Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study.

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria.

The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria.

Argininosuccinate lyase (ASL) is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide (NO) biosynthesis cycle. Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide 123 I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal 123 I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorder with cell-autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy.

Enzyme replacement therapy for late-onset Pompe disease.

BACKGROUND: Pompe disease is caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). People with infantile-onset disease have either a complete or a near-complete enzyme deficiency; people with late-onset Pompe disease (LOPD) retain some residual enzyme activity. GAA deficiency is treated with an intravenous infusion of recombinant human acid alglucosidase alfa, an enzyme replacement therapy (ERT). Alglucosidase alfa and avalglucosidase alfa are approved treatments, but cipaglucosidase alfa with miglustat is not yet approved. OBJECTIVES: To assess the effects of enzyme replacement therapies in people with late-onset Pompe disease. SEARCH METHODS: We searched the Cochrane Inborn Errors of Metabolism Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched MEDLINE OvidSP, clinical trial registries, and the reference lists of relevant articles and reviews. Date of last search: 21 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of ERT in people with LOPD of any age. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias and the certainty of the evidence (using GRADE). We resolved disagreements through discussion and by consulting a third author. MAIN RESULTS: We included six trials (358 randomised participants) lasting from 12 to 78 weeks. A single trial reported on each comparison listed below. None of the included trials assessed two of our secondary outcomes: need for respiratory support and use of a walking aid or wheelchair. Certainty of evidence was most commonly downgraded for selective reporting bias. Alglucosidase alfa versus placebo (90 participants) After 78 weeks, alglucosidase alfa probably improves the six-minute walk test (6MWT) distance compared to placebo (mean difference (MD) 30.95 metres, 95% confidence interval (CI) 7.98 to 53.92; moderate-certainty evidence) and probably improves respiratory function, measured as the change in per cent (%) predicted forced vital capacity (FVC) (MD 3.55, 95% CI 1.46 to 5.64; moderate-certainty evidence). There may be little or no difference between the groups in occurrence of infusion reactions (risk ratio (RR) 1.21, 95% CI 0.57 to 2.61; low-certainty evidence), quality of life physical component score (MD -1.36 points, 95% CI -5.59 to 2.87; low-certainty evidence), or adverse events (RR 0.94, 95% CI 0.64 to 1.39; low-certainty evidence). Alglucosidase alfa plus clenbuterol versus alglucosidase alfa plus placebo (13 participants) The evidence is very uncertain about the effect of alglucosidase alfa plus clenbuterol compared to alglucosidase alfa plus placebo on: change in 6MWT distance after 52 weeks (MD 34.55 metres, 95% CI-10.11 to 79.21; very low-certainty evidence) and change in % predicted FVC (MD -13.51%, 95% CI -32.44 to 5.41; very low-certainty evidence). This study did not measure infusion reactions, quality of life, and adverse events. Alglucosidase alfa plus albuterol versus alglucosidase alfa plus placebo (13 participants) The evidence is very uncertain about the effect of alglucosidase alfa plus albuterol compared to alglucosidase alfa plus placebo on: change in 6MWT distance after 52 weeks (MD 30.00 metres, 95% CI 0.55 to 59.45; very low-certainty evidence), change in % predicted FVC (MD -4.30%, 95% CI -14.87 to 6.27; very low-certainty evidence), and risk of adverse events (RR 0.67, 95% CI 0.38 to 1.18; very low-certainty evidence). This study did not measure infusion reactions and quality of life. VAL-1221 versus alglucosidase alfa (12 participants) Insufficient information was available about this trial to generate effect estimates measured at one year or later. Compared to alglucosidase alfa, VAL-1221 may increase or reduce infusion-associated reactions at three months, but the evidence is very uncertain (RR 2.80, 95% CI 0.18 to 42.80). This study did not measure quality of life and adverse events. Cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo (125 participants) Compared to alglucosidase alfa plus placebo, cipaglucosidase alfa plus miglustat may make little or no difference to: 6MWT distance at 52 weeks (MD 13.60 metres, 95% CI -2.26 to 29.46); infusion reactions (RR 0.94, 95% CI 0.49 to 1.80); quality of life scores for physical function (MD 1.70, 95% CI -2.13 to 5.53) and fatigue (MD -0.30, 95% CI -2.76 to 2.16); and adverse effects potentially related to treatment (RR 0.83, 95% CI 0.49 to 1.40) (all low-certainty evidence). Cipaglucosidase alfa plus miglustat probably improves % predicted FVC compared to alglucosidase alfa plus placebo (MD 3.10%, 95% CI 1.04 to 5.16; moderate-certainty evidence); however, it may make little or no change in % predicted sniff nasal inspiratory pressure (MD -0.06%, 95% CI -8.91 to 7.71; low-certainty evidence). Avalglucosidase alfa versus alglucosidase alfa (100 participants) After 49 weeks, avalglucosidase alfa probably improves 6MWT compared to alglucosidase alfa (MD 30.02 metres, 95% CI 1.84 to 58.20; moderate-certainty evidence). Avalglucosidase alfa probably makes little or no difference to % predicted FVC compared to alglucosidase alfa (MD 2.43%, 95% CI -0.08 to 4.94; moderate-certainty evidence). Avalglucosidase alfa may make little or no difference to infusion reactions (RR 0.78, 95% CI 0.42 to 1.45), quality of life (MD 0.77, 95% CI -2.09 to 3.63), or treatment-related adverse events (RR 0.92, 95% CI 0.61 to 1.40), all low-certainty evidence. AUTHORS' CONCLUSIONS: One trial compared the effect of ERT to placebo in LOPD, showing that alglucosidase alfa probably improves 6MWT and respiratory function (both moderate-certainty evidence). Avalglucosidase alfa probably improves 6MWT compared with alglucosidase alfa (moderate-certainty evidence). Cipaglucosidase plus miglustat probably improves FVC compared to alglucosidase alfa plus placebo (moderate-certainty evidence). Other trials studied the adjunct effect of clenbuterol and albuterol along with alglucosidase alfa, with little to no evidence of benefit. No significant rise in adverse events was noted with all ERTs. The impact of ERT on some outcomes remains unclear, and longer RCTs are needed to generate relevant information due to the progressive nature of LOPD. Alternative resources, such as post-marketing registries, could capture some of this information.

Improving Delirium Assessment in Palliative Homecare - A Quality Improvement Project at CanSupport.

Objectives: Delirium increases distress in patients and caregivers and often leads to hospitalisation and increased health-care costs. It is early diagnosis and management improves the quality of life (QoL) of advanced cancer patients as well as their families. This quality improvement (QI) project aimed at increasing delirium assessment in poor performance advanced cancer patients receiving palliative homecare. Material and Methods: The A3 methodology for QI was used. Our SMART goal was to increase the assessment of delirium in poor performance advanced cancer patients from 25% to 50%. The Fishbone and Pareto analysis helped to determine the reasons for low assessment rates. A validated screening tool for delirium assessment was selected and the homecare team doctors and nurses were trained to use it. A flier was designed to help educate families about delirium. Results: Regular use of the tool helped to increase delirium assessment from an initial 25-50% at the time of project completion. The homecare teams learnt the importance of early delirium diagnosis and the need for regular delirium screening. Family caregivers were empowered through education and use of fliers. Conclusion: The QI project helped to improve delirium assessment and leading to improved QoL of patients and their caregivers. Regular training and awareness and continued use of a validated screening tool should help to sustain the results.

Duckweed: a potential phytosensor for heavy metals.

Globally, heavy metal (HM) contamination is one of the primary causes of environmental pollution leading to decreased quality of life for those affected. In particular, HM contamination in groundwater poses a serious risk to human health and the potential for destabilization of aquatic ecosystems. At present, strategies to remove HM contamination from wastewater are inefficient, costly, laborious, and often the removal poses as much risk to the environment as the initial contamination. Phytoremediation, plant-based removal of contaminants from soil or water, has long been viewed as an economical and sustainable solution to remove toxic metals from the environment. However, to date, phytoremediation has demonstrated limited successes despite a large volume of literature supporting its potential. A key aspect for achieving robust and meaningful phytoremediation is the selection of a plant species that is well suited to the task. For the removal of pollutants from wastewater, hydrophytes, like duckweed, exhibit significant potential due to their rapid growth on nutrient-rich water, ease of collection, and ability to survive in various ecosystems. As a model for ecotoxicity studies, duckweed is an ideal candidate, as it is easy to cultivate under controlled and even sterile conditions, and the rapid growth enables multi-generational studies. Similarly, recent advances in the genetic engineering and genome-editing of duckweed will enable the transition from fundamental ecotoxicity studies to engineered solutions for phytoremediation of HMs. This review will provide insight into the suitability of duckweeds for phytoremediation of HMs and strategies for engineering next-generation duckweed to provide real-world environmental solutions.

Cardiomyopathy and echocardiographic abnormalities in Indian patients with psoriasis: Results of a pilot study.

BACKGROUND: The relationship between psoriasis and cardiomyopathy is understudied in Indian patients. OBJECTIVE: We evaluated psoriasis patients for cardiomyopathy and other echocardiographic abnormalities. METHODS: About 98 (M:F = 67:31) patients with mild to moderate psoriasis aged 18-75 years (mean ± SD = 42.12 ± 12.79 years) having no pre-existing metabolic syndrome and cardiovascular disorders were studied. X-ray chest, electrocardiogram and echocardiography were performed and interpreted by cardiologist for size of the left and right ventricles, left ventricle ejection fraction, diastolic function, pulmonary artery pressure and valve abnormality/regurgitation and their severity as per current guidelines/recommendations. The cardiomyopathies were defined according to standard diagnostic guidelines. RESULTS: Echocardiographic abnormalities were noted in 13 (13.3%) patients aged 19-75 years (mean ± SD = 43.30 ± 15.71 years). The left ventricular diastolic dysfunction (grade 1) was observed in nine patients (moderate severe psoriasis in four patients) and one of them also had concentric left ventricular hypertrophy; a precursor of restrictive cardiomyopathy. Mild tricuspid valve regurgitation was present in other four patients. There was no statistically significant difference in age, gender, duration and the severity of psoriasis when compared with patients having normal echocardiography. The mitral or aortic valves, pulmonary artery pressure, mid-right-ventricular diameter and the left atrial volume showed no abnormality. CONCLUSIONS: Psoriasis perhaps plays a role in left ventricular dysfunction and possibly cardiomyopathy even with moderately severe disease and in the absence of clinical symptoms. However, these observations need to be interpreted with caution in the absence of any statistically significant difference between age, gender, duration and severity of psoriasis in the patients having normal and abnormal echocardiography.

Linear perioral atrophoderma along blaschko's lines- a retrospective study describing 14 cases of atrophia maculosa varioliformis cutis.

BACKGROUND: Spontaneous atrophic scarring is characterised by an idiopathic, non-inflammatory macular atrophy that typically occurs on the face and presents as shallow atrophic scars having sharp margins and may be linear, rectangular or varioliform. AIM: To describe the cases of spontaneous atrophic scarring over perioral region of face having specific feline band pattern in a retrospective study. MATERIALS AND METHODS: All patients with facial atrophoderma (perioral region) were evaluated clinically and histopathologically in tertiary care centres over 3 years. Patients with facial atrophoderma but no perioral involvement and secondary atrophoderma were excluded from the study. Patients were evaluated for number, sites, size and shape of lesions and were confirmed histopathologically. RESULTS: There were 14 patients (10 females) with facial atrophoderma particularly over the perioral region. Three patients had perioral involvement with a few lesions on the cheeks and forehead. All patients developed atrophoderma spontaneously without preceding inflammation. Most of the patients were asymptomatic except for mild pain or burning at the time of development of atrophic lesions; however, none of the patients were symptomatic at the time of presentation. Histopathology in 5 patients showed epidermal and upper dermal atrophy with no/minimal signs of inflammation. CONCLUSION: Idiopathic atrophodermas over the face can be due to spontaneous atrophia maculosa varioliformis cutis or atrophoderma of Moulin.

Adults with a more extensive body involvement, moderate to extremely severe vitiligo and a prolonged clinical course have an early onset in childhood in addition to other prognostic factors as compared to individuals with later-onset vitiligo.

BACKGROUND: The extent and disease severity, duration and other associated prognostic cofactors in vitiligo in adults may vary with the age of onset (before or after 10 years of age). OBJECTIVES: To compare extent and disease severity, duration and other cofactors in adults with early-onset and late-onset vitiligo. METHODS: The medical records of 408 (M:F 1:1.1) adults aged 20-75 years diagnosed with vitiligo between January 2016 and December 2019 were examined retrospectively. The extent and severity of vitiligo were defined. Characteristics of vitiligo with early onset and late onset were compared statistically and odds ratios calculated for risk assessment. RESULTS: 31 (7.6%, M:F 1:2.4) patients had early-onset vitiligo, and 377 (92.4%, M:F 0.8:1) patients had later-onset vitiligo. Compared to late onset, patients with early-onset vitiligo had a significant number of males (71% vs 45.9%), higher percentages of body surface area involvement and moderate to extremely severe disease (29% vs 10.6%), longer duration of disease (41.9% vs 9%), Koebner's phenomenon (48.4% vs 15.6%) and halo nevus (9.7% vs 1.9%). Differences between the two groups were not significant for types of vitiligo, family history of vitiligo and presence of cutaneous and systemic/autoimmune diseases. CONCLUSION: The adults, males in particular, with generalised vitiligo (>10% BSA involvement) appear to have an early onset and a prolonged clinical course. The presence of Koebner's phenomenon and halo nevus in patients with early-onset vitiligo was other poor prognostic factors compared to patients with late-onset vitiligo. The retrospective, hospital-based cross-sectional design and small sample size for stratification remain major limitations.

The dual benefit of a dominant mutation in Arabidopsis IRON DEFICIENCY TOLERANT1 for iron biofortification and heavy metal phytoremediation.

One of the goals of biofortification is to generate iron-enriched crops to combat growth and developmental defects especially iron (Fe) deficiency anaemia. Fe-fortification of food is challenging because soluble Fe is unstable and insoluble Fe is nonbioavailable. Genetic engineering is an alternative approach for Fe-biofortification, but so far strategies to increase Fe content have only encompassed a few genes with limited success. In this study, we demonstrate that the ethyl methanesulfonate (EMS) mutant, iron deficiency tolerant1 (idt1), can accumulate 4-7 times higher amounts of Fe than the wild type in roots, shoots and seeds, and exhibits the metal tolerance and iron accumulation (Metina) phenotype in Arabidopsis. Fe-regulated protein stability and nuclear localisation of the upstream transcriptional regulator bHLH34 were uncovered. The C to T transition mutation resulting in substitution of alanine to valine at amino acid position 320 of bHLH34 (designated as IDT1A320V ) in a conserved motif among mono- and dicots was found to be responsible for a dominant phenotype that possesses constitutive activation of the Fe regulatory pathway. Overexpression of IDT1A320V in Arabidopsis and tobacco led to the Metina phenotype; a phenotype that has escalated specificity towards optimising Fe homeostasis and may be useful in Fe-biofortification. Knowledge of the high tolerance and accumulation of heavy metals of this mutant can aid the development of tools for phytoremediation of contaminants.

Sebelipase alfa for lysosomal acid lipase deficiency: 5-year treatment experience from a phase 2 open-label extension study.

BACKGROUND AND AIMS: Lysosomal acid lipase deficiency is characterized by hepatomegaly and dyslipidaemia, which can lead to cirrhosis and premature atherosclerosis. Sebelipase alfa is an approved recombinant human lysosomal acid lipase. In an open-label extension study of adults with lysosomal acid lipase deficiency (LAL-CL04), sebelipase alfa treatment for 1 year reduced serum transaminase levels and liver fat content and improved serum lipid levels. METHODS: Final data from LAL-CL04 are reported herein for patients who received sebelipase alfa infusions (1.0 or 3.0 mg/kg every other week) for up to 5 years. RESULTS: Of 8 patients enrolled, 7 received sebelipase alfa for 224-260 weeks; 1 was lost to follow-up. Median baseline levels of alanine aminotransferase and aspartate aminotransferase (81.5 and 50.0 U/L, respectively) were decreased through the end-of-study visit (54.0 and 34.0 U/L). Median low-density lipoprotein cholesterol decreased from 113 to 78 mg/dL, total cholesterol decreased from 171 to 132 mg/dL, and high-density lipoprotein cholesterol increased from 37 to 42 mg/dL. Most treatment-emergent adverse events were nonserious (99%), mild/moderate (98%) and unrelated to sebelipase alfa (87%); no patient discontinued as a result of treatment-emergent adverse events. One patient had 2 serious treatment-emergent adverse events (cholecystitis and cholelithiasis; assessed as unlikely related to sebelipase alfa). Two patients had 20 nonserious infusion-associated reactions in weeks 6-38; all were manageable. One patient tested positive for antidrug antibodies (single occurrence). CONCLUSIONS: Sebelipase alfa was well tolerated and improved serum transaminase and lipid levels for up to 5 years in adults with lysosomal acid lipase deficiency. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov record NCT01488097.

The association of anti-gliadin and anti-transglutaminase antibodies and chronic plaque psoriasis in Indian patients: Preliminary results of a descriptive cross-sectional study.

BACKGROUND: Gluten sensitivity among psoriasis patients and its association with gender, age, disease duration and severity of psoriasis are under studied in Indians. OBJECTIVE: To examine association among serum levels of anti-tTG and anti-gliadin antibodies and clinical features including gender, age, duration and severity of psoriasis. METHODS: Serum levels of anti-transglutaminase and anti-gliadin antibodies were measured quantitatively in 80 (M:F 57:23) psoriasis patients aged 15 to 83 years and matched healthy subjects. RESULTS: Forty-five (56.3%) patients were aged ≥41years, duration of disease was >5years in 43(53.8%) patients, and 22 (27.5%) patients had moderate-to-severe psoriasis. Two (2.5%) patients had arthritis and elevated serum anti-gliadin antibody. Significantly more patients than controls had elevated serum anti-gliadin antibody (67.5% vs. 2.5%) and anti-transglutaminase antibody levels (62.5% vs. 0%). Two patients, each with mild and moderate-to-severe psoriasis, had highly elevated serum anti-gliadin antibody and symptoms akin to coeliac disease. Except for a longer duration of psoriasis in patients with elevated anti-gliadin antibodies, there was no statistically significant difference in gender, age, and severity of psoriasis when compared with patients having normal levels. CONCLUSION: Significant elevation of serum anti-transglutaminase and anti-gliadin antibodies levels is noted in psoriasis patients reflecting a possible link. However, results need careful interpretation for any significance of gluten sensitivity in pathogenesis of psoriasis/arthritis or as a stand-alone risk factor for chronicity/severity of psoriasis or whether gluten-free diet will be ameliorating. Small number of subjects, cross-sectional study design, lack of pathological/endoscopic diagnosis and follow-up are study limitations.

Chemo-Geographic Variations in Wild Population of Asteriscus graveolens in Israel Based on Volatile Composition Analyses.

Asteriscus graveolens is an aromatic desert shrub which holds medicinal potential. This species belongs to the Asteraceae family and is endemic to the Mediterranean region. In the present study, wild plants were sampled from eleven locations throughout southern Israel and the volatile profiles from leaves and flowers were analyzed using GC/MS. Three methods for volatile sampling were tested for a representative population: solvent extraction (methyl tert-butyl ether), hydrodistillation of the essential oil and headspace solid-phase microextraction. In all methods, the majority of volatiles were characterized as oxygenated mono- and sesquiterpenes. Only solvent extraction was able to detect asteriscunolides that were previously reported as anticancer molecules. Hence, that method was chosen for further analyses. The leaves were dominated by three asteriscunolide isomers, cis-chrysanthenyl acetate and intermedeol. The flowers were dominated by bisabolone, 6-hydroxybisabol-2-en-1-one, cis-chrysanthenyl acetate, epi-α-cadinol, and germacrene-D. k-Means clustering analysis of these data divided the population into four clusters that significantly differ in their volatile composition as was further demonstrated by MANOVA analysis. Geographically, A. graveolens populations growing in Israel were found to be chemically diverse with unique varieties in the Dead Sea basin and the Arava region. This work demonstrates that chemo-geographic variation of volatile composition exists within A. graveolens population growing in Israel, so future research evaluating the medicinal potential of that plant should take this into consideration.

Providing Palliative Home Care during COVID-19 Pandemic Lockdown in India.

INTRODUCTION: The COVID-19 pandemic and subsequent lockdown in India affected all medical services including palliative care and most consultations were provided remotely through phone or video calls. During this period CanSupport also switched to tele-consultations for the safety of its patients and staff. MATERIALS AND METHODS: Some patients still needed home visits so CanSupport developed need-based criteria in order to continue providing palliative homecare to those who suffered the most. RESULTS: CanSupport's homecare teams visited 847 patients during the lockdown decided by the criteria developed. Majority of the visits were for supplying morphine and other medications followed by patients with severe pain and those requiring procedures. CONCLUSION: If guidelines and safety measures are followed, home visits are possible in the present environment.

Enzyme replacement therapy initiated in adulthood: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program.

OBJECTIVE: To evaluate the impact of galsulfase enzyme replacement therapy (ERT) when initiated in adulthood for patients with mucopolysaccharidosis (MPS) VI. METHODS: In 2005, the multi-national, MPS VI Clinical Surveillance Program (CSP) was established to collect long-term observational data from routine clinical and laboratory assessments. A sub-analysis was performed in patients who started ERT at ≥16 years of age and had received galsulfase for ≥6 months. Urinary glycosaminoglycans (uGAG), 6-min walk test (6MWT), 3-min stair climb test (3MSCT), pulmonary function measures, cardiac function, ophthalmology measures, liver and spleen sizes, and safety were evaluated. RESULTS: Of 223 patients enrolled in the CSP, 51 were included in the sub-analysis. Patients were between 16 and 63 years of age at first infusion. From pre-treatment baseline, uGAG level decreased by a mean (±standard deviation [SD]) of 66 (±45)% (N = 29) after a median follow-up of 7.2 years. 6MWT distance decreased slightly by a mean of 17 (±107) meters (N = 23) after 6.6 years. Stairs/min in the 3MSCT increased by a mean of 26 (±33) (N = 14) after 2.8 years. Pulmonary function measures, forced expiratory volume in 1 second and forced vital capacity, increased by a mean of 0.06 (±0.21) L after 7.3 years and 0.05 (±0.28) L after 7.2 years, respectively (N = 19 for both measures). Overall, galsulfase was well tolerated, with most adverse events reported being MPS-related clinical manifestations and not related to galsulfase. CONCLUSIONS: Results of this sub-analysis of the CSP suggest that initiation of galsulfase in adulthood is well tolerated and can possibly stabilize MPS VI in the long term.

Enzyme replacement therapy outcomes across the disease spectrum: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program.

The impact of galsulfase enzyme replacement therapy in patients with mucopolysaccharidosis (MPS) VI with phenotypes at either end of the disease spectrum was evaluated. The MPS VI Clinical Surveillance Program (CSP) was established to collect long-term observational data from routine clinical and laboratory assessments. A subanalysis of the CSP was performed in patients with pretreatment urinary glycosaminoglycan (uGAG) levels <100 µg/mg and ≥200 µg/mg creatinine (low- and high-uGAG) who had received galsulfase for ≥6 months. uGAG, 6-minute walk test (6MWT), 3-minute stair climb test (3MSCT), pulmonary function measures, height/growth, cardiac function, and safety were evaluated. Patients with a high-uGAG level at pre-treatment baseline (N = 68) showed greater impairments in endurance and pulmonary function than those with low-baseline uGAG levels (N = 39). From pre-treatment baseline, the distance walked on the 6MWT in the low- and high-uGAG groups increased by a mean (±SD) of 49 (±151) meters and 42 (±165) meters (median follow-up 5.5 and 7.7 years), respectively. The number of stairs/min climbed in the 3MSCT in the low- and high-uGAG groups increased by a mean of 18 (±33) and 30 (±45) (median follow-up 2.8 and 3.5 years), respectively. Overall, pulmonary function remained unchanged for both groups. No impact was seen on cardiac function. Galsulfase was generally well tolerated in both groups, with most adverse events being MPS-related complications unrelated to galsulfase. Results of this CSP sub-analysis suggest that galsulfase stabilizes MPS VI in the long-term and has an acceptable safety profile, regardless of baseline disease severity.

Metabolic myopathies: a practical approach.

Metabolic myopathies are a diverse group of rare genetic disorders and their associated muscle symptoms may be subtle. Patients may present with indolent myopathic features, exercise intolerance or recurrent rhabdomyolysis. Diagnostic delays are common and clinicians need a high index of suspicion to recognise and differentiate metabolic myopathies from other conditions that present in a similar fashion. Standard laboratory tests may be normal or non-specific, particularly between symptomatic episodes. Targeted enzyme activity measurement and next-generation genetic sequencing are increasingly used. There are now specific enzyme replacement therapies available, and other metabolic strategies and gene therapies are undergoing clinical trials. Here, we discuss our approach to the adult patient with suspected metabolic myopathy. We outline key features in the history and examination and discuss some mimics of metabolic myopathies. We highlight some disorders of glycogen and fatty acid utilisation that present in adulthood and outline current recommendations on management.

Observational clinical study of 22 adult-onset Pompe disease patients undergoing enzyme replacement therapy over 5years.

Pompe disease is an autosomal recessive disease resulting from deficiency of the acid alpha-glucosidase (GAA). The late-onset Pompe Disease (LOPD) patients develop muscular and respiratory complications later in life. We describe a retrospective observational cohort study including 22 patients with LOPD. The cohort was assessed at baseline before Enzyme Replacement Therapy (ERT) with alglucosidase alpha (20mg/kg biweekly) was commenced and subsequently relevant information was collected at 2, 4 and 5years later. The median age of the patients at study entry was 44years (16-64years), with median disease duration of 11.5years (4-31years). At baseline, 10 patients (45%) could walk without support, 12 (55%) could walk with unilateral or bilateral support including 3/12 were wheelchair bound. Mean predicted FVC % was 55.7 (95% CI 45-66) of predicted normal at baseline and showed no significant change after 5years (54.6 (95% CI 43-66)), (all p=0.9815). Mean FVC % supine was 41.8 (95% CI 33.8-49) of predicted normal at baseline and remained significantly unchanged at 5years (48.4 (95% CI 37-59.6)), (all p=0.8680). The overnight non-invasive ventilator dependence increased by 18.2% as compared with baseline and requirement of mobility aids increased during this period by 5.2% as compared with the baseline. Mean walking distance at 6min walk test was 411.5 (95% CI 338-485) at baseline, 266.5 (95% CI 187-346) m at 2years, 238.6 (95% CI 162-315) m at 4years and 286.8 (95% CI 203-370) m at 5years (p=0.1981; ANOVA was completed only for 14 patients). A gradual decline in FVC% predicted was noted only in four cases and a decline in FVC% supine in two other. Only one patient showed a decline in both pulmonary function tests. In all remaining cases (17/22) respiratory function remains stable. In conclusion overall pulmonary function tests and mobility remained stable for 5years in majority of patients on ERT. However, in some patients they continued to decline in spite of ERT resulting in increased number of patients requiring ventilation and increase wheel chair dependence at the end of 5years.

Clinical Features of Lysosomal Acid Lipase Deficiency.

OBJECTIVE: The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults. METHODS: Investigators reviewed medical records of LAL D patients ages ≥5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset. RESULTS: A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease-related abnormality was 9.0 years (range 0-42); mean age at diagnosis was 15.2 years (range 1-46). Twenty-nine (60%) were male patients, and 27 (56%) were <20 years of age at the time of consent/assent. Serum transaminases were elevated in most patients with 458 of 499 (92%) of alanine aminotransferase values and 265 of 448 (59%) of aspartate aminotransferase values above the upper limit of normal. Most patients had elevated low-density lipoprotein (64% patients) and total cholesterol (63%) at baseline despite most being on lipid-lowering therapies, and 44% had high-density lipoprotein levels below the lower limit of normal. More than half of the patients with liver biopsies (n = 31, mean age 13 years) had documented evidence of steatosis (87%) and/or fibrosis (52%). Imaging assessments revealed that the median liver volume was ∼1.15 multiples of normal (MN) and median spleen volume was ∼2.2 MN. Six (13%) patients had undergone a liver transplant (ages 9-43.5 years). CONCLUSION: This study provides the largest longitudinal case review of patients with LAL D and confirms that LAL D is predominantly a pediatric disease causing early and progressive hepatic dysfunction associated with dyslipidemia that often leads to liver failure and transplantation.

Biodegradable and conducting hydrogels based on Guar gum polysaccharide for antibacterial and dye removal applications.

Conducting hydrogels possessing antibacterial activity were developed using a two-step free-radical aqueous polymerization method to incorporate polyaniline chains into an adsorbent Guar gum/acrylic acid hydrogel network. The material properties of the synthesized samples were characterized using FTIR spectroscopy, thermal analysis and scanning electron microscopy techniques. Conducting hydrogels were tested for antibacterial activities against gram-positive Staphylococcus aureus and gram-negative Escherichia coli bacteria and demonstrated antibacterial activity. Synthesized hydrogel samples can be potential adsorbent materials for dye removal applications.