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Objective: To evaluate the cost-effectiveness and budget impact of using standard care (no advanced treatment, NAT) compared with an advanced treatment (AT), dehydrated human amnion/chorion membrane (DHACM), when following parameters for use (FPFU) in treating lower extremity diabetic ulcers (LEDUs). Method: We analysed a retrospective cohort of Medicare patients (2015–2019) to generate four propensity-matched cohorts of LEDU episodes. Outcomes for DHACM and NAT, such as amputations, and healthcare utilisation were tracked from claims codes, analysed and used to build a hybrid economic model, combining a one-year decision tree and a four-year Markov model. The budget impact was evaluated in the difference in per member per month spending following completion of the decision tree. Likewise, the cost-effectiveness was analysed before and after the Markov model at a willingness to pay (WTP) threshold of $100,000 per quality adjusted life year (QALY). The analysis was conducted from the healthcare sector perspective. Results: There were 10,900,127 patients with a diagnosis of diabetes, of whom 1,213,614 had an LEDU. Propensity-matched Group 1 was generated from the 19,910 episodes that received AT. Only 9.2% of episodes were FPFU and DHACM was identified as the most widely used AT product among Medicare episodes. Propensity-matched Group 4 was limited by the 590 episodes that used DHACM FPFU. Episodes treated with DHACM FPFU had statistically fewer amputations and healthcare utilisation. In year one, DHACM FPFU provided an additional 0.013 QALYs, while saving $3,670 per patient. At a WTP of $100,000 per QALY, the five-year net monetary benefit was $5003. Conclusion: The findings of this study showed that DHACM FPFU reduced costs and improved clinical benefits compared with NAT for LEDU Medicare patients. DHACM FPFU provided better clinical outcomes than NAT by reducing major amputations, ED visits, inpatient admissions and readmissions. These clinical gains were achieved at a lower cost, in years 1–5, and were likely to be cost-effective at any WTP threshold. Adoption of best practices identified in this retrospective analysis is expected to generate clinically significant decreases in amputations and hospital utilisation while saving money.

In Tombs in Early Modern Rome (1400–1600), Jan L. de Jong reveals how funerary monuments, far from simply marking a grave, offered an image of the deceased that was carefully crafted to generate a laudable memory and prompt meditative reflections on life, death, and the hereafter. This leads to such questions as: which image of themselves did cardinals create when they commissioned their own tomb monuments? Why were most popes buried in a grandiose tomb monument that they claimed they did not want? Which memory of their mother did children create, and what do tombs for children tell about mothers? Were certain couples buried together so as to demonstrate their eternal love, expecting an afterlife in each other’s company?

Objective: To evaluate large propensity-matched cohorts to assess outcomes in patients receiving advanced treatment (AT) with skin substitutes for lower extremity diabetic ulcers (LEDUs) versus no AT (NAT) for the management of LEDUs. Method: The Medicare Limited Dataset (1 October 2015 through 2 October 2018) were used to retrospectively analyse people receiving care for a LEDU treated with AT or NAT (propensity-matched Group 1). Analysis included major and minor amputations, emergency department (ED) visits and hospital readmissions. In addition, AT following parameters for use (FPFU) was compared with AT not FPFU (propensity-matched Group 2). A paired t-test was used for comparisons of the two groups. For comparisons of three groups, the Kruskal–Wallis test was used. A Bonferroni correction was performed when multiple comparisons were calculated. Results: There were 9,738,760 patients with a diagnosis of diabetes, of whom 909,813 had a LEDU. In propensity-matched Group 1 (12,676 episodes per cohort), AT patients had statistically fewer minor amputations (p=0.0367), major amputations (pConclusion: AT for the management of LEDUs was associated with significant reductions in major and minor amputation, ED use, and hospital readmission compared with LEDUs managed with NAT. Clinics should implement AT in accordance with the highlighted parameters for use to improve outcomes and reduce costs.

Objective: To determine the role of debridement when patients are using placental-derived allografts (PDAs), data from two prospective, multicentre, randomised controlled trials (RCTs) were evaluated for the quality or adequacy of debridement on diabetic foot ulcers (DFUs) treated with PDAs. Results were compared with real-world findings via a retrospective analysis of 2015–2019 Medicare claims for DFUs. Method: Debridement adequacy in the prospective RCTs was adjudicated by three blinded wound care specialists. Treatments included two PDAs, dehydrated human amnion/chorion membrane (DHACM, n=54) or dehydrated human umbilical cord (DHUC, n=101), compared with standard of care (SOC, n=110). The key outcome was the influence of adequate debridement on rates of complete closure within 12 weeks. Additionally, a retrospective analysis of 2015–2019 Medicare claims for DFUs that received routine debridement at intervals ranging from every 1–7 days (18,900 total episodes), 8–14 days (35,728 total episodes), and every 15 days or greater (34,330 total episodes) was performed. Results: Within the RCTs, adequate debridement occurred in 202/265 (76%) of patients, 90/110 (82%) SOC ulcers, 45/54 (83%) of DHACM-treated ulcers, and in 67/101 (66%) of DHUC-treated ulcers. Complete closure occurred in 150/202 (74%) of adequately debrided ulcers, and in only 13/63 (21%) of ulcers without adequate debridement, pConclusion: Prospectively collected data examining the quality of debridement and retrospectively analysed data examining the frequency of debridement supports routine adequate wound debridement, particularly at intervals of seven days, as an essential component of wound care. Optimal use of placental-derived allografts improves outcomes and lowers the use of healthcare resources.

Review of: K.D. Botke & H.T. van Veen (eds.), A Cultural Symbiosis. Patrician Art Patronage and Medicean Cultural Politics in Florence (1530-1610), Leuven, Leuven University Press, 2021, p. 320, ISBN 9789462702967, € 59.50.

Background:Sinus node dysfunction (SND) and atrial tachyarrhythmias frequently co-exist in the aging patient with congenital heart disease (CHD), even after surgical correction early in life. We examined differences in electrophysiological properties of the sino-atrial node (SAN) area between pediatric and adult patients with CHD.MethodsEpicardial mapping of the SAN was performed during sinus rhythm in 12 pediatric (0.6 [0.4–2.4] years) and 15 adult (47 [40–55] years) patients. Unipolar potentials were classified as single-, short or long double- and fractionated potentials. Unipolar voltage, relative R-to-S-amplitude ratio and duration of all potentials was calculated. Conduction velocity (CV) and the amount of conduction block (CB) was calculated.ResultsSAN activity in pediatric patients was solely observed near the junction of the superior caval vein and the right atrium, while in adults SAN activity was observed even up to the middle part of the right atrium. Compared to pediatric patients, the SAN region of adults was characterized by lower CV, lower voltages, more CB and a higher degree of fractionation. At the earliest site of activation, single potentials from pediatrics consisted of broad monophasic S-waves with high amplitudes, while adults had smaller rS-potentials with longer duration which were more often fractionated.ConclusionsCompared to pediatric patients, adults with uncorrected CHD have more inhomogeneous conduction and variations in preferential SAN exit site, which are presumable caused by aging related remodeling. Long-term follow-up of these patients is essential to demonstrate whether these changes are related to development of SND and also atrial tachyarrhythmias early in life.

Bespreking van: José van der Helm, Roos Hamelink en Geertje Wilmsen (eds.), Delitiae Italiae. Een reis door het zeventiende-eeuwse Italië, Hilversum, Verloren, 2021, p. 264, ISBN 9789087049225, € 35.

For mills making paper with recovered fiber, removal of hydrophobic contaminants is essential for trouble-free operation of paper machines. Significant cost savings on paper machine operation can be achieved by reducing deposits, which results in better quality, reduced downtime, increased fiber yield, and reduced energy consumption. Bubble nucleation separation (BNS) is a relatively new process for removing hydrophobic particles. When vacu-um is applied to a slurry, dissolved gas bubbles nucleate on hydrophobic particles and drag them to the surface for easy removal. We constructed a 16-L batch unit to evaluate the effect of operating parameters on removal of hydro-phobic particles, using statistical design of experiments. These results were used to guide our design of a 16-L con-tinuous unit. We tested this unit on laboratory and mill samples. The removal of 60%–80% of hydrophobic particles was achieved with a low reject rate of < 2%. Following on this success, we built a 200-L pilot unit and tested it in our pilot plant. With promising results there, we installed the pilot unit at a commercial paper recycling mill. Over the course of several mill trials, we showed that it was possible to remove a considerable amount of suspended solids from paper machine white water with less than 2% rejects. Unfortunately, due to the unit only treating 50 L/min and the mill flow being 12000 L/min, we were not able treat a sufficient portion of the white water to know whether a large-scale implementation of BNS would improve paper machine runnability.

Background This study evaluates clinical and echocardiographic outcomes in patients who underwent tricuspid valve replacement (TVR) for carcinoid heart disease (CaHD) stratified to prosthesis type (biological vs mechanical). Methods All patients undergoing TVR for CaHD between 1991 and 2017 were analyzed retrospectively in four tertiary centers. Cox-proportional hazard models were used to analyze survival data and mixed-models for repeated measurements of echo and laboratory data. Results In total, 49 patients (median age: 59 [51–66], 45% male) underwent biological (n = 20, 41%) or mechanical (n = 29, 59%) TVR. Three (6%) patients died in-hospital and 3-year actuarial survival was 73.3 ± 8.7% (biological) and 56.1 ± 10.0% (mechanical) (P = 0.69). During a median follow-up of 17 months, two patients with a biological prosthesis required reoperation for structural valve deterioration, while one patient with mechanical prostheses had a reoperation due to valve thrombosis. No significant differences in bleeding, thrombosis, thromboembolism and heart failure admissions were noted between prosthesis types. Postoperative valve regurgitation increased more in patients with a biological prosthesis (p = 0.022). Maximum tricuspid inflow gradient was higher in patients with biological prostheses (p = 0.02); however, course over time was comparable between prosthesis types (p = 0.136). Conclusion Tricuspid valve surgery for CaHD can be performed with acceptable hospital mortality risk. This data shows no apparent benefit of biological valves over mechanical prosthesis or vice versa. Valve choice should be made in a multi-disciplinary team taking into account expected lifespan, planned treatment for the carcinoid syndrome and neuroendocrine tumor and patient preferences.

Increasingly, research funders include societal impact as a criterion in evaluation procedures. The European Commission is no exception to this trend. Societal impact determines one-third of a project’s success in receiving funding from the Societal Challenges in Horizon 2020 (H2020). Yet, there are large differences in terms of science and technology performance between countries that participate in the programme. In this article, we (1) compare societal impact practices in the social sciences and humanities in high-performing countries (HPCs) and low-performing countries (LPCs) to the evaluation of societal impact in funding procedures at the European level and (2) reflect upon consequences for the competition for research funding in the European funding arena. To this end, we introduce the concept of ‘societal impact capacity’ as well as a framework to analyse it. The analysis of 60 case studies from 16 countries across Europe shows that (1) researchers from HPCs have a higher impact capacity than those from LPCs and (2) researchers from HPCs report more details about impact than those from LPCs. This suggests that researchers from HPCs are better equipped to score well on the impact criterion when applying for funding than researchers from LPCs. We conclude with policy recommendations for the organization and evaluation of societal impact.

SummaryWe developed a miniaturized two-photon microscope (MINI2P) for fast, high-resolution, multiplane calcium imaging of over 1,000 neurons at a time in freely moving mice. With a microscope weight below 3g and a highly flexible connection cable, MINI2P allowed imaging to proceed with no impediment of behavior in half-hour free-foraging trials compared to untethered, unimplanted animals. The improved cell yield was achieved through a new optical system design featuring an enlarged field of view (FOV) and a new micro-tunable lens with increased z-scanning range and speed that allowed for fast and stable imaging of multiple, interleaved planes as well as 3D functional imaging. A novel technique for successive imaging across multiple, adjacent FOVs enabled recordings from more than 10,000 neurons in the same animal. Large-scale proof-of-principle data were obtained from cell populations in visual cortex, medial entorhinal cortex, and hippocampus, revealing spatial tuning of cells in all areas, including visual cortex.HighlightsWe developed a lightweight 2-photon miniscope for imaging in freely-foraging miceActivity can be monitored in volumes of over 1,000 visual or entorhinal-cortex cellsA new z-scanning module allows fast imaging across multiple interleaved planesSuccessive imaging from adjacent regions enables imaging from more than 10,000 cells

This study addressed the conceptualization of the societal impact of research from the perspective of programme evaluation, by focusing on the three ‘result’ elements of logic models: outputs, outcomes, and impact. In research evaluation, the distinction could resemble a difference between product, use, and benefit. The study established whether researchers in sub-Saharan Africa (SSA), South Africa excluded, view societal impact as extending across all three elements or as confined to the last element only. A web survey of 485 SSA researchers was conducted, as researchers from this region are not yet bounded by policy definitions of impact. The survey imposed the three elements of logic models onto five hypothetical descriptions of ‘impactful’ research initiatives. Respondents rated each element in terms of how much it reflects the societal impact of research. For any initiative, use was more likely to be considered a strong example of societal impact compared to a product, but less likely so compared to benefit. Between 23% and 43% of respondents rated all three elements as strong examples of the societal impact of research. Responses were analyzed by SSA region and the research domain and years of research experience of survey participants. An open-ended question about own understandings of societal impact was included as well in the survey. The responses portrayed impact as a (generally) positive effect that contributes to change in the daily life of human kind. The expectation that research should have impact at an almost general level of aggregation could be unique to the SSA context.

Purpose The purpose is to design and validate an anthropomorphic polyvinyl alcohol (PVA) liver phantom with respiratory motion to simulate needle-based interventions. Such a system can, for example, be used as a validation tool for novel needles. Methods Image segmentations of CT scans of four patients during inspiration and expiration were used to measure liver and rib displacement. An anthropomorphic liver mold based on a CT scan was 3D printed and filled with 5% w/w PVA-to-water, undergoing two freeze–thaw cycles, in addition to a 3D-printed compliant rib cage. They were both held in place by a PVA abdominal phantom. A sinusoidal motion vector, based on the measured liver displacement, was applied to the liver phantom by means of a motion stage. Liver, rib cage and needle deflection were tracked by placing electromagnetic sensors on the phantom. Liver and rib cage phantom motion was validated by comparison with the CT images of the patients, whereas needle deflection was compared with the literature. Results CT analysis showed that from the state of expiration to inspiration, the livers moved predominantly toward the right (mean: 2 mm, range: − 11 to 11 mm), anterior (mean: 15 mm, range: 9–21 mm) and caudal (mean: 16 mm, range: 6–24 mm) direction. The mechatronic design of the liver phantom gives the freedom to set direction and amplitude of the motion and was able to mimic the direction of liver motion of one patient. Needle deflection inside the phantom increased from 1.6 to 3.8 mm from the initial expiration state to inspiration. Conclusions The developed liver phantom allows for applying different motion patterns and shapes/sizes and thus allows for patient-specific simulation of needle-based interventions. Moreover, it is able to mimic appropriate respiratory motion and needle deflection as observed in patients. Electronic supplementary material The online version of this article (10.1007/s11548-019-02029-6) contains supplementary material, which is available to authorized users.

Aims: The aims of this study are to investigate the incidence and determinants of post-operative atrial arrhythmias, conduction disorders and mortality in hypertrophic obstructive cardiomyopathy (HOCM) patients undergoing transaortic myectomy. Methods and results: This retrospective single-center study was conducted in 249 patients (median age 54 years [40–64], 42% female) undergoing transaortic myectomy. Post-operative atrial fibrillation (AF) was reported in 84 patients (33.7%), including 56 patients (22.5%) with de novo AF. Older age (HR = 1.027 (1.003–1.052), p = 0.029) and hypercholesterolemia (HR = 2.296 (1.091–4.832) p = 0.029) were independent predictors for de novo post-operative AF. Late post-operative AF and atrial flutter (AFL) occurred in 18.9% and 6.8% of the patients, respectively. De novo early post-operative AF increased the risk of late post-operative AF (HR = 3.138 (1.450–6.789), p = 0.004). Patients with a right bundle branch block had a higher risk of early-postoperative pacemaker implantation (p = 0.003, HR = 9.771 (2.195–43.505)). Higher age at time of surgery (HR = 1.053 (1.026–1.081), p < 0.001) was a predictor for late mortality (n = 47, 18.9%). Conclusion: Early and late post-operative AF, AFL and other SVTs are common sequelae after myectomy and are associated with older age at surgery, history of AF and early post-operative AF. Early post-operative arrhythmias are not transient and periodic rhythm monitoring is therefore essential to initiate therapy as soon as possible.

Background: Sex disparities are common in hypertrophic cardiomyopathy (HCM). Previous research has shown that at time of myectomy, women are older, have greater impairment of diastolic function and more advanced cardiac remodeling. The clinical impact of these differences is unknown. Method: This study included 162 HCM patients (61% men) who underwent septal myectomy. Time to treatment was calculated in relation to symptom onset and diagnosis. Pre- and post-operative echocardiographic data were collected. Sex differences were assessed at baseline and in time-to-event survival analyses for the composite endpoint of all-cause mortality, cardiac transplantation, re-intervention and aborted sudden cardiac death. Results: Women were generally older at time of myectomy (57 vs. 49 years, p < 0.01), with similar time to treatment as measured from symptom onset (2.3 [1.3–6.0] vs. 2.8 [1.1–5.3] years, p > 0.05), but a shorter time since diagnosis compared to men (2.6 [1.2–7.0] vs. 4.3 [2.4–8.3] years, p = 0.02). Mean wall thickness and left atrial diameter were the same for men and women, but were higher in women when correcting for body surface area (absolute: 20 vs. 19 mm, 48 vs 46 mm, p ≥ 0.05; corrected: 9.7 vs. 11.2 mm/m2, 23.4 vs. 26.3 mm/m2, p < 0.01). After 5.9 [3.0–9.1] years, 15% of men and 8% of women had reached the composite endpoint (p > 0.05). Conclusion: In conclusion, although women present later in life and seem to have more advanced disease on echocardiography, time until myectomy was similar and clinical outcomes after myectomy are favourable for both men and women.

Understanding attitudes towards science is crucial to safeguard the future of science, the application of its results and the inclusivity of decision-making processes related to science and technology. Most studies focus on attributes of social groups to explain attitudes towards science. In this study, we aim to move the discussion forward by focusing on perceived attributes of science itself by analysing over 300 letters to the editor in two Dutch national newspapers. The authors of these letters express a large degree of trust in science as a source of societal progress, if research is conducted according to a specific set of rules. Yet, they believe that these rules are under attack. The interests of universities as organizations and individual academics as well as the involvement of industry and government in research are perceived as conflicting with these rules. We conclude with recommendations for further research and practice.

This paper presents the findings of the ENRESSH network with relevance to academic and policy communities. As a recently completed COST action running between April 2016 and April 2020, ENRESSH consists of over 150 researchers and policy makers from 40 countries across Europe and beyond. Through its ongoing research and networking, ENRESSH has worked towards two goals: 1) to enhance the visibility of research in the social sciences and humanities (SSH), as well as its potential to address questions around major societal challenges and 2) to develop comprehensive evaluation methods that better fit how researchers in the SSH communicate. In response to the first goal, ENRESSH proposes that, in order to enhance the visibility of the SSH, impact assessments need to be more inclusive, in particular towards the values and practices of the SSH. This could be achieved by focusing on the interaction processes between researchers and stakeholders, by acknowledging different types of impact and impact pathways, and by improving the understanding of impact by SSH researchers. In response to the second goal of improving evaluation methods, ENRESSH recommends that (extended) peer review constitutes the basis for evaluation, given that it is more suitable to meet the specific cognitive, and often context-dependent, challenges of SSH research. While peer review may continue to be supported by quantitative measurements, these need to be aligned with the types of output and communication patterns prevalent in the SSH. Finally, in order to implement our research-based vision, the ENRESSH community advocates a closer a collaboration between SSH researchers, policy makers and societal stakeholders.

Pulper consistency affects production capacity, defibering efficiency, and particle size distribution of contaminants, and in particular, stickies and inks. The effect of pulper consistency on stickies size distribution, though important, has not been studied in detail. In this project, pressure-sensitive adhesive (PSA)-containing furnish was pulped in a laboratory at 5%, 10% and 15% consistency. Results show that 15% consistency pulp produced many more small-sized stickies compared to pulps produced at 5% and 10% consistency. This is contrary to the generally accepted hypothesis and needs further investigation. Calcium carbonate, usually present in varying proportions in many recovered paper grades, is known to have some pacifying effect on stickies. A new pacifying agent prepared from silicone release liner, called desiliconized pulp (DSP), behaves like bleached virgin hardwood kraft pulp. DSP seems to have a pacifying effect similar to that of calcium carbonate. Thus, DSP may potentially replace a small amount of bleached virgin hardwood kraft pulp, with a bonus stickies-pacifying effect.

Objectives Although homografts are often the preferred valve conduits for right ventricular outflow tract (RVOT) reconstruction, data on long-term homograft-related outcomes, durability and impact on quality of life (QoL) are scarce. The aim of this study was therefore to describe the long-term homograft function, clinical outcomes and QoL after RVOT reconstruction. Methods We performed a single-centre retrospective analysis of all consecutive patients who underwent RVOT reconstruction with a homograft. Multiple subsequent allografts in the same patients were regarded as separate subjects. Valve-related events were analysed by Kaplan-Meier and Life Table methods. Serial echocardiographic measurements were analysed with mixed effects models. In addition, QoL was repeatedly assessed and compared with a matched general population. Results In total, 701 consecutive homografts were implanted in 604 patients [59.6% males, mean age at operation 19.5 ± 15.2 (standard deviation)]. Hospital mortality was 3.3%. After 25 years follow-up, survival and freedom from valve replacement were 84 ± 4% and 56 ± 6%, respectively. Freedom from valve replacement after 15 years for patients under 1 year of age was 28 ± 14% years, for those between 1 and 18 years, 59 ± 8%, and for those older than 18 years, 82 ± 5%. The peak gradient increased predominantly in the first postoperative decade in infants and paediatric patients from 19 to 54 mmHg. In adults, the average gradient increased from 9 to 31 mmHg after 14 years. Compared to a gender- and age-matched Dutch population, patients reported lower vitality and general health but less bodily pain. Patients, in whom QoL was repeatedly assessed, reported lower scores on physical functioning and vitality after a 5-year follow-up period. However, we found no differences in any of the subscales in patients who underwent valve replacement during the 5-year interval. Conclusions Homografts are a durable valve alternative for RVOT reconstruction; in particular, adults show extensive freedom from valve replacement and report QoL comparable with healthy subjects. An online interactive application form created by our institution can be used to assess patient outcome after RVOT reconstruction with a homograft for different patient profiles.

Objective To evaluate drug survival, effectiveness, pharmacokinetics, immunogenicity, and safety in daily practice after transitioning treatment from original reference infliximab (Remicade [REM]) to a biosimilar infliximab (CT-P13 [Remsima; Inflectra]) in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. Methods Of the initial 222 REM-treated patients, 192 agreed to transition to CT-P13 and were included in this multicenter prospective cohort study. Changes in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and changes in the CRP levels, infliximab trough levels, and anti-infliximab antibody levels were assessed after 6 months, and adverse events (AEs) were documented. Drug survival and prognostic factors were analyzed using Kaplan-Meier and Cox regression analyses. Results During 6 months follow-up, 24% of the patients (n = 47) discontinued CT-P13. Thirty-seven patients restarted REM, 7 switched to another biologic drug, and 3 continued without a biologic drug. The DAS28-CRP remained stable from baseline to month 6, with a mean ± SD score of 2.2 ± 0.9 at baseline to 2.2 ± 0.8 at 6 months (difference of 0.0 [95% confidence interval (95% CI) -0.1, 0.2]). The BASDAI increased from a mean ± SD of 3.8 ± 2.0 at baseline to 4.3 ± 2.1 at 6 months (difference of +0.5 [95% CI 0.1, 0.9]). The CRP levels, infliximab trough levels, and anti-infliximab antibody levels did not change. Just prior to CT-P13 discontinuation, the DAS28-CRP components tender joint count and patient's global assessment of disease activity, as well as the BASDAI were increased compared to baseline. The most frequently reported AEs were arthralgia, fatigue, pruritus, and myalgia. A shorter REM infusion interval (hazard ratio: 0.77 [95% CI 0.62, 0.95]) at baseline was predictive of discontinuing CT-P13. Conclusion In our cohort, one-fourth of patients discontinued CT-P13 during 6 months of follow-up, mainly due to an increase in the subjective features of the tender joint count and the patient's global assessment of disease activity and/or subjective AEs, possibly explained by nocebo effects and/or incorrect causal attribution effects.