Move blocking strategies in receding horizon control

Abstract — In order to deal with the computational burden of optimal control, it is common practice to reduce the degrees of freedom by fixing the input or its derivatives to be constant over several time-steps. This policy is referred to as “move blocking”. This paper will address two issues. First, a survey of various move blocking strategies is presented and the shortcomings of these blocking policies, such as the lack of stability and constraint satisfaction guarantees, will be illustrated. Second, a novel move blocking scheme, “Moving Window Blocking” (MWB), will be presented. In MWB, the blocking strategy is time-dependent such that the scheme yields stability and feasibility guarantees for the closed-loop system. Finally, the results of a large case-study are presented that illustrate the advantages and drawbacks of the various control strategies discussed in this paper

Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial.

Trial designThis analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.MethodsMales aged 5-18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13-17 years), renal function, and glycolipid levels (plasma, urine).ResultsPlasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m(2) (range 90.4-161.0 mL/min/1.73 m(2)) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0-27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.ConclusionsThese data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.Trial registrationClinicalTrials.gov NCT00701415

Conjectures on an algorithm for convex parametric quadratic programs

An algorithm for convex parametric QPs is studied. The algorithm explores the parameter space by stepping a sufficiently small distance over the facets of each critical region and thereby identifying the neighboring regions. Some conjectures concerning this algorithm and the structure of the solution of a parametric QP are presented

On the facet-to-facet property of solutions to convex parametric quadratic programs

In some of the recently developed algorithms for convex parametric quadratic programs it is implicitly assumed that the intersection of the closures of two adjacent critical regions is a facet of both closures; this will be referred to as the facet-to-facet property. It is shown by an example, whose solution is unique, that the facet-to-facet property does not hold in general. Consequently, some existing algorithms cannot guarantee that the entire parameter space will be explored. A simple modification, applicable to several existing algorithms, is presented for the purpose of overcoming this problem. Numerical results indicate that, compared to the original algorithms for parametric quadratic programs, the proposed method has lower computational complexity for problems whose solutions consist of a large number of critical regions

Consensus recommendations for the treatment and management of patients with Fabry disease on migalastat: a modified Delphi study

Objective: Fabry disease is a progressive disorder caused by deficiency of the α-galactosidase A enzyme (α-Gal A), leading to multisystemic organ damage with heterogenous clinical presentation. The addition of the oral chaperone therapy migalastat to the available treatment options for Fabry disease is not yet universally reflected in all treatment guidelines. These consensus recommendations are intended to provide guidance for the treatment and monitoring of patients with Fabry disease receiving migalastat. Methods: A modified Delphi process was conducted to determine consensus on treatment decisions and monitoring of patients with Fabry disease receiving migalastat. The multidisciplinary panel comprised 14 expert physicians across nine specialties and two patients with Fabry disease. Two rounds of Delphi surveys were completed and recommendations on the use of biomarkers, multidisciplinary monitoring, and treatment decisions were generated based on statements that reached consensus. Results: The expert panel reached consensus agreement on 49 of 54 statements, including 16 that reached consensus in round 1. Statements that reached consensus agreement are summarized in recommendations for migalastat treatment and monitoring, including baseline and follow-up assessments and frequency. All patients with Fabry disease and an amenable mutation may initiate migalastat treatment if they have evidence of Fabry-related symptoms and/or organ involvement. Treatment decisions should include holistic assessment of the patient, considering clinical symptoms and organ involvement as well as patient-reported outcomes and patient preference. The reliability of α-Gal A and globotriaosylsphingosine as pharmacodynamic response biomarkers remains unclear. Conclusion: These recommendations build on previously published guidelines to highlight the importance of holistic, multidisciplinary monitoring for patients with Fabry disease receiving migalastat, in addition to shared decision-making regarding treatments and monitoring throughout the patient journey. (Figure presented.)

Safety and efficacy of pegunigalsidase alfa in patients with Fabry disease who were previously treated with agalsidase alfa: results from BRIDGE, a phase 3 open-label study

BACKGROUND: Pegunigalsidase alfa is a novel, PEGylated α-galactosidase-A enzyme-replacement therapy approved in the EU and US to treat patients with Fabry disease (FD). OBJECTIVE/METHODS: BRIDGE is a phase 3 open-label, switch-over study designed to assess safety and efficacy of 12 months of pegunigalsidase alfa (1 mg/kg every 2 weeks) treatment in adults with FD who had been previously treated with agalsidase alfa (0.2 mg/kg every 2 weeks) for ≥ 2 years. RESULTS: Twenty-seven patients were screened; 22 met eligibility criteria; and 20 (13 men, 7 women) completed the study. Pegunigalsidase alfa was well-tolerated, with 97% of treatment-emergent adverse events (TEAEs) being of mild or moderate severity. The incidence of treatment-related TEAEs was low, with 2 (9%) discontinuations due to TEAEs. Five patients (23%) reported infusion-related reactions. Overall mean (SD; n = 22) baseline estimated glomerular filtration rate (eGFR) was 82.5 (23.4) mL/min/1.73 m2 and plasma lyso-Gb3 level was 38.3 (41.2) nmol/L (men: 49.7 [45.8] nmol/L; women: 13.8 [6.1] nmol/L). Before switching to pegunigalsidase alfa, mean (standard error [SE]) annualized eGFR slope was − 5.90 (1.34) mL/min/1.73 m2/year; 12 months post-switch, the mean eGFR slope was − 1.19 (1.77) mL/min/1.73 m2/year; and mean plasma lyso-Gb3 reduced by 31%. Seven (35%) out of 20 patients were positive for pegunigalsidase alfa antidrug antibodies (ADAs) at ≥ 1 study timepoint, two of whom had pre-existing ADAs at baseline. Mean (SE) changes in eGFR slope for ADA-positive and ADA-negative patients were + 5.47 (3.03) and + 4.29 (3.15) mL/min/1.73 m2/year, respectively, suggesting no negative impact of anti-pegunigalsidase alfa ADAs on eGFR slope. CONCLUSION: Pegunigalsidase alfa may offer a safe and effective treatment option for patients with FD, including those previously treated with agalsidase alfa. TRN: NCT03018730. Date of registration: January 2017

Clinical outcomes among young patients with Fabry disease who initiated agalsidase beta treatment before 30 years of age: An analysis from the Fabry registry

Background Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop in adulthood. Outcomes of Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes among patients aged 5–30 years at initiation of treatment with agalsidase beta using data from the Fabry Registry (NCT00196742, sponsor: Sanofi). Methods Reported GLA variants were predicted to be associated with the classic phenotype or not classified in fabry-database.org. Linear mixed models were conducted to assess changes over ≥2-year follow-up in the estimated glomerular filtration rate (eGFR) stratified by low (LRI) and high (HRI) renal involvement (defined by proteinuria/albuminuria levels), and changes in interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) Z-scores stratified by median age at first treatment. Self-reports (‘yes’/‘no’) of abdominal pain, diarrhea, chronic peripheral pain (denoting neuropathic pain), and acute pain crises at baseline were compared with reports after ≥0.5-year and ≥2.5-year follow-up using McNemar's test. Results Male (n = 117) and female patients (n = 59) with LRI initiated treatment at a median age of 19.9 and 23.6 years, respectively, and were followed for a median of 6.3 and 5.0 years, respectively. The eGFR slopes were −1.18 (Pfrom 0 5.5 years and ≥4.5 years, respectively). Older females (treatment initiation at median age 27.5 years) had a slope of LVPWT Z-scores of 0.18/year (n = 12, Pfrom 0 = 0.028), whereas IVST Z-scores remained stable (n = 13, 0.10/year, Pfrom 0 = 0.304) during a median follow-up of ≥3.7 years. These slopes did not significantly differ from slopes of younger females. Reports of chronic peripheral pain and acute pain crises by males, and of diarrhea and acute pain crises by females, significantly reduced after a median follow-up of ≥4.0 years. After a median follow-up of ≥5.4 years, reports of all four symptoms significantly decreased among males, whereas among females only reports of abdominal pain significantly decreased. Conclusions During sustained treatment with agalsidase beta in young Fabry patients with a predicted classic phenotype or with unclassified GLA variants with similar characteristics, the decline in eGFR was modest among male and female patients with LRI. The greater decline in eGFR among older, proteinuric (i.e., HRI) males may suggest a benefit of earlier treatment. Overall, echocardiographic variables remained stable, particularly among males and younger females. Significant reductions in symptom reports occurred primarily among males after longer follow-up and were less noticeable among females. These observed trends are suggestive of an overall improvement after treatment in young patients, but warrant larger longitudinal studies.publishedVersio

Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD.A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement.For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m(2)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped.The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.Ministry of Health (ZonMw

Correction to: Being active with a total hip or knee prosthesis: a systematic review into physical activity and sports recommendations and interventions to improve physical activity behavior

Objectives: Regular physical activity (PA) is considered important after total hip and knee arthroplasty (THA/TKA). Objective was to systematically assess literature on recommendations given by healthcare professionals to persons after THA and TKA and to provide an overview of existing interventions to stimulate PA and sports participation. Methods: A systematic review with a narrative synthesis including articles published between January 1995 and January 2021 reporting on recommendations and interventions. The PubMed, Embase, CINAHL and PsycInfo databases were systematically searched for original articles reporting on physical activity and sports recommendations given by healthcare professionals to persons after THA and TKA, and articles reporting on interventions/programs to stimulate a physically active lifestyle after rehabilitation or explicitly defined as part of the rehabilitation. Methodological quality was assessed with the Mixed Methods Appraisal Tool (MMAT). The review was registered in Prospero (PROSPERO:CRD42020178556). Results: Twenty-one articles reported on recommendations. Low-impact activities were allowed. Contact sports, most ball sports, and martial arts were not recommended. One study informed on whether health-enhancing PA recommendations were used to stimulate persons to become physically active. No studies included recommendations on sedentary behavior. Eleven studies reported on interventions. Interventions used guidance from a coach/physiotherapist; feedback on PA behavior from technology; and face-to-face, education, goal-setting, financial incentives and coaching/financial incentives combined, of which feedback and education seem to be most effective. For methodological quality, 18 out of 21 (86%) articles about recommendations and 7 out of 11 (64%) articles about interventions scored yes on more than half of the MMAT questions (0–5 score). Conclusion: There is general agreement on what kind of sports activities can be recommended by healthcare professionals like orthopedic surgeons and physiotherapists. No attention is given to amount of PA. The same is true for limiting sedentary behavior. The number of interventions is limited and diverse, so no conclusions can be drawn. Interventions including provision of feedback about PA, seem to be effective and feasible

Being active with a total hip or knee prosthesis: a systematic review into physical activity and sports recommendations and interventions to improve physical activity behavior

Objectives Regular physical activity (PA) is considered important after total hip and knee arthroplasty (THA/TKA). Objective was to systematically assess literature on recommendations given by healthcare professionals to persons after THA and TKA and to provide an overview of existing interventions to stimulate PA and sports participation. Methods A systematic review with a narrative synthesis including articles published between January 1995 and January 2021 reporting on recommendations and interventions. The PubMed, Embase, CINAHL and PsycInfo databases were systematically searched for original articles reporting on physical activity and sports recommendations given by healthcare professionals to persons after THA and TKA, and articles reporting on interventions/programs to stimulate a physically active lifestyle after rehabilitation or explicitly defined as part of the rehabilitation. Methodological quality was assessed with the Mixed Methods Appraisal Tool (MMAT). The review was registered in Prospero (PROSPERO:CRD42020178556). Results Twenty-one articles reported on recommendations. Low-impact activities were allowed. Contact sports, most ball sports, and martial arts were not recommended. One study informed on whether health-enhancing PA recommendations were used to stimulate persons to become physically active. No studies included recommendations on sedentary behavior. Eleven studies reported on interventions. Interventions used guidance from a coach/physiotherapist; feedback on PA behavior from technology; and face-to-face, education, goal-setting, financial incentives and coaching/financial incentives combined, of which feedback and education seem to be most effective. For methodological quality, 18 out of 21 (86%) articles about recommendations and 7 out of 11 (64%) articles about interventions scored yes on more than half of the MMAT questions (0-5 score). Conclusion There is general agreement on what kind of sports activities can be recommended by healthcare professionals like orthopedic surgeons and physiotherapists. No attention is given to amount of PA. The same is true for limiting sedentary behavior. The number of interventions is limited and diverse, so no conclusions can be drawn. Interventions including provision of feedback about PA, seem to be effective and feasible