverting stoma in patients with Crohn's disease (CD) can counteract luminal inflammation. The clinical utility of a diverting stoma with the prospect of restoration of gastrointestinal continuity warrants further investigation. The aim of this work was to evaluate the long‐term effects of creation of a diverting stoma on the disease course in patients with luminal colonic CD. Method: In this retrospective, multicentre cohort study we investigated the disease course of patients who received a diverting stoma in the biological era. Clinical characteristics, medication use and surgical course were assessed at the time of creation of the diverting stoma and during follow‐up. The primary outcome was the rate of successful and lasting reestablishment of gastrointestinal continuity. Results: Thirty six patients with refractory luminal CD from four institutions underwent creation of a diverting stoma. Of the overall cohort, 20 (56%) patients had their gastrointestinal continuity reestablished after initial stoma creation and 14 (39%) who had their stoma reversed remained stoma‐free during a median of 3.3 years follow‐up (interquartile range 2.1–6.1 years). Absence of stoma reversal was associated with the presence of proctitis (p = 0.02). Colorectal resection after creation of a diverting stoma was performed in 28 (78%) patients, with 7 (19%) having a less extensive resection and 6 (17%) having a more extensive resection compared with the surgical plan before stoma creation. Conclusion: A diverting stoma could potentially be an alternative to immediate definitive stoma placement in specific populations consisting of patients with luminal colonic CD, especially in the absence of proctitis. [ABSTRACT FROM AUTHOR]

A substantial part of critically ill patients suffer from sepsis‐induced immunosuppression. Reversal of immunosuppression through PD‐1 checkpoint inhibition has been proposed as a treatment strategy to overcome immunosuppression in these patients. The PD‐1 inhibitor nivolumab, currently used in treatment of cancer, has been evaluated in phase I/II studies in patients with sepsis, demonstrating tolerability and signs of clinical efficacy. No proper dose finding was performed in these studies and, after a single high dose of 480 mg or 960 mg nivolumab, PD‐1 inhibition persisted beyond 90 days in the majority of cases. As the duration of sepsis is ~7–10 days, prolonged PD‐1 inhibition may unnecessarily induce longer‐term immune‐related side effects. Based on previously published pharmacokinetic and pharmacodynamic data of nivolumab, a thorough in silico dose finding study for nivolumab in critically ill patients was performed. We found that volume of distribution and clearance of nivolumab were not higher in patients with sepsis compared to the cancer population for which nivolumab is currently approved and showed profound variability. We found that with a single dose of 20 mg nivolumab, the PD‐1 receptor occupancy is predicted to stay above the 90% threshold for a median of 23 days (90% prediction interval of 7–78 days). We propose to investigate this dose in critically ill patients as a potential safe and cost‐effective pharmacotherapeutic intervention to treat sepsis‐induced immunosuppression. [ABSTRACT FROM AUTHOR]

Aim: In‐hospital prescribing errors (PEs) may result in patient harm, prolonged hospitalization and hospital (re)admission. These events are associated with pressure on healthcare services and significant healthcare costs. To develop targeted interventions to prevent or reduce in‐hospital PEs, identification and understanding of facilitating and protective factors influencing in‐hospital PEs in current daily practice is necessary, adopting a Safety‐II perspective. The aim of this systematic review was to create an overview of all factors reported in the literature, both protective and facilitating, as influencing in‐hospital PEs. Methods: PubMed, EMBASE.com and the Cochrane Library (via Wiley) were searched, according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) statement, for studies that identified factors influencing in‐hospital PEs. Both qualitative and quantitative study designs were included. Results: Overall, 19 articles (6 qualitative and 13 quantitative studies) were included and 40 unique factors influencing in‐hospital PEs were identified. These factors were categorized into five domains according to the Eindhoven classification ('organization‐related', 'prescriber‐related', 'prescription‐related', 'technology‐related' and 'unclassified') and visualized in an Ishikawa (Fishbone) diagram. Most of the identified factors (87.5%; n = 40) facilitated in‐hospital PEs. The most frequently identified facilitating factor (39.6%; n = 19) was 'insufficient (drug) knowledge, prescribing skills and/or experience of prescribers'. Conclusion: The findings of this review could be used to identify points of engagement for future intervention studies and help hospitals determine how to optimize prescribing. A multifaceted intervention, targeting multiple factors might help to circumvent the complex challenge of in‐hospital PEs. [ABSTRACT FROM AUTHOR]

This paper analyzes the impact of source‐country culture on the labor supply of female immigrants in Europe. We find that the labor supply of immigrant women is positively associated with the female‐to‐male labor force participation ratio in their source country, which serves as a proxy for the country's preferences and beliefs regarding women's roles. This suggests that the culture and norms of their source country play an important role for immigrant women's labor supply. However, contradicting previous evidence for the US, we do not find evidence that the cultural effect persists through the second generation. [ABSTRACT FROM AUTHOR]

Background: Time trend analysis of cutaneous melanoma (CM) mortality in fair skin populations shows both a gradual decrease and/or an increase. To explain these differences, we analyzed long‐term time trends in the incidence of the most common histological subtypes of CM: superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), and nodular melanoma (NM). Methods: Using data from the Netherlands Cancer Registry and Statistics Netherlands, the number and rates of cases diagnosed with SSM, LLM, and NM from 1989 to 2016 were analyzed by age, calendar period, and birth cohort of people born in successive periods from 1925 to 1973. Results: Primary CM was diagnosed in 52,000 men and 66,588 women in the study period. The annual age‐standardized incidence rate increased three‐fold from 14 to 42 per 100,000 person‐years. The most common subtype was SSM (50%), followed by LMM (23%) and NM (14%). Age‐specific subtype rates showed an upward trend over time for both men and women. Younger birth cohorts had higher rates of SSM and LMM diagnosis than older birth cohorts. This birth cohort pattern was not observed for NM. Conclusions: We observed a strong increase in the melanoma epidemic curves in the light‐skinned Dutch population over the last three decades. This increase is explained by younger generations having higher rates of SSM and LMM than older generations. [ABSTRACT FROM AUTHOR]

Wildlife translocation is often used as a mitigation strategy for construction projects and other disturbances to habitat. In 2010, one of the largest freshwater oil spills in the United States occurred in the Kalamazoo River in Michigan, when over 3.2 million L of diluted bitumen crude oil impacted nearly 56 km of riverine habitat. During 2010 and 2011 cleanup efforts, 686 northern map turtles (Graptemys geographica) were captured from oil‐impacted stretches of the river, cleaned, rehabilitated, and translocated 2.5–84.3 km from their original capture location. The goal of this translocation effort was to release turtles within the same watershed, but away from ongoing cleanup operations, so individuals could potentially return to their original home range after it had been cleaned of oil and restored. In this study, we evaluated the success of translocation as an emergency mitigation strategy for freshwater turtles by quantifying recapture probability and homing by northern map turtles translocated varying distances from their home ranges. During subsequent years of survey up to 10 years post‐spill, 230 of the translocated turtles were recaptured, of which 104 exhibited homing by returning to their original home ranges. Turtles translocated to sites nearest their original capture location had a higher probability of recapture and homing than those translocated further away. Females had a higher probability of returning to original home ranges than males when translocated greater distances. In addition, four females and one male are known to have traveled >50 km between capture and release locations, which to our knowledge is the greatest travel distance recorded for any freshwater turtle species in the United States. Our results demonstrate that riverine turtles have considerable homing ability when displaced long distances, which has important implications for design and success of translocation projects. [ABSTRACT FROM AUTHOR]

The increasing use of the zebrafish model in biomedical and (eco)toxicological studies aimed at understanding the function of various proteins highlight the importance of optimizing existing methods to study gene and protein expression and localization in this model. In this context, zebrafish cryosections are still underutilized compared with whole‐mount preparations. In this study, we used zebrafish embryos (24–120 hpf) to determine key factors for the preparation of high‐quality zebrafish cryosections and to determine the optimal protocol for (immuno)fluorescence analyses of Na+/K+‐ATPase and F‐actin, across developmental stages from 1 to 5 dpf. The results showed that the highest quality zebrafish cryosections were obtained after the samples were fixed in 4% paraformaldehyde (PFA) for 1 h, incubated in 2.5% bovine gelatin/25% sucrose mixture, embedded in OCT, and then sectioned to 8 μm thickness at −20°C. Fluorescence microscopy analysis of phalloidin‐labeled zebrafish skeletal muscle revealed that 1‐h‐4% PFA‐fixed samples allowed optimal binding of phalloidin to F‐actin. Further immunofluorescence analyses revealed detailed localization of F‐actin and Na+/K+‐ATPase in various tissues of the zebrafish and a stage‐dependent increase in their respective expression in the somitic muscles and pronephros. Finally, staining of zebrafish cryosections and whole‐mount samples revealed organ‐specific and zone‐dependent localizations of the Na+/K+‐ATPase α1‐subunit. Research Highlights: This study brings optimization of existing protocols for preparation and use of zebrafish embryos cryosections in (immuno)histological analyses. It reveals stage‐dependent localization/expression of F‐actin and Na+/K+‐ATPase in zebrafish embryos. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID‐19) pandemic continues to alter US household food consumption and food spending. Although terminology used to describe food insecurity has varied during the COVID‐19 pandemic, many reliable estimates illustrate a dramatic increase in food insecurity from approximately 10% of US households before the pandemic to 25%–30% of households during the pandemic, with an even higher prevalence reported by more vulnerable and socially disadvantaged populations. To address the increase in food and economic insecurity, food and nutrition assistance policies and programs made innovative and temporary changes, and enrollment in these programs generally increased. However, some changes to food, nutrition, and income assistance programs are now expiring or contracting even as food insecurity prevalence is again on the rise and elevated food and nutrition assistance needs are expected to persist based on historical patterns. American Society for Parenteral and Enteral Nutrition (ASPEN) practitioners can play an important role in identifying clients at elevated risk of food insecurity–related acute and chronic conditions and connecting high‐risk clients to resources. ASPEN practitioners can contribute to the evidence base linking food insecurity and nutrition outcomes. ASPEN practitioners can also advocate for addressing the root social and structural determinants of food insecurity and for the continuation of effective food and nutrition policy changes and innovations. [ABSTRACT FROM AUTHOR]

Antibodies against Rho GDP‐dissociation inhibitor 2 (RhoGDI2) are associated with inferior graft survival in transplant patients receiving a kidney from deceased donors. Although this suggests that these antibodies contribute to graft injury because of ischemia, it remains unknown whether they are also pathogenically involved in the process of graft loss. To study this, we firstly analyzed the IgG subclass profile of anti‐RhoGDI2 antibodies in kidney transplant recipients, and whether antibody titers change over time or because of acute rejection. Next, we investigated the expression of RhoGDI2 on primary kidney and lung endothelial cells (ECs) upon hypoxia reperfusion. In addition, the complement‐fixing properties of anti‐RhoGDI2 antibodies were studied using imaging flow cytometry. Anti‐RhoGDI2 antibodies in patients are mainly IgG1, and titers remained stable and seemed not be changed because of rejection. Antibodies against RhoGDI2, which surface expression seemed to increase upon hypoxia reperfusion, co‐localized with C3 on ECs. Binding of human IgG1 monoclonal anti‐RhoGDI2 antibodies as well as patient derived antibodies, resulted in complement activation, suggesting that these antibodies are complement fixing. This study suggested a potential pathogenic role of anti‐RhoGDI2 antibodies in kidney graft loss. During ischemia reperfusion, the ability of these antibodies to fix complement could be one of the mechanisms resulting in tissue injury. [ABSTRACT FROM AUTHOR]

Amphiphilic glycan‐functionalized oligomers are derived by solid‐phase polymer synthesis and applied in both, self‐assembled micelles as well as giant unilamellar vesicles, as simplified models of the cell's glycocalyx. Additionally, an aggregation‐induced luminophore is introduced into the amphiphilic glycomacromolecules showing no fluorescence when the molecule is free in solution. Combining glycomacromolecules carrying a binding glycan motif and the luminophore with glycomacromolecules or other amphiphiles with no binding motifs and no luminophore in self‐assembled structures, micelles and vesicles exhibiting no or only very little fluorescence are obtained. Only upon clustering of the binding glycan motifs through interaction with a multivalent lectin receptor, an increase in fluorescence is observed. Thus, clustering events within these self‐assembled structures can be detected and localized. [ABSTRACT FROM AUTHOR]

[Co(HBMIMPh2)2](BF4)2 (1) [HBMIMPh2=bis(1‐methyl‐4,5‐diphenyl‐1H‐imidazol‐2‐yl)methane] was investigated for its electrocatalytic hydrogen evolution performance in DMF using voltammetry and during controlled potential/current electrolysis (CPE/CCE) in a novel in‐line product detection setup. Performances were benchmarked against three reported molecular cobalt hydrogen evolution reaction (HER) electrocatalysts, [Co(dmgBF2)2(solv)2] (2) (dmgBF2=difluoroboryldimethylglyoximato), [Co(TPP)] (3) (TPP=5,10,15,20‐tetraphenylporphyrinato), and [Co(bapbpy)Cl](Cl) (4) [bapbpy=6,6′‐bis‐(2‐aminopyridyl)‐2,2′‐bipyridine], showing distinct performances differences with 1 being the runner up in H2 evolution during CPE and the best catalyst in terms of overpotential and Faradaic efficiency during CCE. After bulk electrolysis, for all of the complexes, a deposit on the glassy carbon electrode was observed, and post‐electrolysis X‐ray photoelectron spectroscopy (XPS) analysis of the deposit formed from 1 demonstrated only a minor cobalt contribution (0.23 %), mainly consisting of Co2+. Rinse tests on the deposits derived from 1 and 2 showed that the initially observed distinct activity was (partly) preserved for the deposits. These observations indicate that the molecular design of the complexes dictates the features of the formed deposit and therewith the observed activity. [ABSTRACT FROM AUTHOR]