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Background: Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In current clinical practice, patients are usually treated with ICIs for up to two years or until disease progression or the occurrence of unacceptable AEs. The incidence of irAEs gradually increases with duration of treatment. While durable tumour responses have been observed after early discontinuation of treatment, no consensus has been reached on optimal treatment duration. The objective of the Safe Stop IPI-NIVO trial is to evaluate whether early discontinuation of ICIs is safe in patients with irresectable stage III or metastatic melanoma who are treated with combination therapy. Methods: The Safe Stop IPI-NIVO trial is a nationwide, multicentre, prospective, single-arm, interventional study in the Netherlands. A total of 80 patients with irresectable stage III or metastatic melanoma who are treated with combination therapy of ipilimumab-nivolumab and have a complete or partial response (CR/PR) according to RECIST v1.1 will be included to early discontinue maintenance therapy with anti-PD-1. The primary endpoint is the rate of ongoing response at 12 months after start of ICI. Secondary endpoints include ongoing response at 24 months, disease control at different time points, melanoma specific and overall survival, the incidence of irAEs and health-related quality of life. Discussion: From a medical, healthcare and economic perspective, overtreatment should be prevented and shorter treatment duration of ICIs is preferred. If early discontinuation of ICIs is safe for patients who are treated with the combination of ipilimumab-nivolumab, the treatment duration of nivolumab could be shortened in patients with a favourable

Youth justice settings should provide safe, therapeutic environments, tailored to young people's needs. Current custodial models rarely meet these aims, mainly because a focus on security tends to outweigh an emphasis on care, diminishing rather than encouraging young people's positive development. This article reports on a three-year evaluation of youth justice reforms in the Netherlands, including small-scale, community-embedded facilities with an emphasis on relational security. We outline key operational elements and conditions for implementation of these facilities to provide guidance for youth justice professionals, and for managers and policymakers seeking to promote political and financial investments in effective youth justice strategies.

Item does not contain fulltext, Neutrophils are among the fastest-moving immune cells. Their speed is critical to their function as 'first responder' cells at sites of damage or infection, and it has been postulated that the unique segmented nucleus of neutrophils functions to assist their rapid migration. Here, we tested this hypothesis by imaging primary human neutrophils traversing narrow channels in custom-designed microfluidic devices. Individuals were given an intravenous low dose of endotoxin to elicit recruitment of neutrophils into the blood with a high diversity of nuclear phenotypes, ranging from hypo- to hyper-segmented. Both by cell sorting of neutrophils from the blood using markers that correlate with lobularity and by directly quantifying the migration of neutrophils with distinct lobe numbers, we found that neutrophils with one or two nuclear lobes were significantly slower to traverse narrower channels, compared to neutrophils with more than two nuclear lobes. Thus, our data show that nuclear segmentation in primary human neutrophils provides a speed advantage during migration through confined spaces.

01 augustus 2023, Contains fulltext : 295998.pdf (Publisher’s version ) (Open Access), PURPOSE: Orthostatic intolerance commonly occurs following immobilization or space flight. We hypothesized that daily artificial gravity training through short-arm centrifugation could help to maintain orthostatic tolerance following head-down tilt bedrest, which is an established terrestrial model for weightlessness. METHODS: We studied 24 healthy persons (eight women; age 33.3 ± 9.0 years; BMI 24.3 ± 2.1 kg/m(2)) who participated in the 60-days head-down tilt bedrest (AGBRESA) study. They were assigned to 30 min/day continuous or 6 × 5 min intermittent short-arm centrifugation with 1Gz at the center of mass or a control group. We performed head-up tilt testing with incremental lower-body negative pressure until presyncope before and after bedrest. We recorded an electrocardiogram, beat-to-beat finger blood pressure, and brachial blood pressure and obtained blood samples from an antecubital venous catheter. Orthostatic tolerance was defined as time to presyncope. We related changes in orthostatic tolerance to changes in plasma volume determined by carbon dioxide rebreathing. RESULTS: Compared with baseline measurements, supine and upright heart rate increased in all three groups following head-down tilt bedrest. Compared with baseline measurements, time to presyncope decreased by 323 ± 235 s with continuous centrifugation, by 296 ± 508 s with intermittent centrifugation, and by 801 ± 354 s in the control group (p = 0.0249 between interventions). The change in orthostatic tolerance was not correlated with changes in plasma volume. CONCLUSIONS: Daily artificial gravity training on a short-arm centrifuge attenuated the reduction in orthostatic tolerance after 60 days of head-down tilt bedrest.

Objective: To develop a prediction model for the development of hypertension in the decade following pre-eclampsia in women who were normotensive shortly after pregnancy. Methods: This was a longitudinal cohort study of formerly pre-eclamptic women attending a university hospital in The Netherlands between 1996 and 2019. We developed a prediction model for incident hypertension using multivariable logistic regression analysis. The model was validated internally using bootstrapping techniques. Results: Of 259 women, 185 (71%) were normotensive at the first cardiovascular assessment, at a median of 10 (interquartile range (IQR), 6–24) months after a pre-eclamptic pregnancy, of whom 49 (26%) had developed hypertension by the second visit, at a median of 11 (IQR, 6–14) years postpartum. The prediction model, based on birth-weight centile, mean arterial pressure, total cholesterol, left ventricular mass index and left ventricular ejection fraction, had good-to-excellent discriminative ability, with an area under the receiver-operating-characteristics curve (AUC) of 0.82 (95% CI, 0.75–0.89) and an optimism-corrected AUC of 0.80. The sensitivity and specificity of our model to predict hypertension were 98% and 34%, respectively, and positive and negative predictive values were 35% and 98%, respectively. Conclusions: Based on five variables, we developed a good-to-excellent predictive tool to identify incident hypertension following pre-eclampsia in women who were normotensive shortly after pregnancy. After external validation, this model could have considerable clinical utility in tackling the cardiovascular legacy of pre-eclampsia.

Background & Aims: HBV coinfection is common among people living with HIV (PLWH) and is the most important cause of hepatocellular carcinoma (HCC). While risk prediction tools for HCC have been validated in patients with HBV monoinfection, they have not been evaluated in PLWH. Thus, we performed an external validation of PAGE-B in people with HIV/HBV coinfection. Methods: We included data on PLWH from four European cohorts who were positive for HBsAg and did not have HCC before starting tenofovir. We estimated the predictive performance of PAGE-B for HCC occurrence over 15 years in patients receiving tenofovir-containing antiretroviral therapy. Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as a covariate, and by calculating Harrell's c-index. Calibration was assessed by comparing our cumulative incidence with the PAGE-B derivation study using Kaplan-Meier curves. Results: In total, 2,963 individuals with HIV/HBV coinfection on tenofovir-containing antiretroviral therapy were included. PAGE-B was <10 in 26.5%, 10–17 in 57.7%, and ≥18 in 15.7% of patients. Within a median follow-up of 9.6 years, HCC occurred in 68 individuals (2.58/1,000 patient-years, 95% CI 2.03–3.27). The regression slope of the prognostic index for developing HCC within 15 years was 0.93 (95% CI 0.61–1.25), and the pooled c-index was 0.77 (range 0.73–0.80), both indicating good model discrimination. The cumulative incidence of HCC was lower in our study compared to the derivation study. A PAGE-B cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. Restricting efforts to individuals with a PAGE-B of ≥10 would spare unnecessary HCC screening in 27% of individuals. Conclusions: For individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening. Impact and impl

The Artificial Gravity Bed Rest – European Space Agency (AGBRESA) study was the first joint bed rest study by ESA, DLR, and NASA that examined the effect of simulated weightlessness on the human body and assessed the potential benefits of artificial gravity as a countermeasure in an analog of long-duration spaceflight. In this study, we investigated the impact of simulated microgravity on the gut microbiome of 12 participants during a 60-day head-down tilt bed rest at the :envihab facilities. Over 60 days of simulated microgravity resulted in a mild change in the gut microbiome, with distinct microbial patterns and pathway expression in the feces of the countermeasure group compared to the microgravity simulation-only group. Additionally, we found that the countermeasure protocols selectively increased the abundance of beneficial short-chain fatty acids in the gut, such as acetate, butyrate, and propionate. Some physiological signatures also included the modulation of taxa reported to be either beneficial or opportunistic, indicating a mild adaptation in the microbiome network balance. Our results suggest that monitoring the gut microbial catalog along with pathway clustering and metabolite profiling is an informative synergistic strategy to determine health disturbances and the outcome of countermeasure protocols for future space missions.

Contains fulltext : 250792.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 249885.pdf (Publisher’s version ) (Open Access), Gestational hypertensive complications are preceded by deviant hemodynamic adjustments affecting blood pressure. Our objective was to determine the timing and magnitude of changes in blood pressure during singleton normotensive and hypertensive pregnancies. PubMed (NCBI) and Embase (Ovid) databases were searched for relevant studies up to November 2019. Studies reporting original blood pressure measurements during pregnancy together with a non-pregnant reference measurement were included. Studies including women with a history of cardiovascular or metabolic disease, or women using antihypertensive drugs were excluded. Pooled mean differences between pregnant and non-pregnant women, and absolute blood pressure values were calculated for predefined gestational intervals in normotensive and hypertensive pregnancy, using a random-effects model. Meta-regression analysis was used to analyze group differences in adjustments. In early normotensive pregnancy, both systolic and diastolic blood pressure decreased, reaching their maximum reduction of -4 mmHg (95%CI -6 to -1 mmHg) and -4 mmHg (95%CI, -5 to -3 mmHg), respectively in the second trimester. Thereafter, blood pressure gradually increased towards non-pregnant values. All absolute blood pressure measurements throughout normotensive pregnancy were below 130/80 mmHg. In hypertensive pregnancies, only diastolic blood pressure decreased early in pregnancy. In conclusion, this meta-analysis showed a clinically moderate, but significant mid-pregnancy drop in blood pressure during normotensive pregnancy. Reference curves with absolute values underscore the current liberal cut-off limit for gestational hypertension. A lack of a mid-pregnancy systolic blood pressure drop might reflect increased vascular resistance in women destined to develop hypertensive pregnancy complications.

Aim: After environmental disasters, species with large population losses may need urgent protection to prevent extinction and support recovery. Following the 2019–2020 Australian megafires, we estimated population losses and recovery in fire-affected fauna, to inform conservation status assessments and management. Location: Temperate and subtropical Australia. Time period: 2019–2030 and beyond. Major taxa: Australian terrestrial and freshwater vertebrates; one invertebrate group. Methods: From > 1,050 fire-affected taxa, we selected 173 whose distributions substantially overlapped the fire extent. We estimated the proportion of each taxon’s distribution affected by fires, using fire severity and aquatic impact mapping, and new distribution mapping. Using expert elicitation informed by evidence of responses to previous wildfires, we estimated local population responses to fires of varying severity. We combined the spatial and elicitation data to estimate overall population loss and recovery trajectories, and thus indicate potential eligibility for listing as threatened, or uplisting, under Australian legislation. Results: We estimate that the 2019–2020 Australian megafires caused, or contributed to, population declines that make 70–82 taxa eligible for listing as threatened; and another 21–27 taxa eligible for uplisting. If so-listed, this represents a 22–26% increase in Australian statutory lists of threatened terrestrial and freshwater vertebrates and spiny crayfish, and uplisting for 8–10% of threatened taxa. Such changes would cause an abrupt worsening of underlying trajectories in vertebrates, as measured by Red List Indices. We predict that 54–88% of 173 assessed taxa will not recover to pre-fire population size within 10 years/three generations. Main conclusions: We suggest the 2019–2020 Australian megafires have worsened the conservation prospects for many species. Of the 91 taxa recommended for listing/uplisting consideration, 84 are now under formal review

Item does not contain fulltext, BACKGROUND: A Dutch committee for National Guidelines in Neonatology developed nineteen evidence- and consensus-based guidelines to be used in all Dutch neonatal intensive care units (NICUs). The primary goal was to make clinical practices more uniform and consistent. OBJECTIVE: This study investigated to what extent the guidelines were implemented and which factors played a role in implementation. STUDY DESIGN: A mixed method study design was used to investigate both the level and the process of implementation. A nationwide, multicenter, cross-sectional survey was performed using a validated instrument for measuring the level of implementation (Normalization MeAsure Development questionnaire, NoMAD). The number of implemented guidelines per NICU and the frequency and content of the amendments that NICUs made to the original consensus guidelines were analyzed. Through semi-structured interviews, perceived barriers and facilitators for implementation were explored. PARTICIPANTS: Fellows and neonatologists working at all ten Dutch level 3-4 NICUs were eligible. RESULTS: On an average, NICUs implemented 12.6 (of 19) guidelines (range 6-17). The Normalization Process Scale was 54 (of 65). Main influencing factors impeding implementation were guideline-related (e.g., unpractical, lengthy guidelines) and personal (e.g., an active representative responsible for local implementation). CONCLUSION: The implementation of our guidelines appears to be successful. Ways for improvement can be distinguished in personal, guideline-related and external factors. Empowerment of local representatives was considered most essential.

Aim After environmental disasters, species with large population losses may need urgent protection to prevent extinction and support recovery. Following the 2019–2020 Australian megafires, we estimated population losses and recovery in fire-affected fauna, to inform conservation status assessments and management. Location Temperate and subtropical Australia. Time period 2019–2030 and beyond. Major taxa Australian terrestrial and freshwater vertebrates; one invertebrate group. Methods From > 1,050 fire-affected taxa, we selected 173 whose distributions substantially overlapped the fire extent. We estimated the proportion of each taxon’s distribution affected by fires, using fire severity and aquatic impact mapping, and new distribution mapping. Using expert elicitation informed by evidence of responses to previous wildfires, we estimated local population responses to fires of varying severity. We combined the spatial and elicitation data to estimate overall population loss and recovery trajectories, and thus indicate potential eligibility for listing as threatened, or uplisting, under Australian legislation. Results We estimate that the 2019–2020 Australian megafires caused, or contributed to, population declines that make 70–82 taxa eligible for listing as threatened; and another 21–27 taxa eligible for uplisting. If so-listed, this represents a 22–26% increase in Australian statutory lists of threatened terrestrial and freshwater vertebrates and spiny crayfish, and uplisting for 8–10% of threatened taxa. Such changes would cause an abrupt worsening of underlying trajectories in vertebrates, as measured by Red List Indices. We predict that 54–88% of 173 assessed taxa will not recover to pre-fire population size within 10 years/three generations. Main conclusions We suggest the 2019–2020 Australian megafires have worsened the conservation prospects for many species. Of the 91 taxa recommended for listing/uplisting consideration, 84 a

BACKGROUND: The incidence of melanoma is increasing and 37% of patients with metastatic melanoma eventually have brain metastasis (BM). Currently, there is no consensus on screening for BM in patients with resected stage III melanoma. However, given the high incidence of BM, routine screening magnetic resonance imaging (MRI) of the brain is considered in patients with completely resected stage III melanoma before the start of adjuvant treatment. The aim of this study was to assess the yield of screening for BM in these patients.MATERIALS AND METHODS: A single-center cohort study was carried out in the Erasmus MC, Rotterdam, The Netherlands, a large tertiary referral center for patients with melanoma. Eligible patients with complete resection of stage III melanoma and a screening MRI of the brain, made within 12 weeks after resection and before adjuvant treatment (programmed cell death protein 1 inhibitors, dabrafenib-trametinib), available between 1 August 2018 and 1 January 2021, were included.RESULTS: A total of 202 patients were included. Eighteen (8.9%) of 202 patients had extracranial metastasis at screening. Two (1.1%) of the remaining 184 patients had BM at screening, resulting in a switch from adjuvant treatment to ipilimumab-nivolumab. At a median follow-up of 21.2 months, BM was detected in another 4 (2.4%) of 166 patients who started with adjuvant treatment.CONCLUSIONS: The yield of screening MRI of the brain is low after complete resection of stage III melanoma, before the start of adjuvant treatment. Therefore, routine screening MRI is not recommended in this setting.