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Many older patients with cancer depend on their family members for care and support and involve their family members in treatment decision-making in different stages of the cancer trajectory. Although family involvement is advocated in person-centered care, little is known about family involvement in decision-making specifically for older patients, and evidence-based strategies are scarce. The aim of this scoping review is to provide deeper understanding of factors influencing family involvement in treatment decision-making for older patients with cancer. Four databases were searched for quantitative-, qualitative- and mixed-method empirical studies describing factors influencing family involvement in treatment decision-making for older patients with cancer: PubMed, EMBASE, CINAHL and PsycINFO. Three independent researchers reviewed the papers for eligibility and quality and contributed to the data extraction and analysis. Twenty-seven papers were included, sixteen quantitative studies, nine qualitative studies and two mixed-method studies. Five categories of factors influencing family involvement emerged: 1) patient characteristics, 2) family member characteristics, 3) family system characteristics, 4) physician’s role and 5) cultural influences. These factors affect the level of family control in decision-making, treatment choice, decision agreement, and levels of stress and coping strategies of patients and family members. This review reveals a complex interplay of factors influencing family involvement in treatment decision-making for older patients with cancer that is rooted in characteristics of the family system. The findings underscore the need for development and implementation of evidence-based strategies for family involvement in treatment decision-making as part of patient-centered care for older patients with cancer.

Contains fulltext : 244034.pdf (Publisher’s version ) (Open Access) PURPOSE: To describe the treatment outcomes and recurrence risk of chronic central serous chorioretinopathy (cCSC) in patients who had complete resolution of subretinal fluid (SRF) after either primary half-dose photodynamic therapy (PDT) or high-density subthreshold micropulse laser (HSML) in the PLACE trial. METHODS: This multicentre prospective follow-up study evaluated cCSC patients at 1 year after completion of the PLACE trial. Outcomes included: complete resolution of SRF on OCT, best-corrected visual acuity (BCVA) in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, retinal sensitivity on microperimetry and a visual function questionnaire (NEI-VFQ25). RESULTS: Twenty-nine out of 37 patients who received half-dose PDT and 15 out of 17 patients who received HSML could be evaluated at final visit. At final visit, 93% of the patients treated with half-dose PDT had complete resolution of SRF, compared with 53% of HSML-treated patients (p = 0.006). At final visit, the mean estimate increase in the PDT group compared with the HSML group was + 2.1 ETDRS letters, +0.15 dB for the retinal sensitivity and + 5.1 NEI-VFQ25 points (p = 0.103, p = 0.784 and p = 0.071, respectively). The mean estimated central retinal thickness in the half-dose PDT group was -7.0 µm compared with the HSML group (p = 0.566). The mean estimated subfoveal choroidal thickness in the half-dose PDT group was -16.6 µm compared with the HSML group (p = 0.359). CONCLUSION: At 20 months after treatment, cCSC patients successfully treated with half-dose PDT are less likely to have recurrences of SRF compared with those successfully treated with HSML. However, functional outcomes did not differ.

ObjectiveTo investigate the efficacy of automated control of inspired oxygen (FiO2) by Predictive Intelligent Control of Oxygenation (PRICO) on the Fabian ventilator in maintaining oxygen saturation (SpO2) in preterm infants on high flow nasal cannula (HFNC) support.DesignSingle-centre randomised two-period crossover study.SettingTertiary neonatal intensive care unit.Patients27 preterm infants (gestational age (GA) 0.25.InterventionA 24-hour period on automated FiO2-control with PRICO compared with a 24-hour period on routine manual control (RMC) to maintain a SpO2 level within target range of 88%–95% measured at 30 s intervals.Main outcome measuresPrimary outcome: time spent within target range (88%–95%). Secondary outcomes: time spent above and below target range, in severe hypoxia (SpO2 98%), mean SpO2 and FiO2 and manual FiO2 adjustments.Results15 patients received PRICO-RMC and 12 RMC-PRICO. The mean time within the target range increased with PRICO: 10.8% (95% CI 7.6 to 13.9). There was a decrease in time below target range: 7.6% (95% CI 4.2 to 11.0), above target range: 3.1% (95% CI 2.9 to 6.2) and in severe hypoxia: 0.9% (95% CI 1.5 to 0.2). We found no difference in time spent in severe hyperoxia. Mean FiO2 was higher during PRICO: 0.019 (95% CI 0.006 to 0.030). With PRICO there was a reduction of manual adjustments: 9/24 hours (95% CI 6 to 12).ConclusionIn preterm infants on HFNC support, automated FiO2-control by PRICO is superior to RMC in maintaining SpO2 within target range. Further validation studies with a higher sample frequency and different ventilation modes are needed.

Summary Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease that affects long‐term outcomes in heart transplant (HTx) patients. We prospectively evaluated the feasibility of coronary computed tomography angiography (CCTA) for the detection of CAV during clinical implementation at our center. All consecutive HTx patients >4 years post‐transplant were actively converted from myocardial perfusion imaging to CCTA for the annual assessment of CAV. Between February 2018 and May 2019, 129/172 (75%) HTx patients underwent a CCTA. Renal impairment (n = 21/43) was the most frequent reason for patients could not undergo CCTA. CCTA image quality was good–excellent in 118/129 (92%) patients, and the radiation dose was 2.1 (1.6–2.8) mSv. CCTA showed obstructive CAV in 19/129 (15%) patients. Thirteen (10%) patients underwent additional tests, of which 8 patients underwent coronary revascularization within 90 days of CCTA. After 1 year, 3 additional coronary angiograms were performed, resulting in one revascularization in a patient with known severe CAV who developed ventricular tachycardia. One myocardial infarction after coronary stenting and 2 non‐cardiac deaths were observed. CCTA can be successfully implemented for routine detection of CAV with good image quality and low radiation dose. CCTA allows CAV evaluation with the limited need for additional invasive testing., CCTA can be safely and successfully implemented as a noninvasive alternative for routine detection of CAV in HTx patients with good image quality and low radiation dose.

This paper reviews the rapidly changing global demands for animal-source foods, examines the agri-food systems behind these changes, and discusses the potential responses required by public-sector Veterinary Services to meet these new demands.

In the first months of the COVID-19 pandemic in Europe, many patients were treated in hospitals using mechanical ventilation. However, due to a shortage of ICU ventilators, hospitals worldwide needed to deploy anesthesia machines for ICU ventilation (which is off-label use). A joint guidance was written to apply anesthesia machines for long-term ventilation. The goal of this research is to retrospectively evaluate the differences in measurable ventilation parameters between the ICU ventilator and the anesthesia machine as used for COVID-19 patients. In this study, we included 32 patients treated in March and April 2020, who had more than 3 days of mechanical ventilation, either in the regular ICU with ICU ventilators (Hamilton S1), or in the temporary emergency ICU with anesthetic ventilators (Aisys, GE). The data acquired during regular clinical treatment was collected from the Patient Data Management Systems. Available ventilation parameters (pressures and volumes: PEEP, Ppeak, Pinsp, Vtidal), monitored parameters EtCO2, SpO2, derived compliance C, and resistance R were processed and analyzed. A sub-analysis was performed to compare closed-loop ventilation (INTELLiVENT-ASV) to other ventilation modes. The results showed no major differences in the compared parameters, except for Pinsp. PEEP was reduced over time in the with Hamilton treated patients. This is most likely attributed to changing clinical protocol as more clinical experience and literature became available. A comparison of compliance between the 2 ventilators could not be made due to variances in the measurement of compliance. Closed loop ventilation could be used in 79% of the time, resulting in more stable EtCO2. From the analysis it can be concluded that the off-label usage of the anesthetic ventilator in our hospital did not result in differences in ventilation parameters compared to the ICU treatment in the first 4 days of ventilation.

ObjectiveIn the Netherlands, the threshold for offering active treatment for spontaneous birth was lowered from 25+0 to 24+0 weeks’ gestation in 2010. This study aimed to evaluate the impact of guideline implementation on survival and causes and timing of death in the years following implementation.DesignNational cohort study, using data from the Netherlands Perinatal Registry.PatientsThe study population included all 3312 stillborn and live born infants with a gestational age (GA) between 240/7 and 266/7 weeks born between January 2011 and December 2017. Infants with the same GA born between January 2007 and December 2009 (N=1400) were used as the reference group.Main outcome measuresSurvival to discharge, as well as cause and timing of death.ResultsAfter guideline implementation, there was a significant increase in neonatal intensive care unit (NICU) admission rate for live born infants born at 24 weeks’ GA (27%–69%, pConclusionsImplementation of the 2010 guideline resulted as expected in increased NICU admissions rate and postnatal survival of infants born at 24 weeks’ GA. In the years after implementation, a shift in cause of death was seen from respiratory insufficiency towards necrotising enterocolitis and sepsis.

This systematic review summarizes published studies on the effect of cranial nerve stimulation (CNS) on swallowing and determines the level of evidence of the included studies to guide the development of future research on new treatment strategies for oropharyngeal dysphagia (OD) using CNS. Studies published between January 1990 and October 2019 were found via a systematic comprehensive electronic database search using PubMed, Embase, and the Cochrane Library. Two independent reviewers screened all articles based on the title and abstract using strict inclusion criteria. They independently screened the full text of this initial set of articles. The level of evidence of the included studies was assessed independently by the two reviewers using the A–B–C rating scale. In total, 3267 articles were found in the databases. In the majority of these studies, CNS was used for treatment-resistant depression or intractable epilepsy. Finally, twenty-eight studies were included; seven studies on treatment of depression, thirteen on epilepsy, and eight on heterogeneous indications. Of these, eight studies reported the effects of CNS on swallowing and in 20 studies the swallowing outcome was described as an adverse reaction. A meta-analysis could not be carried out due to the poor methodological quality and heterogeneity of study designs of the included studies. These preliminary data suggest that specific well-indicated CNS might be effective in reducing OD symptoms in selective patient groups. But it is much too early for conclusive statements on this topic. In conclusion, the results of these studies are encouraging for future research on CNS for OD. However, randomized, double-blind, sham-controlled clinical trials with sufficiently large sample sizes are necessary.

No literature is available on the benign versus malignant breast lesion ratio in trans women (male sex assigned at birth, female gender identity). As hormone treatment in trans women results in breast tissue histologically comparable with cis (non-trans) women, breast pathology may be expected. Previously, an increased breast cancer risk compared with cis men have been observed. We aimed to investigate the frequency and outcomes of breast biopsies in trans women. Therefore, we retrospectively examined the medical files of 2616 trans women. To gain data on breast lesions, we linked our cohort to a national pathology database. In this study we found that 126 people (5%) had one or more breast biopsies (n = 139). Of these, 21 trans women had a breast biopsy before the start of hormone treatment, and 53 after the start of hormone treatment. Breast biopsies were performed predominantly because of abnormalities during physical examination (37%, n = 51/139 biopsies), or because of capsular formation or contraction (28%, n = 16/57 biopsies) in trans women with breast implants. The most common breast lesions after the start of hormone treatment were fibroadenomas (n = 20), breast cancer (n = 6), fibrosis (n = 5), cysts (n = 4), and infections (n = 4). The benign versus malignant breast biopsy ratio was 88:12, which is comparable to the ratio in cis women (90:10). This study shows breast lesions in a limited number of trans women. Since the indications and outcomes of biopsies in trans women were similar to those in cis women, it seems reasonable to follow breast care guidelines as developed for cis women.

Contains fulltext : 235444.pdf (Publisher’s version ) (Open Access) PURPOSE: Compare patients treated for Retinopathy of Prematurity (ROP) in two consecutive periods. METHODS: Retrospective inventory of anonymized neonatal and ophthalmological data of all patients treated for ROP from 2010 to 2017 in the Netherlands, subdivided in period (P)1: 1-1-2010 to 31-3-2013 and P2: 1-4-2013 to 31-12-2016. Treatment characteristics, adherence to early treatment for ROP (ETROP) criteria, outcome of treatment and changes in neonatal parameters and policy of care were compared. RESULTS: Overall 196 infants were included, 57 infants (113 eyes) in P1 and 139 (275 eyes) in P2, indicating a 2.1-fold increase in ROP treatment. No differences were found in mean gestational age (GA) (25.9 ± 1.7 versus 26.0 ± 1.7 weeks, p = 0.711), mean birth weight (791 ± 311 versus 764 ± 204 grams, p = 0.967) and other neonatal risk factors for ROP. In P2, the number of premature infants born

Context Breast development is important for most trans women. An important limitation of current breast development measurement methods is that these do not allow for 3D volume analyses. Objectives To examine breast development and change in anthropometry during the first 3 years of gender-affirming hormone treatment using 3D imaging. Associations with clinical or laboratory parameters and satisfaction with the gained breast development were also studied. Design Prospective cohort study. Setting Specialized tertiary gender identity clinic in Amsterdam, the Netherlands. Participants Participants were 69 adult trans women with a median age of 26 years (interquartile range, 21-38). Interventions Gender-affirming hormone treatment. Main Outcome Measures Volumetric and anthropometric breast development and satisfaction. Results Breast volume increased by 72 cc (95% confidence interval [CI], 48-97) to 100 cc (standard deviation 48). This resulted in a cup-size Conclusions Sustained breast growth and development during hormone treatment was observed during the full 3-year observation period. The breasts of trans women are positioned more laterally and caudally on the chest compared with cis women. Although modest breast volumes were observed, breast development was satisfactory to most trans women.

Objective: To perform a temporal and geographical validation of a prognostic model, considered of highest methodological quality in a recently published systematic review, for predicting survival in very preterm infants admitted to the neonatal intensive care unit. The original model was developed in the UK and included gestational age, birthweight and gender. Design: External validation study in a population-based cohort. Setting: Dutch neonatal wards. Population or sample: All admitted white, singleton infants born between 23+0 and 32+6 weeks of gestation between 1 January 2015 and 31 December 2019. Additionally, the model’s performance was assessed in four populations of admitted infants born between 24+0 and 31+6 weeks of gestation: white singletons, non-white singletons, all singletons and all multiples. Methods: The original model was applied in all five validation sets. Model performance was assessed in terms of calibration and discrimination and, if indicated, it was updated. Main outcome measures: Calibration (calibration-in-the-large and calibration slope) and discrimination (c statistic). Results: Out of 6092 infants, 5659 (92.9%) survived. The model showed good external validity as indicated by good discrimination (c statistic 0.82, 95% CI 0.79–0.84) and calibration (calibration-in-the-large 0.003, calibration slope 0.92, 95% CI 0.84–1.00). The model also showed good external validity in the other singleton populations, but required a small intercept update in the multiples population. Conclusions: A high-quality prognostic model predicting survival in very preterm infants had good external validity in an independent, nationwide cohort. The accurate performance of the model indicates that after impact assessment, implementation of the model in clinical practice in the neonatal intensive care unit could be considered. Tweetable abstract: A high-quality model predicting survival in very preterm infants is externally valid in an independent cohort.

Background: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a monogenic small vessel disease caused by mutations in TREX1. Several organs, including retina and brain, are affected. Analyzing retinal anatomy is increasingly used as a biomarker for ophthalmological and neurological disorders (due to the shared embryological origin of retina and brain). Optical coherence tomography (OCT) provides a noninvasive cross-sectional visualization of optic disc and macula. We aimed to use OCT to investigate retinal layer thickness in RVCL-S. Methods: Cross-sectional, 17 TREX1 mutation carriers (34 eyes) and 9 controls (18 eyes) underwent comprehensive ophthalmologic assessment followed by spectral domain OCT for measuring peripapillary retinal nerve fiber layer (pRNFL) thickness and total macular volume (TMV). Secondary outcomes included measuring thickness of individual macular retinal layers and peripapillary sectors. Findings were analyzed using generalized estimating equations to account for intereye correlation. Results: TREX1 mutation carriers had decreased pRNFL thickness (median [interquartile range] 76 [60-99] vs 99 [87-108] mu m, P < 0.001) and TMV (8.1 [7.4-8.5] vs 8.7 [8.4-8.8] mm(3), P = 0.006) compared with controls. With the exception of the temporal sector, the thickness of all peripapillary sectors was decreased in TREX1 mutation carriers. Ganglion cell layer (30 [22-37] vs 39 [36-41] mu m, P < 0.001) and inner plexiform layer (27 [24-34] vs 34 [31-35], P = 0.001) were thinner in TREX1 mutation carriers. Notably, in 9 of 12 eyes with normal funduscopic examination, retinal thinning was already detected. Conclusions: RVCL-S, which may serve as a vascular retinopathy model, is associated with retinal thinning in the peripapillary and macular area. OCT findings can potentially serve as early biomarkers for RVCL-S and other vascular retinopathies.

OBJECTIVE Degenerative cervical myelopathy (DCM) is a major global cause of spinal cord dysfunction. Surgical treatment is considered a safe and effective way to improve functional outcome, although information about long-term functional outcome remains scarce despite increasing longevity. The objective of this study was to describe functional outcome 10 years after surgery for DCM. METHODS A prospective observational cohort study was undertaken in a university-affiliated neurosurgery department. All patients who underwent surgery for DCM between 2008 and 2010 as part of the multicenter Cervical Spondylotic Myelopathy International trial were included. Participants were approached for additional virtual assessment 10 years after surgery. Functional outcome was assessed according to the modified Japanese Orthopaedic Association (mJOA; scores 0–18) score at baseline and 1, 2, and 10 years after surgery. The minimal clinically important difference was defined as 1-, 2-, or 3-point improvement for mild, moderate, and severe myelopathy, respectively. Outcome was considered durable when stabilization or improvement after 2 years was maintained at 10 years. Self-evaluated effect of surgery was assessed using a 4-point Likert-like scale. Demographic, clinical, and surgical data were compared between groups that worsened and improved or remained stable using descriptive statistics. Functional outcome was compared between various time points during follow-up with linear mixed models. RESULTS Of the 42 originally included patients, 37 participated at follow-up (11.9% loss to follow-up, 100% response rate). The mean patient age was 56.1 years, and 42.9% of patients were female. Surgical approaches were anterior (76.2%), posterior (21.4%), or posterior with fusion (2.4%). The mean follow-up was 10.8 years (range 10–12 years). The mean mJOA score increased significantly from 13.1 (SD 2.3) at baseline to 14.2 (SD 3.3) at 10 years (p = 0.01). A minimal clinically important difference was achieved in 54.1%, and stabilization of functional status was maintained in 75.0% in the long term. Patients who worsened were older (median 63 vs 52 years, p < 0.01) and had more comorbidities (70.0% vs 25.9%, p < 0.01). A beneficial effect of surgery was self-reported by 78.3% of patients. CONCLUSIONS Surgical treatment for DCM results in satisfactory improvement of functional outcome that is maintained at 10-year follow-up.

Purpose: To compare the efficacy and safety between half-dose photodynamic therapy (PDT) and eplerenone therapy for treating chronic central serous chorioretinopathy (cCSC). Design: This was a multicenter, open-label, randomized controlled trial. Methods: This investigator-initiated trial was conducted in 3 academic medical centers in the Netherlands. Eligible patients were randomized at a 1:1 ratio to receive either indocyanine green angiography-guided half-dose PDT or oral eplerenone for 12 weeks. Both anatomical and functional outcomes were evaluated at 3 months after the start of treatment. Results: A total of 107 patients were randomly assigned to receive either half-dose PDT (n = 53) or eplerenone treatment (n = 54). Thirteen patients (3 in the PDT group and 10 in the eplerenone group) did not adhere to the study protocol. At the 3-month evaluation visit, 78% of patients in the PDT group had complete resolution of subretinal fluid accumulation compared to only 17% of patients in the eplerenone group (P < .001). Mean best-corrected visual acuity in Early Treatment of Diabetic Retinopathy Study letters at the 3-month evaluation visit was 83.7 ± 10.8 and 82.8 ± 9.0 in the PDT and eplerenone groups, respectively (P = .555). In addition, mean retinal sensitivity on microperimetry was 25.4 ± 3.4 dB and 23.9 ± 4.0 dB in the PDT and eplerenone groups, respectively (P = .041). Finally, mean vision-related quality of life scores were 87.2 ± 8.5 and 83.8 ± 12.1 in the PDT and eplerenone groups, respectively (P = .094). Three patients (6%) in the PDT group experienced adverse events during the study compared to 18 patients (33%) in the eplerenone group. Conclusions: Half-dose PDT is superior to oral eplerenone for cCSC with respect to both short-term safety and efficacy outcomes.

Purpose: To generate conclusive evidence regarding the noninferiority of intravitreal bevacizumab compared with ranibizumab in patients with diabetic macular edema (DME). Design: Comparative, randomized, double-masked, multicenter, noninferiority clinical trial. Participants: Eligible patients were older than 18 years, diagnosed with type 1 or type 2 diabetes mellitus, with glycosylated hemoglobin of less than 12%, central area thickness of more than 325 mm, and visual impairment from DME with a best-corrected visual acuity (BCVA) between 24 letters and 78 letters. Methods: From June 2012 through February 2018, a total of 170 participants were randomized to receive 6 monthly injections of either 1.25 mg bevacizumab (n ¼ 86) or 0.5 mg ranibizumab (n ¼ 84). Main Outcome Measures: Primary outcome was change in BCVA from baseline to month 6 compared between the 2 treatment arms. The noninferiority margin was 3.5 letters. Results: The difference in mean BCVA between treatment arms was 1.8 letters in favor of ranibizumab after 6 months of follow-up; BCVA improved by 4.96.7 letters in the bevacizumab group and 6.78.7 letters in the ranibizumab group. The lower bound of the 2-sided 90% confidence interval (CI) was e3.626 letters, exceeding the noninferiority margin of 3.5 letters. Central area thickness decreased more with ranibizumab (138.2114.3 mm) compared with bevacizumab (64.2104.2 mm). In a post hoc subgroup analysis, participants with a worse BCVA at baseline (69 letters) improved by 6.77.0 letters with bevacizumab and 10.410.0 letters with ranibizumab, and central area thickness decreased significantly more in the ranibizumab arm of this subgroup compared with the bevacizumab arm. Participants with an initially better BCVA at baseline (70 letters) did not demonstrate differences in BCVA or OCT outcomes between treatment arms. Conclusions: Based on change in BCVA from baseline to month 6, the noninferiority of 1.25 mg bevacizumab to 0.5 mg ranibizumab was not confirmed. Only the subgroup of patients with a lower BCVA at baseline showed better visual acuity and anatomic outcomes with ranibizumab. Our study confirmed the potential differential efficacy of antievascular endothelial growth factor agents in the treatment of DME as well as the difference in response between patient groups with different baseline visual acuities

Purpose: Comparing the efficacy of intravitreal injections of bevacizumab to ranibizumab in the treatment of macular edema (ME) resulting from retinal vein occlusion (RVO). Design: Comparative, randomized, double-masked, multicenter, noninferiority clinical trial. The noninferiority margin was 4 letters. Participants: Patients with vision loss resulting from ME secondary to a branch or (hemi) central RVO who might benefit from anti–vascular endothelial growth factor treatment were eligible for participation. Methods: From June 2012 through February 2018, 277 participants were randomized to receive injections of 1.25 mg bevacizumab (n = 139) or 0.5 mg ranibizumab (n = 138). The follow-up was 6 months with a monthly dosing interval. Main Outcome Measures: The primary outcome was a change in visual acuity from baseline at 6 months. Changes in the central area thickness and safety were studied as secondary outcomes. Results: The mean visual acuity (±standard deviation) improved, with 15.3±13.0 letters for bevacizumab and 15.5±13.3 letters for ranibizumab after 6 months of monthly treatment. The lower limit of the 2-sided 90% confidence interval was –1.724 letters, which is within the noninferiority margin of 4 letters. Even in the branch and (hemi-)central RVO subgroups, minimal differences were found in visual acuity outcomes between treatment arms. Changes in central area thickness on OCT at 6 months did not differ significantly between treatment groups, with a decrease of 287.0±231.3 μm in the bevacizumab group and 300.8±224.8 μm in the ranibizumab group. Severe adverse events (SAEs) were also distributed equally over both treatment groups: 10 participants (7.1%) in the bevacizumab group and 13 participants (9.2%) in the ranibizumab group experienced SAEs. Conclusions: This study showed, based on the change in visual acuity, that bevacizumab is noninferior to ranibizumab for patients with ME resulting from RVO of either subtype when receiving monthly injections for a period of 6 months. In addition, anatomic and safety outcomes did not differ between treatment groups. Based on our findings, bevacizumab may be an effective alternative to ranibizumab.

Anti-Thy1.1 transgenic mice develop glomerular lesions that mimic collapsing focal segmental glomerulosclerosis (FSGS) in humans with collapse of the glomerular tuft and marked hyperplasia of the parietal epithelial cells (PECs). Immunostaining of phosphor-S6 ribosomal protein (pS6RP) revealed high mTOR activity in PECs of the FSGS lesions of these mice. In this study we questioned whether the mTOR inhibitor rapamycin (sirolimus) could attenuate the development and progression of glomerulosclerotic lesions in the anti-Thy1.1 transgenic mice. We observed reduced mTOR signalling and proliferation in human parietal epithelial cells after rapamycin treatment. Experiments with anti-Thy1.1. mice showed that early treatment with sirolimus reduced the development of glomerular lesions and glomerular cell proliferation at day 4. Levels of albuminuria, podocyte injury and podocyte number were similar in the sirolimus and vehicle treated groups. The initial beneficial effects of sirolimus treatment were not observed at day 7. Late sirolimus treatment did not reduce albuminuria or the progression of glomerulosclerosis. Taken together, rapamycin attenuated PEC proliferation and the formation of early FSGS lesions in experimental FSGS and reduced human PEC proliferation in vitro. However, the initial inhibition of PEC proliferation did not translate into a decline of albuminuria nor in a sustained reduction in sclerotic lesions.

Background Health care professionals can routinely face potential critical incidents in the workplace, which can cause high levels of occupational distress and mental health problems. Peer support, in which a trained colleague provides psychosocial support after a work-related critical incident, is an early intervention strategy to support health care professionals. This study describes the development and evaluation of an innovative new online program to educate peer supporters. Methods An interactive Web-based peer support education program (e-learning Peer Support) was developed to teach health care professionals the theory of peer support in preparation for face-to-face training (hybrid learning). User acceptance was determined with a 21-item online survey and technical user data. Results Forty-four health care professionals completed the e-learning Peer Support and the online evaluation survey. Participants were nurses (68.2%), physicians (18.2%), residents (6.8%), and staff (6.8%). The e-learning was well received and positively evaluated with regard to all studied indicators of acceptance, including perceived usefulness, ease of use, actual use, and effectivity. All participants would recommend the e-learning to future trainees. Conclusion The e-learning is a valuable addition to the theoretical peer support training curriculum. Future steps include implementing the e-learning as a yearly continuing education meeting, as a clinical lecture, or as part of the standard curriculum for health care professionals in medical training. Developments like this e-learning may contribute to a standardized training method and, eventually, the implementation of peer support programs.

Aim The long-term value of coronary artery calcium (CAC) scanning has not been studied extensively in symptomatic patients, but was evaluated by us in 644 consecutive patients referred for stable chest pain. Methods We excluded patients with a history of cardiovascular disease and with a CAC score of zero. CAC scanning was done with a 16-row MDCT scanner. Endpoints were: (a) overall mortality, (b) mortality or non-fatal myocardial infarction and (c) the composite of mortality, myocardial infarction or coronary revascularisation. Revascularisations within 1 year following CAC scanning were not considered. Results The mean age of the 320 women and 324 men was 63 years. Follow-up was over 8 years. There were 58 mortalities, while 22 patients suffered non-fatal myocardial infarction and 24 underwent coronary revascularisation, providing 104 combined endpoints. Cumulative 8‑year survival was 95% with CAC score 100 and 100 and ≥400 units was 2.6 [95% confidence interval (CI) 1.23–5.54], and 4.6 (95% CI 2.1–9.47) respectively. After correction for clinical risk factors, CAC score remained independently associated with increased risk of cardiac events. Conclusions Risk increased with increasing CAC score. Patients with CAC >100 or ≥400 Agatston units were at increased risk of major adverse cardiac events and are eligible for preventive measures. CAC scanning provided incremental prognostic information to guide the choice of diagnostic and therapeutic options in many subjects evaluated for chest pain.

Aims Screening for a high cardiovascular disease (CVD) risk followed by preventive treatment can potentially reduce coronary heart disease-related morbidity and mortality. ROBINSCA (Risk Or Benefit IN Screening for CArdiovascular disease) is a population-based randomized controlled screening trial that investigates the effectiveness of CVD screening in asymptomatic participants using the Systematic COronary Risk Evaluation (SCORE) model or coronary artery calcium (CAC) scoring. This study describes the distributions in risk and treatment in the ROBINSCA trial. Methods and results Individuals at expected elevated CVD risk were randomized into screening arm A (n = 14 478; SCORE, 10-year fatal and non-fatal risk); or screening arm B (n = 14 450; CAC scoring). Preventive treatment was largely advised according to current Dutch guidelines. Risk and treatment differences between the screening arms were analysed. A total of 12 185 participants (84.2%) in arm A and 12 950 (89.6%) in arm B were screened. In total, 48.7% were women, and median age was 62 (interquartile range 10) years. SCORE screening identified 45.1% at low risk (SCORE Conclusion We showed that compared to risk stratification based on SCORE, CAC scoring classified significantly fewer men and women at increased risk, and less preventive treatment was indicated. Trial registration number NTR6471.

The ability to track & trace materials is a key feature in the entire chain, and it ensures circularity principles. Examples from plastic recycling show the enormous added value that analytical technology can have for the circular economy. During polymer production and recycling processes, pigments can be added for different purposes; e.g. as colouring agent of the polymeric product but also as tracer for tracking process development and control in the final recycle products versus possible by-products. An analytical method for tracking the pigment Solvent Blue 15 in input materials, in intermediates as well as in recyclates was developed by tracing and quantifying an indicator metal which is copper (Cu). Therefore, suitable digestion procedures and a quantification method by high resolution inductively coupled plasma mass spectrometry (HR-ICP-MS) were developed and used for measuring the polymeric digests. The method was tested on relevant samples from chemical recycling processes. The background concentrations in base/raw material are in the range of 0.05 - 0.1 mg∙kg−1 Cu. The processing concentrations are in the range of 4.2 to 28 mg∙kg−1 Cu, while the pigment starting material (polyethylene, PE) has a concentration of around 50 mg∙kg−1 Cu.

Objectives This study assessed whether adenosine stress-only perfusion cardiac magnetic resonance (CMR) following a positive coronary artery calcium (CAC) score improved the diagnostic yield of invasive coronary angiography (CAG) in patients with stable chest pain. The study also established the association between positive CAC scores and stress-induced myocardial ischemia. Background The diagnostic yield of catheterization among patients with suspected coronary artery disease (CAD) is low. Improved patient selection and diagnostic testing are necessary. The CAC score can minimize unnecessary diagnostic testing, and in low-risk patients, normal CMR results have a high negative predictive value. Less comprehensive protocols may be sufficient to guide further work-up. Methods A total of 642 consecutive patients (mean age: 63 years; 50% women) with stable chest pain and CAC scores of >0 who were referred for CMR were enrolled. Patients with a perfusion defect were subsequently examined by CAG. Patients were followed up for 1 year. Outcome was obstructive CAD. Results Obstructive CAD was present in 12% of patients. For CAD diagnosis, the sensitivity of adenosine CMR was 90.9% (95% confidence interval [CI]: 88.7 to 93.1), specificity was 98.7% (95% CI: 97.9 to 99.6), positive predictive value was 92.0% (95% CI: 89.8 to 94.1), and negative predictive value was 98.6% (95% CI: 97.6 to 99.5). A CAC score between 0.1 and 100 without typical angina was associated with obstructive CAD in only 3% of patients. Patients with nonanginal chest pain and a CAC score ≥400 had obstructive CAD (16%). Conclusions Stress-only adenosine CMR had high diagnostic accuracy and served as an efficient gatekeeper to CAG in stable patients with a CAC score >0. Patients with CAC scores between 0.1 and 100 could be deferred from further testing in the absence of clinical features that suggested high risk. However, in patients with CAC score ≥400, functional testing should be indicated, regardless of the type of chest pain.

Identifying coronary artery disease (CAD) in atrial fibrillation (AF) patients improves risk stratification and defines clinical management. However, the value of screening for subclinical CAD with cardiac CT in AF patients is unknown. Between 2011 and 2015, 94 consecutive patients without known or suspected CAD (66 (57-73) years, 68% male), who were referred for AF evaluation, underwent a noncontrast-enhanced coronary calcium scan and a coronary computed tomography angiography (CCTA) at our center. We retrospectively evaluated the coronary calcium score, the prevalence of obstructive CAD (≥50% stenosis) determined by CCTA, compared clinical management and 5-year outcome in patients with and without obstructive CAD on CCTA, and examined the potential impact of a coronary calcium score and obstructive CAD on CCTA as a manifestation of vascular disease on the CHA2Ds2VASc score and for the cardiovascular risk stratification of AF patients. The median coronary calcium score was 57 (0-275) and 24 patients (26%) had obstructive CAD on CCTA. At baseline, patients with obstructive CAD more often used statins than those without obstructive CAD (54% vs 26%, p = 0.011). After a median clinical follow-up of 2.4 (0.5-4.5) years, patients with obstructive CAD more frequently used oral anticoagulant and/or antiplatelet drugs, statins, angiotensin-II-receptor blockers and/or angiotensin-converting-enzyme inhibitors, and less often used class I antiarrhythmic drugs than patients without obstructive CAD (all p0.050). After a median follow-up of 5.7 (4.8-6.8) years, mortality was higher in patients with obstructive CAD than in those without obstructive CAD (29% vs 11%, log-rank test: p = 0.034). Implementation of a coronary calcium score and/or obstructive CAD on CCTA elevated the CHA2Ds2VASc score and cardiovascular risk stratification in 42 patients (p0.001) and 47 patients (p = 0.006), respectively. In conclusion, we observed a high prevalence of obstructive CAD on CCTA in AF patients without known or suspected CAD. AF patients with obstructive CAD were managed differently and had a worse prognosis than those without obstructive CAD. Cardiac CT could enhance cardiovascular risk stratification of AF patients.

Aims Non-acute chest pain is a common complaint and can be caused by various conditions. With the rising healthcare expenditures of today, it is necessary to use our healthcare resources effectively. This study aims to give insight into the diagnostic effort and costs for patients with non-acute chest pain. Methods and results Financial data of patients without a cardiac history from four hospitals (January 2012–October 2018), who were registered with the national diagnostic code ‘no cardiac pathology’ (ICD-10 Z13.6), ‘chest wall syndrome’ (ICD-10 R07.4), or ‘stable angina pectoris’ (ICD-10 I20.9) were extracted. In total, 74 091 patients were included for analysis and divided into the following final diagnosis groups: no cardiac pathology: N = 19 688 (age 53 ± 18), 46% male; chest wall syndrome: N = 40 858 (age 56 ± 15), 45% male; and stable angina pectoris (AP): N = 13 545 (age 67 ± 11), 61% male. A total of approximately €142.7 million was spent during diagnostic work-up. The total expenditure during diagnostic effort was €1.97, €8.13, and €10.7 million, respectively for no cardiac pathology, chest wall syndrome, and stable AP per year. After 8 years of follow-up, ≥95% of the patients diagnosed with no cardiac pathology or chest wall syndrome had an (cardiac) ischaemic-free survival. Conclusion The diagnostic expenditure and clinical effort to ascertain non-cardiac chest pain are high. We should define what we as society find acceptable as ‘assurance costs’ with an increasing pressure on the healthcare system and costs.

Determining the time since death, i.e., post-mortem interval (PMI), often plays a key role in forensic investigations. The current standard PMI-estimation method empirically correlates rectal temperatures and PMIs, frequently necessitating subjective correction factors. To overcome this, we previously developed a thermodynamic finite-difference (TFD) algorithm, providing a rigorous method to simulate post-mortem temperatures of bodies assuming a straight posture. However, in forensic practice, bodies are often found in non-straight postures, potentially limiting applicability of this algorithm in these cases. Here, we develop an individualised approach, enabling PMI reconstruction for bodies in arbitrary postures, by combining photogrammetry and TFD modelling. Utilising thermal photogrammetry, this approach also represents the first non-contact method for PMI reconstruction. The performed lab and crime scene validations reveal PMI reconstruction accuracies of 0.26 h ± 1.38 h for true PMIs between 2 h and 35 h and total procedural durations of ~15 min. Together, these findings broaden the potential applicability of TFD-based PMI reconstruction., Establishing the time since death (TSD) is vital in many forensic investigations. By combining thermometry, photogrammetry and numerical thermodynamic modelling, the TSD can be determined non-invasively for bodies of arbitrary shape and posture with an unprecedented accuracy of 0.26 h ± 1.38 h.

OBJECTIVETo determine the seroprevalence of SARS-CoV-2 antibodies in employees of the Cantonal Police Bern, Switzerland; to investigate individual and work-related factors associated with seropositivity; and to assess the neutralizing capacity of the antibodies of seropositive study participants.DESIGNCross-sectional analysis of a cohort study.SETTINGWearing face masks was made mandatory for employees of the police during working hours at the rise of the second wave of the pandemic in mid-October 2020. Protests and police fieldwork provided a high exposure environment for SARS-CoV-2 infections. The investigation was performed prior to initiation of a vaccine programme. Study participants were invited for serological testing of SARS-CoV-2 and to complete questionnaires on sociodemographic, work and health-related questions.PARTICIPANTS978 police personnel working in four different geographic districts, representing 35% of the entire staff, participated from February to March 2021.MAIN OUTCOME MEASURESSeroprevalence of anti-SARS-CoV-2 antibodies in February to March 2021, geographic and work-related risk factors for seropositivity, and serum neutralization titres towards the wild-type SARS-CoV-2 spike protein (expressing D614G) and the alpha and beta variants.RESULTSSeroprevalence was 12.9% (126 of 978 employees). It varied by geographic region within the canton; ranged from 9% to 13% in three regions, including the city; and was 22% in Bernese Seeland/Jura. Working in the latter region was associated with higher odds for seropositivity (odds ratio 2.38, 95% confidence interval 1.28 to 4.44, P=0.006). Job roles with mainly office activity were associated with a lower risk of seropositivity (0.33, 0.14 to 0.77, P=0.010). Most seropositive employees (67.5%) reported having had coronavirus disease 2019 (COVID-19) 3 months or longer prior to serological testing, and the proportion of agreement between positive nasopharyngeal test results and seroconversion was 95% to 97%. Among reported symptoms, new loss of smell or taste was the best discriminator for seropositivity (odds ratio 52.4, 30.9 to 89.0, PCONCLUSIONSSeroprevalence in the pre-vaccinated police cohort was similar to that reported in the general population living in the same region. The high compliance with mask wearing and the low proportion of seroconversion after contact with a presumed or proven COVID-19 case during working hours imply that personal protective equipment is effective and that household contacts are the leading transmission venues. The level of serum antibody titres, in particular that of anti-spike antibodies, correlated well with neutralization capacity. Low antibody titres were not effective against the alpha and beta variants.SUMMARY BOXESWHAT IS ALREADY KNOWN ON THIS TOPICThe seroprevalence of anti-SARS-CoV-2 antibodies in the general population shows variations, depending on the geographic location of investigated study participants.Social distancing by avoiding crowds and maintaining a distance of 6 feet from others when in public are recommended. These recommendations are not realistic for security personnel and employees of a police department.Preventive strategies for individuals in a health care setting are warranted and effective to reduce potential exposures. The effect of preventive strategies on individuals working for the police force has not been investigated.WHAT THIS STUDY ADDSThe study suggests that the overall seroprevalence of anti-SARS-CoV-2 antibodies among police officers is not higher than that in the general population, despite presumed higher exposure (e.g., public protests).Compliance with use of personal protective equipment among police officers was very high. The study results suggested that household contacts, rather than exposure during working hours, is the main source for viral transmission.Anti-SARS-CoV-2 antibodies derived from natural infection demonstrated good neutralization capacity towards strains that epidemiologically likely caused the infection, but moderate to poor neutralization capacity towards the alpha and beta variant.

Non-invasive ventilation (NIV) is increasingly used in the supportive treatment of acute respiratory failure in children in the pediatric intensive care unit (PICU). However, finding an optimal fitting commercial available NIV face mask is one of the major challenges in daily practice, in particular for young children and those with specific facial features. Large air leaks and pressure-related skin injury due to suboptimal fit are important complications associated with NIV failure. Here, we describe a case of a 4-year old boy with cardiofaciocutaneous syndrome and rhinovirus-associated hypoxic acute respiratory failure who was successfully supported with NIV delivered by a simple anesthetic mask connected to a headgear by an in-house developed and 3D printed adaptor. This case is an example of the clinical challenge related to pediatric NIV masks in the PICU, but also shows the potential of alternative NIV interfaces e.g., by using a widely available and relatively cheap simple anesthetic mask. Further personalized strategies (e.g., by using 3D scanning and printing techniques) that optimize NIV mask fitting in children are warranted.

In e-commerce markets, on-time delivery is of great importance to customer satisfaction. In this paper, we present a Deep Reinforcement Learning (DRL) approach, together with a heuristic, for deciding how and when arrived orders should be batched and picked in a warehouse to minimize the number of tardy orders. In particular, the technique facilitates making decisions on whether an order should be picked individually (pick-by-order) or picked in a batch with other orders (pick-by-batch), and if so, with which other orders. We approach the problem by formulating it as a semi-Markov decision process and developing a vector-based state representation that includes the characteristics of the warehouse system. This allows us to create a deep reinforcement learning solution that learns a strategy by interacting with the environment and solve the problem with a proximal policy optimization algorithm. We evaluate the performance of the proposed DRL approach by comparing it with several batching and sequencing heuristics in different problem settings. The results show that the DRL approach can develop a strategy that produces consistent, good solutions and performs better than the proposed heuristics in most of the tested cases. We show that the strategy learned by DRL is different from the hand-crafted heuristics.In this paper, we demonstrate that the benefits from recent advancements of Deep Reinforcement Learning can be transferred to solve sequential decision-making problems in warehousing operations.KeywordsDeep reinforcement learningOrder batchingSequential decision makingMachine learningWarehousingE-commerce

Effective broad-spectrum antivirals are critical to prevent and control emerging human coronavirus (hCoV) infections. Despite considerable progress made towards identifying and evaluating several synthetic broad-spectrum antivirals against hCoV infections, a narrow therapeutic window has limited their success. Enhancing the endogenous interferon (IFN) and interferon-stimulated gene (ISG) response is another antiviral strategy known for decades. However, the side effects of pegylated type-I IFNs (IFN-Is) and the pro-inflammatory response detected after delayed IFN-I therapy have discouraged their clinical use. In contrast to IFN-Is, IFN-{lambda}, a dominant IFN at the epithelial surface, is shown to be less pro-inflammatory. Consequently, we evaluated the prophylactic and therapeutic efficacy of IFN-{lambda} in hCoV infected airway epithelial cells and mice. Human primary airway epithelial cells treated with a single dose of IFN-I (IFN-) and IFN-{lambda} showed similar ISG expression, whereas cells treated with two doses of IFN-{lambda} expressed elevated levels of ISG compared to IFN-a treated cells. Similarly, mice treated with two dose IFN-{lambda} were better protected compared to mice receiving a single dose, and a combination of prophylactic and delayed therapeutic regimens completely protected mice from lethal MERS-CoV-infection. A two dose IFN-{lambda} regimen significantly reduced lung viral RNA and inflammatory cytokine levels with marked improvement in lung inflammation. Collectively, we identify an ideal regimen for IFN-{lambda} use and demonstrate the protective efficacy of IFN-{lambda} in MERS-CoV infected mice.

Background The performance of current diagnostic algorithms of the American College of Cardiology/American Heart Association (ACC/AHA), National Institute for Health and Care Excellence (NICE) and European Society of Cardiology (ESC) in patients with stable chest pain and coronary artery calcium (CAC) remains a matter of debate. We compared their merits in patients with CAC and investigated the additional value of the CAC score to improve diagnostic accuracy and risk stratification. Methods and results Patient data were obtained from a prospective registry of 642 consecutive patients. Mean age 63 (SD 11) years, 50% male. According to the guidelines, low and intermediate/high pre-test probability groups were constructed. Patients were reclassified based on their CAC score. Obstructive coronary artery disease (CAD) was observed in 14%. All models performed modestly in accurately predicting CAD (c-statistic

Background The most sensitive method to detect SARS-CoV-2 relies on rRT-PCR; however, viral RNA can be detected weeks/months after clinical resolution. Since rRT-PCR cannot discern between non- and infectious virus, it is unclear whether the presence of viral RNA after recovery reflects infectious SARS-CoV-2. However, recent studies suggest a positive correlation between antigen rapid tests (Ag-RDT) and virus isolation that is more suited to assess contagiousness. Objectives To assess the utility of SARS-CoV-2 diagnostic tests in different settings we evaluated the performance of Ag-RDT-based and a cell culture-based SARS-CoV-2 assay in comparison to rRT-PCR. Study design A total of 61 Nasopharyngeal-Swabs tested positive by cobas��� SARS-CoV-2 rRT-PCR were in parallel evaluated with the Roche Ag-RDT and a cell culture-based assay to detect SARS-CoV-2. Results SARS-CoV-2 was successfully isolated in 51/61 samples corresponding to 83.6%, which was 97.3% or 96.2% when considering samples with E-gene Ct-value

PURPOSE: 'Type A' behavioural characteristics and psychosocial stress have traditionally been associated with chronic central serous chorioretinopathy (cCSC). However, a characteristical personality profile could not be identified in these patients and the presumed association with stress is subject to controversy, due to a lack of convincing studies using validated measuring instruments. In this study, we aimed to assess maladaptive personality traits, psychological morbidity and coping strategies in patients with cCSC, in order to identify potentially modifiable psychosocial aspects which could be used in support to current standard treatment.METHODS: A cross-sectional study in a cohort of 86 patients with cCSC using validated questionnaires. Findings were compared to both Dutch population reference data and reference data from patients treated for Cushing's disease.RESULTS: Maladaptive personality traits were not more prevalent in patients with cCSC than in the general population, and psychological morbidity was not increased. Patients with cCSC were shown to make more use of passive coping, active coping and seeking social support. Interestingly, personality, psychological morbidity and coping characteristics of patients with cCSC were more comparable to features of patients treated for Cushing's disease than to population-based data.CONCLUSION: Maladaptive personality traits such as type A behavioural characteristics are not more prevalent in patients with cCSC. Patients with cCSC make more use of certain coping strategies, which could be addressed by psychosocial care to improve self-management. Further research is needed establish whether the course of disease can be improved by altering coping and reducing 'stress'.

Drawn from numerous sources, including papers in this special issue, this concluding paper synthesizes evidence on the relationship between agricultural research for development and poverty reduction, with particular emphasis on agri-food systems perspectives in shaping programs aimed at rural prosperity. Following our introduction in section 1, we revisit the ex ante set of 18 pathways in section 2 (which were laid out in our introductory paper for this SI), posing some critical questions: Can a manageable set of impact pathways be identified? How are they inter-related? Rather than independent linear pathways, is it better (both conceptually and for clarity of communication) to represent these as impact networks rather than linear pathways? These insights lead to very different and more inclusive partnerships and contain their own implications for program design in section 3. The challenges facing the world today are complex, and no single organization or sector can hope to effectively confront these issues alone. Not only is partnership increasingly seen as a multi-stakeholder phenomenon rather than a bilateral one, but there also is a discernible move towards a network framing (e.g., as “innovation systems” or “boundary spanning”). This change is driven by the progressive inclusion of agricultural research goals as part of the wider development agenda, where complexity and systemic change are central. In turn, this requires more appropriate strategies for knowledge creation, innovation, and partnership. Section 4 presents implications for program design and priority-setting that follow from foregoing insights on the interplay of pathways and partnerships.

Background: Animal models suggest that neuroprotective effects of therapeutic hypothermia (TH) after perinatal asphyxia are reduced in infants with early-onset sepsis. Objectives: To assess the outcome of infants with perinatal asphyxia, neonatal encephalopathy, and TH in the presence of early-onset sepsis. Methods: In a retrospective cohort of 1,084 infants with perinatal asphyxia and TH, the outcome of 42 infants (gestational age 36.1–42.6 weeks and birth weight 2,280–5,240 g) with proven sepsis (n = 14) and probable sepsis (n = 28) was analyzed. Death, cerebral palsy, or a delayed development at 2 years was considered an adverse outcome. Results: Sepsis was caused mostly by group B streptococci (n = 17), other Gram-positive bacteria (n = 5), and Candida albicans (n = 1). Of the 42 infants, 9 (21.4%) died, and 5 (11.9%) showed impairments on follow-up. The outcome is comparable to the previously reported outcome of infants with TH without early-onset sepsis. Conclusion: A good outcome was reported in the majority of infants with perinatal asphyxia, TH, and early-onset sepsis. Cooling should not be withheld from these infants.

IntroductionDistal radius fractures are among the most prevalent traumatic injuries worldwide. These injuries are associated with high healthcare-related and socioeconomic costs, mainly resulting from loss of productivity. To optimise recovery and return to work, wrist exercises are recommended. However, adherence to standard exercise regimens is low. Serious games provide a treatment platform for standardised postoperative care, uniting meaningful recovery with entertainment. Also, mobile serious games, for example, smartphone or tablet applications, are able to send practice reminders believed to improve self-efficacy.Methods and analysisTo test the effectiveness of a mobile serious game for distal radius fracture rehabilitation compared with standard care, a multicentre, randomised controlled clinical trial was designed. Primary outcome will be the Patient-Rated Wrist Evaluation (PRWE) score after 6 weeks of treatment. Secondary outcomes are range of motion, grip strength, pain scores, and self-reported treatment adherence after 2, 6 and 12 weeks of treatment.Adult patients with any type of closed distal radius fracture are included directly after non-operative or operative fracture treatment. Patients are recruited in the outpatient clinics of four teaching hospitals. The intended sample size is 92 patients, based on the minimal clinically important difference of the PRWE score at 6 weeks, using a superiority model.Patients are randomised between using the wearable-controlled mobile serious game ReValidate! (intervention group) and standard care consisting of unsupervised exercises and a referral for physiotherapy or exercise therapy upon request or recommendation by the treating clinician (control group).Ethics and disseminationThe protocol has been approved by the Medical Ethical Review Board of the Amsterdam University Medical Centres, location Academic Medical Centre in Amsterdam, the Netherlands. Results will be made available to involved healthcare providers, funders, and to the general public including patients via peer-reviewed academic journals and international conferences.Trial registration numberDutch Trial Registry (NTR), NL6140, protocol V.2.

Importance Silicone breast implants have been on the market for breast augmentation or breast reconstruction for approximately 60 years but may lead to medical complications, also called breast implant illness. Objective To evaluate the existence of silicone gel bleed and migration over a long time period, including the period in which the newer cohesive silicone gel breast implants were used. Design, setting, and participants In this single-center case series, capsule tissue and lymph node samples were collected from women who underwent removal or revision of silicone breast implants from January 1, 1986, to August 18, 2020, and data were extracted from the pathological reports and revision of the histology if data were missing. All tissues were examined using standard light microscopy, some extended with modified oil red O staining and energy-dispersive radiographic spectroscopy. A total of 365 women had capsular tissue removed, including 15 patients who also had lymph nodes removed, and 24 women had only lymph nodes removed. Data were analyzed from January to May 2021. Exposures Silicone breast implants. Main outcomes and measures The main outcome was presence or absence of silicones inside or outside the capsule. One-way analysis of variance was used to determine significance between groups. Results Among a total of 389 women with silicone breast implants (mean [SD] age, 50.5 [11.2] years), 384 women (98.8%) had silicone particles present in the tissues, indicating silicone gel bleed. In 337 women (86.6%), silicone particles were observed outside the capsule (ie, in tissues surrounding the capsule and/or lymph nodes), indicating silicone migration. In 47 women (12.1%), silicone particles were only present within the capsule. In 5 women (1.2%), no silicone particles were detected in the tissues. Patients were divided into 2 groups, with 46 women who received cohesive silicone gel breast implants and 343 women who received either an older or a newer type of breast implant. There were no differences in silicone gel bleed or migration between groups (silicone detected outside or inside capsule: 44 women [95.7%] vs 340 women [99.1%]; P = .19). Conclusions and relevance In this case series including women with noncohesive or cohesive silicone gel breast implants, silicone leakage occurred in 98.8% of women, indicating silicone gel bleed, and in 86.6% of women, migration of silicone particles outside the capsule was detected.

Results of laboratory investigations of ovine and caprine cases of abortion in the lambing season 2015–2016 were analyzed, using pathology records of submissions to Royal GD (Deventer, the Netherlands) from January until and including April 2016, in comparison with the results of two accessible alternative techniques for sampling aborted lambs and kids, swabbing the fetal oropharynx and puncture of the fetal lung. Chlamydia abortus was the main cause of abortion in sheep as well as in goats. Other causes of abortion were Campylobacter spp., Listeria spp., Escherichia coli, and Yersinia enterocolitica. Ovine pathological submissions resulted more often in detecting an infectious agent compared to caprine submissions. For the three main bacterial causes of abortion, Campylobacter spp., Listeria spp., and Chlamydia spp., compared to results of the pathological examination, oropharynx mucus, and fetal lung puncture samples showed an observed agreement of 0.87 and 0.89, an expected agreement of 0.579 and 0.584, and a kappa value of 0.691 and 0.737 (95% CI: 0.561–0.82 and 0.614–0.859), respectively. The agreement between the results of the pathological examination and both fetal lung puncture and oropharynx mucus samples was classified as good. In conclusion, although a full step-wise post-mortem examination remains the most proper way of investigating small ruminant abortions, the easily accessible, low-threshold tools for practitioners and farmers as described in this paper not only provide reliable results compared to results of the post-mortem examination but also stimulates farmers and veterinarians to submit fetuses and placentas if necessary. Suggestions for further improvement of both alternatives have been summarized. Both alternatives could also be tailor-made for specific regions with their specific causes of abortion.

Aims Screening for a high cardiovascular disease (CVD) risk followed by preventive treatment can potentially reduce coronary heart disease (CHD)-related morbidity and mortality. ROBINSCA (Risk Or Benefit IN Screening for CArdiovascular disease) is a population-based randomized controlled screening trial that investigates the effectiveness of CVD screening in asymptomatic participants using the Systematic COronary Risk Evaluation (SCORE) model or Coronary Artery Calcium (CAC) scoring. This study describes the distributions in risk and treatment in the ROBINSCA trial. Methods and results Individuals at expected elevated CVD risk were randomized (1:1:1) into the control arm (n=14,519; usual care); screening arm A (n=14,478; SCORE, 10-year fatal and non-fatal risk); or screening arm B (n=14,450; CAC scoring). Preventive treatment was largely advised according to current Dutch guidelines. Risk and treatment differences between the screening arms were analysed. 12,185 participants (84.2%) in arm A and 12,950 (89.6%) in arm B were screened. 48.7% were women, and median age was 62 (InterQuartile Range 10) years. SCORE screening identified 45.1% at low risk (SCORE Conclusion We showed that compared to risk stratification based on SCORE, CAC scoring classified significantly fewer men and women at increased risk, and less preventive treatment was indicated. ROBINSCA flowchart Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): Advanced Research Grant

Background To evaluate the cost-effectiveness of a reduction in the number of routine radiographs in the follow-up of patients with ankle fractures. Methods We performed an economic evaluation alongside the multicentre, randomised WARRIOR trial. Participants were randomised to a reduced imaging follow-up protocol (i.e. radiographs at week 6 and 12 follow-up obtained on clinical indication) or usual care (i.e. routine radiography at weeks 6 and 12). The Olerud & Molander Ankle Score (OMAS) was used to assess ankle function and the EQ-5D-3L was used to estimate Quality-Adjusted Life Years (QALYs). Costs and resource use were assessed using self-reported questionnaires and medical records, and analysed from a societal perspective. Multiple imputation was used for missing data, and data were analysed using seemingly unrelated regression analysis and bootstrapping. Results In total, 246 patients had data available for analysis (reduced imaging = 118; usual care = 128). Fewer radiographs were obtained in the reduced imaging group (median = 4) compared with the usual-care group (median = 5). Functional outcome was comparable in both groups. The difference in QALYs was − 0.008 (95% CI:-0.06 to 0.04) and the difference in OMAS was 0.73 (95% CI:-5.29 to 6.76). Imaging costs were lower in the reduced imaging group (−€48; 95% CI:- €72 to -€25). All other cost categories did not statistically differ between the groups. The probability of the reduced imaging protocol being cost-effectiveness was 0.45 at a wiliness-to-pay of €20,000 per QALY. Conclusions Reducing the number of routine follow-up radiographs has a low probability of being cost-effective compared with usual care. Functional outcome, health-related quality of life and societal costs were comparable in both groups, whereas imaging costs were marginally lower in the reduced imaging group. Given this, adherence to a reduced imaging follow-up protocol for those with routine ankle fractures can be followed without sacrificing quality of care, and may result in reduced costs. Trial registration The trial was registered on 26-05-2014 in the Netherlands Trial Registry, with reference number NL4477 (www.trialregister.nl/trial/4477).

Purpose To describe the clinical characteristics and outcome of polypoidal choroidal vasculopathy (PCV), also known as aneurysmal type 1 (sub-retinal pigment epithelium (RPE)) neovascularization, in Caucasian patients. Methods Single-centre study in 66 Caucasian patients with a diagnosis of PCV based on optical coherence tomography scan and indocyanine green angiography. Clinical characteristics and multimodal imaging were collected and assessed by an experienced retina specialist. Results This study involved 74 eyes of 66 patients with PCV, with a mean age at onset of 73 years and a female preponderance of 66%. The mean number of polypoidal lesions per eye was 1 (range: 1–5 lesions), out of which 75% was located in the macula and 19% in the peripapillary region. Of the 74 eyes, 37 eyes (50%) had PCV associated with a drusenoidal neovascular age-related macular degeneration (AMD) phenotype (PCV-AMD) and 18 eyes (24%) had PCV associated with non-polypoidal type 1 choroidal neovascularization/branching vascular network (PCV-BVN) without signs of drusenoidal AMD, while 19 eyes (26%) had idiopathic, isolated PCV (iPCV). The mean subfoveal choroidal thickness measured in 22 patients was 245 μm (range: 71–420 μm). In 51% of patients, the initially performed therapy showed good anatomical recovery (resolution of intra- and subretinal fluid). Conclusions A spectrum of PCV (aneurysmal type 1/sub-RPE neovascularization) can be seen in Caucasian patients. PCV associated with a drusenoidal neovascular AMD phenotype in Caucasians is phenotypically and presumably pathophysiologically more associated with neovascular AMD (PCV-AMD: type A PCV). However, this may not be the case for patients with PCV with non-polypoidal type 1 choroidal neovascularization or BVN and no signs of drusenoidal AMD (PCV-BVN: type B PCV), and for patients with idiopathic PCV without associated drusen or BVN (iPCV; type C PCV). Most patients have a thin choroid, even when drusen are absent. For the entire patient group, a moderate anatomical recovery was observed after treatment.

In the originally published version of this protocol [1], the sample size calculation of the subgroups for age should have been phrased differently. The actual sample size of each subgroup (routine removal 60 years old, routine removal 60 years old, on demand removal 60 years old and on demand removal 60 years old) should be 44, making a total of 176 (unchanged), which would come to a required number of included patients of 196 when incorporating a loss to follow up of 10%.

Purpose: Central serous chorioretinopathy (CSC), a distinct form of macular degeneration, has been associated with glucocorticoid use and possibly also with an increased endogenous activity of the hypothalamic-pituitary-adrenal (HPA) axis. To estimate long-term glucocorticoid exposure, measurement of hair cortisol concentrations (HCC) has emerged. This cross-sectional study aimed to investigate HCC, as a reflection of chronic endogenous steroid exposure, in a cohort of patients with chronic CSC (cCSC).Methods: Hair cortisol concentrations (HCC) were determined in 48 patients with cCSC and 230 population-based controls (Lifelines cohort study), not using exogenous corticosteroids.Results: Increased HCC (defined as >10.49 pg/mg) were present in 2 (4%) patients with cCSC and 13 (6%) controls. Mean HCC values were not different between patients and controls, and no difference in HCC was found between patients with active cCSC disease and patients with inactive disease. No correlation between HCC and urinary free cortisol (UFC) levels in patients with cCSC was found.Conclusions: This study shows that HCC in patients with cCSC are not elevated compared to population-based controls, and no association between HCC and cCSC severity was found. This finding questions the previous suggestion that cCSC is associated with increased HPA axis activity. In line, HCC do not seem useful in monitoring cCSC disease activity.

With currently over 4 million confirmed cases worldwide, including more than 300’000 deaths, the current Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has a major impact on the economy and health care system. Currently, a limited amount of prophylactic or therapeutic intervention options are available against SARS-CoV-2. In this study, we screened 400 compounds from the antimicrobial ‘Pandemic Response Box’ library for inhibiting properties against SARS-CoV-2. We identified sixteen compounds that potently inhibited SARS-CoV-2 replication, of which five compounds displayed equal or even higher antiviral activity compared to Remdesivir. These results show that five compounds should be further investigated for their mode of action, safety and efficacy against SARS-CoV-2.Highlights400 compounds from the pandemic response box were tested for antiviral activity against SARS-CoV-2.5 compounds had an equal or higher antiviral efficacy towards SARS-CoV-2, compared to the nucleoside analogue Remdesivir.