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Recognizing the potential of quantitative imaging biomarkers (QIBs) in radiotherapy, many studies have investigated the prognostic value of quantitative MRI (qMRI). With the introduction of MRI-guided radiotherapy systems, the practical challenges of repeated imaging have been substantially reduced. Since patients are treated inside an MRI scanner, acquisition of qMRI can be done during each fraction with limited or no prolongation of the fraction duration. In this review paper, we identify the steps that need been taken to move from MR as an imaging technique to a useful biomarker for MRI-guided radiotherapy (MRgRT). [ABSTRACT FROM AUTHOR]

INTRODUCTION: The retina may provide non‐invasive, scalable biomarkers for monitoring cerebral neurodegeneration. METHODS: We used cross‐sectional data from The Maastricht study (n = 3436; mean age 59.3 years; 48% men; and 21% with type 2 diabetes [the latter oversampled by design]). We evaluated associations of retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses with cognitive performance and magnetic resonance imaging indices (global grey and white matter volume, hippocampal volume, whole brain node degree, global efficiency, clustering coefficient, and local efficiency). RESULTS: After adjustment, lower thicknesses of most inner retinal layers were significantly associated with worse cognitive performance, lower grey and white matter volume, lower hippocampal volume, and worse brain white matter network structure assessed from lower whole brain node degree, lower global efficiency, higher clustering coefficient, and higher local efficiency. DISCUSSION: The retina may provide biomarkers that are informative of cerebral neurodegenerative changes in the pathobiology of dementia. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Our main objective was to investigate whether retinal neurodegeneration, estimated from lower thickness of inner retinal layers, was associated with incident all‐cause dementia and Alzheimer's disease (AD). METHODS: We performed an individual participant data meta‐analysis using unpublished data from four prospective cohort studies with a total of 69,955 participants (n = 1087 cases of incident all‐cause dementia; n = 520 cases incident AD; follow‐up time median [interquartile range] 11.3 [8.8–11.5] years). RESULTS: General baseline characteristics of the study population were mean (standard deviation) age, 58.1 (8.8) years; 47% women. After adjustment, lower baseline macular retinal nerve fiber layer thickness was significantly associated with a 10% and 11% higher incidence of all‐cause dementia and AD, respectively. Lower baseline macular ganglion cell‐inner plexiform layer thickness was not significantly associated with these outcomes. DISCUSSION: These findings suggest that retinal neurodegeneration precedes the onset of clinical dementia. Retinal imaging tools may be informative biomarkers for the study of the early pathophysiology of dementia. [ABSTRACT FROM AUTHOR]

One of the barriers regarding evidence-informed decision making is the gap between the needs of policy makers and the ways researchers present evidence. This pilot study evaluates the barriers and facilitators to the implementation of a tool to enhance transparent and unambiguous communication on scientific evidence by knowledge workers. Therefore, mixed methods (qualitative and quantitative) were applied. The results indicate that to promote successful implementation of such a tool, efforts should be undertaken to provide time and guidance on how to adapt routines and on how to apply the tool to various products.

Wear and wear-induced debris is a significant factor in causing failure in implants. Reducing contact pressure by using a textured surface between the femoral head and acetabular cup is crucial to improving the implant’s life. This study presented the effect of surface texturing as dimples on the wear evolution of total hip arthroplasty. It was implemented by developing finite element analysis from the prediction model without dimples and with bottom profile dimples of flat, drill, and ball types. Simulations were carried out by performing 3D physiological loading of the hip joint under normal walking conditions. A geometry update was initiated based on the patient’s daily routine activities. Our results showed that the addition of dimples reduced contact pressure and wear. The bottom profile dimples of the ball type had the best ability to reduce wear relative to the other types, reducing cumulative linear wear by 24.3% and cumulative volumetric wear by 31% compared to no dimples. The findings demonstrated that surface texturing with appropriate dimple bottom geometry on a bearing surface is able to extend the lifetime of hip implants.

The Netherlands is a densely populated country. Cities in the metropolitan area (Randstad) will be growing at a fast pace in the coming decades1. Cities like Amsterdam and Rotterdam are being overrun by tourists. Climate change effects are noticed in cities (heavy rains for instance). Call for circular economy rises. Traffic increases. People are more self-reliant. Public space is shared by many functions. These challenges call for smart answers, more specific and directly than ever before. Sensor data is a cornerstone of these answers. In this paper we’ll discuss the approaches of Dutch initiatives using sensor data as the new language to live a happy life in our cities. Those initiatives have been bundled in a knowledge platform called “Making sense for society” 1 https://www.cbs.nl/nl-nl/nieuws/2016/37/pbl-cbs-prognose-groei-steden-zet-door (in dutch)

Abstract Background Obesity is associated with the development and progression of osteoarthritis (OA). Although the infrapatellar fat pad (IFP) could be involved in this association, due to its intracapsular localization in the knee joint, there is currently little known about the effect of obesity on the IFP. Therefore, we investigated cellular and molecular body mass index (BMI)-related features in the IFP of OA patients. Methods Patients with knee OA (N = 155, 68% women, mean age 65 years, mean (SD) BMI 29.9 kg/m2 (5.7)) were recruited: IFP volume was determined by magnetic resonance imaging in 79 patients with knee OA, while IFPs and subcutaneous adipose tissue (SCAT) were obtained from 106 patients undergoing arthroplasty. Crown-like structures (CLS) were determined using immunohistochemical analysis. Adipocyte size was determined by light microscopy and histological analysis. Stromal vascular fraction (SVF) cells were characterized by flow cytometry. Results IFP volume (mean (SD) 23.6 (5.4) mm3) was associated with height, but not with BMI or other obesity-related features. Likewise, volume and size of IFP adipocytes (mean 271 pl, mean 1933 μm) was not correlated with BMI. Few CLS were observed in the IFP, with no differences between overweight/obese and lean individuals. Moreover, high BMI was not associated with higher SVF immune cell numbers in the IFP, nor with changes in their phenotype. No BMI-associated molecular differences were observed, besides an increase in TNFα expression with high BMI. Macrophages in the IFP were mostly pro-inflammatory, producing IL-6 and TNFα, but little IL-10. Interestingly, however, CD206 and CD163 were associated with an anti-inflammatory phenotype, were the most abundantly expressed surface markers on macrophages (81% and 41%, respectively) and CD163+ macrophages had a more activated and pro-inflammatory phenotype than their CD163- counterparts. Conclusions BMI-related features usually observed in SCAT and visceral adipose tissue could not be detected in the IFP of OA patients, a fat depot implicated in OA pathogenesis.

Purpose: Human bone marrow-derived mesenchymal cell (hBMC) reactions to 316L stainless steel (316L-SS) have never been evaluated. The objective of this study was to assess cell viability and interleukin-6 expression of hBMC cultures upon treatment with a 316L-SS implant. Methods: A cytotoxicity analysis was conducted with a 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium (MTT) assay after a period of 24, 48 and 72 hours of incubation. Expression of interleukin-6 was measured using enzyme-linked immunosorbent assay (ELISA). Results: Cell viability measurement was performed via IC50 formula. All treatment group showed a > 50 % cell viability with a range of 56,5 - 96,9 % at 24 hours, 51,8-77,3% at 48 hours and 70,1- 120 % at 72 hours. Interleukin-6 expression was downregulated subsequent to treatment with 316L-SS compared to the control group. Conclusion: We found that 316L-SS did not exhibit toxicity towards hBMC culture.

Abstract Background In the Netherlands, ethnic minority populations visit their general practitioner (GP) more often than the indigenous population. An explanation for this association is lacking. Recently, health literacy is suggested as a possible explaining mechanism. Internationally, associations between health literacy and health care use, and between ethnicity and health literacy have been studied separately, but, so far, have not been linked to each other. In the Netherlands, some expectations have been expressed with regard to supposed low health literacy of ethnic minority groups, however, no empirical study has been done so far. The objectives of this study are therefore to acquire insight into the level of health literacy of ethnic minorities in the Netherlands and to examine whether the relationship between ethnicity and health care use can be (partly) explained by health literacy. Methods A questionnaire was sent to a sample of 2.116 members of the Dutch Health Care Consumer Panel (response rate 46%, 89 respondents of non-western origin). Health literacy was measured with the Health Literacy Questionnaire (HLQ) which covers nine different domains. The health literacy levels of ethnic minority groups were compared to the indigenous population. A negative binomial regression model was used to estimate the association between ethnicity and GP visits. To examine whether health literacy is an explaining factor in this association, health literacy and interaction terms of health literacy and ethnicity were added into the model. Results Differences in levels of health literacy were only found between the Turkish population and the indigenous Dutch population. This study also found an association between ethnicity and GP visits. Ethnic minorities visit their GP 33% more often than the indigenous population. Three domains of the HLQ (the ability to navigate the health care system, the ability to find information and to read and understand health information) partly explained the association between ethnicity and GP visits. Conclusions In general, there are no differences in health literacy between most of the ethnic minority groups in the Netherlands and the indigenous Dutch population. Only the Turkish population scored significantly lower on several health literacy domains. Some domains of health literacy do explain the association between ethnicity and higher frequency of GP visits. Further research is recommended to understand the pathways through which health literacy impacts health care use.

Abstract Tactile perception is a complex system, which depends on frictional interactions between skin and counter-body. The contact mechanics of tactile friction is governed by many factors such as the state and properties of skin and counter-body. In order to discover the connection between perception and tactile friction on textured stainless steel sheets, both perception experiments (subjective) and tactile friction measurements (objective) were performed in this research. The perception experiments were carried out by using a panel test method to identify the perceived roughness, perceived stickiness and comfort level from the participants. For the friction experiments, tactile friction was measured by a multi-axis force/torque transducer in vivo. The perceived stickiness was illustrated as an effective subjective stimulus, which has a negative correlation to the comfort perception. No significant evidence was revealed to the connection between the perceived roughness and comfort perception, and this relationship may be influenced by the participants’ individual experience, gender and moisture level of skin. Furthermore, the kinetic tactile friction was concluded as an objective stimulus to the comfort perception with a negative correlation.

This study focused on active light touch with predefined textures specially-designed for tactile perception. The counter-body material is stainless steel sheet. Three geometric structures (grid, crater and groove) were fabricated by pulsed laser surface texturing. A total number of twenty volunteers participated in the research which contains two parts: perception tests and skin friction measurements. The perception tests focused mainly on the participants׳ perceptual attributes: perceived roughness and perceived stickiness. For the skin friction measurements, a multi-axis force/torque transducer was used to measure the normal force and friction force between skin and counter-surface along with the fingertip position. The results of the predefined textures showed the ability to reduce skin friction due to the reduction of contact area. Moreover, the participants׳ perceptual attributes were greatly influenced by the predefined micro-structures in the light touch regime.

Abstract Tribological interactions between surgical suture and human tissue play an important role in the stitching process. The purpose of the paper is to understanding the tribological behavior of surgical suture interacting with artificial skin, with respect to surgical suture material and structure, by means of a capstan experiment approach and a contact area model. The results indicated that structure and surface topography of the surgical suture had a pronounced effect on the tribological interactions. The apparent coefficient of friction of vicryl surgical suture was the smallest among the three surgical suture materials. As the sliding velocity increased, or the applied load decreased, the coefficient of friction increased. Furthermore, stick-slip phenomena were observed during the sliding procedure.

Introduction: Linac-based stereotactic radiosurgery (SRS) for brain metastases may be influenced by the time interval between treatment preparation and delivery, related to risk of anatomical changes. We studied tumor position shifts and its relations to peritumoral volume edema changes over time, as seen on MRI. Methods: Twenty-six patients who underwent SRS for brain metastases in our institution were included. We evaluated the occurrence of a tumor shift between the diagnostic MRI and radiotherapy planning MRI. For 42 brain metastases the tumor and peritumoral edema were delineated on the contrast enhanced T1weighted and FLAIR images of both the diagnostic MRI and planning MRI examinations. Centre of Mass (CoM) shifts and tumor borders were evaluated. We evaluated the influence of steroids on peritumoral edema and tumor volume and the correlation with CoM and tumor border changes. Results: The median values of the CoM shifts and of the maximum distances between the tumor borders obtained from the diagnostic MRI and radiotherapy planning MRI were 1.3 mm (maximum shift of 5.0 mm) and 1.9 mm (maximum distance of 7.4 mm), respectively. We found significant correlations between the absolute change in edema volume and the tumor shift of the CoM (p

Background and purpose: The introduction of a magnetic resonance (MR)-only workflow in radiotherapy requires that fiducial markers, used for position verification, can be detected on MR images. Here we evaluate a model for marker detection in prostate cancer patients by combining information from our hospital standard multi-parametric (mp-) MRI protocol (T1-weighted – T1w, T2-weighted – T2w, B0) with dedicated sequences (balanced steady-state free precession sequence – bTFE, susceptibility weighted imaging – SWI). Materials and methods: Thirty two patients scheduled for external-beam radiotherapy received a mp-MRI and computed-tomography; the latter was used as ground truth location of the markers. A logistic regression model was implemented for marker detection by combining features from all imaging sequences. The performance of the individual and combined sequences was assessed by determining true and false positive detections. Results: The combination of different sequences (mp-MRI) resulted in a better performance than the best imaging sequence alone (bTFE). Combining mp-MRI + bTFE resulted in good accuracy and a true positive detection rate of 0.94. Conclusions: The standard mp-MRI provides valuable information to detect fiducial markers. The combination of different sequences outperforms the use of a single dedicated sequence. We recommend the addition of a bTFE to the standard mp-MRI protocol to improve fiducial marker detection. Keywords: Prostate cancer, External beam radiotherapy, Fiducial markers, Multi-parametric MRI

The determinants of protective CD8+ memory T cell (CD8+TM) immunity remain incompletely defined and may in fact constitute an evolving agency as aging CD8+TM progressively acquire enhanced rather than impaired recall capacities. Here, we show that old as compared to young antiviral CD8+TM more effectively harness disparate molecular processes (cytokine signaling, trafficking, effector functions, and co-stimulation/inhibition) that in concert confer greater secondary reactivity. The relative reliance on these pathways is contingent on the nature of the secondary challenge (greater for chronic than acute viral infections) and over time, aging CD8+TM re-establish a dependence on the same accessory signals required for effective priming of naïve CD8+T cells in the first place. Thus, our findings reveal a temporal regulation of complementary recall response determinants that is consistent with the recently proposed "rebound model" according to which aging CD8+TM properties are gradually aligned with those of naïve CD8+T cells; our identification of a broadly diversified collection of immunomodulatory targets may further provide a foundation for the potential therapeutic "tuning" of CD8+TM immunity.

Background and study aims To facilitate image guidance during radiotherapy of rectal cancer, we investigated the feasibility of fiducial marker placement. This study aimed to evaluate technical success rate and safety of two endoscopic ultrasound (EUS)-guided placement strategies and four fiducial types for rectal cancer patients. Patients and methods This prospective multicenter study included 20 participants who were scheduled to undergo rectal cancer treatment with neoadjuvant short-course radiotherapy or chemoradiation. EUS-guided endoscopy was used for fiducial placement at the tumor site (n = 10) or in the mesorectal fat and in the tumor (n = 10). Four fiducial types were used (Visicoil 0.75 mm, Visicoil 0.50 mm, Cook, Gold Anchor). The endpoints were technical success rate and retention of fiducials, the latter of which was evaluated on cone-beam computed tomography scans during the first five radiotherapy fractions. Results A total of 64 fiducials were placed in 20 patients. For each fiducial type, at least three fiducials were successfully placed in all patients. Technical failure consisted of fiducial blockage within the needle (n = 2) and ejection of two preloaded fiducials at once (n = 4). No serious adverse events were reported. In three patients, one of the fiducials was misplaced without clinical consequences; two in the prostate and one in the intraperitoneal cavity. After a median time of 17 days after placement (range 7 – 47 days), a total of 42/64 (66 %) fiducials were still present (24/44 intratumoral vs. 18/20 mesorectal fiducials, P = 0.009). Conclusions Placement of fiducials in rectal cancer patients is feasible, however, retention rates for intratumoral fiducials were lower (55 %) than for mesorectal fiducials (90 %).

In the Caribbean, green turtles graze seagrass meadows dominated by Thalassia testudinum through rotational grazing, resulting in the creation of grazed and recovering (abandoned) patches surrounded by ungrazed seagrasses. We evaluated the seagrass community and its environment along a turtle grazing gradient; with the duration of (simulated) grazing as a proxy for the level of grazing pressure. The grazing levels consisted of Short-term (4 months clipping), Medium-term (8 months clipping), Long-term grazing (8 months of clipping in previously grazed areas), 8-months recovery of previously grazed patches, and ungrazed or unclipped patches as controls. We measured biomass and density of the seagrasses and rhizophytic algae, and changes in sediment parameters. Medium- and Long-term grazing promoted a shift in community species composition. At increasing grazing pressure, the total biomass of T. testudinum declined, whereas that of early-successional increased. Ammonium concentrations were highest in the patches of Medium-term (9.2 + 0.8 μM) and Long-term grazing levels (11.0 + 2.2 μM) and were lowest in the control areas (4.6 + 1.5 μM). T. testudinum is a late-successional species that maintains sediment nutrient concentrations at levels below the requirements of early-successional species when dominant. When the abundance of this species declines due to grazing, these resources become available, likely driving a shift in community composition toward a higher abundance of early-successional species.

IntroductionExtended criteria donor (ECD) livers are increasingly accepted for transplantation in an attempt to reduce the gap between the number of patients on the waiting list and the available number of donor livers. ECD livers; however, carry an increased risk of developing primary non-function (PNF), early allograft dysfunction (EAD) or post-transplant cholangiopathy. Ischaemia-reperfusion injury (IRI) plays an important role in the development of these complications. Machine perfusion reduces IRI and allows for reconditioning and subsequent evaluation of liver grafts. Single or dual hypothermic oxygenated machine perfusion (DHOPE) (4°C–12°C) decreases IRI by resuscitation of mitochondria. Controlled oxygenated rewarming (COR) may further reduce IRI by preventing sudden temperature shifts. Subsequent normothermic machine perfusion (NMP) (37°C) allows for ex situ viability assessment to facilitate the selection of ECD livers with a low risk of PNF, EAD or post-transplant cholangiopathy.Methods and analysisThis prospective, single-arm study is designed to resuscitate and evaluate initially nationwide declined ECD livers. End-ischaemic DHOPE will be performed for the initial mitochondrial and graft resuscitation, followed by COR of the donor liver to a normothermic temperature. Subsequently, NMP will be continued to assess viability of the liver. Transplantation into eligible recipients will proceed if all predetermined viability criteria are met within the first 150 min of NMP. To facilitate machine perfusion at different temperatures, a perfusion solution containing a haemoglobin-based oxygen carrier will be used. With this protocol, we aim to transplant extra livers. The primary endpoint is graft survival at 3 months after transplantation.Ethics and disseminationThis protocol was approved by the medical ethical committee of Groningen, METc2016.281 in August 2016 and registered in the Dutch Trial registration numberTrial registration numberNTR5972, NCT02584283.

While much time and effort in terrorism studies has gone into finding an answer to the question of why people radicalise, the question of how to rehabilitate individuals has received renewed attention with the return of many citizens who had joined the Islamic State. This has led to an increase in both programs and interventions aimed at ‘deradicalising’ or ‘disengaging’ individuals as well as studies that aim to assess the effectiveness of such efforts. This article/presentation provides an overview of the main elements of rehabilitation and reintegration programs for violent extremist offenders based on international research assessing 34 rehabilitation and reintegration programs. In the second half of the article, an evaluation of the Dutch approach to reintegrating violent extremist offenders in and after prison is presented. Finally, the main lessons learned from these programs as well as the academic literature are discussed.

This study explores the explanatory value of two theories of desistance – the cessation of criminal behavior – in explaining why 27 individuals left the Islamic State in Syria and Iraq (ISIS). The article focuses specifically on jihadists that turned away from ISIS after March 2011, asking why individuals desist from ISIS and choose to leave the caliphate. A dataset of 27 narratives of desistance was analysed to answer the question to what extent desistance from ISIS by jihadists can be explained by the Laub & Sampson’s life course theory and by Altier, Thorogughood & Horgan’s model of push and pull factors. The primary pathways for desistance are coded according to the two theories. The results show that of the 27 individuals, the majority desisted from the caliphate because of their perception of the excessive use of force by ISIS and their inability to cope with the effects. A minority desisted because of their perception of alternative options outside the terrorist group or because of important life events that happened ‘at home’. Thus, the article concludes that the push and pull factors model is valid in the explanation of desistance from the Islamic State in Syria and Iraq whereas life course theory does not hold explanatory value

Intensifying drought has caused massive die-offs in ecosystems worldwide. Here, Angelini et al.use observations, experiments, and models in US salt marshes to show that a key mutualism increases ecosystem resilience by maintaining stress-resistant habitat patches that aid post-drought recovery.

The isthmic organizer (IsO) is a signaling center that specifies the correct and distinct embryonic development of the dopaminergic midbrain and serotonergic hindbrain. The IsO is a linear boundary between the two brain regions, emerging at around embryonic day 7-8 of murine embryonic development, that shapes its surroundings through the expression of instructive signals such as Wnt and growth factors. Homeobox transcription factor engrailed 1 (En1) is present in midbrain and rostral hindbrain (i.e. rhombomere 1, R1). Its expression spans the IsO, and it is known to be an important survival factor for both dopaminergic and serotonergic neurons. Erroneous composition of dopaminergic neurons in the midbrain or serotonergic neurons in the hindbrain is associated with severe pathologies such as Parkinson's disease, depression or autism. Here we investigated the role of En1 in early mid-hindbrain development, using multiple En1-ablated mouse models as well as lineage-tracing techniques, and observed the appearance of ectopic dopaminergic neurons, indistinguishable from midbrain dopaminergic neurons based on molecular profile and intrinsic electrophysiological properties. We propose that this change is the direct result of a caudal relocation of the IsO as represented by ectopic presence of Fgf8, Otx2, Wnt1 and canonical Wnt-signalling. Our work suggests a newly-discovered role for En1: the repression of Otx2, Wnt1 and canonical Wnt-signaling in R1. Overall, our results suggest that En1 is essential for proper IsO maintenance and function.

During adolescence there is a normative increase in risk-taking behavior, which is reflected in, for example, increases in alcohol consumption. Prior research has demonstrated a link between testosterone and alcohol consumption, and between testosterone and neural responses to rewards. Yet, no study to date tested how testosterone levels and neural responses to rewards relate to and predict individual differences in alcohol use. The current study aimed to investigate this by assessing alcohol use, testosterone levels and neural responses to rewards in adolescents (12–17 years old) and young adults (18–26 years old). Participants were measured twice with a two-year interval between testing sessions. Cross-sectional analysis showed that at the second time point higher neural activity to rewards, but not testosterone levels, explained significant variance above age in reported alcohol use. Predictive analyses showed that, higher testosterone level at the first time point, but not neural activity to rewards at the first time point, was predictive of more alcohol use at the second time point. These results suggest that neural responses to rewards are correlated with current alcohol consumption, and that testosterone level is predictive of future alcohol consumption. These results are interpreted in the context of trajectory models of adolescent development.

In this article, we explore rituals and ritualized care practices in a hospice in the Netherlands. The research is guided by two research questions. First, we want to know what kind of rituals and ritualized care practices are taking place in the hospice. Second, we aim to understand these practices from a cultural perspective, i.e., to what cultural values do these practices refer? We distinguish five types of ritual: (1) care practices in the morning; (2) meals; (3) care practices in the evening; (4) care practices in the dying phase; (5) a farewell ritual after a patient has died. Ritualization takes place in various degrees and forms, depending on changes in the state of liminality. Analysis of ritualized care practices shows that everyday care practices are enriched with non-instrumental elements that have a strong symbolic meaning, referring to the cultural value of the ‘good death’.

The ability to develop ferroelectric materials using binary oxides is critical to enable novel low-power, high-density non-volatile memory and fast switching logic. The discovery of ferroelectricity in hafnia-based thin films, has focused the hopes of the community on this class of materials to overcome the existing problems of perovskite-based integrated ferroelectrics. However, both the control of ferroelectricity in doped-HfO2 and the direct characterization at the nanoscale of ferroelectric phenomena, are increasingly difficult to achieve. The main limitations are imposed by the inherent intertwining of ferroelectric and dielectric properties, the role of strain, interfaces and electric field-mediated phase, and polarization changes. In this work, using Si-doped HfO2 as a material system, we performed a correlative study with four scanning probe techniques for the local sensing of intrinsic ferroelectricity on the oxide surface. Putting each technique in perspective, we demonstrated that different origins of spatially resolved contrast can be obtained, thus highlighting possible crosstalk not originated by a genuine ferroelectric response. By leveraging the strength of each method, we showed how intrinsic processes in ultrathin dielectrics, i.e., electronic leakage, existence and generation of energy states, charge trapping (de-trapping) phenomena, and electrochemical effects, can influence the sensed response. We then proceeded to initiate hysteresis loops by means of tip-induced spectroscopic cycling (i.e., “wake-up”), thus observing the onset of oxide degradation processes associated with this step. Finally, direct piezoelectric effects were studied using the high pressure resulting from the probe’s confinement, noticing the absence of a net time-invariant piezo-generated charge. Our results are critical in providing a general framework of interpretation for multiple nanoscale processes impacting ferroelectricity in doped-hafnia and strategies for sensing it.

BACKGROUND. The optimal immunosuppressive regimen in kidney transplant recipients, delivering maximum efficacy with minimal toxicity, is unknown. METHODS. The Amsterdam, LEiden, GROningen trial is a randomized, multicenter, investigator-driven, noninferiority, open-label trial in 305 kidney transplant recipients, in which 2 immunosuppression minimization strategies—one consisting of early steroid withdrawal, the other of tacrolimus minimization 6 months after transplantation—were compared with standard immunosuppression with basiliximab, corticosteroids, tacrolimus, and mycophenolic acid. The primary endpoint was kidney function. Secondary endpoints included death, primary nonfunction, graft failure, rejection, discontinuation of study medication, and a combined endpoint of treatment failure. An interim analysis was scheduled at 6 months, that is, just before tacrolimus minimization. RESULTS. This interim analysis revealed no significant differences in Modification of Diet in Renal Disease between the early steroid withdrawal group and the standard immunosuppression groups (43.2 mL/min per 1.73 m2 vs 45.0 mL/min per 1.73 m2, P = 0.408). There were also no significant differences in the secondary endpoints of death (1.0% vs 1.5%; P = 0.737), primary nonfunction (4.1% vs 1.5%, P = 0.159), graft failure (3.1% vs 1.5%, P = 0.370), rejection (18.6% vs 13.6%, P = 0.289), and discontinuation of study medication (19.6% vs 12.6%, P = 0.348). Treatment failure, defined as a composite endpoint of these individual secondary endpoints, was more common in the early steroid withdrawal group (P = 0.027), but this group had fewer serious adverse events and a more favorable cardiovascular risk profile. CONCLUSIONS. Based on these interim results, early steroid withdrawal is a safe short-term immunosuppressive strategy. Long-term outcomes, including a comparison with tacrolimus minimization after 6 months, will be reported in the final 2-year analysis.