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Summary Background Pompe disease is a rare disorder characterised by progressive loss of muscle and respiratory function due to acid α-glucosidase deficiency. Enzyme replacement therapy with recombinant human acid α-glucosidase, alglucosidase alfa, is the first approved treatment for the disease, but some patients do not respond, and many do not show a sustained benefit. We aimed to assess the safety and efficacy of an investigational two-component therapy (cipaglucosidase alfa, a novel recombinant human acid α-glucosidase, plus miglustat, an enzyme stabiliser) for late-onset Pompe disease. Methods We did a randomised, double-blind, parallel-group, phase 3 trial at 62 neuromuscular and metabolic medical centres in 24 countries in the Americas, Asia-Pacific, and Europe. Eligible participants were aged 18 years or older with late-onset Pompe disease, and had either been receiving alglucosidase alfa for at least 2 years or were enzyme replacement therapy-naive. Participants were randomly assigned (2:1) using interactive response technology software, stratified by 6-min walk distance and previous enzyme replacement therapy status, to intravenous cipaglucosidase alfa (20 mg/kg) plus oral miglustat or to intravenous alglucosidase alfa (20 mg/kg) plus oral placebo once every 2 weeks for 52 weeks. Patients, investigators, and outcome assessors were masked to treatment assignment. The primary endpoint was change from baseline to week 52 in 6-min walk distance, assessed using a mixed-effect model for repeated measures analysis for comparison of superiority in the intention-to-treat population (all patients who received at least one dose of study drug). This study is now complete and is registered with ClinicalTrials.gov , NCT03729362 . Findings Between Dec 3, 2018, and Nov 26, 2019, 130 patients were screened for eligibility and 125 were enrolled and randomly assigned to receive cipaglucosidase alfa plus miglustat (n=85) or alglucosidase alfa plus placebo (n=40). Two patients in the alglucosidase alfa plus placebo group did not receive any dose due to absence of genotype confirmation of late-onset Pompe disease and were excluded from analysis. Six patients discontinued (one in the alglucosidase alfa plus placebo group, five in the cipaglucosidase alfa plus miglustat group), and 117 completed the study. At week 52, mean change from baseline in 6-min walk distance was 20·8 m (SE 4·6) in the cipaglucosidase alfa plus miglustat group versus 7·2 m (6·6) in the alglucosidase alfa plus placebo group using last observation carried forward (between-group difference 13·6 m [95% CI −2·8 to 29·9]). 118 (96%) of 123 patients experienced at least one treatment-emergent adverse event during the study; the incidence was similar between the cipaglucosidase alfa plus miglustat group (n=81 [95%]) and the alglucosidase alfa plus placebo group (n=37 [97%]). The most frequently reported treatment-emergent adverse events were fall (25 [29%] patients in the cipaglucosidase alfa plus miglustat group vs 15 [39%] in the alglucosidase alfa plus placebo group), headache (20 [24%] vs 9 [24%]), nasopharyngitis (19 [22%] vs 3 [8%]), myalgia (14 [16%] vs 5 [13%]), and arthralgia (13 [15%]) vs 5 [13%]). 12 serious adverse events occurred in eight patients in the cipaglucosidase alfa plus miglustat group; only one event (anaphylaxis) was deemed related to study drug. One serious adverse event (stroke) occurred in the alglucosidase alfa plus placebo group, which was deemed unrelated to study drug. There were no deaths. Interpretation Cipaglucosidase alfa plus miglustat did not achieve statistical superiority to alglucosidase alfa plus placebo for improving 6-min walk distance in our overall population of patients with late-onset Pompe disease. Further studies should investigate the longer-term safety and efficacy of cipaglucosidase alfa plus miglustat and whether this investigational two-component therapy might provide benefits, particularly in respiratory function and in patients who have been receiving enzyme replacement therapy for more than 2 years, as suggested by our secondary and subgroup analyses. Funding Amicus Therapeutics.

Background: Crucial evidence gaps regarding: (1) the joint association of physical activity and sedentary time with health outcomes and (2) the benefits of light-intensity physical activity were identified during the development of recommendations for the World Health Organization Guidelines on physical activity and sedentary behavior (SB). The authors present alternative ways to evidence the relationship between health outcomes and time spent in physical activity and SB and examine how this could be translated into a combined recommendation in future guidelines. Methods: We used compositional data analysis to quantify the dose–response associations between the balance of time spent in physical activity and SB with all-cause mortality. The authors applied this approach using 2005–2006 National Health and Nutrition Examination Survey accelerometer data. Results: Different combinations of time spent in moderate- to vigorous-intensity physical activity, light-intensity physical activity, and SB are associated with similar all-cause mortality risk level. A balance of more than 2.5 minutes of moderate- to vigorous-intensity physical activity per hour of daily sedentary time is associated with the same magnitude of risk reduction for all-cause mortality as obtained by being physically active according to the current recommendations. Conclusion: This method could be applied to provide evidence for more flexible recommendations in the future with options to act on different behaviors depending on individuals’ circumstances and capacity.

The aim of this exploratory study was to evaluate diaphragmatic function across various neuromuscular diseases using spirometry-controlled MRI. We measured motion of the diaphragm relative to that of the thoracic wall (cranial-caudal ratio vs. anterior posterior ratio; CC-AP ratio), and changes in the diaphragmatic curvature (diaphragm height and area ratio) during inspiration in 12 adults with a neuromuscular disease having signs of respiratory muscle weakness, 18 healthy controls, and 35 adult Pompe patients – a group with prominent diaphragmatic weakness. CC-AP ratio was lower in patients with myopathies (n=7, 1.25±0.30) and motor neuron diseases (n=5, 1.30±0.10) than in healthy controls (1.37±0.14; p=0.001 and p=0.008), but not as abnormal as in Pompe patients (1.12±0.18; p=0.011 and p=0.024). The mean diaphragm height ratio was 1.17±0.33 in patients with myopathies, pointing at an insufficient diaphragmatic contraction. This was also seen in patients with Pompe disease (1.28±0.36), but not in healthy controls (0.82±0.33) or patients with motor neuron disease (0.82±0.24). We conclude that spirometry-controlled MRI enables us to investigate respiratory dysfunction across neuromuscular diseases, suggesting that the diaphragm is affected in a different way in myopathies and motor neuron diseases. Whether MRI can also be used to evaluate progression of diaphragmatic dysfunction requires additional studies.

Background: A thyroid incidentaloma (TI) is an unexpected, asymptomatic thyroid lesion discovered during the investigation of an unrelated condition. The aim of the present study is to examine the ...

Objective. To determine the clinical benefit of monotherapy with PI3K/AKT/mTOR inhibitors in patients diagnosed with advanced or recurrent ovarian cancer and to investigate the predictive value of current PI3K/AKT/ mTOR biomarkers on therapy response. Methods. A systematic search was conducted in PubMed, Embase and the Cochrane Library for articles reporting on treatment with PI3K/AKT/mTOR inhibitors in ovarian cancer. The primary endpoint was defined as the clinical benefit rate (CBR), including the proportion of patients with complete (CR) and partial response (PR) and stable disease (SD). Secondary endpoints included the overall response rate (ORR, including CR and PR) and drug-related grade 3 and 4 adverse events. Results. We included 233 patients from 19 studies and observed a pooled CBR of 32% (95% CI 20-44%) and ORR of 3% (95% CI 0-6%) in advanced or recurrent ovarian cancer patients treated with PI3K/AKT/mTOR inhibitors. Subgroup analysis tended to favor the studies who selected patients based on current PI3K/AKT/mTOR biomarker criteria (e.g. genomic alterations or loss of PTEN protein expression), but the difference in CBR was not statistically significant from studies with unselected populations (respectively, CBR of 42% (95% CI 23-62%) and 27% (95% CI 14-42%), P = 0.217). To better reflect true patient benefit, we excluded SD

Purpose Mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma are rare autosomal recessive lysosomal storage disorders. Data on the natural course of the diseases are scarce. These data are important for counseling, therapies development, and improvement of outcome. The aim of this study is to gain knowledge on the natural history of ML by obtaining data on survival, symptom onset, presenting symptoms, diagnosis, and pathogenic variants associated with the MLII or MLIII phenotype. Methods A systematic review on all published MLII and MLIII cases between 1968 and August 2019 was performed. Results Three hundred one articles provided data on 843 patients. Median age at diagnosis: 0.7 for MLII and 9.0 years for MLIII. Median survival: 5.0 for MLII and 62.0 years for MLIIIII. Median age of death: 1.8 for MLII and 33.0 years for MLIII. Most frequent causes of death in all ML were pulmonary and/or cardiac complications. Pathogenic variants were described in 388 patients (GNPTAB: 571, GNPTG 179). Conclusion This review provides unique insights into the natural history of MLII and MLIII, with a clear genotype–phenotype correlation with the most frequent pathogenic variant c.3503_3504del in MLII and in MLIII alpha/beta c.22A>G for GNPTAB. All pathogenic GNPTG variants resulted in MLIII gamma.

Background: Asthma exacerbations are frequently induced by respiratory tract infections (RTIs). Bacterial lysates have been described to possess immune-modulatory effects and reduce RTIs as well as asthma symptoms in children. However, whether bacterial lysates have similar effects in adult asthma patients is unknown. Aims: To reduce asthma exacerbations by add-on bacterial lysate therapy in adults with severe asthma and to characterize the clinical and immune-modulatory effects of this treatment. Methods: Asthma patients (GINA 4) with ≥2 annual exacerbations in the previous year were included. The intervention regimen consisted of OM-85/placebo for 10 consecutive days per month for 6 months during two winter seasons. Primary end-point was the number of severe asthma exacerbations within 18 months. The study was approved by the national and local ethical review board and registered in the Dutch Trial Registry (NL5752). All participants provided written informed consent. Results: Seventy-five participants were included (38 OM-85; 37 placebo). Exacerbation frequencies were not different between the groups after 18 months (incidence rate ratio 1.07, 95%CI [0.68–1.69], p = 0.77). With the use of OM-85, FEV1% increased by 3.81% (p = 0.04) compared with placebo. Nasopharyngeal swabs taken during RTIs detected a virus less frequently in patients using OM-85 compared to placebo (30.5% vs. 48.0%, p = 0.02). In subjects with type 2 inflammation adherent to the protocol (22 OM-85; 20 placebo), a non-statistically significant decrease in exacerbations in the OM-85 group was observed (IRR = 0.71, 95%CI [0.39–1.26], p = 0.25). Immune-modulatory effects included an increase in several plasma cytokines in the OM-85 group, especially IL-10 and interferons. Peripheral blood T- and B cell subtyping, including regulatory T cells, did not show differences between the groups. Conclusion: Although OM-85 may have immune-modulatory effects, it did not reduce asthma exacerbations in this heterogeneous severe adult asthma group. Post hoc analysis showed a potential clinical benefit in patients with type 2 inflammation.

Background and objective: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inborn errors of metabolism. While survival of MMA and PA patients has improved in recent decades, long-term outcome is still unsatisfactory. A protein restricted diet is the mainstay for treatment. Additional amino acid mixtures (AAM) can be prescribed if natural protein is insufficient. It is unknown if dietary treatment can have an impact on outcome. Design: We performed a nationwide retrospective cohort study and evaluated both longitudinal dietary treatment and clinical course of Dutch MMA and PA patients. Protein prescription was compared to the recommended daily allowances (RDA); the safe level of protein intake as provided by the World Health Organization. The association of longitudinal dietary treatment with long-term outcome was evaluated. Results: The cohort included 76 patients with a median retrospective follow-up period of 15 years (min -max: 0-48 years) and a total of 1063 patient years on a protein restricted diet. Natural protein prescription exceeded the RDA in 37% (470/1287) of all prescriptions and due to AAM prescription, the total protein prescription exceeded RDA in 84% (1070/1277). Higher protein prescriptions were associated with adverse outcomes in severely affected patients. In PA early onset patients a higher natural protein prescription was associated with more frequent AMD. In MMA vitamin B12 unresponsive patients, both a higher total protein prescription and AAM protein prescription were associated with more mitochondrial complications. A higher AAM protein prescription was associated with an increased frequency of cognitive impairment in the entire. Conclusion: Protein intake in excess of recommendations is frequent and is associated with poor outcome. 0 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Objective: To advance the prediction of the neurocognitive development in MPS II patients by jointly analyzing MRI and neurocognitive data in mucopolysaccharidosis (MPS) II patients. Methods: Cognitive ability scores (CAS) were obtained by neuropsychological testing. Cerebral MRIs were quantified using a disease-specific protocol. MRI sumscores were calculated for atrophy, white-matter abnormalities (WMA) and Virchow-Robin spaces (VRS). To distinguish between atrophy and hydrocephalus the Evans' index and the callosal angle (CA) were measured. A random effects repeated measurement model was used to correlate CAS with the three MRI sumscores. Results: MRI (n = 47) and CAS scores (n = 78) of 19 male patients were analyzed. Ten patients were classified as neuronopathic and nine as non-neuronopathic. Neuronopathic patients had normal cognitive development until age 3 years. Mental age plateaued between ages 3 and 6, and subsequently declined with loss of skills at a maximum developmental age of 4 years. MRIs of neuronopathic patients showed abnormal atrophy sumscores before CAS dropped below the threshold for intellectual disability (

Introduction: Thyroid cancer is one of the most common carcinomas diagnosed in adolescents and young adults, with a rapidly rising incidence for the past three decades. Surgery is the standard trea...

Background There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. Objectives The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. Methods Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (

Pompe disease is a rare inherited metabolic and neuromuscular disorder, presenting as a spectrum, with the classic infantile form on one end and the more slowly progressive non-classic form on the other end. While being a hallmark in classic infantile Pompe disease, cardiac involvement in non-classic Pompe disease seems rare. Vascular abnormalities, such as aneurysms and arterial dolichoectasia, likely caused by glycogen accumulation in arterial walls, have been reported in non-classic Pompe patients. With this first systematic review on cardiovascular disease in non-classic Pompe disease, we aim to gain insight in the prevalence and etiology of cardiovascular disease in these patients. Forty-eight studies (eight case-control studies, 15 cohort studies and 25 case reports/series) were included. Fourteen studies reported cardiac findings, 25 studies described vascular findings, and nine studies reported both cardiac and vascular findings. Severe cardiac involvement in non-classic Pompe disease patients has rarely been reported, particularly in adult-onset patients carrying the common IVS1 mutation. There are indications that intracranial dolichoectasia and aneurysms are more prevalent in non-classic Pompe patients compared to the general population. To further investigate the prevalence of cardiovascular disease in non-classic Pompe patients, larger case-control studies that also study established cardiovascular risk factors should be conducted.

BackgroundIn Pompe disease, an inherited metabolic muscle disorder, severe diaphragmatic weakness often occurs. Enzyme replacement treatment is relatively ineffective for respiratory function, possibly because of irreversible damage to the diaphragm early in the disease course. Mildly impaired diaphragmatic function may not be recognized by spirometry, which is commonly used to study respiratory function. In this cross-sectional study, we aimed to identify early signs of diaphragmatic weakness in Pompe patients using chest MRI.MethodsPompe patients covering the spectrum of disease severity, and sex and age matched healthy controls were prospectively included and studied using spirometry-controlled sagittal MR images of both mid-hemidiaphragms during forced inspiration. The motions of the diaphragm and thoracic wall were evaluated by measuring thoracic cranial-caudal and anterior–posterior distance ratios between inspiration and expiration. The diaphragm shape was evaluated by measuring the height of the diaphragm curvature. We used multiple linear regression analysis to compare different groups.ResultsWe included 22 Pompe patients with decreased spirometry results (forced vital capacity in supine position p p = 0.001), indicating an increased curvature of the diaphragm during inspiration in Pompe patients.ConclusionsEven in early-stage Pompe disease, when spirometry results are still within normal range, the motion of the diaphragm is already reduced and the shape is more curved during inspiration. MRI can be used to detect early signs of diaphragmatic weakness in patients with Pompe disease, which might help to select patients for early intervention to prevent possible irreversible damage to the diaphragm.

Objective: Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency at birth due to disorders of the thyroid gland (thyroidal CH, CH-T), or the hypothalamus or pituitary (central CH, CH-C). The Dutch Newborn Screening (NBS) strategy is primarily based on determination of thyroxine (T4) concentrations in dried blood spots followed, if necessary, by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurement enabling detection of both CH-T and CH-C. A calculated T4/TBG ratio serves as an indirect measure for free T4. A T4/TBG ratio ≤ 17 in a second heel puncture is suggestive of CH-C. Design and methods: In the present study, we evaluated 11 years of Dutch CH NBS using a database of referred cases by assessing the contribution of each criterion in the unique stepwise T4-TSH-TBG NBS algorithm. Results: Between 2007 and the end of 2017, 1 963 465 newborns were screened in the Netherlands. Use of the stepwise algorithm led to 3044 referrals and the identification of 612 CH cases, consisting of 496 CH-T, 86 CH-C, and 30 CH of unknown origin diagnoses. We detected 62.8% of CH-C cases by the T4/TBG ratio in the second heel puncture. The positive predictive value (PPV) of the stepwise T4-TSH-TBG NBS algorithm was 21.0%. Conclusion: This evaluation shows that the Dutch stepwise T4-TSH-TBG NBS algorithm with a calculated T4/TBG ratio is of great value for the detection of both CH-T and CH-C in the Netherlands, at the cost of a lower PPV compared to TSH-based NBS strategies.

Objective: To assess the cost-effectiveness and return-on-investment (ROI) of the Dynamic Work (DW) Intervention, a worksite intervention aimed at reducing sitting time among office workers.Methods: In total, 244 workers were randomized to the intervention or control group. Overall sitting time, standing time, step counts, quality-adjusted life years (QALYs), and costs were measured over 12 months. The cost-effectiveness analysis was performed from the societal perspective and the ROI analysis from the employers’ perspective.Results: No significant differences in effects and societal costs were observed between groups. Presenteeism costs were significantly lower in the intervention group. The probability of the intervention being cost-effective was 0.90 at a willingness-to-pay of 20,000€/QALY. The probability of financial savings was 0.86.Conclusion: The intervention may be considered cost-effective from the societal perspective depending on the willingness-to-pay. From the employer perspective, the intervention seems cost-beneficial.

Evidence for effectiveness of newborn screening (NBS) for propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is scarce. Prior to implementation in the Netherlands, we aim to estimate the expected health gain of NBS for PA and MMA. In this national retrospective cohort study, the clinical course of 76/83 Dutch PA and MMA patients, diagnosed between January 1979 and July 2019, was evaluated. Five clinical outcome parameters were defined: adverse outcome of the first symptomatic phase, frequency of acute metabolic decompensations (AMD), cognitive function, mitochondrial complications, and treatment‐related complications. Outcomes of patients identified by family testing were compared with the outcomes of their index siblings. An adverse outcome due to the first symptomatic phase was recorded in 46% of the clinically diagnosed patients. Outcome of the first symptomatic phase was similar in 5/9 sibling pairs and better in 4/9 pairs. Based on the day of diagnosis of the clinically diagnosed patients and sibling pair analysis, a preliminary estimated reduction of adverse outcome due to the first symptomatic phase from 46% to 36%‐38% was calculated. Among the sibling pairs, AMD frequency, cognitive function, mitochondrial, and treatment‐related complications were comparable. These results suggest that the health gain of NBS for PA and MMA in overall outcome may be limited, as only a modest decrease of adverse outcomes due to the first symptomatic phase is expected. With current clinical practice, no reduced AMD frequency, improved cognitive function, or reduced frequency of mitochondrial or treatment‐related complications can be expected.

The aim of this cross-sectional study was to develop a Frailty at Risk Scale (FARS) incorporating ten well-known determinants of frailty: age, sex, marital status, ethnicity, education, income, lifestyle, multimorbidity, life events, and home living environment. In addition, a second aim was to develop an online calculator that can easily support healthcare professionals in determining the risk of frailty among community-dwelling older people. The FARS was developed using data of 373 people aged >= 75 years. The Tilburg Frailty Indicator (TFI) was used for assessing frailty. Multivariate logistic regression analysis showed that the determinants multimorbidity, unhealthy lifestyle, and ethnicity (ethnic minority) were the most important predictors. The area under the curve (AUC) of the model was 0.811 (optimism 0.019, 95% bootstrap CI = -0.029; 0.064). The FARS is offered on a Web site, so that it can be easily used by healthcare professionals, allowing quick intervention in promoting quality of life among community-dwelling older people.

Several initiatives at establishing a classification of inherited metabolic disorders have been published previously, some focusing on pathomechanisms, others on clinical manifestations, while yet another attempted a simplified approach of a comprehensive nosology. Some of these classifications suffered from shortcomings, such as lack of a mechanism for continuous update in light of a rapidly evolving field, or lack of widespread input from the metabolic community at large. Our classification-the International Classification of Inherited Metabolic Disorders, or International Classification of Inborn Metabolic Disorders (ICIMD)-includes 1450 disorders, and differs from prior approaches in that it benefited from input by a large number of experts in the field, and was endorsed by major metabolic societies around the globe. Several criteria such as pathway involvement and pathomechanisms were considered. The main purpose of the hierarchical, group-based approach of the ICIMD is an improved understanding of the interconnections between many individual conditions that may share functional, clinical, and diagnostic features. The ICIMD aims to include any primary genetic condition in which alteration of a biochemical pathway is intrinsic to specific biochemical, clinical, and/or pathophysiological features. As new disorders are discovered, we will seek the opinion of experts in the advisory board prior to inclusion in the appropriate group of the ICIMD, thus guaranteeing the continuing relevance of this classification via regular curation and expert advice.

Funder: PAL Technologies, Funder: Public Health Agency of Canada; doi: http://dx.doi.org/10.13039/100011094, Funder: Government of Norway, Background: In 2018, the World Health Organisation (WHO) commenced a program of work to update the 2010 Global Recommendations on Physical Activity for Health, for the first-time providing population-based guidelines on sedentary behaviour. This paper briefly summarizes and highlights the scientific evidence behind the new sedentary behaviour guidelines for all adults and discusses its strengths and limitations, including evidence gaps/research needs and potential implications for public health practice. Methods: An overview of the scope and methods used to update the evidence is provided, along with quality assessment and grading methods for the eligible new systematic reviews. The literature search update was conducted for WHO by an external team and reviewers used the AMSTAR 2 (Assessment of Multiple Systematic Reviews) tool for critical appraisal of the systematic reviews under consideration for inclusion. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) method was used to rate the certainty (i.e. very low to high) of the evidence. Results: The updated systematic review identified 22 new reviews published from 2017 up to August 2019, 14 of which were incorporated into the final evidence profiles. Overall, there was moderate certainty evidence that higher amounts of sedentary behaviour increase the risk for all-cause, cardiovascular disease (CVD) and cancer mortality, as well as incidence of CVD, cancer, and type 2 diabetes. However, evidence was deemed insufficient at present to set quantified (time-based) recommendations for sedentary time. Moderate certainty evidence also showed that associations between sedentary behaviour and all-cause, CVD and cancer mortality vary by level of moderate-to-vigorous physical activity (MVPA), which underpinned additional guidance around MVPA in the context of high sedentary time. Finally, there was insufficient or low-certainty systematic review evidence on the type or domain of sedentary behaviour, or the frequency and/or duration of bouts or breaks in sedentary behaviour, to make specific recommendations for the health outcomes examined. Conclusions: The WHO 2020 guidelines are based on the latest evidence on sedentary behaviour and health, along with interactions between sedentary behaviour and MVPA, and support implementing public health programmes and policies aimed at increasing MVPA and limiting sedentary behaviour. Important evidence gaps and research opportunities are identified.

This study sought to provide insight into how art activities influence the well-being of long-term care residents, and how artists and caregivers collaborate in offering these activities. In two long-term care facilities for people with dementia and one for older people with chronic psychiatric disorders, an uncontrolled pre- and post-test study was conducted using a mixed-method design. Forty-six residents participated in the study. Three art activities—(a) dance, (b) music and movement, and (c) visual arts—were studied and co-created with the residents and executed by artists and caregivers together in eight to ten weeks. The Face expression scale (FACE) was used to examine the extent to which participating in the art activity influenced resident mood. Qualitative data were collected via group discussions with artists, caregivers, residents, and an informal caregiver. The results indicated that participating in an art activity positively influenced resident mood (p &lt, 0.000). p-values for the three art activities were: p &lt, 0.000 for dance, p = 0.048 for music and movement, and p = 0.023 for visual arts. The qualitative data revealed that joining an art activity provided a positive effect, increased social relationships, and improved self-esteem for residents. The collaboration between artists and caregivers stimulated creativity, beauty, and learning from each other, as well as evoking emotions.

Background translation of the available evidence concerning primary cardiovascular prevention into clinical guidance for the heterogeneous population of older adults is challenging. With this review, we aimed to give an overview of the thresholds and targets of antihypertensive drug therapy for older adults in currently used guidelines on primary cardiovascular prevention. Secondly, we evaluated the relationship between the advised targets and guideline characteristics, including guideline quality. Methods we systematically searched PubMed, Embase, Emcare and five guideline databases. We selected guidelines with (i) numerical thresholds for the initiation or target values of antihypertensive drug therapy in context of primary prevention (January 2008–July 2020) and (ii) specific advice concerning antihypertensive drug therapy in older adults. We extracted the recommendations and appraised the quality of included guidelines with the AGREE II instrument. Results thirty-four guidelines provided recommendations concerning antihypertensive drug therapy in older adults. Twenty advised a higher target of systolic blood pressure (SBP) for octogenarians in comparison with the general population and three advised a lower target. Over half of the guidelines (n = 18) recommended to target a SBP Conclusion the ongoing debate concerning targets of antihypertensive treatment in older adults, is reflected in an inconsistency of recommendations across guidelines. Recommended targets are largely set on chronological rather than biological age.

High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, has a high mortality rate. Although there are some factors associated with survival, such as stage of disease, there are remarkable differences in survival among women diagnosed with advanced stage disease. In this study, we investigate possible relations between survival and signal transduction pathway (STP) activity. We assessed the functional activity of the androgen receptor (AR), estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathway in 85 primary tumor samples of patients with FIGO stage IIIC to IVB HGSC and disease-free survival (DFS) below 12 (n = 52) or over 24 months (n = 33). There were no significant differences in median pathway activity between patients with a short and long DFS. In univariate Cox proportional hazards analysis, ER pathway activity was related to a favorable DFS and overall survival (OS) in postmenopausal women (p = 0.033 and p = 0.041, respectively), but not in premenopausal women. We divided the postmenopausal group into subgroups based on ER pathway activity quartiles. Survival analysis revealed that postmenopausal women in the lowest ER quartile had a shorter DFS and OS (log-rank p = 0.006 and p &lt, 0.001, respectively). Furthermore, we were able to form subgroups of patients based on an inverse relation between ER and PI3K pathway activity. In conclusion, in postmenopausal patients with advanced stage HGSC, a poorer survival outcome was associated with low functional ER pathway activity.

Purpose A prostate-specific membrane antigen (PSMA) thyroid incidentaloma (PTI) is an unexpected, PSMA-avid thyroid lesion, newly detected during the investigation of an unrelated condition using PSMA PET/CT. The aim of this study is to examine the incidence and clinical significance of PTI and the associated management strategies since the implementation of the PSMA PET/CT scan. Methods This study involves a retrospective cohort study of 61 PTI cases depicted on PSMA PET/CT scans performed between January 2016 and July 2021, almost exclusively for (re)staging prostate cancer. The medical records of the included cases were retrospectively reviewed and data of the PSMA PET/CT scans, primary malignancy, thyroid diagnostics, treatment and follow-up were collected. Results PTI was reported in 1.1% of the oncologic PSMA PET/CT scans included in this study. Two PTI cases had a histologically proven thyroid cancer, one a benign thyroid lesion and one a metastasis of a renal cell carcinoma. In none of the cases in whom any form of further thyroid work-up was withheld, the PTI became clinically relevant during follow-up (median 1.8 years (1.1-3.3)). Six patients (10%) died due to their primary cancer.Conclusion The incidence of thyroid incidentalomas on PSMA PET/CT was low (1.1%) in this large, two-center experience. Less than half of the PTI cases were analyzed and the risk of malignancy, despite being low, was not negligible. The clinical outcome was good using a standard diagnostic work-up for PTI, while the prognosis of the patient was determined by the primary malignancy. The consideration to analyze and treat PTI cases should be part of the shared decision making in cancer patients.

Objective To examine respiratory muscle function among late-onset Pompe disease (LOPD) patients in the Pompe Registry (NCT00231400/Sanofi Genzyme) during enzyme replacement therapy (ERT) with alglucosidase alfa by assessing the longitudinal course of forced vital capacity (FVC), prognostic factors for FVC, and impact of time from diagnosis to ERT initiation. Methods Longitudinal FVC data from LOPD (symptom onset > 12 months or ≤ 12 months without cardiomyopathy) patients were analyzed. Patients had to have baseline FVC (percent predicted upright) assessments at ERT start and ≥ 2 valid post-baseline assessments. Longitudinal analyses used linear mixed-regression models. Results Among 396 eligible patients, median baseline FVC was 66.9% (range 9.3–126.0). FVC remained stable during the 5-year follow-up (slope = − 0.17%, p = 0.21). Baseline FVC was lower among various subgroups, including patients who were male; older at ERT initiation; had a longer duration from symptom onset to ERT initiation; and had more advanced disease at baseline (based on respiratory support use, inability to ambulate, ambulation device use). Age at symptom onset was not associated with baseline degree of respiratory dysfunction. Differences between subgroups observed at baseline remained during follow-up. Shorter time from diagnosis to ERT initiation was associated with higher FVC after 5 years in all patients and the above subgroups using a cut-off of 1.7 years. Conclusion FVC stability over 5 years suggests that respiratory function is preserved during long-term ERT in real-world settings. Early initiation of alglucosidase alfa was associated with preservation of FVC in LOPD patients with better respiratory function at the time of treatment initiation.

BACKGROUND & AIMS: Peppermint oil is frequently used to treat irritable bowel syndrome (IBS), despite a lack of evidence for efficacy from high-quality controlled trials. We studied the efficacy and safety of small-intestinal-release peppermint oil in patients with IBS and explored the effects of targeted ileocolonic-release peppermint oil. METHODS: We performed a double-blind trial of 190 patients with IBS (according to Rome IV criteria) at 4 hospitals in The Netherlands from August 2016 through March 2018; 189 patients were included in the intent-to-treat analysis (mean age, 34.0 years; 77.8% female; 57.7% in primary care), and 178 completed the study. Patients were randomly assigned to groups given 182 mg small-intestinal-release peppermint oil, 182 mg ileocolonic-release peppermint oil, or placebo for 8 weeks. The primary endpoint was abdominal pain response, as defined by the US Food and Drug Administration: at least a 30% decrease in the weekly average of worst daily abdominal pain compared with baseline in at least 4 weeks. The co-primary endpoint was overall relief of IBS symptoms, as defined by the European Medicines Agency. Secondary endpoints included abdominal pain, discomfort, symptom severity, and adverse events. RESULTS: Abdominal pain response did not differ significantly between the peppermint oil and placebo groups: 29 of 62 patients in the small-intestinal-release peppermint oil group had a response (46.8%, P = .170 vs placebo), 26 of 63 patients in the ileocolonic-release peppermint oil group had a response (41.3%, P = .385 vs placebo), and 22 of 64 patients in the placebo group had a response (34.4%). We did not find differences among the groups in overall relief (9.7%, P = .317 and 1.6%, P = .351 vs 4.7% for placebo). The small intestinal peppermint oil did, however, produce greater improvements than placebo in secondary outcomes of abdominal pain (P = .016), discomfort (P = .020), and IBS severity (P = .020). Adverse events, although mild, were more common in both peppermint oil groups (P < .005). CONCLUSIONS: In a randomized trial of patients with IBS, we found that neither small-intestinal-release nor ileocolonic-release peppermint oil (8 weeks) produced statistically significant reductions in abdominal pain response or overall symptom relief, when using US Food and Drug Administration/European Medicines Agency recommended endpoints. The small-intestinal-release peppermint oil did, however, significantly reduce abdominal pain, discomfort, and IBS severity. These findings do not support further development of ileocolonic-release peppermint oil for treatment of IBS. Clinicaltrials.gov, Number: NCT02716285. ispartof: GASTROENTEROLOGY vol:158 issue:1 pages:123-136 ispartof: location:United States status: published

Enzyme replacement therapy for Pompe disease received market authorization in 2006. To implement this costly treatment in the Netherlands in the most sensible way, a multidisciplinary expert committee was installed. We evaluated decision making in adult patients in relation to the European POmpe Consortium stop criteria. Of 125 adult Pompe patients, 111 started treatment; subsequently treatment stopped in 24 patients (21%). In 10 patients, treatment was discontinued for medical or personal reasons, as defined in the six stop criteria (median treatment duration: 2.1 years, range: 0.3-14.6 years). Three of these patients continued follow-up (follow-up: 1.3-8.0 years), these patients did not display a more rapid decline after discontinuation. In 14 of 24 patients, therapy ended at time of death. In 10 patients death was related to Pompe disease (median treatment duration: 7.2 years, range: 0.4-10.3 years). All 10 patients were severely affected at start of treatment, treatment had elicited positive effects in eight. The European POmpe Consortium guidelines worked well in decision making on stopping treatment. However, (re)evaluation of the rationale for continuation of treatment in advanced disease stage is not addressed. We suggest to add this to the treatment evaluation and to handle treatment decisions in a multidisciplinary expert team. (C) 2019 The Author(s). Published by Elsevier B.V.

Background The dietary management of methylmalonic acidaemia (MMA) is a low-protein diet providing sufficient energy to avoid catabolism and to limit production of methylmalonic acid. The goal is to achieve normal growth, good nutritional status and the maintenance of metabolic stability. Aim To describe the dietary management of patients with MMA across Europe. Methods A cross-sectional questionnaire was sent to European colleagues managing inherited metabolic disorders (IMDs) (n=53) with 27 questions about the nutritional management of organic acidaemias. Data were analysed by different age ranges (0–6 months; 7–12 months; 1–10 years; 11–16 years; >16 years). Results Questionnaires were returned from 53 centres. Twenty-five centres cared for 80 patients with MMA vitamin B12 responsive (MMAB12r) and 43 centres managed 215 patients with MMA vitamin B12 non-responsive (MMAB12nr). For MMAB12r patients, 44% of centres (n=11/25) prescribed natural protein below the World Health Organization/Food and Agriculture Organization/United Nations University (WHO/FAO/UNU) 2007 safe levels of protein intake in at least one age range. Precursor-free amino acids (PFAA) were prescribed by 40% of centres (10/25) caring for 36% (29/80) of all the patients. For MMAB12nr patients, 72% of centres (n=31/43) prescribed natural protein below the safe levels of protein intake (WHO/FAO/UNU 2007) in at least one age range. PFAA were prescribed by 77% of centres (n=33/43) managing 81% (n=174/215) of patients. In MMAB12nr patients, 90 (42%) required tube feeding: 25 via a nasogastric tube and 65 via a gastrostomy. Conclusions A high percentage of centres used PFAA in MMA patients together with a protein prescription that provided less than the safe levels of natural protein intake. However, there was inconsistent practices across Europe. Long-term efficacy studies are needed to study patient outcome when using PFAA with different severities of natural protein restrictions in patients with MMA to guide future practice.

Objectives:One-on-one structured Montessori-based activities conducted with people with dementia can improve agitation and enhance engagement. These activities may however not always be implemented by nursing home staff. Family members may present an untapped resource for enabling these activities. This study aimed to evaluate the impact of the Montessori activities implemented by family members on visitation experiences with people who have dementia.Design:Cluster-randomized crossover design.Setting:General and psychogeriatric nursing homes in the state of Victoria, Australia.Participants:Forty participants (20 residents and 20 carers) were recruited.Intervention:During visits, family members interacted with their relative either through engaging in Montessori-based activities or reading a newspaper (the control condition) for four 30-minute sessions over 2 weeks.Measurements:Residents’ predominant affect and engagement were rated for each 30-second interval using the Philadelphia Geriatric Center Affect Rating Scale and the Menorah Park Engagement Scale. The Pearlin Mastery Scale was used to rate carers satisfaction with visits. The 15-item Mutuality Scale measured the carers quality of their relationship with the resident. Carers’ mood and overall quality of life were measured using the Center for Epidemiological Studies Depression Scale and Carer-QoL questionnaires, respectively.Results:Linear regressions within the generalized estimating equations approach assessed residents’ and carers’ outcomes. Relative to the control condition, the Montessori condition resulted in more positive engagement (b = 13.0, 95%CI 6.3–19.7, p < 0.001) and affect (b = 0.4, 95%CI 0.2–0.6, p < 0.001) for the residents and higher satisfaction with visits for carers (b = 1.7, 95%CI 0.45–3.00, p = 0.008). No correction was applied to p-values for multiple comparisons.Conclusion:This study strengthens the evidence base for the use of the Montessori programs in increasing well-being in nursing home residents. The findings also provide evidence that family members are an additional valuable resource in implementing structured activities such as the Montessori program with residents.

OBJECTIVES Lymphoscintigraphy is considered a useful tool to optimize sentinel lymph node (SLN) identification. Nonvisualization of the SLN is associated with a lower SLN identification rate. The aim of this study was to identify preoperative factors associated with SLN nonvisualization on lymphoscintigraphy. PATIENTS AND METHODS A total of 2050 consecutive SLN procedures were evaluated from clinically node-negative breast cancer patients. Planar lymphoscintigraphy was performed at 3 h after an intratumoral injection of technetium-99m-nanocolloid. This technique was used for extra-axillary SLN identification. Patient, tumor, and treatment characteristics were analyzed for association with SLN nonvisualization. Factors with a P-value less than 0.1 in univariate analysis were included in a multivariate logistic regression model. RESULTS The SLN visualization rate was 86.7%. In multivariate logistic regression, age of at least 70 years [odds ratio (OR): 3.24; 95% confidence interval (CI): 2.14-4.91)], BMI of at least 30 (OR: 1.93; 95% CI: 1.39-2.69), T3/T4-tumors (OR: 2.70; 95% CI: 1.37-5.32), medially/centrally located tumors (OR: 1.52; 95% CI: 1.17-1.99), previous mantle field radiation (OR: 4.04; 95% CI: 1.74-9.35), nonpalpable tumors (OR: 1.88; 95% CI: 1.36-2.60), and presence of iodine seeds (OR: 1.35; 95% CI: 1.02-1.78) were associated significantly with nonvisualization on lymphoscintigraphy. Nonvisualization was the strongest independent predictor of unsuccessful intraoperative SLN identification (P

Background: There is limited information about the agreement and reliability of clinical shoulder tests. Objectives: To assess the interrater agreement and reliability of clinical shoulder tests in patients with shoulder pain treated in primary care. Methods: Patients with a primary report of shoulder pain underwent a set of 21 clinical shoulder tests twice on the same day, by pairs of independent physical therapists. The outcome parameters were observed and specific interrater agreement for positive and negative scores, and interrater reliability (Cohen’s kappa (κ)). Positive and negative interrater agreement values of ≥0.75 were regarded as sufficient for clinical use. For Cohen’s κ, the following classification was used

Chronic lung allograft dysfunction (CLAD) is the major long-term cause of morbidity and mortality after lung transplantation. Both bronchiolitis obliterans syndrome and restrictive lung allograft syndrome, two main types of CLAD, lead to fibrosis in either the small airways or alveoli and pleura. Pathological pathways in CLAD and other types of fibrosis, for example idiopathic pulmonary fibrosis, are assumed to overlap and therefore fibrosis biomarkers could aid in the early detection of CLAD. These biomarkers could help to differentiate between different phenotypes of CLAD and could, in comparison to biomarkers of inflammation, possibly distinguish an infectious event from CLAD when a decline in lung function is present. This review gives an overview of known CLAD specific biomarkers, describes new promising fibrosis biomarkers currently investigated in other types of fibrosis, and discusses the possible use of these fibrosis biomarkers for CLAD.

Introduction: Newborn screening (NBS) for congenital hypothyroidism (CH) in the Netherlands consists of thyroxine (T4), thyroid-stimulating hormone (TSH), and T4-binding globulin (TBG) measurements to detect thyroidal CH and central CH (CH-C). CH-C is detected by T4 or a calculated T4/TBG ratio, which serves as an indirect measure of free T4. TSH and TBG are only measured in the lowest 20 and 5% of daily T4 values, respectively. A recent evaluation of the Dutch NBS for CH showed that the T4 and T4/TBG ratio contribute to the detection of CH-C but also lead to a low positive predictive value (PPV). Dried blood spot (DBS) reference intervals (RIs) are currently unknown and may contribute to improvement of our NBS algorithm. Materials and Methods: RIs of T4, TSH, TBG, and the T4/TBG ratio were determined according to Clinical & Laboratory Standards Institute guidelines in heel puncture cards from routine NBS in both sexes and at the common NBS sampling ages. Scatter plots were used to compare the healthy reference population to previously published data of CH-C patients and false positives. Results: Analyses of 1,670 heel puncture cards showed small differences between subgroups and led to the formulation of total sample DBS RIs for T4 (56–118 nmol/L), TSH (20). 46% of false-positive referrals based on T4 alone had a TBG below the RI, indicating preventable referral due to partial TBG deficiency. One case of CH-C also had partial TBG deficiency (TBG 59 and T4 12 nmol/L blood). Discussion/Conclusion: Established DBS RIs provided possibilities to improve the PPV of the Dutch CH NBS algorithm. We conclude that by taking partial TBG deficiency into account, approximately half of T4 false-positive referrals may be prevented while maintaining NBS sensitivity at the current level.

Summary Background Treatment with one standard dose (2 g/kg) of intravenous immunoglobulin is insufficient in a proportion of patients with severe Guillain-Barre syndrome. Worldwide, around 25% of patients severely affected with the syndrome are given a second intravenous immunoglobulin dose (SID), although it has not been proven effective. We aimed to investigate whether a SID is effective in patients with Guillain-Barre syndrome with a predicted poor outcome. Methods In this randomised, double-blind, placebo-controlled trial (SID-GBS), we included patients (≥12 years) with Guillain-Barre syndrome admitted to one of 59 participating hospitals in the Netherlands. Patients were included on the first day of standard intravenous immunoglobulin treatment (2 g/kg over 5 days). Only patients with a poor prognosis (score of ≥6) according to the modified Erasmus Guillain-Barre syndrome Outcome Score were randomly assigned, via block randomisation stratified by centre, to SID (2 g/kg over 5 days) or to placebo, 7–9 days after inclusion. Patients, outcome adjudicators, monitors, and the steering committee were masked to treatment allocation. The primary outcome measure was the Guillain-Barre syndrome disability score 4 weeks after inclusion. All patients in whom allocated trial medication was started were included in the modified intention-to-treat analysis. This study is registered with the Netherlands Trial Register, NTR 2224/NL2107. Findings Between Feb 16, 2010, and June 5, 2018, 327 of 339 patients assessed for eligibility were included. 112 had a poor prognosis. Of those, 93 patients with a poor prognosis were included in the modified intention-to-treat analysis: 49 (53%) received SID and 44 (47%) received placebo. The adjusted common odds ratio for improvement on the Guillain-Barre syndrome disability score at 4 weeks was 1·4 (95% CI 0·6–3·3; p=0·45). Patients given SID had more serious adverse events (35% vs 16% in the first 30 days), including thromboembolic events, than those in the placebo group. Four patients died in the intervention group (13–24 weeks after randomisation). Interpretation Our study does not provide evidence that patients with Guillain-Barre syndrome with a poor prognosis benefit from a second intravenous immunoglobulin course; moreover, it entails a risk of serious adverse events. Therefore, a second intravenous immunoglobulin course should not be considered for treatment of Guillain-Barre syndrome because of a poor prognosis. The results indicate the need for treatment trials with other immune modulators in patients severely affected by Guillain-Barre syndrome. Funding Prinses Beatrix Spierfonds and Sanquin Plasma Products.

Background Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare rapidly progressive neurodegenerative disorder, resulting in early death. Intracerebroventricular enzyme replacement therapy (ERT) with cerliponase alfa is now available and has shown to delay disease progression in symptomatic patients. It is yet unknown if cerliponase alfa can prevent disease onset in presymptomatic patients. Results We evaluated the effect of 2 years of intracerebroventricular ERT in two siblings with CLN2 disease, one symptomatic (age 47 months) and one presymptomatic (age 23 months) at treatment start, using the CLN2 Clinical Rating Scale (CLN2 CRS), Gross Motor Function Measure-66 (GMFM-66) for motor function, Bayley Scales of Infant and Toddler Development, 3rd Edition, Dutch (BSID-III-NL) for neurocognitive development, brain MRI, and visual evoked potentials (VEP), electroretinogram (ERG) and retinoscopy for visual function. On the CLN2 CRS patient 1 showed a decline from 3 to 2 in the combined motor and language score due to regression in language use (CLN2 CRS total score after 2 years of treatment: 8), whereas a decline of 2 or more points in the combined motor and language score would be expected without treatment. Patient 2 retained the maximum score of 3 in all 4 subdomains (CLN2 CRS total score after 2 years of treatment: 12). The GMFM-66 total score declined from 46 to 39 in patient 1 and showed an age-appropriate increase from 66 to 84 in patient 2. Cognitive-developmental age decreased from 24 to 11 months in patient 1, whereas an increase in cognitive-developmental age from 21 to 39 months was seen in patient 2. Cerebral and cerebellar atrophy observed on MRI in patient 1 at age 42 months (before treatment) was not observed in patient 2 at age 48 months (after 2 years of treatment). Conclusion We show that cerliponase alfa is able to delay the onset of symptoms when treatment is started in a presymptomatic stage of CLN2 disease. Our results advocate the start of treatment at an early age before symptom onset, but should be confirmed in a larger cohort study.

Pompe disease is a lysosomal and neuromuscular disorder caused by deficiency of acid alpha-glucosidase (GAA), and causes classic infantile, childhood onset, or adulthood onset phenotypes. The biochemical diagnosis is based on GAA activity assays in dried blood spots, leukocytes, or fibroblasts. Diagnosis can be complicated by the existence of pseudodeficiencies, i.e., GAA variants that lower GAA activity but do not cause Pompe disease. A large-scale comparison between these assays for patient samples, including exceptions and borderline cases, along with clinical diagnoses has not been reported so far. Here we analyzed GAA activity in a total of 1709 diagnostic cases over the past 28 years using a total of 2591 analyses and we confirmed the clinical diagnosis in 174 patients. We compared the following assays: leukocytes using glycogen or 4MUG as substrate, fibroblasts using 4MUG as substrate, and dried blood spots using 4MUG as substrate. In 794 individuals, two or more assays were performed. We found that phenotypes could only be distinguished using fibroblasts with 4MUG as substrate. Pseudodeficiencies caused by the GAA2 allele could be ruled out using 4MUG rather than glycogen as substrate in leukocytes or fibroblasts. The Asian pseudodeficiency could only be ruled out in fibroblasts using 4MUG as substrate. We conclude that fibroblasts using 4MUG as substrate provides the most reliable assay for biochemical diagnosis and can serve to validate results from leukocytes or dried blood spots.

Purpose To determine the predictive value of quality of life for mortality at the domain and item levels. Methods This longitudinal study was carried out in a sample of 479 Dutch people aged 75 years or older living independently, using a follow-up of 7 years. Participants completed a self-report questionnaire. Quality of life was assessed with the WHOQOL-BREF, including four domains: physical health, psychological, social relationships, and environment. The municipality of Roosendaal (a town in the Netherlands) indicated the dates of death of the individuals. Results Based on mean, all quality of life domains predicted mortality adjusted for gender, age, marital status, education, and income. The hazard ratios ranged from 0.811 (psychological) to 0.933 (social relationships). The areas under the curve (AUCs) of the four domains were 0.730 (physical health), 0.723 (psychological), 0.693 (social relationships), and 0.700 (environment). In all quality of life domains, at least one item predicted mortality (adjusted). Conclusion Our study showed that all four quality of life domains belonging to the WHOQOL-BREF predict mortality in a sample of Dutch community-dwelling older people using a follow-up period of 7 years. Two AUCs were above threshold (psychological, physical health). The findings offer health care and welfare professionals evidence for conducting interventions to reduce the risk of premature death.

Background General practitioners (GPs) should regularly review patients’ medications and, if necessary, deprescribe, as inappropriate polypharmacy may harm patients’ health. However, deprescribing can be challenging for physicians. This study investigates GPs’ deprescribing decisions in 31 countries. Methods In this case vignette study, GPs were invited to participate in an online survey containing three clinical cases of oldest-old multimorbid patients with potentially inappropriate polypharmacy. Patients differed in terms of dependency in activities of daily living (ADL) and were presented with and without history of cardiovascular disease (CVD). For each case, we asked GPs if they would deprescribe in their usual practice. We calculated proportions of GPs who reported they would deprescribe and performed a multilevel logistic regression to examine the association between history of CVD and level of dependency on GPs’ deprescribing decisions. Results Of 3,175 invited GPs, 54% responded (N = 1,706). The mean age was 50 years and 60% of respondents were female. Despite differences across GP characteristics, such as age (with older GPs being more likely to take deprescribing decisions), and across countries, overall more than 80% of GPs reported they would deprescribe the dosage of at least one medication in oldest-old patients (> 80 years) with polypharmacy irrespective of history of CVD. The odds of deprescribing was higher in patients with a higher level of dependency in ADL (OR =1.5, 95%CI 1.25 to 1.80) and absence of CVD (OR =3.04, 95%CI 2.58 to 3.57). Interpretation The majority of GPs in this study were willing to deprescribe one or more medications in oldest-old multimorbid patients with polypharmacy. Willingness was higher in patients with increased dependency in ADL and lower in patients with CVD.

Background: The World Health Organization has released the first global public health guidelines on physical activity and sedentary behavior for people living with disability. This paper presents the guidelines, related processes, and evidence, and elaborates upon how the guidelines can support inclusive policy, practice, and research. Methods: Methods were consistent with the World Health Organization protocols for developing guidelines. Systematic reviews of the evidence on physical activity for health for people living with disability were appraised, along with a consideration of the evidence used to inform the general 2020 World Health Organization guidelines. Results: Evidence supported the development of recommendations for people living with disability, stressing that there are no major risks to engaging in physical activity appropriate to an individual’s current activity level, health status, and physical function, and that the health benefits accrued generally outweigh the risks. They also emphasize the benefits of limiting sedentary behavior. Conclusions: The guidelines mark a positive step forward for disability inclusion, but considerable effort is needed to advance the agenda. This paper highlights key considerations for the implementation of the new recommendations for people living with disability, in line with the human rights agenda underpinning the Global Action Plan on Physical Activity 2018–2030 and allied policies.

Summary Background Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease. Methods We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged ≥3 years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non-inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1·1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to-treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov , NCT02782741 . We report results of the 49-week primary analysis period. Findings Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2·89% (SE 0·88) compared with 0·46% (0·93) with alglucosidase alfa at week 49 (difference 2·43% [95% CI −0·13 to 4·99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non-inferiority margin but did not exclude 0 (p=0·0074). Superiority was not reached (p=0·063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 30·01 m [95% CI 1·33 to 58·69]) and percent predicted (4·71% [0·25 to 9·17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres (≥12 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%]). Interpretation We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended-treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease. Funding Sanofi Genzyme.

Funder: Public Health Agency of Canada, Funder: Government of Norway, BACKGROUND: In July, 2019, the World Health Organization (WHO) commenced work to update the 2010 Global Recommendations on Physical Activity for Health and established a Guideline Development Group (GDG) comprising expert public health scientists and practitioners to inform the drafting of the 2020 Guidelines on Physical Activity and Sedentary Behavior. The overall task of the GDG was to review the scientific evidence and provide expert advice to the WHO on the amount of physical activity and sedentary behavior associated with optimal health in children and adolescents, adults, older adults (> 64 years), and also specifically in pregnant and postpartum women and people living with chronic conditions or disabilities. METHODS: The GDG reviewed the available evidence specific to each sub-population using systematic protocols and in doing so, identified a number of gaps in the existing literature. These proposed research gaps were discussed and verified by expert consensus among the entire GDG. RESULTS: Evidence gaps across population sub-groups included a lack of information on: 1) the precise shape of the dose-response curve between physical activity and/or sedentary behavior and several of the health outcomes studied; 2) the health benefits of light-intensity physical activity and of breaking up sedentary time with light-intensity activity; 3) differences in the health effects of different types and domains of physical activity (leisure-time; occupational; transportation; household; education) and of sedentary behavior (occupational; screen time; television viewing); and 4) the joint association between physical activity and sedentary time with health outcomes across the life course. In addition, we acknowledge the need to conduct more population-based studies in low- and middle-income countries and in people living with disabilities and/or chronic disease, and to identify how various sociodemographic factors (age, sex, race/ethnicity, socioeconomic status) modify the health effects of physical activity, in order to address global health disparities. CONCLUSIONS: Although the 2020 WHO Guidelines for Physical Activity and Sedentary Behavior were informed by the most up-to-date research on the health effects of physical activity and sedentary time, there is still substantial work to be done in advancing the global physical activity agenda.

In this editorial we discuss the new 2020 World Health Organization guidelines on physical activity and sedentary behaviour and a series of related papers that are published simultaneously in IJBNPA. The new guidelines reaffirm that physical activity is a ‘best buy’ for public health and should be used to support governments to increase investment in policy and research to promote and ensure physical activity opportunities are available for everyone. New recommendations on sedentary behaviour and inclusion of specific guidelines for people living with disability and/or chronic disease and pregnant and postpartum women are major developments since 2010. We discuss research priorities, as well as policy implementation and the contribution to the sustainable development agenda. The new guidelines can catalyse the paradigm shifts needed to enable equitable opportunities to be physically active for everyone, everywhere, every day.

Background Pompe disease is a rare, progressive metabolic myopathy. The aim of this study is to investigate the associations of physical outcomes with patient-reported outcome measures (PROMs) in late-onset Pompe disease. Methods We included 121 Dutch adult patients with Pompe disease. Physical outcomes comprised muscle strength (manual muscle testing using Medical Research Council [MRC] grading, hand-held dynamometry [HHD]), walking ability (6-min walk test [6MWT]), and pulmonary function (forced vital capacity [FVC] in upright and supine positions). PROMs comprised quality of life (Short Form 36 health survey [SF-36]), participation (Rotterdam Handicap Scale [RHS]) and daily-life activities (Rasch-Built Pompe-Specific Activity [R-PAct] Scale). Analyses were cross-sectional: the time-point before, and closest to, start of Enzyme Replacement Therapy was chosen. Associations between PROMs and physical outcomes were investigated using linear regression models. Results RHS and R-PAct scores were better in patients with higher FVC supine and upright, HHD, MRC and 6MWT scores, accounting for the effect of sex, disease duration, use of wheelchair and ventilator support. While the SF-36 Physical Component Summary (PCS) was correlated positively with FVC upright, HHD, MRC and 6MWT scores, there was no significant relationship between the SF-36 Mental Component Summary (MCS) and any of the physical outcomes. Conclusions Participation, daily-life activities, and the physical component of quality of life of adult Pompe patients are positively correlated to physical outcomes. This work serves as a first step towards assessing how changes over time in physical outcomes are related to changes in PROMs, and to define the minimal change in physical outcomes required to make an important difference for the patient.

Introduction In the Netherlands, Diagnostic Reference Levels (DRLs) have not been based on a national survey as proposed by ICRP. Instead, local exposure data, expert judgment and the international scientific literature were used as sources. This study investigated whether the current DRLs are reasonable for Dutch radiological practice. Methods A national project was set up, in which radiography students carried out dose measurements in hospitals supervised by medical physicists. The project ran from 2014 to 2017 and dose values were analysed for a trend over time. In the absence of such a trend, the joint yearly data sets were considered a single data set and were analysed together. In this way the national project mimicked a national survey. Results For six out of eleven radiological procedures enough data was collected for further analysis. In the first step of the analysis no trend was found over time for any of these procedures. In the second step the joint analysis lead to suggestions for five new DRL values that are far below the current ones. The new DRLs are based on the 75 percentile values of the distributions of all dose data per procedure. Conclusion The results show that the current DRLs are too high for five of the six procedures that have been analysed. For the other five procedures more data needs to be collected. Moreover, the mean weights of the patients are higher than expected. This introduces bias when these are not recorded and the mean weight is assumed to be 77 kg. Implications for practice The current checking of doses for compliance with the DRLs needs to be changed. Both the procedure (regarding weights) and the values of the DRLs should be updated.

Abstract. Stress-related stimuli may be presented outside of awareness and may ultimately influence health by causing repetitive increases in physiological parameters, such as blood pressure (BP). In this study, we aimed to corroborate previous studies that demonstrated BP effects of subliminally presented stress-related stimuli. This would add evidence to the hypothesis that unconscious manifestations of stress can affect somatic health. Additionally, we suggest that these findings may be extended by measuring affective changes relating to these physiological changes, using measures for self-reported and implicit positive and negative affectivity. Using a repeated measures between-subject design, we presented either the prime word “angry” ( n = 26) or “relax” ( n = 28) subliminally (17 ms) for 100 trials to a student sample and measured systolic and diastolic BP, heart rate (HR), and affect. The “angry” prime, compared to the “relax” prime, did not affect any of the outcome variables. During the priming task, a higher level of implicit negative affect (INA) was associated with a lower systolic BP and diastolic BP. No association was found with HR. Self-reported affect and implicit positive affect were not related to the cardiovascular (CV) activity. In sum, anger and relax primes elicited similar CV activity patterns, but implicit measures of affect may provide a new method to examine the relationship between (unconscious) stress and health.

Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%), and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine:L-leucine:L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine, and L-leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. In conclusion, while MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs-UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC-D, CPS1-D, and HHH syndrome, selective L-citrulline seemed preferable to selective L-arginine supplementation.

Введение. Болезнь Помпе – редкое наследственное мышечное заболевание, для лечения которого с 2006 г. применяют ферментную заместительную терапию. В документе представлены последние рекомендации по началу и прекращению ферментной заместительной терапии у взрослых пациентов. Методы. В ходе Европейского консорциума по болезни Помпе эксперты из 11 европейских стран обсудили данные литературы об эффективности ферментной заместительной терапии у взрослых пациентов на основании оценки показателей прогноза клинического течения и качества жизни больных. В данной статье представлены результаты обсуждений 3 согласительных совещаний во время консорциума. Результаты. Специалисты пришли к соглашению относительно подтверждения диагноза болезни Помпе, сроков начала ферментной заместительной терапии, показаний и условий ее прекращения и применения во время беременности. Общее соглашение по перечисленным вопросам принято на основании мнения экспертов и подтверждено данными литературы. При проведении исследований в группах были получены данные о положительном эффекте ферментной заместительной терапии. Анализ проводили при оценке 586 взрослых пациентов из 1 клинического испытания и 43 наблюдательных исследований. Обратили внимание на индивидуальные различия в эффективности лечения, обнаруженные в отдельных сообщениях. В 11 наблюдательных исследованиях, включающих пациентов с тяжелой степенью поражения, также была доказана эффективность ферментной заместительной терапии. Исследования эффектов лечения у больных на доклинической стадии заболевания отсутствуют. Выводы. В ходе 1-го Европейского консорциума на основании международного экспертного мнения составлены рекомендации по началу и прекращению ферментной заместительной терапии у взрослых пациентов с болезнью Помпе. Ключевые слова: взрослые пациенты, алглюкозидаза альфа, ферментная заместительная терапия, руководство, болезнь Помпе, рекомендации по лечению

This multicenter/multinational, open-label, ascending-dose study (NCT01898364) evaluated safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of repeat-dose avalglucosidase alfa (neoGAA), a second-generation, recombinant acid α-glucosidase replacement therapy, in late-onset Pompe disease (LOPD). Patients ≥18 years, alglucosidase alfa naïve (Naïve) or previously receiving alglucosidase alfa for ≥9 months (Switch), with baseline FVC ≥50% predicted and independently ambulatory, received every-other-week avalglucosidase alfa 5, 10, or 20 mg/kg over 24 weeks. 9/10 Naïve and 12/14 Switch patients completed the study. Avalglucosidase alfa was well-tolerated; no deaths/life-threatening serious adverse events (SAEs). One Naïve patient withdrew for study drug-related SAEs (respiratory distress/chest discomfort). Infusion-associated reactions (IARs) affected 8 patients. Most treatment-emergent AEs/IARs were non-serious with mild-to-moderate intensity. At screening, 5 Switch patients tested positive for anti-avalglucosidase alfa antibodies; on-treatment, 2 Switch and 9 Naïve patients seroconverted. Post-infusion, avalglucosidase alfa plasma concentrations declined monoexponentially (t1/2z∼1.0 h). AUC was 5-6 × higher in the 20 vs 5 mg/kg group. Pharmacokinetics were similar between Switch and Naïve groups and over time. Baseline quadriceps muscle glycogen was low (∼6%) in most patients, generally remaining unchanged thereafter. Exploratory efficacy parameters (pulmonary function/functional capacity) generally remained stable or improved. Avalglucosidase alfa's well-tolerated safety profile and exploratory efficacy results support further avalglucosidase alfa development. ispartof: NEUROMUSCULAR DISORDERS vol:29 issue:3 pages:167-186 ispartof: location:England status: published

Background Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1) variant/null (i.e. fully deleterious) acid α-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset. Methods We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays. Findings In compound heterozygous IVS1 patients, the synonymous variant c.510C>T was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c.510C>T than it was in patients without c.510C>T. By reducing the extent of leaky wild-type splicing, c.510C>T modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510C>T was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510C>T variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510C>T caused reduced leaky wild-type splicing. Interpretation c.510C>T is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. Fund This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17–32) and Metakids (2016–063).

Scalp cooling as a method to reduce the incidence of chemotherapy-induced alopecia (CIA) is increasingly used in daily practice worldwide. However, in patients treated with 5-fluorouracil, epirubicin and cyclophosphamide (FEC), scalp cooling fails in 48–67% of patients. This study investigated the efficacy of extended duration of post-infusion scalp cooling in breast cancer patients treated with this regimen. In this prospective multi-centre randomised study, 102 patients with early breast cancer treated with adjuvant FEC chemotherapy were randomly assigned in a 1:1 ratio to a post-infusion cooling time of 90 or 150 min. The primary endpoint was the need to wear a wig or other head covering to mask visible hair loss. Sixteen out of 48 patients (33%) treated with 90 min of post-infusion cooling did not need any head covering, compared with 21 out of 46 patients (45%) treated with 150 min of post-infusion cooling (p = 0.2). WHO grades 2–3 (moderate-complete) alopecia were reported more often in patients treated with 90-min post-infusion cooling time (n = 25/51 (49%) versus n = 17/51 (33%); p = 0,02). Scalp cooling was well-tolerated (mean Visual Analogue Score 7.4) and only three patients (3%) stopped due to intolerance during treatment. Extending the duration of 90-min post-infusion scalp cooling to 150 min in patients treated with adjuvant FEC chemotherapy was well-tolerated but did not significantly diminish the need for head covering. However, grades 2–3 alopecia was seen less often with prolonged post-infusion scalp cooling.

Sit&ndash, stand workstations have shown to reduce sitting time in office workers on a group level. However, movement behaviour patterns might differ between subgroups of workers. Therefore, the objective of this study was to examine sitting, standing and stepping outcomes between habitual users and non-users of sit&ndash, stand workstations. From an international office population based in the Netherlands, 24 users and 25 non-users of sit&ndash, stand workstations were included (all had long-term access to these workstations). Using the ActivPAL, sitting, standing and stepping were objectively measured during and outside working hours. Differences in outcomes between users and non-users were analysed using linear regression. During working hours, users sat less (&minus, 1.64, 95% IC= &minus, 2.27&ndash, &minus, 1.01 hour/8 hour workday) and stood more (1.51, 95% IC= 0.92&ndash, 2.10 hour/8 hour workday) than non-users. Attenuated but similar differences were also found for total sitting time over the whole week. Furthermore, time in static standing bouts was relatively high for users during working hours (median= 0.56, IQR = 0.19&minus, 1.08 hour/8 hour workday). During non-working hours on workdays and during non-working days, no differences were found between users and non-users. During working hours, habitual users of their sit&ndash, stand workstation sat substantially less and stood proportionally more than non-users. No differences were observed outside working hours, leading to attenuated but similar differences in total sitting and standing time between users and non-users for total days. This indicated that the users of sit&ndash, stand workstations reduced their sitting time at work, but this seemed not to be accompanied by major carry-over or compensatory effects outside working hours.