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Purpose: Hostile aortic neck characteristics, including short length, severe suprarenal and infrarenal angulation, conicity, and large diameter, have been associated with increased risk for type Ia endoleak (T1aEL) after endovascular aneurysm repair (EVAR). This study investigates the mid-term discriminative ability of a statistical shape model (SSM) of the infrarenal aortic neck morphology compared with or in combination with conventional measurements in patients who developed T1aEL post-EVAR. Materials and Methods: The dataset composed of EVAR patients who developed a T1aEL during follow-up and a control group without T1aEL. Principal component (PC) analysis was performed using a parametrization to create an SSM. Three logistic regression models were created. To discriminate between patients with and without T1aEL, sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve (AUC) were calculated. Results: In total, 126 patients (84% male) were included. Median follow-up time in T1aEl group and control group was 52 (31, 78.5) and 51 (40, 62.5) months, respectively. Median follow-up time was not statistically different between the groups (p=0.72). A statistically significant difference between the median PC scores of the T1aEL and control groups was found for the first, eighth, and ninth PC. Sensitivity, specificity, and AUC values for the SSM-based versus the conventional measurements–based logistic regression models were 79%, 70%, and 0.82 versus 74%, 73%, and 0.85, respectively. The model of the SSM and conventional measurements combined resulted in sensitivity, specificity, and AUC of 81%, 81%, and 0.92. Conclusion: An SSM of the infrarenal aortic neck determines its 3-dimensional geometry. The SSM is a potential valuable tool for risk stratification and T1aEL prediction in EVAR. The SSM complements the conventional measurements of the individual preoperative infrarenal aortic neck geometry by increasing the predictive value for late type Ia endoleak after standard EVAR. Clinical Impact A statistical shape model (SSM) determines the 3-dimensional geometry of the infrarenal aortic neck. The SSM complements the conventional measurements of the individual pre-operative infrarenal aortic neck geometry by increasing the predictive value for late type Ia endoleaks post-EVAR. The SSM is a potential valuable tool for risk stratification and late T1aEL prediction in EVAR and it is a first step toward implementation of a treatment planning support tool in daily clinical practice.

We evaluated the immunological responses of lymph-node involved (stage III) melanoma patients to adjuvant dendritic cell vaccination with subsets of naturally occurring dendritic cells (nDCs). Fifteen patients with completely resected stage III melanoma were randomized to receive adjuvant dendritic cell vaccination with CD1c

The role of nutrition in health and disease is well established. However, more research on this topic is needed to fill gaps in our current knowledge. The Lifelines cohort study, a large Dutch prospective cohort study, was established as a resource for international researchers, aiming to obtain insight into the aetiology of healthy ageing. The study started with 167,729 participants, covering three generations, aiming to follow them for thirty years. This article describes the habitual dietary intake, assessed using the Flower Food Frequency Questionnaire (FFQ), among Lifelines cohort study participants at baseline, stratified by sex and different categories of age, socioeconomic status (SES) and body mass index (BMI). A total of 59,982 adults (23,703 men and 36,279 women), who completed the Flower FFQ and reported plausible habitual dietary intake, were included in the analyses. Median daily energy intake was higher in men (2368 kcal) than in women (1848 kcal), as well as macronutrient intake. Energy and macronutrient intake decreased with increasing age and BMI categories; no differences were observed between SES categories. Intake of most micronutrients was higher in men than in women. Differences were observed between age categories, but not between SES and BMI categories. Food groups were consumed in different amounts by men and women; differences between age, SES and BMI categories were observed as well. The Lifelines cohort study provides extensive dietary intake data, which are generalisable to the general Dutch population. As such, highly valuable dietary intake data are available to study associations between dietary intake and the development of chronic diseases and healthy aging.

Background Preoperative telemonitoring of vital signs, physical activity, and well-being might be able to optimize prehabilitation of the patient’s physical and mental condition prior to surgery, support setting alarms during in-hospital monitoring, and allow personalization of the postoperative recovery process. Objective The primary aim of this study was to evaluate when and how long patients awaiting major abdominal surgery should be monitored to get reliable preoperative individual baseline values of heart rate (HR), daily step count, and patient-reported outcome measures (PROMs). The secondary aim was to describe the perioperative course of these measurements at home. Methods In this observational single-center cohort study, patients used a wearable sensor during waking hours and reported PROMs (pain, anxiety, fatigue, nausea) on a tablet twice a day. Intraclass correlation coefficients (ICCs) were used to evaluate the reliability of mean values on 2 specific preoperative days (the first day of telemonitoring and the day before hospital admission) and randomly selected preoperative periods compared to individual reference values. Mean values of HR, step count, and PROMs per day were visualized in a boxplot from 14 days before hospital admission until 30 days after surgery. Results A total of 16 patients were included in the data analyses. The ICCs of mean values on the first day of telemonitoring were 0.91 for HR, 0.71 for steps, and at least 0.86 for PROMs. The day before hospital admission showed reliability coefficients of 0.76 for HR, 0.71 for steps, and 0.92-0.99 for PROMs. ICC values of randomly selected measurement periods increased over the continuous period of time from 0.68 to 0.99 for HR and daily step counts. A lower bound of the 95% CI of at least 0.75 was determined after 3 days of measurements. The ICCs of randomly selected PROM measurements were 0.89-0.94. Visualization of mean values per day mainly showed variable preoperative daily step counts (median 2409, IQR 1735-4661 steps/day) and lower postoperative daily step counts (median 884, IQR 474-1605 steps/day). In addition, pain was visually reduced until 30 days after surgery at home. Conclusions In this prospective pilot study, for patients awaiting major abdominal surgery, baseline values for HR and daily step count could be measured reliably by a wearable sensor worn for at least 3 consecutive days and PROMs during any preoperative day. No clear conclusions were drawn from the description of the perioperative course by showing mean values of HR, daily step count, and PROM values over time in the home situation.

Penile cancer (PeCa) is rare, and the survival of patients with advanced disease remains poor. A better understanding of where treatment fails could aid the development of new treatment strategies.To describe the disease course after pelvic lymph node (LN) treatment for PeCa.We retrospectively analysed 228 patients who underwent pelvic LN treatment with curative intent from 1969 to 2016. The main treatment modalities were neoadjuvant chemotherapy, chemoradiation, and pelvic LN dissection.In the case of multiple recurrence locations, the most distant location was taken and recorded as follows: local (penis), regional (inguinal and pelvic LN), and distant (any other location). A competing risk analysis was used to calculate the time to recurrence per location, and a Kaplan-Meier analysis was used for overall survival (OS).The median follow-up of the surviving patients was 79 mo. The reason for pelvic treatment was pelvic involvement on imaging (29%), two or more tumour-positive inguinal LNs (61%), or inguinal extranodal extension (52%). More than half of the patients (61%) developed a recurrence. The median recurrence-free survival was 11 mo. The distribution was local in 9%, regional in 27%, and distant in 64% of patients. The infield control rate of nonsystemically treated patients was 61% (113/184). From the start of pelvic treatment, the median OS was 17 mo (95% confidence interval 12-22). After regional or distant recurrence, all but one patient died of PeCa with median OS after a recurrence of 4.4 (regional) and 3.1 (distant) mo. This study is limited by its retrospective nature.The prognosis of PeCa patients treated on their pelvis who recur despite locoregional treatment is poor. The tendency for systemic spread emphasises the need for more effective systemic treatment strategies.In this report, we looked at the outcomes of penile cancer patients in an expert centre undergoing various treatments on their pelvis. We found that survival is poor after recurrence despite locoregional treatment. Therefore, better systemic treatments are necessary.

Highlights • Penile cancer impacts numerous quality of life aspects for patients. • Perienal urethrostomy is a reliable mechanism of urinary diversion for many patients with penile cancer. • This study describes that receipt of radiotherapy was not associated with increased risk of stenosis., Objective A lack of demonstrated clinical benefit precludes radiotherapy (RT) from being recommended for pN1/pN2 penile cancer (PeCa) lesions; but it may be recommended in case of extranodal (pN3) disease or for positive resection margins. Perineal urethrostomy (PU) is a technique of urinary diversion in patients with PeCa requiring total or subtotal penectomy as primary therapy. Prior studies suggest PU failure rates of up to 30%, without specific mention of the potential role of RT. When RT is delivered for PeCa it is usually to the pre-pubic fat, groin and lateral pelvis, and not to the region of the PU. Here we describe the role of perioperative RT in a large, multi-institutional registry of PU for PeCa. Methods In our cohort, 299 patients from seven international, high-volume centers in Belgium, Brazil, China, Netherlands, United Kingdom and the United States underwent PU as urinary diversion for PeCa between 2000 and 2020. Demographic and clinicopathologic characteristics were reviewed. Results Median patient age was 67 years and median follow-up was 19 months. Seven patients (2.3%) received pre-operative RT; six of them with chemotherapy. 37 received RT post-operatively, 21 (57%) with chemotherapy. Stenosis of the PU occurred in 35 (12%) of the total population. The majority of these patients (74%) required surgical revision at a median of 6.1 months post-operatively. RT delivery was neither significantly related to PU stenosis (p = 0.16) or to subsequent revision (p = 0.75). Conclusion Receipt of RT was not significantly associated with increased stenosis risk in PeCa patients who underwent PU.

Purpose: To analyze sac evolution patterns in matched patients with hostile neck anatomy (HNA) treated with standard endovascular aneurysm repair (sEVAR) and endosutured aneurysm repair (ESAR). Methods: Observational retrospective study using prospectively collected data between June 2010 and December 2019. ESAR group data were extracted from the primary arm of the PERU registry with an assigned identifier (NCT04100499) at 8 centers and those from the sEVAR came from 4 centers. Suitability for inclusion required: no proximal endograft adjuncts (besides EndoAnchor use), ≤15 mm neck length and minimum of 12-months follow-up imaging. Bubble-shaped neck (noncylindrical short neck with discontinuous seal) aspect was analyzed. Both groups were analyzed using propensity score matching (PSM) for aortic neck length, width, angulation, and device fixation type. Main outcome assessed was sac evolution patterns (sac expansion and regression were defined as >5mm increase or decrease, of the maximum sac diameter respectively; all AAAs within this ±5 mm range in diameter change were considered stable) and secondary outcomes were type-Ia endoleaks; other endoleaks and mortality. A power analysis calculation >80% was confirmed for sac regression evaluation. Results: After exclusions, PSM resulted in 96 ESAR and 96 sEVAR patients. Mean imaging follow-up (months) was 44.4±21.3 versus 43.0±19.6 (p=0.643), respectively. The overall number of patients achieving sac regression was higher in the ESAR group ( n=57, 59.4% vs n=31, 32.3%; pConclusion: Endosutured aneurysm repair provided improved rates of sac regression for patients with AAA and HNA when compared with sEVAR at midterm and up to 5 years, despite similar rates of type-Ia endoleaks, and the need to consider some important limitations. The presence of bubble-shaped neck was a predictor of sac regression failure for both groups equally. Clinical Impact The use of EndoAnchors aids and improves EVAR treatment in hostile neck anatomies by an increased rate of sac regression when compared to EVAR treatment alone in up to 5 year analysis. Moreover, a trend to reduced number of type Ia endoleaks is also achieved, although not significant in the present study. This data, adds to current and growing evidence on the usefulness of EndoAnchors for AAA endovascular treatment.

Specialized versus generic physiotherapy (PT) reduces Parkinson's disease (PD)-related complications. It is unclear (1) whether other specialized allied heath disciplines, including occupational therapy (OT) and speech and language therapy (SLT), also reduce complications; (2) whether there is a synergistic effect among multiple specialized disciplines; and (3) whether each allied health discipline prevents specific complications.To longitudinally assessed whether the level of expertise (specialized vs. generic training) of PT, OT, and SLT was associated with the incidence rate of PD-related complications.We used claims data of all insured persons with PD in the Netherlands between January 1, 2010, and December 31, 2018. ParkinsonNet-trained therapists were classified as specialized, and other therapists as generic. We used mixed-effects Poisson regression models to estimate rate ratios adjusting for sociodemographic and clinical characteristics.The population of 51,464 persons with PD (mean age, 72.4 years; standard deviation 9.8) sustained 10,525 PD-related complications during follow-up (median 3.3 years). Specialized PT was associated with fewer complications (incidence rate ratio [IRR] of specialized versus generic = 0.79; 95% confidence interval, [0.74-0.83]; P 0.0001), as was specialized OT (IRR = 0.88 [0.77-0.99]; P = 0.03). We found a trend of an association between specialized SLT and a lower rate of PD-related complications (IRR = 0.88 [0.74-1.04]; P = 0.18). The inverse association of specialized OT persisted in the stratum, which also received specialized PT (IRR = 0.62 [0.42-0.90]; P = 0.001). The strongest inverse association of PT was seen with orthopedic injuries (IRR = 0.78 [0.73-0.82]; P 0.0001) and of SLT with pneumonia (IRR = 0.70 [0.53-0.93]; P = 0.03).These findings support a wider introduction of specialized allied health therapy expertise in PD care and conceivably for other medical conditions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background In spring 2021, several countries, among which the Netherlands, suspended vaccinations against COVID-19 with the Vaxzevria vaccine from AstraZeneca (AZ) after reports of rare but severe adverse events (SAE). We investigated the impact of this news and the suspension on the Dutch public’s COVID-19 vaccination intentions, COVID-19 vaccination perceptions (attitudes and feelings) and their trust in the government’s COVID-19 vaccination campaign. Methods We conducted two surveys (N = 2628), one shortly before the AZ suspension in the Netherlands and one shortly thereafter when all vaccinations were resumed. Chi2 tests were conducted to study changes in COVID-19 vaccination perceptions, intentions and trust before and after the suspension, and differences between perceptions and intentions regarding AZ vaccines compared to COVID-19 vaccines in general. All variables were measured on a 5-point Likert scale. Results No significant changes were observed in COVID-19 vaccination perceptions and intentions, but trust in the campaign declined slightly (mean diff.(ΔM)=-0.2, 95% CI=-0.3/-0.2). In addition, compared to COVID-19 vaccinations in general, respondents were less likely to vaccinate with AZ (ΔM=-0.7, 95% CI=-0.7/-0.7), reported less positive vaccine attitudes (ΔM=-0.7, 95% CI=-0.7/-0.7), and more negative feelings (ΔM=0.5, 95% CI = 0.4/0.5). Conclusions The news on SAE and the AZ suspension might have caused a decline in trust in the government’s COVID-19 vaccination campaign, as well as negatively impacted AZ vaccination perceptions and intentions. These results stress the need to adapt vaccination policies to anticipated public perceptions and responses following a vaccine safety scare, as well as the importance of informing citizens about the possibility of very rare SAE prior to the introduction of novel vaccines. Key messages • Trust in the COVID-19 vaccination campaign declined following the news on rare but severe adverse events (SAE) and the suspension of AstraZeneca vaccines. • While the news on SAE and the vaccination suspension did not seem to impact COVID-19 vaccination intentions in general, intentions to vaccinate with AstraZeneca were considerably lower.

Background To control the COVID-19 pandemic, non-pharmaceutical interventions (NPIs) were implemented worldwide, that heavily impacted the daily lives of citizens. Occasionally, the public expressed discontent about NPIs, as NPIs did not always corresponded with their preferences. The question is if and how public engagement (PE) could aid in development and implementation of NPIs, in order to improve legitimacy, quality and compliance. Methods An online survey was conducted from 27 October to 9 November 2021, with a representative sample of the public in the Netherlands on gender, age, education, place of residency and migration background. In total 4981 respondents participated. Perceptions and preferences about PE in decision-making on NPIs to control COVID-19 was collected. Four NPIs were used: Nightly curfew (NC); Digital Covid Certificate (DCC); Closure of schools and daycares (CSD); and 1.5meter social distance. Results Around 25% of respondents expressed a desire to engage in decision-making, as it would increase understanding and quality of NPIs, and their trust in the government. Especially for the NPIs DCC and NC, respondents found it valuable to engage, by providing their perspective on certain trade-offs in values in decision-making (e.g. opening up society vs division in society by vaccination status). The public could play a role by giving feedback on bottlenecks during decision-making, however overall responsibility should stay with experts and policy-makers. Desire for engagement was lowest for CSD. Around 50% of the respondents did not want to engage, as they felt they were not knowledgeable enough to do so and did not perceive a need to engage. The other 25% had a neutral disposition. Conclusions Engagement was not self-evident for most respondents, yet the ones willing to engage revealed important possibilities for future outbreaks. Next, a deliberative process for PE in decision-making could be executed, in order to implement our findings in practice. Key messages

It is widely acknowledged that context is of the utmost importance for the interpretation of the archaeological record. Context is often interpreted in terms of the feature or settlement in which a particular find was made, but context is also formed through association with other finds or finds categories. This conceptual contribution approaches the theme of context from the perspective of two major archaeological finds categories and/or disciplines: plants and ceramic objects. It is not the context of either of these categories in itself but, rather, the spatial relationship between these categories that forms the core of a model for systematically analysing botany–ceramics relations (BCR). The model comprises six spatial categories, based on the position of the plant remains relative to the studied ceramic object. The model further comprises the type of plant remains involved, the type of preservation (both at the point when the relationship was first established and at the point when the relationship was encountered in the archaeological record), and the degree to which the relationship was created intentionally (degree of intention: DoI). The applicability of the model is by no means restricted in time and space, and it could easily be extended to other, non-botanical or non-ceramic proxies.

The aims of this study were to assess changes in tissue perfusion up to 6 weeks after endovascular therapy (EVT), in hospital and at home, and to determine differences in tissue perfusion between patients with and without clinical improvement or good angiographic result. This single-center prospective cohort study included patients undergoing EVT for Rutherford stages two to six. Hyperspectral and thermal imaging were performed at the dorsal and plantar sides of the foot. These measurements consisted of a baseline measurement pre-EVT, and six follow-up measurements obtained at 1 and 4 h and 6 weeks in hospital, and 1 day, 7 days, and 14 days at home. Clinical improvement was defined as a decrease of one or more Rutherford class or decrease in the wound surface area and a good angiographic result was accomplished when a Transatlantic Inter-Society Consensus for the Management of PAD II C or D lesion was treated and uninterrupted flow continued in at least one below-the-knee artery in continuation with the inframalleolar arteries. The study included 34 patients with 41 treated limbs. Deoxyhemoglobin values were lower 1 h post-EVT compared with baseline and increased over time up to 6 weeks post-EVT. Significant differences in deoxyhemoglobin levels at 7 and 14 days post-EVT were determined between patients with and without clinical or angiographic success. This prospective pilot study shows the feasibility of hyperspectral imaging and thermal imaging post-EVT at home, which may decrease the need for hospital visits.

Introduction Gap and step-off measurements are generally used in the surgical decision-making process of distal radius fractures. Unfortunately, there is no consensus on treatment choice as these measurements are prone to inter- and intraobserver variability. In this study, we aim to introduce a new 3D fracture quantification method and compare it to conventional fracture analysis. Methods Forty patients with a minimally displaced intra-articular distal radius fracture that was treated nonoperatively between 2008–2015 were included. 2D-CT images were reassessed by three orthopedic trauma surgeons who performed gap and step-off measurements. Subsequently, 3D models were created and a 3D measurement method for fracture displacement was developed. For each fracture, the ‘3D gap area’ (3D surface between all fracture fragments) was determined by three observers. Interobserver agreements were calculated for all measurements, and the intraobserver agreement was calculated for the new 3D measurement. All patients completed two questionnaires in order to link our measurements to functional outcome. Results The interobserver agreement of the 2D measurements was fair (ICC = 0.54) for the gap and poor (ICC = 0.21) for the step-off. The median gap was 2.8 (IQR: 1.9–3.5) mm and step-off was 0.9 (IQR: 0.0–1.6) mm. Interobserver agreement on 3D gap area measurements was excellent (ICC = 0.81), with a median difference between measurements of 6.0 (IQR: 2.0–19.0) mm2, which indicates reliable assessment of 3D fracture displacement. Intraobserver agreement was also excellent (ICC = 0.98), with a median difference of 4.0 (IQR: 1.5–5.5) mm2. No significant differences in clinical outcome were found between the above and below 2mm displacement groups. The score of the DASH was 3.4 (IQR: 0.4–8.8) versus 4.2 (IQR: 0.0–11.6) respectively. Results from the PRWE questionnaire shows a similar result of 3.5 (IQR: 0.0–12.6) versus 5.0 (IQR: 0.0–25.5). Conclusion 3D gap area is a more objective measurement method compared to the conventional gap and step-off measurements to quantify the level of fracture displacement of distal radius fractures. 3D fracture assessment can be used in addition to the currently used classification systems of distal radius fractures.

This study aims to develop a three-dimensional (3D) measurement for acetabular fracture displacement, determine the inter- and intra-observer variability, and correlate the measurement with clinical outcome. Three-dimensional models were created for 100 patients surgically treated for acetabular fractures. The ‘3D gap area’, the 3D surface between all the fracture fragments, was developed. The association between the 3D gap area and the risk of conversion to a total hip arthroplasty (THA) was determined by an ROC curve and a Cox regression analysis. The 3D gap area had an excellent inter-observer and intra-observer reliability. The preoperative median 3D gap area for patients without and with a THA was 1731 mm2 versus 2237 mm2. The median postoperative 3D gap area was 640 mm2 versus 845 mm2. The area under the curve was 0.63. The Cox regression analysis showed that a preoperative 3D gap area > 2103 mm2 and a postoperative 3D gap area > 1058 mm2 were independently associated with a 3.0 versus 2.4 times higher risk of conversion to a THA. A 3D assessment of acetabular fractures is feasible, reproducible, and correlates with clinical outcome. Three-dimensional measurements could be added to the current classification systems to quantify the level of fracture displacement and to assess operative results.

Currently used classification systems and measurement methods are insufficient to assess fracture displacement. In this study, a novel 3D measure for fracture displacement is introduced and associated with risk on conversion to total knee arthroplasty (TKA).A multicenter cross-sectional study was performed including 997 patients treated for a tibial plateau fracture between 2003 and 2018. All patients were contacted for follow-up and 534 (54%) responded. For all patients, the 3D gap area was determined in order to quantify the degree of initial fracture displacement. A cut-off value was determined using ROC curves. Multivariate analysis was performed to assess the association of 3D gap area with conversion to TKA. Subgroups with increasing levels of 3D gap area were identified, and Kaplan-Meier survival curves were plotted to assess survivorship of the knee free from conversion to TKA.A total of 58 (11%) patients underwent conversation to TKA. An initial 3D gap area ≥ 550 mmA novel 3D measurement method was developed to quantify initial fracture displacement of tibial plateau fractures. 3D fracture assessment adds to current classification methods, identifies patients at risk for conversion to TKA at follow-up, and could be used for patient counselling about prognosis.Prognostic Level III.

AIM: To evaluate the clinical relevance of indeterminate lung nodules (ILN) in patients with locally recurrent rectal cancer (LRRC) treated in a tertiary referral centre.METHODS: All patients with LRRC diagnosed between 2000 and 2017 were retrospectively reviewed. Reports of staging chest CT-scans were evaluated for ILN. Patients with distant metastases including lung metastases at time of LRRC diagnosis were excluded. Overall (OS), progression-free survival (PFS) and the cumulative incidence of lung metastases were compared between patients with and without ILN.RESULTS: In total 556 patients with LRRC were treated during the study period. In the 243 patients eligible for analysis, 68 (28%) had ILN at LRRC diagnosis. Median OS was 37 months for both the patients with and without ILN (p = 0.37). Median PFS was 14 months for the patients with ILN and 16 months for patients without ILN (p = 0.80). After correction for potential confounding, ILN present at LRRC diagnosis was not associated with impaired OS or PFS (adjusted hazards ratio [95% confidence interval]: 0.81 [0.54-1.22] and 1.09 [0.75-1.59]). The 5-year cumulative incidence of lung metastases was 31% in patients with ILN and 28% in patients without ILN (p = 0.19).CONCLUSION: Our study shows that ILN are present in roughly a quarter of patients with LRRC. No differences in OS, PFS, or the cumulative incidence of lung metastases were found between patients with and without ILN at LRRC diagnosis. These results suggest that ILN are of little to no clinical relevance in patients with LRRC.

Dendritic cells (DCs) are key regulators of the immune system that shape T cell responses. Regulation of T cell induction by DCs may occur via the intracellular enzyme indoleamine 2,3‐dioxygenase 1 (IDO), which catalyzes conversion of the essential amino acid tryptophan into kynurenine. Here, we examined the role of IDO in human peripheral blood plasmacytoid DCs (pDCs), and type 1 and type 2 conventional DCs (cDC1s and cDC2s). Our data demonstrate that under homeostatic conditions, IDO is selectively expressed by cDC1s. IFN‐γ or TLR ligation further increases IDO expression in cDC1s and induces modest expression of the enzyme in cDC2s, but not pDCs. IDO expressed by conventional DCs is functionally active as measured by kynurenine production. Furthermore, IDO activity in TLR‐stimulated cDC1s and cDC2s inhibits T cell proliferation in settings were DC‐T cell cell‐cell contact does not play a role. Selective inhibition of IDO1 with epacadostat, an inhibitor currently tested in clinical trials, rescued T cell proliferation without affecting DC maturation status or their ability to cross‐present soluble antigen. Our findings provide new insights into the functional specialization of human blood DC subsets and suggest a possible synergistic enhancement of therapeutic efficacy by combining DC‐based cancer vaccines with IDO inhibition., Among human blood dendritic cell subsets, cDC1s uniquely express biologically active IDO at steady‐state, whereas cDC2s express IDO upon IFN‐γ‐ or TLR agonist‐mediated signaling. The enzyme converts tryptophan into kynurenine, thereby limiting T cell proliferation. Selective inhibition of IDO by epacadostat impedes IDO‐mediated immunosuppressive effects in conventional DCs.

BACKGROUND: When vaccines increase longevity, vaccinated people may experience costs and benefits during added life-years. These future benefits and costs may include increased productivity as well as medical and non-medical costs. Such impacts should be considered in cost-effectiveness analyses (CEA) of vaccines but are often omitted. Here, we illustrate the impact of including future costs on the cost-effectiveness of vaccination against pneumococcus disease. We emphasize the relevance of differentiating cost estimates between risk groups.METHODS: We updated an existing Dutch CEA of vaccination against pneumococcus disease with the 13-valent pneumococcal conjugate vaccine (PCV13) to include all future medical and non-medical costs. We linked costs by age and risk with survival information and estimates of cases prevented per vaccination strategy based on the original study to calculate the impact of inclusion. Future medical costs were adjusted for relevant risk groups.RESULTS: For the base-case strategy, the original incremental cost-effectiveness ratio (ICER) of PVC13 was €9,157 per quality adjusted life-year (QALY). Including all future medical costs increased the ICER to €28,540 per QALY. Also including future non-medical costs resulted in an ICER of €45,691 per QALY. The impact of future medical costs varied considerably per risk group and generally increased with age.DISCUSSION AND CONCLUSION: This study showed a substantial effect of the inclusion of future costs on the ICER of vaccinating with PCV13. Especially when lives of people with underlying health conditions are extended, the impact of future medical costs is large. This inclusion may make vaccination a less attractive option, especially in relation to low thresholds as often applied for prevention. Although this raises important questions, ignoring these real future costs may lead to an inefficient use of healthcare resources. Our results may imply that prices for some vaccines need to be lowered to be cost-effective.

The inhibition of the nuclear receptor retinoic-acid-receptor-related orphan receptor γt (RORγt) is a promising strategy in the treatment of autoimmune diseases. RORγt features an allosteric binding site within its ligand-binding domain that provides an opportunity to overcome drawbacks associated with orthosteric modulators. Recently, trisubstituted isoxazoles were identified as a novel class of allosteric RORγt inverse agonists. This chemotype offers new opportunities for optimization into selective and efficacious allosteric drug-like molecules. Here, we explore the structure-activity relationship profile of the isoxazole series utilizing a combination of structure-based design, X-ray crystallography, and biochemical assays. The initial lead isoxazole (FM26) was optimized, resulting in compounds with a ∼10-fold increase in potency (low nM), significant cellular activity, promising pharmacokinetic properties, and a good selectivity profile over the peroxisome-proliferated-activated receptor γ and the farnesoid X receptor. We envisage that this work will serve as a platform for the accelerated development of isoxazoles and other novel chemotypes for the effective allosteric targeting of RORγt.

Purpose Hyperspectral imaging (HSI) and thermal imaging allow contact-free tissue perfusion measurements and may help determine the effect of endovascular treatment (EVT) in patients with peripheral arterial disease. This study aimed to detect changes in perfusion with HSI and thermal imaging peri-procedurally and determine whether these changes can identify limbs that show clinical improvement after 6 weeks. Methods Patients with Rutherford class 2–6 scheduled for EVT were included prospectively. Hyperspectral imaging and thermal imaging were performed directly before and after EVT. Images were taken from the lateral side of the calves and plantar side of the feet. Concentrations of (de)oxyhemoglobin, oxygen saturation, and skin temperature were recorded. Angiographic results were determined on completion angiogram. Clinical improvement 6 weeks after EVT was defined as a decrease ≥ one Rutherford class. Peri-procedural changes in perfusion parameters were compared between limbs with and without good angiographic results or clinical improvement. To identify limbs with clinical improvement, receiver operating characteristic (ROC) curves were used to determine cutoff values for change in HSI. Results Included were 23 patients with 29 treated limbs. Change in HSI values and temperature was not significantly different between limbs with good and poor angiographic results. Change in peri-procedural deoxyhemoglobin, determined by HSI, at the calves and feet was significantly different between limbs with and without clinical improvement at 6 week follow-up (p=0.027 and p=0.017, respectively). The ROC curve for change in deoxyhemoglobin at the calves showed a cutoff value of ≤1.0, and ≤−0.5 at the feet, which were discriminative for clinical improvement (sensitivity 77%; specificity 75% and sensitivity 62%; specificity 88%, respectively). Conclusions HSI can detect changes in perfusion at the calves after EVT in patients with Rutherford class 2–6. Peri-procedural deoxyhemoglobin changes at the calves and feet are significantly different between limbs with and without clinical improvement. Decrease in deoxyhemoglobin directly after EVT may identify limbs that show clinical improvement 6 weeks after EVT.

This study is the ninth cross-sectional community study of fetal alcohol spectrum disorders (FASD) conducted by the multidisciplinary Fetal Alcohol Syndrome Epidemiology Research team in the Western Cape Province of South Africa. It is the third comprehensive study of FASD in a rural, agricultural region of South Africa.Population-based, active case ascertainment methods were employed among a school-based cohort to assess child physical and neurobehavioral traits, and maternal risk factor interviews were conducted to identify all children with FASD to determine its prevalence.Consent was obtained for 76.7% of 1158 children attending first grade in the region's public schools. Case-control results are presented for 95 with fetal alcohol syndrome (FAS), 64 with partial fetal alcohol syndrome (PFAS), 77 with alcohol-related neurodevelopmental disorder (ARND), 2 with alcohol-related birth defects (ARBD), and 213 randomly-selected controls. Four techniques estimating FASD prevalence from in-person examinations and testing yielded a range of total FASD prevalence of 206-366 per 1000. The final weighted, estimated prevalence of FAS was 104.5 per 1000, PFAS was 77.7 per 1000, ARND was 125.2 per 1000, and total FASD prevalence was 310 per 1000 (95% CI = 283.4-336.7). Expressed as a percentage, 31% had FASD. Although the rate of total FASD remained steady over 9 years, the proportion of children within the FASD group has changed significantly: FAS trended down and ARND trended up. A detailed evaluation is presented of the specific child physical and neurobehavioral traits integral to assessing the full continuum of FASD. The diagnosis of a child with FASD was significantly associated with maternal proximal risk factors such as: co-morbid prenatal use of alcohol and tobacco (OR = 19.1); maternal drinking of two (OR = 5.9), three (OR = 5.9), four (OR = 38.3), or more alcoholic drinks per drinking day; and drinking in the first trimester (OR = 8.4), first and second trimesters (OR = 17.7), or throughout pregnancy (OR = 18.6). Distal maternal risk factors included the following: slight or small physical status (height, weight, and head circumference), lower BMI, less formal education, late recognition of pregnancy, and higher gravidity, parity, and older age during the index pregnancy.The prevalence of FASD remained a significant problem in this region, but the severity of physical traits and anomalies within the continuum of FASD is trending downwards.

Contains fulltext : 283345.pdf (Publisher’s version ) (Open Access) Dendritic cell (DC)-based vaccination for cancer treatment has seen considerable development over recent decades. However, this field is currently in a state of flux toward niche-applications, owing to recent paradigm-shifts in immuno-oncology mobilized by T cell-targeting immunotherapies. DC vaccines are typically generated using autologous (patient-derived) DCs exposed to tumor-associated or -specific antigens (TAAs or TSAs), in the presence of immunostimulatory molecules to induce DC maturation, followed by reinfusion into patients. Accordingly, DC vaccines can induce TAA/TSA-specific CD8(+)/CD4(+) T cell responses. Yet, DC vaccination still shows suboptimal anti-tumor efficacy in the clinic. Extensive efforts are ongoing to improve the immunogenicity and efficacy of DC vaccines, often by employing combinatorial chemo-immunotherapy regimens. In this Trial Watch, we summarize the recent preclinical and clinical developments in this field and discuss the ongoing trends and future perspectives of DC-based immunotherapy for oncological indications.

Tolerogenic dendritic cell (tolDC) therapies aim to restore self-tolerance in patients suffering from autoimmune diseases. Phase 1 clinical trials with tolDC have shown the feasibility and safety of this approach, but have also highlighted a lack of understanding of their distribution

Background: In this study, we assessed the ability of the EPOS system (Perimed AB, Jarfalla, Stockholm, Sweden) to detect differences in tissue perfusion between healthy volunteers and patients with peripheral arterial disease (PAD) with different severity of disease.Methods: This singlecenter prospective pilot study included 10 healthy volunteers and 20 patients with PAD scheduled for endovascular therapy (EVT). EPOS measurements were performed at rest at 32 degrees C and 44 degrees C, followed by transcutaneous oxygen pressure (TcPo2) measurements. The measurements were performed on the dorsal and medial side of the foot, as well as the lateral side of the calf. EPOS parameters included hemoglobin oxygen saturation (HbSO(2)) and speed-resolved red blood cell (RBC) perfusion.Results: HbSO(2) at 44 degrees C was significantly different between the three groups for all measurement locations. The overall speed-resolved RBC perfusion at 44 degrees C was statistically significant between the groups on the dorsal and medial side of the foot but not on the calf. TcPO2 values were not significantly different between the three groups.Conclusions: This study demonstrates that the EPOS system can depict differences in tissue perfusion between healthy volunteers, patients with Fontaine class IIb PAD, and those with Fontaine class III or IV PAD but only after heating to 44 degrees C.

Evidence for ancestral gene transfer between Epichloë fungal endophyte ancestors and their host grass species is described. From genomes of cool-season grasses (the Poeae tribe), two Epichloë-originated genes were identified through DNA sequence similarity analysis. The two genes showed 96% and 85% DNA sequence identities between the corresponding Epichloë genes. One of the genes was specific to the Loliinae sub-tribe. The other gene was more widely conserved in the Poeae and Triticeae tribes, including wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.). The genes were independently transferred during the last 39 million years. The transferred genes were expressed in plant tissues, presumably retaining molecular functions. Multiple gene transfer events between the specific plant and fungal lineages are unique. A range of cereal crops is included in the Poeae and Triticeae tribes, and the Loliinae sub-tribe is consisted of economically important pasture and forage crops. Identification and characterisation of the 'natural' adaptation transgenes in the genomes of cereals, and pasture and forage grasses, that worldwide underpin the production of major foods, such as bread, meat, and milk, may change the ‘unnatural’ perception status of transgenic and gene-edited plants.

INTRODUCTION: Ongoing developments in prenatal anomaly screening necessitate continuous updating of counsellors' knowledge. We explored the effect of a refresher counselling course on participants' knowledge of prenatal screening. METHODS: We investigated the association between knowledge and counsellors' working experience. Also, the association between knowledge and counsellors' attitude towards prenatal screening was determined. All counsellors in the North-West region of the Netherlands were invited to attend a refresher counselling course and fill in both a pre-course and a post-course questionnaire. The participants consisted of midwifes, sonographers and gynaecologists. A 55-item questionnaire assessed pre-course (T0) and post-course (T1) knowledge. At T0, counsellors' attitude towards the prenatal screening program was assessed and its association with knowledge analysed. RESULTS: Of 387 counsellors, 68 (18%) attended the course and completed both questionnaires. Knowledge increased significantly from 77.7% to 84.6% (p

Purpose Visual reading of 18F-florbetapir positron emission tomography (PET) scans is used in the diagnostic process of patients with cognitive disorders for assessment of amyloid-ß (Aß) depositions. However, this can be time-consuming, and difficult in case of borderline amyloid pathology. Computer-aided pattern recognition can be helpful in this process but needs to be validated. The aim of this work was to develop, train, validate and test a convolutional neural network (CNN) for discriminating between Aß negative and positive 18F-florbetapir PET scans in patients with subjective cognitive decline (SCD). Methods 18F-florbetapir PET images were acquired and visually assessed. The SCD cohort consisted of 133 patients from the SCIENCe cohort and 22 patients from the ADNI database. From the SCIENCe cohort, standardized uptake value ratio (SUVR) images were computed. From the ADNI database, SUVR images were extracted. 2D CNNs (axial, coronal and sagittal) were built to capture features of the scans. The SCIENCe scans were randomly divided into training and validation set (5-fold cross-validation), and the ADNI scans were used as test set. Performance was evaluated based on average accuracy, sensitivity and specificity from the cross-validation. Next, the best performing CNN was evaluated on the test set. Results The sagittal 2D-CNN classified the SCIENCe scans with the highest average accuracy of 99% ± 2 (SD), sensitivity of 97% ± 7 and specificity of 100%. The ADNI scans were classified with a 95% accuracy, 100% sensitivity and 92.3% specificity. Conclusion The 2D-CNN algorithm can classify Aß negative and positive 18F-florbetapir PET scans with high performance in SCD patients.

Objectives To develop and externally validate a risk calculator for prediction of any cancer recurrence in patients with penile squamous cell carcinoma (pSCC) and inguinal lymph node metastases (ILNM), as to date no validated prognostic tool is available for patients with pSCC and ILNM. Patients and methods The development cohort included 234 patients from seven referral centres. The external validation cohort included 273 patients from two additional referral centres. Cox regression identified predictors of any recurrence, which were used to develop a risk calculator. The risk-calculator grouped the development and the validation cohorts according to the individual risk of any recurrence at 24 months (24m-R). Adjuvant treatment effects were tested on overall survival (OS) according to the derived tertiles, within the development and validation cohorts. Results Positive surgical margins, pN3 , and ILNM ratio were associated with higher recurrence rate. The 2-year OS rates were lower for patients with high (>37%) and intermediate (19-37%) compared to low ( 0.1). Conclusion Adjuvant treatment planning is crucial in patients with pSCC with ILNM, where only weak evidence is available. The current tool proved to successfully stratify patients according to their individual risk, potentially allowing better tailoring of adjuvant treatments.

Parkinson’s disease (PD) is a progressive neurological disorder characterized by motor and non-motor symptoms for which only symptomatic treatments exist. Exercise is a widely studied complementary treatment option. Aerobic exercise, defined as continuous movement of the body’s large muscles in a rhythmic manner for a sustained period that increases caloric requirements and aims at maintaining or improving physical fitness, appears promising. We performed both a scoping review and a systematic review on the generic and disease-specific health benefits of aerobic exercise for people with PD. We support this by a meta-analysis on the effects on physical fitness (VO2max), motor symptoms (Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor section), and health-related quality of life (39-item Parkinson’s disease Questionnaire (PDQ-39)). Aerobic exercise has generic health benefits for people with PD, including a reduced incidence of cardiovascular disease, a lower mortality, and an improved bone health. Additionally, there is level 1 evidence that aerobic exercise improves physical fitness (VO2max) and attenuates motor symptoms (MDS-UPDRS motor section) in the off-medication state, although the long-term effects (beyond 6 months) remain unclear. Dosing the exercise matters: improvements appear to be greater after training at higher intensities compared with moderate intensities. We found insufficient evidence for a beneficial effect of aerobic exercise on health-related quality of life (PDQ-39) and conflicting results regarding non-motor symptoms. Compliance to exercise regimes is challenging for PD patients but may be improved by adding exergaming elements to the training program. Aerobic exercise seems a safe intervention for people with PD, although care must be taken to avoid falls in at-risk individuals. Further studies are needed to establish the long term of aerobic exercise, including a focus on non-motor symptoms and health-related quality of life. Electronic supplementary material The online version of this article (10.1007/s13311-020-00904-8) contains supplementary material, which is available to authorized users.

Purpose Quantitative prostate-specific membrane antigen (PSMA) PET analysis may provide for non-invasive and objective risk stratification of primary prostate cancer (PCa) patients. We determined the ability of machine learning-based analysis of quantitative [18F]DCFPyL PET metrics to predict metastatic disease or high-risk pathological tumor features. Methods In a prospective cohort study, 76 patients with intermediate- to high-risk PCa scheduled for robot-assisted radical prostatectomy with extended pelvic lymph node dissection underwent pre-operative [18F]DCFPyL PET-CT. Primary tumors were delineated using 50–70% peak isocontour thresholds on images with and without partial-volume correction (PVC). Four hundred and eighty standardized radiomic features were extracted per tumor. Random forest models were trained to predict lymph node involvement (LNI), presence of any metastasis, Gleason score ≥ 8, and presence of extracapsular extension (ECE). For comparison, models were also trained using standard PET features (SUVs, volume, total PSMA uptake). Model performance was validated using 50 times repeated 5-fold cross-validation yielding the mean receiver-operator characteristic curve AUC. Results The radiomics-based machine learning models predicted LNI (AUC 0.86 ± 0.15, p p p p Conclusion Machine learning-based analysis of quantitative [18F]DCFPyL PET metrics can predict LNI and high-risk pathological tumor features in primary PCa patients. These findings indicate that PSMA expression detected on PET is related to both primary tumor histopathology and metastatic tendency. Multicenter external validation is needed to determine the benefits of using radiomics versus standard PET metrics in clinical practice.

OBJECTIVE: The new 2019 guideline of the European Society for Vascular Surgery (ESVS) recommends consideration for elective iliac artery aneurysm (eIAA) repair when the iliac diameter exceeds 3.5 cm, as opposed to 3.0 cm previously. The current study assessed diameters at time of eIAA repair and ruptured IAA (rIAA) repair and compared clinical outcomes after open surgical repair (OSR) and endovascular aneurysm repair (EVAR).METHODS: This retrospective observational study used the nationwide Dutch Surgical Aneurysm Audit (DSAA) registry that includes all patients who undergo aorto-iliac aneurysm repair in the Netherlands. All patients who underwent primary IAA repair between 1 January 2014 and 1 January 2018 were included. Diameters at time of eIAA and rIAA repair were compared in a descriptive fashion. The anatomical location of the IAA was not registered in the registry. Patient characteristics and outcomes of OSR and EVAR were compared with appropriate statistical tests.RESULTS: The DSAA registry comprised 974 patients who underwent IAA repair. A total of 851 patients were included after exclusion of patients undergoing revision surgery and patients with missing essential variables. eIAA repair was carried out in 713 patients, rIAA repair in 102, and symptomatic IAA repair in 36. OSR was performed in 205, EVAR in 618, and hybrid repairs and conversions in 28. The median maximum IAA diameter at the time of eIAA and rIAA repair was 43 (IQR 38-50) mm and 68 (IQR 58-85) mm, respectively. Mortality was 1.3% (95% CI 0.7-2.4) after eIAA repair and 25.5% (95% CI 18.0-34.7) after rIAA repair. Mortality was not significantly different between the OSR and EVAR subgroups. Elective OSR was associated with significantly more complications than EVAR (intra-operative: 9.8% vs. 3.6%, post-operative: 34.0% vs. 13.8%, respectively).CONCLUSION: In the Netherlands, most eIAA repairs are performed at diameters larger than recommended by the ESVS guideline. These findings appear to support the recent increase in the threshold diameter for eIAA repair.

The demand for allosteric targeting of nuclear receptors is high, but examples are limited, and structural information is scarce. The retinoic acid‐related orphan receptor gamma t (RORγt) is an important transcriptional regulator for the differentiation of T helper 17 cells for which the first, and some of the most promising, examples of allosteric nuclear receptor modulation have been reported and structurally proven. In a 2015 patent, filed by the pharmaceutical company Glenmark, a new class of small molecules was reported that act as potent inverse agonists for RORγt. A compound library around the central thienopyrazole scaffold captured a clear structure‐activity relationship, but the binding mechanism of this new class of RORγt modulators has not been elucidated. Using a combination of biochemical and X‐ray crystallography studies, here the allosteric mechanism for the inverse agonism for the most potent compound, classified in the patent as “example 13”, is reported, providing a strongly desired additional example of allosteric nuclear receptor targeting., Example 13: Inhibition of the RAR‐related orphan receptor gamma t (RORγt) nuclear receptor has proven to be a novel approach for targeting autoimmune diseases. Recently, RORγt was shown to feature an allosteric pocket. Using X‐ray crystallography, we now show that compound 13, a promising thienopyrazole analogue of previously reported RORγt modulators, exerts its inverse agonism by binding to this allosteric pocket.

Purpose of review The level of evidence for current (adjuvant) treatment strategies after node positive inguinal lymphadenectomy is relatively low because of a paucity of prospective studies and controversy exist between the two major guidelines. The present review aims to provide a review of current literature on the available treatment options of patients after a tumor positive inguinal lymph node dissection. Recent findings Patients without inguinal extranodal extension or less than two tumor positive inguinal nodes are at low risk of ipsilateral pelvic nodal disease. Patients with pN1 disease are unlikely to benefit from adjuvant treatment, whereas patients with pN2 disease might benefit from adjuvant radiotherapy. For patients with high risk of pelvic nodal disease, prophylactic pelvic lymph node dissection (PLND) is advised by current guidelines. The InPACT study investigates whether adjuvant chemoradiotherapy could be used instead of prophylactic PLND. Subgroup analyses of retrospective cohorts suggest that patients with pN3 disease based on tumor positive pelvic nodes may benefit from adjuvant radiotherapy or chemotherapy. Given the weak level of evidence and substantial toxicity associated with current regimens, adjuvant chemotherapy cannot be generally recommended. Summary Despite current treatment strategies, patients with pN2-pN3 disease still have a poor prognosis. Prospective international multicenter studies are necessary to identify the best treatment options for patients with advanced node positive penile squamous cell carcinoma.

It has been suggested that covered stents may lower restenosis rates compared with bare-metal stents after endovascular treatment of the common iliac artery. The aim of this trial was to provide additional evidence on the efficacy of covered versus bare-metal stents in the common iliac artery.We performed a multicenter, randomized, single-blind controlled superiority trial comparing covered and bare-metal balloon-expandable stents for advanced atherosclerotic lesions in the common iliac artery. This was defined as stenosis longer than 3 cm, or occlusion. The primary end point was freedom from binary restenosis after 2 years of follow-up. The study was conducted according to the principles of the Declaration of Helsinki (version: October 2008) and is registered with the Dutch Trial register (NTR3381).A total of 174 limbs were included between 2012 and 2019, 87 limbs in each group. Six patients crossed over from the bare-metal stent (BMS) group to the covered stent (CS) group, but were analyzed according to an intention-to-treat principle. Freedom from binary restenosis after 2 years of follow-up was 84.7% (95% CI 76.7%-92.7%) in the BMS group and 89.1% (95% CI 82.4%-95.8%) in the CS group (p = 0.40). Freedom from occlusion was 95.0% (95% CI 90.3%-95.7%) in the BMS group and 96.4% (95% CI 92.5%-100%) in the CS group (p = 0.66). Freedom from target lesion revascularization was 91.1% (95% CI 84.8%-97.3%) and 95.2% (95% CI 90.7%-99.7%), respectively (p = 0.31). Technical success, complications, hemodynamic success and clinical success were also comparable between both groups. Per-protocol analysis did not affect the outcomes of the study.In this trial, no difference was found between covered and bare-metal balloon-expandable stents for treating advanced atherosclerotic lesions of the common iliac artery.