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Pompe's disease is a fatal muscular disorder caused by lysosomal alpha-glucosidase deficiency. In an open-label study, four babies with characteristic cardiomyopathy were treated with recombinant human alpha-glucosidase (rhGAA) from rabbit milk at starting doses of 15 mg/kg or 20 mg/kg, and later 40 mg/kg. The enzyme was generally well tolerated. Activity of alpha-glucosidase normalised in muscle. Tissue morphology and motor and cardiac function improved. The left-ventricular-mass index decreased significantly. We recommend early treatment. Long-term effects are being studied. [ABSTRACT FROM AUTHOR]

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.

Objective: To assess the relationship between anti-Iduronate 2-sulfatase (IDS) antibodies, IDS genotypes, phenotypes and their impact in patients with enzyme replacement therapy (ERT)-treated Mucopolysaccharidosis type II., Study Design: Dutch patients treated with ERT were analyzed in this observational cohort study. Antibody titers were determined by enzyme-linked immunosorbent assay. Neutralizing effects were measured in fibroblasts. Pharmacokinetic analysis of ERT was combined with immunoprecipitation. Urinary glycosaminoglycans were measured using mass spectrometry and dimethylmethylene blue., Results: Eight of 17 patients (47%) developed anti-IDS antibodies. Three patients with the severe, neuronopathic phenotype, two of whom did not express IDS protein, showed sustained antibodies for up to 10 years of ERT. Titers of 1:5120 or greater inhibited cellular IDS uptake and/or intracellular activity in vitro. In 1 patient who was neuronopathic with a titer of 1:20 480, pharmacokinetic analysis showed that all plasma recombinant IDS was antibody bound. This finding was not the case in 2 patients who were not neuronopathic with a titer of 1:1280 or less. Patients with sustained antibody titers showed increased urinary glycosaminoglycan levels compared with patients with nonsustained or no-low titers., Conclusions: Patients with the neuronopathic form and lack of IDS protein expression were most at risk to develop sustained anti-IDS antibody titers, which inhibited IDS uptake and/or activity in vitro, and the efficacy of ERT in patients by lowering urinary glycosaminoglycan levels., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: There is growing interest to implement multiparametric magnetic resonance imaging (mpMRI) and MR-guided biopsy (MRGB) for biopsy-naïve men with suspected prostate cancer., Objective: Primary objective was to compare and evaluate an MRI pathway and a transrectal ultrasound-guided biopsy (TRUSGB) pathway in biopsy-naïve men with prostate-specific antigen levels of ≥3ng/ml., Design, Setting, and Population: A prospective, multicenter, powered, comparative effectiveness study included 626 biopsy-naïve patients (from February 2015 to February 2018)., Intervention: All patients underwent prebiopsy mpMRI followed by systematic TRUSGB. Men with suspicious lesions on mpMRI also underwent MRGB prior to TRUSGB. MRGB was performed using the in-bore approach., Outcome Measurements and Statistical Analysis: Clinically significant prostate cancer (csPCa) was defined as grade group ≥2 (Gleason score ≥3+4) in any core. The main secondary objectives were the number of men who could avoid biopsy after nonsuspicious mpMRI, the number of biopsy cores taken, and oncologic follow-up. Differences in proportions were tested using McNemar's test with adjusted Wald confidence intervals for differences of proportions with matched pairs., Results and Limitations: The MRI pathway detected csPCa in 159/626 (25%) patients and insignificant prostate cancer (insignPCa) in 88/626 patients (14%). TRUSGB detected csPCa in 146/626 patients (23%) and insignPCa in 155/626 patients (25%). Relative sensitivity of the MRI pathway versus the TRUSGB pathway was 1.09 for csPCa (p=0.17) and 0.57 for insignPCa (p<0.0001). The total number of biopsy cores reduced from 7512 to 849 (-89%). The MRI pathway enabled biopsy avoidance in 309/626 (49%) patients due to nonsuspicious mpMRI. Immediate TRUSGB detected csPCa in only 3% (10/309) of these patients, increasing to 4% (13/309) with 1-yr follow-up. At the same time, TRUSGB would overdetect insignPCa in 20% (63/309). "Focal saturation" by four additional perilesional cores to MRGB improved the detection of csPCa in 21/317 (7%) patients. Compared with the literature, our proportion of nonsuspicious mpMRI cases is significantly higher (27-36% vs 49%) and that of equivocal cases is lower (15-28% vs 6%). This is probably due to the high-quality standard in this study. Therefore, a limitation is the duplication of these results in less experienced centers., Conclusions: In biopsy-naïve men, the MRI pathway compared with the TRUSGB pathway results in an identical detection rate of csPCa, with significantly fewer insignPCa cases. In this high-quality standard study, almost half of men have nonsuspicious MRI, which is higher compared with other studies. Not performing TRUS biopsy is at the cost of missing csPCa only in 4%., Patient Summary: We compared magnetic resonance imaging (MRI) with MRI-guided biopsy against standard transrectal ultrasound biopsy for the diagnosis of prostate cancer in biopsy-naïve men. Our results show that patients can benefit from MRI because biopsy may be omitted in half of men, and fewer indolent cancers are detected, without compromising the detection of harmful disease. Men also need fewer needles to make a diagnosis., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Quality indicators (QIs) have been developed to define appropriate antibiotic use in hospitalized patients. We evaluated whether a checklist based on these QIs affects appropriate antibiotic use and length of hospital stay., Methods: An antibiotic checklist for patients treated with intravenous antibiotics was introduced in nine Dutch hospitals in a stepped wedge cluster randomized trial. Prophylaxis was excluded. We included a random sample before (baseline), and all eligible patients after (intervention) checklist introduction. Baseline and intervention outcomes were compared. Primary endpoint was length of stay (LOS), analysed by intention to treat. Secondary endpoints, including QI performances, QI sum score (performance on all QIs per patient), and quality of checklist use, were analysed per protocol., Results: Between 1 November 2014 and 1 October 2015 we included 853 baseline and 5354 intervention patients, of whom 993 (19%) had a completed checklist. The LOS did not change (baseline geometric mean 10.0 days (95% CI 8.6-11.5) versus intervention 10.1 days (95% CI 8.9-11.5), p 0.8). QI performances increased between +3.0% and +23.9% per QI, and the percentage of patients with a QI sum score above 50% increased significantly (OR 2.4 (95% CI 2.0-3.0), p<0.001). Higher QI sum scores were significantly associated with shorter LOS. Discordance existed between checklist-answers and actual performance., Conclusions: Use of an antibiotic checklist resulted in a significant increase in appropriateness of antibiotic use, but not in a reduction of LOS. Low overall checklist completion rates and discordance between checklist-answers and actual provided care might have attenuated the impact of the checklist., (Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Clinical decision-making in patients with early stage breast cancer requires adequate risk estimation by medical oncologists. This survey evaluates the agreement among oncologists on risk estimations and adjuvant systemic treatment (AST) decisions and the impact of adding the 70-gene signature to known clinico-pathological factors., Methods: Twelve medical oncologists assessed 37 breast cancer cases (cT1-3N0M0) and estimated their risk of recurrence (high or low) and gave a recommendation for AST. Cases were presented in two written questionnaires sent 4 weeks apart. Only the second questionnaire included the 70-gene signature result., Results: The level of agreement among oncologists in risk estimation (κ=0.57) and AST recommendation (κ=0.57) was 'moderate' in the first questionnaire. Adding the 70-gene signature result significantly increased the agreement in risk estimation to 'substantial' (κ=0.61), while agreement in AST recommendations remained 'moderate' (κ=0.56). Overall, the proportion of high risk was reduced with 7.4% (range: 6.9-22.9%; p<0.001) and the proportion of chemotherapy that was recommended was reduced with 12.2% (range: 5.4-29.5%; p<0.001)., Conclusion: Oncologists' risk estimations and AST recommendations vary greatly. Even though the number of participating oncologists is low, our results underline the need for a better standardisation tool in clinical decision-making, in which integration of the 70-gene signature may be helpful in certain subgroups to provide patients with individualised, but standardised treatment., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

The prevalence of morbid obesity is increasing, with a corresponding increase in the demand for bariatric surgery, a proven effective treatment option. Bariatric surgery has potentially severe complications, including micro- and macronutrient deficiencies. Additionally, stenosis and ulceration of the anastomosis, reflux oesophagitis, cholelithiasis, steatohepatitis and altered pharmacokinetics and -dynamics may occur. Doctors in both the hospital setting and general practice will be increasingly confronted with the occasionally adverse long-term effects of bariatric surgery. Early detection, efficient follow-up and a multidisciplinary team approach are crucial in preventing and adequately treating the complications of bariatric surgery.

Objective: In peripheral arterial disease (PAD), mortality is high. Incidental renal artery stenosis (RAS) is a predictor of mortality in PAD patients undergoing angiography. This might be relevant for risk-benefit assessment when vascular surgery is considered, both in terms of perioperative risk, and in terms of life expectancy., Methods: We studied the prognostic impact of incidental RAS in 488 subjects (334 men, 154 women; mean follow-up 6.0 ± 3.4 years) who underwent angiography for PAD in a single center between 1997 and 2000. Renal arteries were visualized and follow-up data concerning vascular procedures were analyzed., Results: RAS (diameter reduction >50%) was present in 26%. Forty-six percent of study patients underwent a vascular procedure (85% vascular surgery, remainder underwent amputation). Patients that underwent vascular surgery had a better renal function at baseline, less history of stroke, and a larger proportion of smokers. Overall mortality was similar for patients that underwent surgery (54.5%) and those without surgery (49.6%). There was no difference in 90-day postoperative mortality for patients without or with RAS (7.2% vs 10.3%; NS). For subjects that underwent bypass surgery, long-term mortality was substantially and significantly higher among those with RAS (65.1%) vs those without RAS (43.5%). On Cox regression analysis, age was the only independent predictor of 90-day postoperative mortality. The well-known cardiovascular risk factors of age, diabetes mellitus, history of prior peripheral vascular disease, smoking, prior myocardial infarction, prior stroke, and amputation, as well as presence of RAS, were independent predictors for overall mortality., Conclusion: In PAD, incidental RAS predicts long-term mortality independent of other risk factors. The elevated mortality is not due to a higher postoperative risk. Subjects presenting with PAD and RAS can therefore undergo vascular procedures with the same risk as other patients., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

In patients with peripheral vascular disease (PVD), mortality is high and renal artery stenosis (RAS) is a frequent incidental finding. RAS carries a high risk for mortality, but whether incidentally discovered RAS is a risk factor for mortality is unknown. The prognostic impact of incidental RAS for mortality was studied in 550 consecutive patients who underwent intra-arterial digital subtraction angiography for PVD in a single center between 1997 and 2000. In 491 patients (336 men, 155 women; mean follow-up 3.8 +/- 1.9 yr), the renal arteries were visualized and follow-up data were available. RAS (diameter reduction > 50%) was present in 26% of the patients. Mortality in the RAS group was 59 versus 28% in the non-RAS group (odds ratio 3.8; 95% confidence interval 2.5 to 5.7; P < 0.0001). Diabetes, previous myocardial infarction, history of PVD, stroke, and hypertension were more frequent in the RAS group; age was higher and GFR was lower in the RAS group. Therefore, RAS was associated with elevated mortality and increased prevalence of cardiovascular risk factors. Cox regression analysis showed that RAS was an independent predictor for mortality (P = 0.005), along with age, diabetes, smoking, previous myocardial infarction, history of PVD, and stroke. In patients who were evaluated for PVD by digital subtraction angiography, mortality was high. Incidental RAS was a frequent finding and an independent predictor for mortality. Whether RAS is a marker for or, alternatively, a mediator of the poor prognosis and whether prognosis can be improved by specific intervention should be the subject of future prospective studies.

Unlabelled: Pompe disease or glycogen storage disease type II (OMIM 232300) is a metabolic myopathy with a broad clinical spectrum. Generalised muscle weakness combined with cardiomegaly presents within the first 3 months after birth, if the lysosomal alpha-glucosidase (AGLU) deficiency is complete. Residual enzyme activity prevents cardiac involvement and delays onset of muscle weakness. Enzyme therapy, by intravenous administration of acid AGLU, aims to supplement the missing enzyme activity. At the SHS symposium on Glycogen Storage Diseases Type I and II, in Fulda, two interim accounts were given of studies on the efficacy of enzyme therapy for Pompe disease; one with recombinant human acid AGLU produced in Chinese hamster ovary cells and the other with the same enzyme produced in the milk of transgenic rabbits., Conclusion: this review focuses on the latter study, discusses the scientific, technological and commercial aspects of the enterprise, and addresses the prospects and challenges of enzyme therapy for Pompe disease.

We report a patient who presented with progressive exertional dyspnoea, chronic cough and radiographic signs of interstitial lung disease. Since several of his family members were known to have familial idiopathic pulmonary fibrosis he was also suspected to suffer from this disease. After thorough investigation, including histological examination of lung biopsies obtained by thoracoscopy, a diagnosis of chronic extrinsic allergic alveolitis was made. Current knowledge of familial idiopathic pulmonary fibrosis is discussed. This case report underlines the importance of a histological diagnosis in interstitial lung disease.