The design and application of an extensible operating system

Tanenbaum, A.S. [Promotor

The efficacy of topical imiquimod in high-grade cervical intraepithelial neoplasia:A systematic review and meta-analysis

Objective: A major side effect of cervical excision for high-grade cervical intraepithelial neoplasia (CIN) is premature birth. A non-invasive treatment for reproductive age women is warranted. The aim of the present study was to determine the efficacy of topical imiquimod in the treatment of high-grade CIN, defined as a regression to ≤CIN 1, and to determine the clearance rate of high-risk human papillomavirus (hr-HPV), compared with surgical treatment and placebo. Methods: Databases were searched for articles from their inception to February 2023.The study protocol number was INPLASY2022110046. Original studies reporting the efficacy of topical imiquimod in CIN 2, CIN 3 or persistent hr-HPV infections were included. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses checklist. Results: Five studies were included (n = 463). Histological regression to ≤CIN 1 was 55% in imiquimod versus 29% in placebo, and 93% in surgical treatment. Imiquimod-treated women had a greater odds of histological regression to ≤CIN 1 than placebo (odds ratio [OR] 4.17, 95% confidence interval [CI] 2.03–8.54). In comparison to imiquimod, surgical treatment had an OR of 14.81(95% CI 6.59–33.27) for histological regression to ≤CIN 1. The hr-HPV clearance rate was 53.4% after imiquimod and 66% after surgical treatment (95% CI 0.62–23.77). Conclusions: The histological regression rate is highest for surgical treatment followed by imiquimod treatment and placebo.</p

Families with BAP1-tumor predisposition syndrome in The Netherlands: Path to identification and a proposal for genetic screening guidelines

Germline pathogenic variants in the BRCA1-associated protein-1 (BAP1) gene cause the BAP1-tumor predisposition syndrome (BAP1-TPDS, OMIM 614327). BAP1-TPDS is associated with an increased risk of developing uveal melanoma (UM), cutaneous melanoma (CM), malignant mesothelioma (MMe), renal cell carcinoma (RCC), meningioma, cholangiocarcinoma, multiple non-melanoma skin cancers, and BAP1-inactivated nevi. Because of this increased risk, it is important to identify patients with BAP1-TPDS. The associated tumors are treated by different medical disciplines, emphasizing the need for generally applicable guidelines for initiating genetic analysis. In this study, we describe the path to identification of BAP1-TPDS in 21 probands found in the Netherlands and the family history at the time of presentation. We report two cases of de novo BAP1 germline mutations (2/21, 9.5%). Findings of this study combined with previously published literature, led to a proposal of guidelines for genetic referral. We recommend genetic analysis in patients with ≥2 BAP1-TPDS-associated tumors in their medical history and/or family history. We also propose to test germline BAP1 in patients diagnosed with UM <40 years, CM <18 years, MMe <50 years, or RCC <46 years. Furthermore, other candidate susceptibility genes for tumor types associated with BAP1-TPDS are discussed, which can be included in gene panels when testing patients

Costs and advance directives at the end of life: a case of the ‘Coaching Older Adults and Carers to have their preferences Heard (COACH)’ trial

Background Total costs associated with care for older people nearing the end of life and the cost variations related with end of life care decisions are not well documented in the literature. Healthcare utilisation and associated health care costs for a group of older Australians who entered Transition Care following an acute hospital admission were calculated. Costs were differentiated according to a number of health care decisions and outcomes including advance directives (ADs). Methods Study participants were drawn from the Coaching Older Adults and Carers to have their preferences Heard (COACH) trial funded by the Australian National Health and Medical Research Council. Data collected included total health care costs, the type of (and when) ADs were completed and the place of death. Two-step endogenous treatment-regression models were employed to test the relationship between costs and a number of variables including completion of ADs. Results The trial recruited 230 older adults with mean age 84 years. At the end of the trial, 53 had died and 80 had completed ADs. Total healthcare costs were higher for younger participants and those who had died. No statistically significant association was found between costs and completion of ADs. Conclusion For our frail study population, the completion of ADs did not have an effect on health care utilisation and costs. Further research is needed to substantiate these findings in larger and more diverse clinical cohorts of older people

Stakeholder values and preferences in lower limb amputation for no-option chronic limb threatening ischemia

Health and self-regulatio

Validation of the Dutch translation of the Cardiff wound impact schedule for evaluation of the health-related quality of life of patients with chronic wounds

The aim of this study was to validate a Dutch translation of the Cardiff wound impact schedule (CWIS), a disease-specific instrument to measure the health-related quality of life (HRQoL) in patients with chronic leg ulcers. To achieve this, the original instrument was translated. A total of 83 patients with chronic lower leg ulcers were included and completed the translated instrument and SF36 at baseline after assessment of their wound severity. Follow-up was performed 1 week after inclusion. The psychometric properties of the instrument were assessed. Construct validity was positively evaluated by an expert panel. Face validity was positively evaluated in a cognitive debriefing of a pilot group. Discriminant validity was assessed by correlating 1-year amputation risk according to the Wound, Ischaemia, foot Infection classification system with the instrument scores. Significant correlation could not be proven. Criterion validity was assessed by correlating domain scores of the instrument with domain scores of the gold standard: SF36. Moderate to high correlation was calculated for most domains of the instrument. Test-retest reliability and internal consistency were evaluated as acceptable. In conclusion, the Dutch translation of the CWIS is a valid and reliable disease-specific instrument to assess the HRQoL in patients with chronic lower leg ulcers.Vascular Surger

Using maximal systolic acceleration to diagnose and assess the severity of peripheral artery disease in a flow model study

Background: Because of the presence of medial calcific sclerosis, both ankle-branchial index and toe pressure measures can yield misleading results when attempting to diagnose peripheral artery disease (PAD). A new ultrasound parameter, maximal systolic acceleration (ACC(max)), can be an accurate tool for diagnosing PAD, including in diabetic patients. However, it has not been evaluated thoroughly. The aim of this study was to assess the feasibility of using ACC(max) to diagnose and assess the severity of PAD.Methods: The human circulatory system was simulated using an in vitro circulatory system driven by a pulsatile pneumatic pump. Arterial stenosis of various degrees (50%, 70%, 80%, and 90%) was simulated in order to investigate the change in several ultrasound parameters (including ACC(max)), as well as the intraluminal mean arterial pressure gradient. In a separate set of measurements, interobserver variability was measured using two investigators who were unaware of the degree of stenosis.Results: ACC(max) significantly decreased (P < .001), and the pressure gradient increased (P < .001) as the degree of stenosis increased. Moreover, we found a strong correlation between ACC(max) and the pressure gradient (R-2 = 0.937). Finally, interobserver variability with respect to ACC(max) was extremely low, with an intraclass correlation coefficient of 0.99.Conclusions: The results of this flow model study suggest that ACC(max) can be a valid, noninvasive tool for diagnosing PAD. Moreover, our finding that ACC(max) decreases as the severity of stenosis increases, together with the strong correlation between ACC(max) and the pressure gradient, suggests that ACC(max) may be useful as an alternative diagnostic tool for assessing the severity of PAD. These promising in vitro data warrant further study in a clinical setting.Vascular Surger

Doppler Ultrasonography Derived Maximal Systolic Acceleration: Value Determination With Artificially Induced Stenosis

Background In diagnosing peripheral arterial disease (PAD), medial arterial calcification (MAC) hampers arterial compression and could lead to unreliable ankle brachial index (ABI), toe brachial index (TBI) and toe pressure (TP). Doppler ultrasonography (DUS) derived maximal systolic acceleration (ACCmax) might be more accurate to diagnose PAD. In an in vitro study, a strong correlation between ACCmax and the severity of stenotic disease was determined. The aim of this study was to investigate the ACCmax in correlation with conventional non-invasive diagnostics in an in vivo setting. Methods: In twelve healthy individuals, an arterial stenosis was mimicked by compression on the common femoral artery by an ultrasounds probe, creating a local stenosis of 50%, 70% and 90%. The ABI, TBI, TP and several DUS parameters (including ACCmax) were assessed at the ankle during these different degrees of stenosis. All DUS parameters were measured separately by two observers to determine the interobserver variability. Results: Overall the ABI, TBI, TP, ACCmax, ACCsys and PSV decreased significantly when the degree of stenosis increased. The ACCmax showed the highest correlation with the degree of stenosis (r -.884), compared to ABI (r -.726), TBI (r -.716) and TP (r -.758). Furthermore, the interobserver variability of ACCmax was excellent, with an intraclass correlation coefficient (ICC) of .97. Conclusion: ACCmax is an accurate non-invasive DUS parameter to diagnose and assess the severity of a mimicked arterial stenosis in healthy individuals. Further prospective assessment of the clinical value of ACCmax and its potential benefits in patients with PAD is needed.Vascular Surger

Doppler Ultrasonography Derived Maximal Systolic Acceleration: Value Determination With Artificially Induced Stenosis

Background In diagnosing peripheral arterial disease (PAD), medial arterial calcification (MAC) hampers arterial compression and could lead to unreliable ankle brachial index (ABI), toe brachial index (TBI) and toe pressure (TP). Doppler ultrasonography (DUS) derived maximal systolic acceleration (ACCmax) might be more accurate to diagnose PAD. In an in vitro study, a strong correlation between ACCmax and the severity of stenotic disease was determined. The aim of this study was to investigate the ACCmax in correlation with conventional non-invasive diagnostics in an in vivo setting. Methods: In twelve healthy individuals, an arterial stenosis was mimicked by compression on the common femoral artery by an ultrasounds probe, creating a local stenosis of 50%, 70% and 90%. The ABI, TBI, TP and several DUS parameters (including ACCmax) were assessed at the ankle during these different degrees of stenosis. All DUS parameters were measured separately by two observers to determine the interobserver variability. Results: Overall the ABI, TBI, TP, ACCmax, ACCsys and PSV decreased significantly when the degree of stenosis increased. The ACCmax showed the highest correlation with the degree of stenosis (r -.884), compared to ABI (r -.726), TBI (r -.716) and TP (r -.758). Furthermore, the interobserver variability of ACCmax was excellent, with an intraclass correlation coefficient (ICC) of .97. Conclusion: ACCmax is an accurate non-invasive DUS parameter to diagnose and assess the severity of a mimicked arterial stenosis in healthy individuals. Further prospective assessment of the clinical value of ACCmax and its potential benefits in patients with PAD is needed

A New Doppler-Derived Parameter to Quantify Internal Carotid Artery Stenosis: Maximal Systolic Acceleration

Objective: Doppler ultrasonography (DUS) is used as initial measurement to diagnose and classify carotid artery stenosis. Local distorting factors such as vascular calcification can influence the ability to obtain DUS measurements. The DUS derived maximal systolic acceleration (ACCmax) provides a different way to determine the degree of stenosis. While conventional DUS parameters are measured at the stenosis itself, ACCmax is measured distal to the internal carotid artery (ICA) stenosis. The value of ACCmax in ICA stenosis was investigated in this study.Material and Methods: All carotid artery DUS studies of a tertiary academic center were reviewed from October 2007 until December 2017. Every ICA was included once. The ACCmax was compared to conventional DUS parameters: ICA peak systolic velocity (PSV), and PSV ratio (ICA PSV/CCA PSV). ROC-curve analysis was used to evaluate accuracy of ACCmax, ICA PSV and PSV ratio as compared to CT-angiography (CTA) derived stenosis measurement as reference test.Results: The study population consisted of 947 carotid arteries and was divided into 3 groups: = 70% (128/947). Between these groups ACCmax was significantly different. Strong correlations between ACCmax and ICA PSV (R-2 0.88) and PSV ratio (R-2 0.87) were found. In ROC subanalysis, the ACCmax had a sensitivity of 90% and a specificity of 89% to diagnose a >= 70% ICA stenosis, and a sensitivity of 82% and a specificity of 88% to diagnose a >= 50% ICA stenosis. For diagnosing a >= 50% ICA stenosis the area under the curve (AUC) of ACCmax (0.88) was significantly lower than the AUC of PSV ratio (0.94) and ICA PSV (0.94). To diagnose a >= 70% ICA stenosis there were no significant differences in AUC between ACCmax (0.89), PSV ratio (0.93) and ICA PSV (0.94).Conclusions: ACCmax is an interesting additional DUS measurement in determining the degree of ICA stenosis. ACCmax is measured distal to the stenosis and is not hampered by local distorting factors at the site of the stenosis. ACCmax can accurately diagnose an ICA stenosis, but was somewhat inferior compared to ICA PSV and PSV ratio to diagnose a >= 50% ICA stenosis.Vascular Surger