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Background and Objective: Chronic obstructive pulmonary disease (COPD) exhibits diverse patterns of disease progression, due to underlying disease activity. We hypothesized that changes in static hyperinflation or KCO % predicted would reveal subgroups with disease progression unidentified by preestablished markers (FEV 1 , SGRQ, exacerbation history) and associated with unique baseline biomarker profiles. We explored 18-month measures of disease progression associated with 18-54-month mortality, including changes in hyperinflation parameters and transfer factor, in a large German COPD cohort., Methods: Analysing data of 1364 patients from the German observational COSYCONET-cohort, disease progression and improvement patterns were assessed for their impact on mortality via Cox hazard regression models. Association of biomarkers and COPD Assessment test items with phenotypes of disease progression or improvement were evaluated using logistic regression and random forest models., Results: Increased risk of 18-54-month mortality was linked to decrease in KCO % predicted (7.5% increments) and FEV 1 (20 mL increments), increase in RV/TLC (2% increments) and SGRQ (≥6 points), and an exacerbation grade of 2 at 18 months. Decrease in KCO % predicted ≥7.5% and an increase of RV/TLC ≥2% were the most frequent measures of 18-month disease progression occurring in ~52% and ~46% of patients, respectively. IL-6 and CRP thresholds exhibited significant associations with medium- and long-term disease measures., Conclusion: In a multicentric cohort of COPD, new markers of current disease activity predicted mid-term mortality and could not be anticipated by baseline biomarkers., (© 2024 The Author(s). Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Rapamycin, also known as sirolimus, has demonstrated great potential for application in longevity medicine. However, the dynamics of low-dose rapamycin bioavailability, and any differences in bioavailability for different formulations (e.g., compounded or commercial), remain poorly understood. We thus explored rapamycin bioavailability in two real-world cohorts to begin providing a foundational understanding of differences in effects between formulations over time. The small trial study cohort was utilized to explore the blood rapamycin levels of commercial (n = 44, dosages 2, 3, 6, or 8 mg) or compounded (n = 23, dosages 5, 10, or 15 mg) rapamycin 24 h after dose self-administration. Results suggested dose-to-blood level relationships were linear for both formulations, though compounded had a lower bioavailability per milligram of rapamycin (estimated to be 31.03% of the same dose of commercial). While substantial inter-individual heterogeneity in blood rapamycin levels was observed for both formulations, repeat tests for individuals over time demonstrated relative consistency. Extending exploration to 316 real-world longevity rapamycin users from the AgelessRx Observational Research Database produced similar findings, and additionally suggested that blood rapamycin levels peak after 2 days with gradual decline thereafter. Taken together, our findings suggest that individualized dosing and routine monitoring of blood rapamycin levels should be utilized to ensure optimal dosing and efficacy for healthy longevity., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Institutional Review Board of the Institute of Regenerative and Cellular Medicine (IRCM, approval number IRCM-2022–352), and was conducted in accordance with Good Clinical Practice (GCP) standards. Informed consent and consent to use de-identified information for research and research publication purposes were obtained from all participants. Consent for publication: All participants and authors consented to publish the data contained in this manuscript. Competing interests: GH, VL, AN, MM, BV, CT, SN, SLM, AI, and SZ are employees and shareholders of AgelessRx. MW and JH have received financial compensation from AgelessRx for their contributions. KK is an employee and shareholder of Venture Plant AB and Rapamycin Longevity Lab, which has received a donation from AgelessRx for research coordination in partnership with Ora Biomedical., (© 2025. The Author(s).)

Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype which encompasses vasculopathy including livedo racemosa and lacunar strokes, as well as hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in the ADA2 gene. DADA2 carriers harbor a single pathogenic variant in ADA2 and are mostly considered healthy and asymptomatic. However, some DADA2 carriers present a phenotype compatible with DADA2. Here, we report ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant (p.G47R, p.G47V, p.R169Q, p.H424N) was identified. To test whether being heterozygote for specific variants could explain the patients' phenotype, we investigated the effect of the ADA2 missense variants p.G47A, p.G47R, p.G47V, p.G47W, p.R169Q, p.E328K, p.T360A, p.N370K, p.H424N and p.Y453C on ADA2 protein expression, secretion and enzymatic activity. Functional studies indicate that they exert a dominant negative effect on ADA2 enzymatic activity, dimerization and/or secretion. At the molecular level, heterozygosity for these variants mimics what is observed in DADA2. We conclude that humans with heterozygous dominant negative missense variants in ADA2 are at risk of DADA2., Competing Interests: Conflict-of-interest statement: LRD KU Leuven receives advisory board honorary from Boehringer-Ingelheim and Takeda for IM. IM is the chair of the CSL Behring Chair in Primary Immunodeficiencies, paid to KU Leuven.

Background: Adjuvant anti-PD-1 therapy improves relapse free survival in stage III melanoma, but also leads to immune-related adverse events (irAEs). Older patients are of particular interest due to comorbidities and frailty, which may impact their ability to tolerate irAEs and benefit from anti-PD-1 therapy. This study aimed to explore associations between clinical parameters and the occurrence of grade ≥ 3 irAEs and recurrence-free survival (RFS) in older patients with radically resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy., Methods: Patients aged ≥ 65 with resected stage III/IV cutaneous melanoma treated with adjuvant anti-PD-1 therapy between 2018 and 2022 were selected using real-world data from the nationwide Dutch Melanoma Treatment Registry (DMTR). A univariate and multivariable logistic regression was used to compare determinants of grade ≥ 3 irAEs, and univariate and multivariable Cox-proportional hazard models were fitted to identify factors influencing RFS., Results: The study included 885 patients, with 280 aged 75 and older. The incidence of grade ≥ 3 irAEs was 15.5 % in the 65-74 age group and 13.9 % in the ≥ 75 age group. No significant correlation was found between age and grade ≥ 3 irAEs. However, an increasing number of comorbidities was associated with a higher risk of grade ≥ 3 irAEs (multivariable analyses: OR 1.83, 95 % C.I. 0.99-3.40). The 1-year RFS rate of 80.0 % of this study was comparable to those reported in previous registration trials and real-world data. Having ≥ 3 comorbidities was significantly associated with a decrease in RFS (HR: 1.68, 95 % C.I. 1.15-2.44)., Conclusion: Older patients had similar benefit of adjuvant immunotherapy compared to older subgroups in previous trials. However, patients with multiple comorbidities were at increased risk of grade ≥ 3 irAEs and had a lower RFS. This should be considered when deciding upon adjuvant treatment., Competing Interests: Declaration of Competing Interest All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Localization of non-palpable melanoma, Merkel cell carcinoma (MCC) and soft tissue sarcoma (STS) lesions can be difficult due to size, location, and obesity of patients or fibrosis due to previous treatments. Magnetic seed localization (MSL) is a common method to localize non-palpable breast lesions, but the feasibility of MSL for non-palpable melanoma, MCC and STS lesions has not yet been described., Methods: In this retrospective single center cohort study, all consecutive patients between January 2021 and October 2023 who had a resection of a non-palpable melanoma, MCC or STS lesion guided by Sirius Pintuition, a MSL technique, were included. The primary endpoint was successful lesion localization during surgery and the secondary endpoints were seed migration, negative resection margins, and complications., Results: Seventy-nine seeds were placed for 76 lesions, which were resected during 68 surgeries in 61 patients. All lesions (100 %) were localized and resected. Median time of surgery was 44 min. No seed migration was observed. A negative resection margin was achieved for 60 (78.9 %) lesions. Clavien Dindo grade ≥2 complications occurred in 7.4 %., Conclusion: Magnetic seed localization with Sirius Pintuition is feasible for both non-palpable melanoma, MCC, and STS lesions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: WJ Van Houdt reports financial support was provided by Sirius Medical Systems B.V. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose: Patient-reported outcome measures (PROMs) are questionnaires completed by patients to gain insight in their health-related quality of life. However, patients often find the interpretation of PROMS challenging. A personalized narrative, i.e., a story with patients' experiences tailored to the reader, could help explain PROMs and might be appreciated alongside numerical outcomes. We studied how cancer patients perceive PROMs feedback presented in a regular numerical and a novel narrative format., Methods: Cancer patients who completed PROMs in routine clinical practice were recruited. All participants received numerical feedback and a personalized narrative. Semi-structured interviews were conducted to uncover perceptions of both formats. Interviews were analyzed with an inductive reflexive approach to thematic analysis., Results: Twenty-nine patients with breast cancer, melanoma, and bladder cancer participated. Thematic analysis identified six themes: "Understanding: I get the gist of it!"; "Usefulness: Tell me why I should complete PROMs"; "Format preferences: Numbers are cold, narratives are warm"; "Taking action: Can I do something about my score?"; "Personal relevance: Personalized narratives show me what life has in store for me"; and "Personal relevance: That's (not) me!" Numbers seemed to help participants act, whereas narratives may provide emotional support and recognition. Participants identified with the content of the narrative yet differed in how they related to the main character., Conclusion: Personalized narratives could be a useful addition to PROMs feedback. The studied formats seem to serve different purposes; numbers help to facilitate action, personalized narratives provide recognition., Implications for Cancer Survivors: Personalized narratives may be a useful new way to communicate about quality of life to cancer survivors and help them to envision what the impact of cancer can be., (© 2024. The Author(s).)

Ventilator-associated pneumonia (VAP) remains one of the most common hospital-acquired infections (HAI). Considering the complicated diagnosis and the lack of effective treatment, prophylactic measures are suggested as the new standard to prevent the disease. Although VAP often manifests a polymicrobial nature, Pseudomonas aeruginosa remains one of the pathogens associated with the highest morbidity and mortality rates within these mechanically ventilated patients. In this paper, we report on the development of an antibacterial hydrogel coating using the polymyxin B (PMB) peptide to prevent bacterial adhesion to the polymeric substrate. We fully characterized the properties of the coating using atomic force microscopy (AFM), scanning electron microscopy (SEM), wettability analyses and Fourier-transform infrared (FTIR) and Raman spectroscopy. Furthermore, several biological assays confirmed the antibacterial and anti-biofilm effect of the tubing for at least 8 days against P. aeruginosa . On top of that, the produced coating is compliant with the requirements regarding cytocompatibility stated in the ISO (International Organization for Standardization) 10993 guidelines and an extended release of PMB over a period of at least 42 days was detected. In conclusion, this study serves as a foundation for peptide-releasing hydrogel formulas in the prevention of VAP.

Purpose of Review: In this review, an update is provided on the current knowledge and pending questions about human adenosine deaminase type 2 deficiency. Patients have vasculitis, immunodeficiency and some have bone marrow failure. Although the condition was described ten years ago, the pathophysiology is incompletely understood RECENT FINDINGS: Endothelial instability due to increased proinflammatory macrophage development is key to the pathophysiology. However, the physiological role of ADA2 is a topic of debate as it is hypothesized that ADA2 fulfils an intracellular role. Increasing our knowledge is urgently needed to design better treatments for the bone marrow failure. Indeed, TNFi treatment has been successful in treating DADA2, except for the bone marrow failure. Major advances have been made in our understanding of DADA2. More research is needed into the physiological role of ADA2., (© 2024. The Author(s).)

Background and Objective: The implementation of quality assurance programs (QAPs) within urological practice has gained prominence; yet, their impact on outcomes after radical prostatectomy (RP) remains uncertain. This paper aims to systematically review the current literature regarding the implementation of QAPs and their impact on outcomes after robot-assisted RP, laparoscopic RP, and open prostatectomy, collectively referred to as RP., Methods: A systematic Embase, Medline (OvidSP), and Scopus search was conducted, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) process, on January 12, 2024. Studies were identified and included if these covered implementation of QAPs and their impact on outcomes after RP. QAPs were defined as any intervention seeking quality improvement through critically reviewing, analyzing, and discussing outcomes. Included studies were assessed critically using the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool, with results summarized narratively., Key Findings and Limitations: Ten included studies revealed two methodological strategies: periodic performance feedback and surgical video assessments. Despite conceptual variability, QAPs improved outcomes consistently (ie, surgical margins, urine continence, erectile function, and hospital readmissions). Of the two strategies, video assessments better identified suboptimal surgical practice and technical errors. Although the extent of quality improvements did not appear to correlate with the frequency of QAPs, there was an apparent correlation with whether or not outcomes were evaluated collectively., Conclusions and Clinical Implications: Current findings suggest that QAPs have a positive impact on outcomes after RP. Caution in interpretation due to limited data is advised. More extensive research is required to explore how conceptual differences impact the extent of quality improvements., Patient Summary: In this paper, we review the available scientific literature regarding the implementation of quality assurance programs and their impact on outcomes after radical prostatectomy. The included studies offered substantial support for the implementation of quality assurance programs as an incentive to improve the quality of care continuously., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Despite lacking clinical data, the Dutch government is considering increasing the minimum annual surgical volume per center from twenty to fifty cytoreductive surgeries (CRS) for advanced-stage ovarian cancer (OC). This study aims to evaluate whether this increase is warranted., Methods: This population-based study included all CRS for FIGO-stage IIB-IVB OC registered in eighteen Dutch hospitals between 2019 and 2022. Short-term outcomes included result of CRS, length of stay, severe complications, 30-day mortality, time to adjuvant chemotherapy, and textbook outcome. Patients were stratified by annual volume: low-volume (nine hospitals, <25), medium-volume (four hospitals, 29-37), and high-volume (five hospitals, 54-84). Descriptive statistics and multilevel logistic regressions were used to assess the (case-mix adjusted) associations of surgical volume and outcomes., Results: A total of 1646 interval CRS (iCRS) and 789 primary CRS (pCRS) were included. No associations were found between surgical volume and different outcomes in the iCRS cohort. In the pCRS cohort, high-volume was associated with increased complete CRS rates (aOR 1.9, 95%-CI 1.2-3.1, p = 0.010). Furthermore, high-volume was associated with increased severe complication rates (aOR 2.3, 1.1-4.6, 95%-CI 1.3-4.2, p = 0.022) and prolonged length of stay (aOR 2.3, 95%-CI 1.3-4.2, p = 0.005). 30-day mortality, time to adjuvant chemotherapy, and textbook outcome were not associated with surgical volume in the pCRS cohort. Subgroup analyses (FIGO-stage IIIC-IVB) showed similar results. Various case-mix factors significantly impacted outcomes, warranting case-mix adjustment., Conclusions: Our analyses do not support further centralization of iCRS for advanced-stage OC. High-volume was associated with higher complete pCRS, suggesting either a more accurate selection in these hospitals or a more aggressive approach. The higher completeness rates were at the expense of higher severe complications and prolonged admissions., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The quantum regression theorem states that the correlations of a system at two different times are governed by the same equations of motion as the single-time averages. This provides a powerful framework for the investigation of the intrinsic microscopic behaviour of physical systems by studying their macroscopic response to a controlled external perturbation. Here we experimentally demonstrate that the two-time particle number correlations in a photon Bose-Einstein condensate inside a dye-filled microcavity exhibit the same dynamics as the response of the condensate to a sudden perturbation of the dye molecule bath. This confirms the regression theorem for a quantum gas, and, moreover, demonstrates it in an unconventional form where the perturbation acts on the bath and only the condensate response is monitored. For strong perturbations, we observe nonlinear relaxation dynamics which our microscopic theory relates to the equilibrium fluctuations, thereby extending the regression theorem beyond the regime of linear response., (© 2024. The Author(s).)

With geroscience research evolving at a fast pace, the need arises for human randomized controlled trials to assess the efficacy of geroprotective interventions to prevent age-related adverse outcomes, disease, and mortality in normative aging cohorts. However, to confirm efficacy requires a long-term and costly approach as time to the event of morbidity and mortality can be decades. While this could be circumvented using sensitive biomarkers of aging, current molecular, physiological, and digital endpoints require further validation. In this review, we discuss how collecting real-world evidence (RWE) by obtaining health data that is amenable for collection from large heterogeneous populations in a real-world setting can help speed up validation of geroprotective interventions. Further, we propose inclusion of quality of life (QoL) data as a biomarker of aging and candidate endpoint for geroscience clinical trials to aid in distinguishing healthy from unhealthy aging. We highlight how QoL assays can aid in accelerating data collection in studies gathering RWE on the geroprotective effects of repurposed drugs to support utilization within healthy longevity medicine. Finally, we summarize key metrics to consider when implementing QoL assays in studies, and present the short-form 36 (SF-36) as the most well-suited candidate endpoint., Competing Interests: Declaration of Competing Interest none., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background : It is assumed that speech comprehension deficits in background noise are caused by age-related or acquired hearing loss. Methods : We examined young, middle-aged, and older individuals with and without hearing threshold loss using pure-tone (PT) audiometry, short-pulsed distortion-product otoacoustic emissions (pDPOAEs), auditory brainstem responses (ABRs), auditory steady-state responses (ASSRs), speech comprehension (OLSA), and syllable discrimination in quiet and noise. Results : A noticeable decline of hearing sensitivity in extended high-frequency regions and its influence on low-frequency-induced ABRs was striking. When testing for differences in OLSA thresholds normalized for PT thresholds (PTTs), marked differences in speech comprehension ability exist not only in noise, but also in quiet, and they exist throughout the whole age range investigated. Listeners with poor speech comprehension in quiet exhibited a relatively lower pDPOAE and, thus, cochlear amplifier performance independent of PTT, smaller and delayed ABRs, and lower performance in vowel-phoneme discrimination below phase-locking limits (/o/-/u/). When OLSA was tested in noise, listeners with poor speech comprehension independent of PTT had larger pDPOAEs and, thus, cochlear amplifier performance, larger ASSR amplitudes, and higher uncomfortable loudness levels, all linked with lower performance of vowel-phoneme discrimination above the phase-locking limit (/i/-/y/). Conslusions : This study indicates that listening in noise in humans has a sizable disadvantage in envelope coding when basilar-membrane compression is compromised. Clearly, and in contrast to previous assumptions, both good and poor speech comprehension can exist independently of differences in PTTs and age, a phenomenon that urgently requires improved techniques to diagnose sound processing at stimulus onset in the clinical routine.

Background: Clinical auditing is a powerful tool to evaluate and improve healthcare. Deviations from the expected quality of care are identified by benchmarking the results of individual hospitals using national averages. This study aimed to evaluate the use of quality indicators for benchmarking hepato-pancreato-biliary (HPB) surgery and when outlier hospitals could be identified., Methods: A population-based study used data from two nationwide Dutch HPB audits (DHBA and DPCA) from 2014 to 2021. Sample size calculations determined the threshold (in percentage points) to identify centres as statistical outliers, based on current volume requirements (annual minimum of 20 resections) on a two-year period (2020-2021), covering mortality rate, failure to rescue (FTR), major morbidity rate and textbook/ideal outcome (TO) for minor liver resection (LR), major LR, pancreaticoduodenectomy (PD) and distal pancreatectomy (DP)., Results: In total, 10 963 and 7365 patients who underwent liver and pancreatic resection respectively were included. Benchmark and corresponding range of mortality rates were 0.6% (0 -3.2%) and 3.3% (0-16.7%) for minor and major LR, and 2.7% (0-7.0%) and 0.6% (0-4.2%) for PD and DP respectively. FTR rates were 5.4% (0-33.3%), 14.2% (0-100%), 7.5% (1.6%-28.5%) and 3.1% (0-14.9%). For major morbidity rate, corresponding rates were 9.8% (0-20.5%), 28.1% (0-47.1%), 36% (15.8%-58.3%) and 22.3% (5.2%-46.1%). For TO, corresponding rates were 73.6% (61.3%-94.4%), 54.1% (35.3-100), 46.8% (25.3%-59.4%) and 63.3% (30.7%-84.6%). Mortality rate thresholds indicating a significant outlier were 8.6% and 15.4% for minor and major LR and 14.2% and 8.6% for PD and DP. For FTR, these thresholds were 17.9%, 31.6%, 22.9% and 15.0%. For major morbidity rate, these thresholds were 26.1%, 49.7%, 57.9% and 52.9% respectively. For TO, lower thresholds were 52.5%, 32.5%, 25.8% and 41.4% respectively. Higher hospital volumes decrease thresholds to detect outliers., Conclusion: Current event rates and minimum volume requirements per hospital are too low to detect any meaningful between hospital differences in mortality rate and FTR. Major morbidity rate and TO are better candidates to use for benchmarking., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: Patient and staff experience is a vital factor to consider in the evaluation of remote patient monitoring (RPM) interventions. However, no comprehensive overview of available RPM patient and staff experience-measuring methods and tools exists., Objective: This review aimed at obtaining a comprehensive set of experience constructs and corresponding measuring instruments used in contemporary RPM research and at proposing an initial set of guidelines for improving methodological standardization in this domain., Methods: Full-text papers reporting on instances of patient or staff experience measuring in RPM interventions, written in English, and published after January 1, 2011, were considered for eligibility. By "RPM interventions," we referred to interventions including sensor-based patient monitoring used for clinical decision-making; papers reporting on other kinds of interventions were therefore excluded. Papers describing primary care interventions, involving participants under 18 years of age, or focusing on attitudes or technologies rather than specific interventions were also excluded. We searched 2 electronic databases, Medline (PubMed) and EMBASE, on February 12, 2021.We explored and structured the obtained corpus of data through correspondence analysis, a multivariate statistical technique., Results: In total, 158 papers were included, covering RPM interventions in a variety of domains. From these studies, we reported 546 experience-measuring instances in RPM, covering the use of 160 unique experience-measuring instruments to measure 120 unique experience constructs. We found that the research landscape has seen a sizeable growth in the past decade, that it is affected by a relative lack of focus on the experience of staff, and that the overall corpus of collected experience measures can be organized in 4 main categories (service system related, care related, usage and adherence related, and health outcome related). In the light of the collected findings, we provided a set of 6 actionable recommendations to RPM patient and staff experience evaluators, in terms of both what to measure and how to measure it. Overall, we suggested that RPM researchers and practitioners include experience measuring as part of integrated, interdisciplinary data strategies for continuous RPM evaluation., Conclusions: At present, there is a lack of consensus and standardization in the methods used to measure patient and staff experience in RPM, leading to a critical knowledge gap in our understanding of the impact of RPM interventions. This review offers targeted support for RPM experience evaluators by providing a structured, comprehensive overview of contemporary patient and staff experience measures and a set of practical guidelines for improving research quality and standardization in this domain., (©Valeria Pannunzio, Hosana Cristina Morales Ornelas, Pema Gurung, Robert van Kooten, Dirk Snelders, Hendrikus van Os, Michel Wouters, Rob Tollenaar, Douwe Atsma, Maaike Kleinsmann. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 22.04.2024.)

Background: Diabetes mellitus forms a slow pandemic. Cardiovascular risk and quality of diabetes care are strongly associated. Quality indicators improve diabetes management and reduce mortality and costs. Various national diabetes registries render national quality indicators. We describe diabetes care indicators for Dutch children and adults with diabetes, and compare them with indicators established by registries worldwide., Methods: Indicator scores were derived from the Dutch Pediatric and Adult Registry of Diabetes Indicator sets of other national diabetes registries were collected and juxtaposed with global and continental initiatives for indicator sets., Results: This observational cohort study included 3738 patients representative of the Dutch diabetic outpatient population. The Dutch Pediatric and Adult Registry of Diabetes harbors ten quality indicators comprising treatment volumes, HbA1c control, foot examination, insulin pump therapy, and real-time continuous glucose monitoring. Worldwide, nine national registries record quality indicators, with great variety between registries. HbA1c control is recorded most frequently, and no indicator is reported among all registries., Conclusions: Wide variety among quality indicators recorded by national diabetes registries hinders international comparison and interpretation of quality of diabetes care. The potential of quality evaluation will be greatly enhanced when diabetes care indicators are aligned in an international standard set with variation across countries taken into consideration., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Max Nieuwdorp reports financial support was provided by Netherlands Organisation for Health Research and Development., (Copyright © 2023. Published by Elsevier Ltd.)

The DNA polymerase δ complex (PolD), comprising catalytic subunit POLD1 and accessory subunits POLD2, POLD3, and POLD4, is essential for DNA synthesis and is central to genome integrity. We identified, by whole exome sequencing, a homozygous missense mutation (c.1118A > C; p.K373T) in POLD3 in a patient with Omenn syndrome. The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination. The patient received hematopoietic stem cell transplantation at age 6 months. He manifested progressive neurological regression and ultimately died at age 4 years. We performed molecular and functional analysis of the mutant POLD3 and assessed cell cycle progression as well as replication-associated DNA damage. Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components. The cell cycle defect was rescued by transduction with WT POLD3. This study validates autosomal recessive POLD3 deficiency as a novel cause of profound T-cell deficiency and Omenn syndrome., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Deficiency of human adenosine deaminase type 2 (DADA2) is a complex systemic autoinflammatory disorder characterized by vasculopathy, immune dysregulation, and hematologic abnormalities. The most notable neurological manifestations of DADA2 are strokes that can manifest with various neurological symptoms and are potentially fatal. However, neurological presentations can be diverse. We here present a review of the neurological manifestations of DADA2 to increase clinical awareness of DADA2 as the underlying diagnosis. We reviewed all published cases of DADA2 from 1 January 2014 until 19 July 2022 found via PubMed. A total of 129 articles describing the clinical features of DADA2 were included in the analysis. Six hundred twenty-eight patients diagnosed with DADA2 were included in the review. 50.3% of patients had at least signs of one reported neurological event, which was the initial or sole manifestation in 5.7% and 0.6%, respectively. 77.5% of patients with neurological manifestations had at least signs of one cerebrovascular accident, with lacunar strokes being the most common and 35.9% of them having multiple stroke episodes. There is a remarkable predilection for the brain stem and deep gray matter, with 37.3% and 41.6% of ischemic strokes, respectively. Other neurological involvement included neuropathies, focal neurological deficits, ophthalmological findings, convulsions, and headaches. In summary, neurological manifestations affect a significant proportion of patients with DADA2, and the phenotype is broad. Neurological manifestations can be the first and single manifestation of DADA2. Therefore, stroke, encephalitis, posterior reversible encephalopathy syndrome, mononeuropathy and polyneuropathy, and Behçet's disease-like presentations should prompt the neurologist to exclude DADA2, especially but not only in childhood., (© 2023. The Author(s).)

As effector molecules of the innate immune system, antimicrobial peptides (AMPs) have gathered substantial interest as a potential future generation of antibiotics. Here, we demonstrate the anti- Pseudomonas activity and lipopolysaccharide (LPS)-binding ability of HC1 and HC10, two cecropin peptides from the black soldier fly ( Hermetia Illucens ). Both peptides are active against a wide range of Pseudomonas aeruginosa strains, including drug-resistant clinical isolates. Moreover, HC1 and HC10 can bind to lipid A, the toxic center of LPS and reduce the LPS-induced nitric oxide and cytokine production in murine macrophage cells. This suggests that the peptide-LPS binding can also lower the strong inflammatory response associated with P. aeruginosa infections. As the activity of AMPs is often influenced by the presence of salts, we studied the LPS-binding activity of HC1 and HC10 in physiological salt concentrations, revealing a strong decrease in activity. Our research confirmed the early potential of HC1 and HC10 as starting points for anti- Pseudomonas drugs, as well as the need for structural or formulation optimization before further preclinical development can be considered. IMPORTANCE The high mortality and morbidity associated with Pseudomonas aeruginosa infections remain an ongoing challenge in clinical practice that requires urgent action. P. aeruginosa mostly infects immunocompromised individuals, and its prevalence is especially high in urgent care hospital settings. Lipopolysaccharides (LPSs) are outer membrane structures that are responsible for inducing the innate immune cascade upon infection. P. aeruginosa LPS can cause local excessive inflammation, or spread systemically throughout the body, leading to multi-organ failure and septic shock. As antimicrobial resistance rates in P. aeruginosa infections are rising, the research and development of new antimicrobial agents remain indispensable. Especially, antimicrobials that can both kill the bacteria themselves and neutralize their toxins are of great interest in P. aeruginosa research to develop as the next generation of drugs., Competing Interests: The authors declare no conflict of interest.

Arabidopsis (Arabidopsis thaliana) transfer DNA (T-DNA) insertion collections are popular resources for fundamental plant research. Cinnamoyl-CoA reductase 1 (CCR1) catalyzes an essential step in the biosynthesis of the cell wall polymer lignin. Accordingly, the intronic T-DNA insertion mutant ccr1-6 has reduced lignin levels and shows a stunted growth phenotype. Here, we report restoration of the ccr1-6 mutant phenotype and CCR1 expression levels after a genetic cross with a UDP-glucosyltransferase 72e1 (ugt72e1),-e2,-e3 T-DNA mutant. We discovered that the phenotypic recovery was not dependent on the UGT72E family loss of function but due to an epigenetic phenomenon called trans T-DNA suppression. Via trans T-DNA suppression, the gene function of an intronic T-DNA mutant was restored after the introduction of an additional T-DNA sharing identical sequences, leading to heterochromatinization and splicing out of the T-DNA-containing intron. Consequently, the suppressed ccr1-6 allele was named epiccr1-6. Long-read sequencing revealed that epiccr1-6, not ccr1-6, carries dense cytosine methylation over the full length of the T-DNA. We showed that the SAIL T-DNA in the UGT72E3 locus could trigger the trans T-DNA suppression of the GABI-Kat T-DNA in the CCR1 locus. Furthermore, we scanned the literature for other potential cases of trans T-DNA suppression in Arabidopsis and found that 22% of the publications matching our query report on double or higher-order T-DNA mutants that meet the minimal requirements for trans T-DNA suppression. These combined observations indicate that intronic T-DNA mutants need to be used with caution since methylation of intronic T-DNA might derepress gene expression and can thereby confound results., Competing Interests: Conflict of interest statement. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© American Society of Plant Biologists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Textbook outcome (TO) is a composite outcome measure used in surgical oncology to compare hospital outcomes using multiple quality indicators. This study aimed to develop TO as an outcome measure to assess healthcare quality for patients undergoing cytoreductive surgery (CRS) for advanced-stage ovarian cancer., Methods: This population-based study included all CRS for FIGO IIIC-IVB primary ovarian cancer registered in the Netherlands between 2017 and 2020. The primary outcome was TO, defined as a complete CRS, combined with the absence of 30-day mortality, severe complications, and prolonged length of admission (≥ten days). Delayed start of adjuvant chemotherapy (≥six weeks) was not included in TO because of missing data. Logistic regressions were used to assess the association of case-mix factors with TO. Hospital variation was displayed using funnel plots., Results: A total of 1909 CRS were included, of which 1434 were interval CRS and 475 were primary CRS. TO was achieved in 54% of the interval CRS cohort and 47% of the primary CRS cohort. Macroscopic residual disease after CRS was the most important factor for not achieving TO. Age ≥ 70 was associated with lower TO rates in multivariable logistic regressions. TO rates ranged from 40% to 69% between hospitals in the interval CRS cohort and 22% to 100% in the primary CRS cohort. In both analyses, one hospital had significantly lower TO rates (different hospitals). Case-mix adjustment significantly affected TO rates in the primary CRS analysis., Conclusions: TO is a suitable composite outcome measure to detect hospital variation in healthcare quality for patients with advanced-stage ovarian cancer undergoing CRS. Case-mix adjustment improves the accuracy of the hospital comparison., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many studies have compared real-world clinical outcomes of immunotherapy in patients with metastatic non-small cell lung cancer (NSCLC) with reported outcomes data from pivotal trials. However, any differences observed could be only limitedly explored further for causation because of the unavailability of individual patient data (IPD) from trial participants. The present study aims to explore the additional benefit of comparison with IPD., Methods: This study compares progression free survival (PFS) and overall survival (OS) of metastatic NSCLC patients treated with second line nivolumab in real-world clinical practice (n = 141) with IPD from participants in the Checkmate-057 clinical trial (n = 292). Univariate and multivariate Cox proportional hazards models were used to construct HRs for real-world practice versus clinical trial., Results: Real-world patients were older (64 vs. 61 years), had more often ECOG PS ≥ 2 (5 vs. 0%) and were less often treated with subsequent anti-cancer treatment (28.4 vs. 42.5%) compared to trial patients. The median PFS in real-world patients was longer (3.84 (95%CI: 3.19-5.49) vs 2.30 (2.20-3.50) months) and the OS shorter than in trial participants (8.25 (6.93-13.2) vs. 12.2 (9.90-15.1) months). Adjustment with available patient characteristics, led to a shift in the hazard ratio (HR) for OS, but not for PFS (HRs from 1.13 (0.88-1.44) to 1.07 (0.83-1.38), and from 0.82 (0.66-1.03) to 0.79 (0.63-1.00), respectively)., Conclusions: This study is an example how IPD from both real-world and trial patients can be applied to search for factors that could explain an efficacy-effectiveness gap. Making IPD from clinical trials available to the international research community allows this., (© 2022. The Author(s).)

Objective: Previous studies have shown low adherence to surgical staging guidelines in patients with clinical early-stage ovarian carcinoma. The aim of this study was to identify guideline adherence for surgical staging and to show the distribution of each surgical item within the study population. In addition, we examined whether regional variation in the Netherlands exists for complete surgical staging., Methods: Patients with ovarian cancer and surgical staging registered in the Dutch Gynecological Oncology Audit between January 1, 2015 and December 31, 2019 in the Netherlands were included. Complete surgical staging was defined according to the Dutch evidence-based guideline. Surgical items were ranked and illustrated. Variation in complete surgical staging for eight regional cancer networks was shown in funnel plots. Manual validation of registered data was performed in three gynecological oncology centers., Results: 604 patients underwent surgical staging, 365 (60%) underwent an incomplete staging procedure, 295 (81%) were registered with early-stage disease (International Federation of Gynecology and Obstetrics I-IIA) and, of these patients, 115 (39%) received adjuvant chemotherapy. Patients with incomplete surgical staging were operated more often with minimal invasive techniques (laparoscopy or robot) compared with patients in the complete staging group (p<0.001). Sampling of cytology/ascites was the most frequently lacking factor (29%). Manual validation of data in three gynecological oncology centers identified reasons for incomplete staging, the most common being 'perioperative findings' such as dense adhesions between tumor and peritoneum, consistent with advanced stage disease (≥IIA). Regional variation for complete surgical staging showed two regions performing outside the confidence intervals (12.5% and 25.5%, mean 40%)., Conclusion: Guideline adherence for staging was lower than expected and validation of data gave additional insights into the reasons that were contributing to incomplete surgical staging. Moreover, this analysis showed that regional variation for surgical staging exists, which forms a starting point to improve and harmonize staging procedures for these patients nationwide., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: This study aims to develop a robust preoperative prediction model for anastomotic leakage (AL) after surgical resection for rectal cancer, based on established risk factors and with the power of a large prospective nation-wide population-based study cohort., Materials and Methods: A development cohort was formed by using the DCRA (Dutch ColoRectal Audit), a mandatory population-based repository of all patients who undergo colorectal cancer resection in the Netherlands. Patients aged 18 years or older were included who underwent surgical resection for rectal cancer with primary anastomosis (with or without deviating ileostomy) between 2011 and 2019. Anastomotic leakage was defined as clinically relevant leakage requiring reintervention. Multivariable logistic regression was used to build a prediction model and cross-validation was used to validate the model., Results: A total of 13.175 patients were included for analysis. AL was diagnosed in 1319 patients (10%). A deviating stoma was constructed in 6853 patients (52%). The following variables were identified as significant risk factors and included in the prediction model: gender, age, BMI, ASA classification, neo-adjuvant (chemo)radiotherapy, cT stage, distance of the tumor from anal verge, and deviating ileostomy. The model had a concordance-index of 0.664, which remained 0.658 after cross-validation. In addition, a nomogram was developed., Conclusion: The present study generated a discriminative prediction model based on preoperatively available variables. The proposed score can be used for patient counselling and risk-stratification before undergoing rectal resection for cancer., Competing Interests: Declaration of competing interest On behalf of the REPAIR research group of the Erasmus University Medical Center (Rotterdam, the Netherlands), I am very pleased to send you this manuscript entitled “A preoperative prediction model for anastomotic leakage after rectal cancer resection based on 13.175 patients” for peer review to European Journal of Surgical Oncology on behalf of the following authors V.T. Hoek, M.D, S. Buettner, M.D. Phd.D, C.L. Sparreboom M.D. Ph.D., R. Detering, M.D. Ph.D., A.G. Menon, M.D. Ph.D., G.J. Kleinrensink Ph.D., M.W.J.M. Wouters, M.D. Ph.D., J.F. Lange, M.D. Ph.D., J.K. Wiggers M.D. Ph.D. All authors have read and complied with the author guidelines and did declare there is no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Lignin is one of the main factors causing lignocellulosic biomass recalcitrance to enzymatic hydrolysis. Glasshouse-grown poplars severely downregulated for CINNAMYL ALCOHOL DEHYDROGENASE 1 (CAD1), the enzyme catalysing the last step in the monolignol-specific branch of lignin biosynthesis, have increased saccharification yields and normal growth. Here, we assess the performance of these hpCAD poplars in the field under short rotation coppice culture for two consecutive rotations of 1 yr and 3 yr. While 1-yr-old hpCAD wood had 10% less lignin, 3-yr-old hpCAD wood had wild-type lignin levels. Because of their altered cell wall composition, including elevated levels of cinnamaldehydes, both 1-yr-old and 3-yr-old hpCAD wood showed enhanced saccharification yields upon harsh alkaline pretreatments (up to +85% and +77%, respectively). In contrast with previous field trials with poplars less severely downregulated for CINNAMYL ALCOHOL DEHYDROGENASE (CAD), the hpCAD poplars displayed leaning phenotypes, early bud set, early flowering and yield penalties. Moreover, hpCAD wood had enlarged vessels, decreased wood density and reduced relative and free water contents. Our data show that the phenotypes of CAD-deficient poplars are strongly dependent on the environment and underpin the importance of field trials in translating basic research towards applications., (© 2022 The Authors. New Phytologist © 2022 New Phytologist Foundation.)

Introduction: Clinical Quality Registries (CQRs) were initiated in order to compare clinical outcomes between hospitals or regions within a country. To get an overview of these CQRs worldwide the aim of this study was to identify these CQRs for gynecological oncology and to summarize their characteristics, processes and QI's and to establish whether it is feasible to make an international comparison in the future., Methods: To identify CQRs in gynecological oncology a literature search in Pubmed was performed. All papers describing the use of a CQR were included. Administrative, epidemiological and cancer registries were excluded as these registries do not primarily serve to measure quality of care through QI's. The taskforce or contact person of the included CQR were asked to participate and share information on registered items, processes and indicators., Results: Five nations agreed to collaborate: Australia, Denmark, Italy, the Netherlands and Sweden. Denmark, Netherlands and Sweden established a nationwide registry, collecting data on multiple tumor types, and various QI's. Australia and Italy included patients with ovarian cancer only. All nations had a different process to report feedback results to participating hospitals., Conclusion: CQRs serve the same purpose to improve quality of care but vary on different aspects. Although similarities are observed in the topics measured by the QI's, an international comparison was not feasible as numerators or denominators differ between registries. In order to compare on an international level it would be useful to harmonize these registries and to set an international standard to measure the quality of care with similar indicators., Competing Interests: Declaration of competing interest There was no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The potential of whole genome duplication to increase plant biomass yield is well-known. In Arabidopsis tetraploids, an increase in biomass yield was accompanied by a reduction in lignin content and, as a result, a higher saccharification efficiency was achieved compared with diploid controls. Here, we evaluated whether the results obtained in Arabidopsis could be translated into poplar and whether the enhanced saccharification yield upon alkaline pretreatment of hairpin-downregulated CINNAMYL ALCOHOL DEHYDROGENASE1 ( hpCAD ) transgenic poplar could be further improved upon a whole genome duplication. Using a colchicine treatment, wild-type (WT) Populus tremula x P. alba cv. INRA 717-1B4, a commonly used model clone in tree biotechnology research, and hpCAD tetraploids were generated and grown in the greenhouse. In parallel, WT tetraploid poplars were grown in the field. In contrast to Arabidopsis, a whole genome duplication of poplar had a negative impact on the biomass yield of both greenhouse- and field-grown trees. Strikingly, field-grown WT tetraploids developed a brittle apex phenotype, i.e., their tip broke off just below the apex. In addition, the chromosome doubling altered the biomass composition of field-grown, but not of greenhouse-grown tetraploid poplars. More specifically, the lignin content of field-grown tetraploid poplars was increased at the expense of matrix polysaccharides. This increase in lignin deposition in biomass is likely the cause of the observed brittle apex phenotype, though no major differences in stem anatomy or in mechanical properties could be found between di- and tetraploid WT poplars grown in the field. Finally, without biomass pretreatment, the saccharification efficiency of greenhouse- and field-grown WT diploids was not different from that of tetraploids, whereas that of greenhouse-grown hpCAD tetraploids was higher than that of greenhouse-grown diploids. Upon alkaline pretreatment, the saccharification yield of diploids was similar to that of tetraploids for all genotypes and growth conditions tested. This study showed that a whole genome duplication in hybrid WT and hpCAD poplar did neither result in further improvements in biomass yield, nor in improved biomass composition and, hence, saccharification performance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wouters, Corneillie, Dewitte, Van Doorsselaere, Van den Bulcke, Van Acker, Vanholme and Boerjan.)

Background: The Dutch Surgical Aneurysm Audit (DSAA) is a nationwide mandatory quality registry that evaluates the perioperative outcomes of abdominal aortic aneurysms (AAAs). The DSAA includes perioperative outcomes that occur up to 30 days, but various complications following AAA repair occur after this period. Administrative healthcare data yield the possibility to evaluate later occuring outcomes such as reinterventions, without increasing the registration burden. The aim of this study is to assess the feasibility and the potential benefit of administrative healthcare data to evaluate mid-term reinterventions following intact AAA repair., Method: All patients that underwent primary endovascular aneurysm repair (EVAR) or open surgical repair (OSR) for an intact infrarenal AAA between January 2017 and December 2018 were selected from the DSAA. Subsequently, these patients were identified in a database containing reimbursement data. Healthcare activity codes that refer to reinterventions following AAA repair were examined to assess reinterventions within 12 and 15 months following EVAR and OSR., Results: We selected 4043 patients from the DSAA, and 2059 (51%) patients could be identified in the administrative healthcare database. Reintervention rates of 10.4% following EVAR and 9.5% following OSR within 12 months (p = 0.719), and 11.5% following EVAR and 10.8% following OSR within 15 months (p = 0.785) were reported., Conclusion: Administrative healthcare data as an addition to the DSAA is potentially beneficial to evaluate mid-term reinterventions following intact AAA repair without increasing the registration burden for clinicians. Further validation is necessary before reliable implementation of this tool is warranted., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Revealing universal behaviours is a hallmark of statistical physics. Phenomena such as the stochastic growth of crystalline surfaces 1 and of interfaces in bacterial colonies 2 , and spin transport in quantum magnets 3-6 all belong to the same universality class, despite the great plurality of physical mechanisms they involve at the microscopic level. More specifically, in all these systems, space-time correlations show power-law scalings characterized by universal critical exponents. This universality stems from a common underlying effective dynamics governed by the nonlinear stochastic Kardar-Parisi-Zhang (KPZ) equation 7 . Recent theoretical works have suggested that this dynamics also emerges in the phase of out-of-equilibrium systems showing macroscopic spontaneous coherence 8-17 . Here we experimentally demonstrate that the evolution of the phase in a driven-dissipative one-dimensional polariton condensate falls in the KPZ universality class. Our demonstration relies on a direct measurement of KPZ space-time scaling laws 18,19 , combined with a theoretical analysis that reveals other key signatures of this universality class. Our results highlight fundamental physical differences between out-of-equilibrium condensates and their equilibrium counterparts, and open a paradigm for exploring universal behaviours in driven open quantum systems., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Lignin is the main factor limiting the enzymatic conversion of lignocellulosic biomass into fermentable sugars. To reduce the recalcitrance engendered by the lignin polymer, the coumarin scopoletin was incorporated into the lignin polymer through the simultaneous expression of FERULOYL-CoA 6'-HYDROXYLASE 1 ( F6'H1 ) and COUMARIN SYNTHASE ( COSY ) in lignifying cells in Arabidopsis . The transgenic lines overproduced scopoletin and incorporated it into the lignin polymer, without adversely affecting plant growth. About 3.3% of the lignin units in the transgenic lines were derived from scopoletin, thereby exceeding the levels of the traditional p- hydroxyphenyl units. Saccharification efficiency of alkali-pretreated scopoletin-overproducing lines was 40% higher than for wild type.

Background: The Dutch Institute for Clinical Auditing (DICA) Medicines Program was set up in September 2018 to evaluate expensive medicine use in daily practice in terms of real-world effectiveness using only existing data sources., Objective: The aim of this study is to describe the potential of the addition of declaration data to quality registries to provide participating centers with benchmark information about the use of medicines and outcomes among patients., Methods: A total of 3 national population-based registries were linked to clinical and financial data from the hospital pharmacy, the Dutch diagnosis treatment combinations information system including in-hospital activities, and survival data from health care insurers. The first results of the real-world data (RWD) linkage are presented using descriptive statistics to assess patient, tumor, and treatment characteristics. Time-to-next-treatment (TTNT) and overall survival (OS) were estimated using the Kaplan-Meier method., Results: A total of 21 Dutch hospitals participated in the DICA Medicines Program, which included 7412 patients with colorectal cancer, 1981 patients with metastasized colon cancer, 3860 patients with lung cancer, 1253 patients with metastasized breast cancer, and 7564 patients with rheumatic disease. The data were used for hospital benchmarking to gain insights into medication use in specific patient populations, treatment information, clinical outcomes, and costs. Detailed treatment information (duration and treatment steps) led to insights into differences between hospitals in daily clinical practices. Furthermore, exploratory analyses on clinical outcomes (TTNT and OS) were possible., Conclusions: The DICA Medicines Program shows that it is possible to gather and link RWD about medicines to 4 disease-specific population-based registries. Since these RWD became available with minimal registration burden and effort for hospitals, this method can be explored in other population-based registries to evaluate real-world efficacy., (©Rawa Kamaran Ismail, Jesper van Breeschoten, Silvia van der Flier, Caspar van Loosen, Anna Maria Gerdina Pasmooij, Maaike van Dartel, Alfons van den Eertwegh, Anthonius de Boer, Michel Wouters, Doranne Hilarius. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 23.06.2022.)

Objective: The COVID-19-pandemic caused drastic healthcare changes worldwide. To date, the impact of these changes on gynecological cancer healthcare is relatively unknown. This study aimed to assess the impact of the COVID-19-pandemic on surgical gynecological-oncology healthcare., Methods: This population-based cohort study included all surgical procedures with curative intent for gynecological malignancies, registered in the Dutch Gynecological Oncology Audit, in 2018-2020. Four periods were identified based on COVID-19 hospital admission rates: 'Pre-COVID-19', 'First wave', 'Interim period', and 'Second wave'. Surgical volume, perioperative care processes, and postoperative outcomes from 2020 were compared with 2018-2019., Results: A total of 11,488 surgical procedures were analyzed. For cervical cancer, surgical volume decreased by 17.2% in 2020 compared to 2018-2019 (mean 2018-2019: n = 542.5, 2020: n = 449). At nadir (interim period), only 51% of the expected cervical cancer procedures were performed. For ovarian, vulvar, and endometrial cancer, volumes remained stable. Patients with advanced-stage ovarian cancer more frequently received neoadjuvant chemotherapy in 2020 compared to 2018-2019 (67.7% (n = 432) vs. 61.8% (n = 783), p = 0.011). Median time to first treatment was significantly shorter in all four malignancies in 2020. For vulvar and endometrial cancer, the length of hospital stay was significantly shorter in 2020. No significant differences in complicated course and 30-day-mortality were observed., Conclusions: The COVID-19-pandemic impacted surgical gynecological-oncology healthcare: in 2020, surgical volume for cervical cancer dropped considerably, waiting time was significantly shorter for all malignancies, while neoadjuvant chemotherapy administration for advanced-stage ovarian cancer increased. The safety of perioperative healthcare was not negatively impacted by the pandemic, as complications and 30-day-mortality remained stable., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

While abroad, a healthy 36-year-old woman slammed head-on into a rock wall at high speed, resulting in significant facial trauma. The initial trauma care and first aid took place abroad. In the Netherlands, the woman was referred to the Department of Oral and Maxillofacial Surgery (OMFS) for reconstruction of her face and alveolar processes, gingiva and dentition. In view of the seriousness of the injuries, a 3D treatment plan was drawn up in a multidisciplinary collaboration with an OMF surgeon, an implantologist, dentist and dental technician. By making a digital setup of both the top and bottom front in advance, it was possible to work predictably. The first step consisted of bone augmentation by means of an iliac crest graft to reconstruct the major bone defects of the superior and inferior alveolar processes. Implants were then placed in the upper and lower jaws in the ideal position for the suprastructure by means of drill jigs. Within 10 months after the trauma, the implant bridges could be placed on individual zirconia frameworks to optimally restore oral function and aesthetics, completing the reconstruction.

Background: Sebaceous carcinoma (SC) is a rare malignant tumour whereby, comprehensive long-term data are scarce. This study aimed to assess the outcome of patients treated with resection for SC., Methods: Patients treated at four tertiary centres were included. Cumulative incidence curves were calculated for recurrences., Results: A total of 100 patients (57 males, 57%) were included with 103 SCs. The median age was 72 (range, 15-95) years with a median follow-up of 52 (interquartile range [IQR], 24-93) months. Most SCs were located (peri)ocular (49.5%). Of all SCs, 17 locally recurred (16.5%) with a median time to recurrence of 19 (IQR, 8-29) months. The cumulative incidence probability for recurrence was statistically higher for (peri)ocular tumours (p = 0.005), and for positive resection margins (p = 0.001). Two patients presented with lymph node metastases and additional seven patients (8.7%) developed lymph node metastases during follow-up with a median time to metastases of 8 (IQR, 0.5-28) months. Three patients had concurrent in-transit metastases and one patient also developed liver and bone metastases during follow-up., Conclusion: SC is a rare, yet locally aggressive tumour. Positive resection margins and (peri)ocular SCs are more frequently associated with local recurrence. SC infrequently presents with locoregional or distant metastases., (© 2022 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Objectives: We wanted to have a more substantiated idea about the extreme values which are possible in patients not dying or being moribund., Methods: for nine regular analytes the five most extreme results registered between 2014 and 2018 in our database were searched. Results had to have been confirmed by multiple analyses in different samples. Patients should have lived at least 28 days after the extreme analyte value was observed. Patient diagnoses and symptoms were checked to understand the pathology and apparent consequences of the extreme values., Results: most extreme values (lowest and highest; mmol/L): sodium 100/178, potassium 1.2/9.8, chloride 58/138, total calcium 1.02/4.98, ionized calcium 0.37/2.44, magnesium 0.07/3.31, phosphate <0.1/7.3, pH <6.8/7.81, hemoglobin 1.3/14.9 in non-newborns; not determined/16.4 in newborns., Conclusion: All extreme values deviated 7 s.d. or more from the means. Patients obviously can survive rather deviant analyte values.

In an atomic Bose-Einstein condensate quenched to the unitary regime, we predict the sequential formation of a significant fraction of condensed pairs and triples. At short distances, we demonstrate the two-body and Efimovian character of the condensed pairs and triples, respectively. As the system evolves, their size becomes comparable to the interparticle distance, such that many-body effects become significant. The structure of the condensed triples depends on the size of Efimov states compared with density scales. Unexpectedly, we find universal condensed triples in the limit where these scales are well separated. Our findings provide a new framework for understanding dynamics in the unitary regime as the Bose-Einstein condensation of few-body composites.

Background: The objective of this study was to evaluate trends in survival and health care costs in metastatic melanoma in the era of targeted and immunotherapeutic drugs., Materials and Methods: Data on survival and health care resource use were retrieved from the Dutch Melanoma Treatment Registry. The Kaplan-Meier method was used to estimate overall survival. Health care costs and budget impact were computed by applying unit costs to individual patient resource use. All outcomes were stratified by year of diagnosis., Results: Baseline characteristics were balanced across cohort years. The percentage of patients receiving systemic treatment increased from 73% in 2013 to 90% in 2018. Patients received on average 1.85 [standard deviation (SD): 1.14] lines of treatment and 41% of patients received at least two lines of treatment. Median survival increased from 11.8 months in 2013 [95% confidence interval (CI): 10.7-13.7 months] to 21.1 months in 2018 (95% CI: 18.2 months-not reached). Total mean costs were €100 330 (SD: €103 699); systemic treatments accounted for 84% of the total costs. Costs for patients who received systemic treatment [€118 905 (SD: €104 166)] remained reasonably stable over the years even after the introduction of additional (combination of) novel drugs. From mid-2013 to 2018, the total budget impact for all patients was €452.79 million., Conclusion: Our study shows a gain in survival in the era of novel targeted and immunotherapeutic drugs. These novel drugs came, however, along with substantial health care costs. Further insights into the cost-effectiveness of the novel drugs are crucial for ensuring value for money in the treatment of patients with metastatic melanoma., Competing Interests: Disclosure ACJvA reports grants and personal fees from Amgen and Merck-Pfizer; and personal fees from Bristol-Myers Squibb, Novartis, MSD-Merck, Pierre Fabre, Sanofi, and 4SC, outside the submitted work. AJMvdE reports personal fees from BMS, MSD, Merck, Sanofi, Roche, Novartis, Eisai, Ipsen, Pfizer, and Pierre Fabre; and grants from Grant for clinical studies, outside the submitted work. MGF reports grants from Roche Nederland B.V., Daiichi Sankyo, Abbvie, Gilead Sciences Netherlands BV, and Astellas Pharma BV, outside the submitted work. JWBdG reports personal fees from BMS, MSD, Pierre Fabre, and Servier, outside the submitted work. JBAGH reports grants and other from BMS, MSD, Novartis, BioNTech, and Amgen; other from Achilles Tx, GSK, Immunocore, Ipsen, Merck Serono, Molecular Partners, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures, and Vaximm; and personal fees from Neogene Tx, outside the submitted work. GAPH reports consulting and advisory role: Amgen, Roche, MSD, BMS, Pfizer, Novartis, Pierre Fabry, paid to the institution (UMCG); and research grant from BMS and Seerave, paid to the institution (UMCG). DP reports personal fees from BMS advisory board and Pierre Fabre advisory board, outside the submitted work. KPMS reports personal fees from Novartis, Roche, Pierre Fabre, MSD, BMS, and Abbvie, outside the submitted work. AAMvdV reports other from BMS, MSD, Merck, Sanofi, Roche, Novartis, Eisai, Ipsen, Pfizer, and Pierre Fabre, outside the submitted work. HMW reports non-financial support from Ipsen; personal fees from Roche; and personal fees and non-financial support from Astellas, outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: This study aimed to provide insights into the real-world use of palbociclib, dose reductions, and drug effectiveness in (older) patients with advanced breast cancer (BC)., Patients and Methods: Patients with advanced BC treated with palbociclib from 2017 to 2020 were included. The Kaplan-Meier method was used to calculate time to next treatment (TTNT) and overall survival (OS) for patients with or without dose reductions. These clinical outcomes were also compared in subgroup analyses for older patients (≥70 years) and younger patients (<70 years) and for patients discontinuing palbociclib early (<4 administrations)., Results: A total of 598 patients with advanced BC were included, with a median age of 64 years. Palbociclib dose reductions occurred in 33% of all patients. Early discontinuation of palbociclib without dose reductions occurred in 23% of the patients. Patients who required a palbociclib dose reduction were older (median age 67 years vs. 63 years). Patients with dose reductions had a significantly higher TTNT of 16.9 vs. 11.4 months (p < 0.001) and median OS of 29.7 vs. 21.9 months (p = 0.003) compared to patients without dose reductions. The TTNT in older patients was significantly longer (16.9 vs. 11.6 months, p = 0.013) than younger patients, but OS was similar (20.7 vs. 26.7 months, p = 0.051)., Conclusion: Palbociclib dose reductions occurred in real-world practice similarly to the PALOMA-3 trial. Patients with dose reductions had no poorer outcomes compared to patients not requiring a dose reduction. Older patients treated with palbociclib had more frequent dose reductions, but this did not appear to affect OS., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Lignin is one of the main factors determining recalcitrance to processing of lignocellulosic biomass towards bio-based materials and fuels. Consequently, wood of plants engineered for low lignin content is typically more amenable to processing. However, lignin-modified plants often exhibit collapsed vessels and associated growth defects. Vessel-specific reintroduction of lignin biosynthesis in dwarfed low-lignin cinnamoyl-CoA reductase1 (ccr1) Arabidopsis mutants using the ProSNBE:AtCCR1 construct overcame the yield penalty while maintaining high saccharification yields, and showed that monolignols can be transported between the different xylem cells acting as 'good neighbors' in Arabidopsis. Here, we translated this research into the bio-energy crop poplar. By expressing ProSNBE:AtCCR1 into CRISPR/Cas9-generated ccr2 poplars, we aimed for vessel-specific lignin biosynthesis to: (i) achieve growth restoration while maintaining high saccharification yields; and (ii) study the existence of 'good neighbors' in poplar wood. Analyzing the resulting ccr2 ProSNBE:AtCCR1 poplars showed that vessels and rays act as good neighbors for lignification in poplar. If sufficient monolignols are produced by these cells, monolignols migrate over multiple cell layers, resulting in a restoration of the lignin amount to wild-type levels. If the supply of monolignols is limited, the monolignols are incorporated into the cell walls of the vessels and rays producing them and their adjoining cells resulting in fiber hypolignification. One such fiber-hypolignified line had 18% less lignin and, despite its small yield penalty, had an increase of up to 71% in sugar release on a plant base upon saccharification., (© 2021 Society for Experimental Biology and John Wiley & Sons Ltd.)

The ordering of particles in the drying process of a colloidal suspension is crucial in determining the properties of the resulting film. For example, microscopic inhomogeneities can lead to the formation of cracks and defects that can deteriorate the quality of the film considerably. This type of problem is inherently multiscale and here we study it numerically, using our recently developed method for the simulation of soft polymeric capsules in multicomponent fluids. We focus on the effect of the particle softness on the film microstructure during the drying phase and how it relates to the formation of defects. We quantify the order of the particles by measuring both the Voronoi entropy and the isotropic order parameter. Surprisingly, both observables exhibit a non-monotonic behaviour when the softness of the particles is increased. We further investigate the correlation between the interparticle interaction and the change in the microstructure during the evaporation phase. We observe that the rigid particles form chain-like structures that tend to scatter into small clusters when the particle softness is increased. This article is part of the theme issue 'Progress in mesoscale methods for fluid dynamics simulation'.

Objectives: The challenge when performing cytoreductive surgery (CRS) is to balance the benefits and risks. The aim of this study was to report short term postoperative morbidity and mortality in relation to surgical outcome in patients undergoing primary debulking surgery (PDS) or interval debulking (IDS) surgery in the Netherlands., Methods: The Dutch Gynecological Oncology Audit (DGOA) was used for retrospective analysis. Patients undergoing PDS or IDS between January 1st, 2015 - December 31st, 2018 were included. Outcome was frequency of postoperative complications. Median time to adjuvant chemotherapy and severity of complications were related to outcome of CRS. Complications with Clavien-Dindo ≥3 were analyzed per region and case mix corrected. Statistical analysis was performed with R.Studio., Results: 1027 patients with PDS and 1355 patients with IDS were included. Complications with re-invention were significantly higher in PDS compared to IDS (5.7% vs. 3.6%, p = 0.048). Complete cytoreduction was 69.7% in PDS and 62.1% IDS, p < 0.001. Time to adjuvant chemotherapy was 49 days in patients with complete CRS and a complication with re-intervention. Regional variation for severe complications showed one region outside confidence intervals., Conclusions: Higher complete cytoreduction rate in the PDS group indicates that the correct patients have been selected, but is associated with a higher percentage of complication with re-intervention. As result, time to start adjuvant chemotherapy is longer in this group. Maintaining a balance in aggressiveness of surgery and outcome of the surgical procedure with respect to severe complications is underlined. Bench marked data should be discussed nationally to improve this balance., Competing Interests: Declaration of Competing Interest There was no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Interhospital referral is a consequence of centralization of complex oncological care but might negatively impact waiting time, a quality indicator in the Netherlands. This study aims to evaluate characteristics and waiting times of patients with primary colorectal cancer who are referred between hospitals., Methods: Data were extracted from the Dutch ColoRectal Audit (2015-2019). Waiting time between first tumor-positive biopsy until first treatment was compared between subgroups stratified for referral status, disease stage, and type of hospital., Results: In total, 46,561 patients were included. Patients treated for colon or rectal cancer in secondary care hospitals were referred in 12.2% and 14.7%, respectively. In tertiary care hospitals, corresponding referral rates were 43.8% and 66.4%. Referred patients in tertiary care hospitals were younger, but had a more advanced disease stage, and underwent more often multivisceral resection and simultaneous metastasectomy than non-referred patients in secondary care hospitals (p<0.001). Referred patients were more often treated within national quality standards for waiting time compared to non-referred patients (p<0.001). For referred patients, longer waiting times prior to MDT were observed compared to non-referred patients within each hospital type, although most time was spent post-MDT., Conclusion: A large proportion of colorectal cancer patients that are treated in tertiary care hospitals are referred from another hospital but mostly treated within standards for waiting time. These patients are younger but often have a more advanced disease. This suggests that these patients are willing to travel more but also reflects successful centralization of complex oncological patients in the Netherlands.

Introduction: The Dutch Gynecological Oncology Audit (DGOA) was initiated in 2014 to serve as a nationwide audit, which registers the four most prevalent gynecological malignancies. This study presents the first results of clinical auditing for ovarian cancer in the Netherlands., Methods: The Dutch Gynecological Oncology Audit is facilitated by the Dutch Institute of Clinical Auditing (DICA) and run by a scientific committee. Items are collected through a web-based registration based on a set of predefined quality indicators. Results of quality indicators are shown, and benchmarked information is given back to the user. Data verification was done in 2016., Results: Between January 01, 2014 and December 31, 2018, 6535 patients with ovarian cancer were registered. The case ascertainment was 98.3% in 2016. The number of patients with ovarian cancer who start therapy within 28 days decreased over time from 68.7% in 2014 to 62.7% in 2018 (p < 0.001). The percentage of patients with primary cytoreductive surgery decreased over time (57.8%-39.7%, P < 0.001). However, patients with complete primary cytoreductive surgery improved over time (53.5%-69.1%, P < 0.001). Other quality indicators did not significantly change over time., Conclusion: The Dutch Gynecological Oncology Audit provides valuable data on the quality of care on patients with ovarian cancer in the Netherlands. Data show variation between hospitals with regard to pre-determined quality indicators. Results of 'best practices' will be shared with all participants of the clinical audit with the aim of improving quality of care nationwide., Competing Interests: Declaration of competing interest There are no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Resolvins (RvD1, RvD2 and RvE1) are endogenous anti-inflammatory lipid mediators that display potent analgesic properties in somatic pain by modulating transient receptor potential vanilloid 1 (TRPV1) activation. To what extent these molecules could also have a beneficial effect on TRPV1 sensitisation and visceral hypersensitivity (VHS), mechanisms involved in IBS, remains unknown., Design: The effect of RvD1, RvD2 and RvE1 on TRPV1 activation and sensitisation by histamine or IBS supernatants was assessed on murine dorsal root ganglion (DRG) neurons using live Ca 2+ imaging. Based on the results obtained in vitro, we further studied the effect of RvD2 in vivo using a murine model of post-infectious IBS and a rat model of post-inflammatory VHS. Finally, we also tested the effect of RvD2 on submucosal neurons in rectal biopsies of patients with IBS., Results: RvD1, RvD2 and RvE1 prevented histamine-induced TRPV1 sensitisation in DRG neurons at doses devoid of an analgesic effect. Of note, RvD2 also reversed TRPV1 sensitisation by histamine and IBS supernatant. This effect was blocked by the G protein receptor 18 (GPR18) antagonist O-1918 (3-30 µM) and by pertussis toxin. In addition, RvD2 reduced the capsaicin-induced Ca 2+ response of rectal submucosal neurons of patients with IBS. Finally, treatment with RvD2 normalised pain responses to colorectal distention in both preclinical models of VHS., Conclusions: Our data suggest that RvD2 and GPR18 agonists may represent interesting novel compounds to be further evaluated as treatment for IBS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)