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Objective: To conduct an open-label, multinational, multicenter study examining the safety and efficacy of recombinant human acid alpha-glucosidase (rhGAA) in treatment of infantile-onset Pompe disease.Study Design: We enrolled 8 infant patients who had Pompe disease with GAA activity <1% of normal, cardiomyopathy, and hypotonia. In the 52-week initial phase, rhGAA was infused intravenously at 10 mg/kg weekly; an extension phase continued survivors' treatment with 10 to 20 mg/kg of rhGAA weekly or 20 mg/kg every 2 weeks for as long as 153 weeks. Safety measurements included adverse events, laboratory tests, and anti-rhGAA antibody titers. Efficacy evaluations included survival, ventilator use, echocardiograms, growth, and motor and cognitive function.Result: After 52 weeks of treatment, 6 of 8 patients were alive, and 5 patients were free of invasive ventilator support. Clinical improvements included ameliorated cardiomyopathy and improved growth and cognition. Five patients acquired new motor milestones; 3 patients walked independently. Four patients died after the initial study phase; the median age at death or treatment withdrawal for all patients was 21.7 months, significantly later than expected for patients who were not treated. Treatment was safe and well tolerated; no death was drug-related.Conclusion: rhGAA improved ventilator-free survival, cardiomyopathy, growth, and motor function in patients with infantile-onset Pompe disease compared with outcomes expected for patients without treatment. [ABSTRACT FROM AUTHOR]

The purpose of this article is to demonstrate: (1) the accuracy and (2) the reduction in amount of time and effort in assessing physical functioning (self-care and mobility domains) of children and adolescents using computer-adaptive testing (CAT). A CAT algorithm selects questions directly tailored to the child's ability level, based on previous responses. Using a CAT algorithm, a simulation study was used to determine the number of items necessary to approximate the score of a full-length assessment. We built simulated CAT (5-, 10-, 15-, and 20-item versions) for self-care and mobility domains and tested their accuracy in a normative sample (n=373; 190 males, 183 females; mean age 6y 11mo [SD 4y 2m], range 4mo to 14y 11mo) and a sample of children and adolescents with Pompe disease (n=26; 21 males, 5 females; mean age 6y 1mo [SD 3y 10mo], range 5mo to 14y 10mo). Results indicated that comparable score estimates (based on computer simulations) to the full-length tests can be achieved in a 20-item CAT version for all age ranges and for normative and clinical samples. No more than 13 to 16% of the items in the full-length tests were needed for any one administration. These results support further consideration of using CAT programs for accurate and efficient clinical assessments of physical functioning. [ABSTRACT FROM AUTHOR]

We report a patient with Pompe disease who developed reversible nephrotic syndrome during prolonged, high-dose, experimental, enzyme replacement therapy with recombinant human acid alpha-glucosidase (rhGAA). Because of the development of antibodies to rhGAA and concomitant clinical decline, escalating doses of rhGAA were administered as part of an experimental immune tolerance regimen. Histologic evaluation of kidney tissue revealed glomerular deposition of immune complexes containing rhGAA itself, in a pattern of membranous nephropathy. To our knowledge, this is the first reported case of nephrotic syndrome occurring during enzyme replacement therapy. The nephrotic syndrome gradually resolved after the rhGAA dose was decreased, indicating that decreasing the antigenic load can ameliorate glomerular immune complex deposition associated with enzyme replacement in a highly sensitized patient. [ABSTRACT FROM AUTHOR]

Background and Objective: Systemic sclerosis (SSc) is a highly heterogeneous disease whose treatment is based mainly on immunosuppressants, antifibrotics, and vasodilators. Intravenous immunoglobulin (IVIG) have proved effective in other autoimmune diseases. The objective of this study is to evaluate the efficacy and safety of IVIG in SSc., Methods: The systematic review was conducted according to the PRISMA Statement. Medline, Embase and Cochrane Library databases were searched until March 2024. We assessed the quality of included studies using the Cochrane Risk of Bias 2.0 tool (RoB 2) for randomised clinical trials and the Cochrane Risk in non-randomized studies (ROBINS-I) tool for observational studies., Results: From 1242 studies identified, 15 studies were included, of which 14 were observational studies. In total, 361 patients with SSc were included, and 295 received treatment with IVIG. Most of the studies used a dose of 2 g/kg IVIG. Ten studies, including the clinical trial, showed high risk of bias, and five had a critical risk. Skin involvement was assessed using modified Rodnan skin score, in 11 studies and the authors reported cutaneous efficacy in 9 of them. The 6 studies that assessed muscle involvement reported an improvement. Six studies reported data on gastrointestinal efficacy. Other domains such as lung and joint involvement and steroid-sparing effect were evaluated. The most frequent adverse events were mild, including headache, abdominal pain, fever, and skin rash., Conclusion: Treatment with IVIG in SSc patients could be helpful and safe in patients with cutaneous, muscular, or digestive manifestations., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Ultra-rare inherited bleeding disorders (BDs) present important challenges for generating a strong evidence foundation for optimal diagnosis and management. Without disorder-appropriate treatment, affected individuals potentially face life-threatening bleeding, delayed diagnosis, suboptimal management of invasive procedures, psychosocial distress, pain, and decreased quality-of-life., Research Design and Methods: The National Hemophilia Foundation (NHF) and the American Thrombosis and Hemostasis Network identified the priorities of people with inherited BDs and their caregivers, through extensive inclusive community consultations, to inform a blueprint for future decades of research. Multidisciplinary expert Working Group (WG) 3 distilled highly feasible transformative ultra-rare inherited BD research opportunities from the community-identified priorities., Results: WG3 identified three focus areas with the potential to advance the needs of all people with ultra-rare inherited BDs and scored the feasibility, impact, and risk of priority initiatives, including 13 in systems biology and mechanistic science; 2 in clinical research, data collection, and research infrastructure; and 5 in the regulatory process for novel therapeutics and required data collection., Conclusions: Centralization and expansion of expertise and resources, flexible innovative research and regulatory approaches, and inclusion of all people with ultra-rare inherited BDs and their health care professionals will be essential to capitalize on the opportunities outlined herein.

Solution-processed metal halide perovskite (MHP) single crystals (SCs) are in high demand for a growing number of printed electronic applications due to their superior optoelectronic properties compared to polycrystalline thin films. There is an urgent need to make SC fabrication facile, scalable, and compatible with the printed electronic manufacturing infrastructure. Here, a universal cosolvent evaporation (CSE) strategy is presented by which perovskite SCs and arrays are produced directly on substrates via printing and coating methods within minutes at room temperature from drying droplets. The CSE strategy successfully guides the supersaturation via controlled drying of droplets to suppress all crystallization pathways but one, and is shown to produce SCs of a wide variety of 3D, 2D, and mixed-cation/halide perovskites with consistency. This approach works with commonly used precursors and solvents, making it universal. Importantly, the SC consumes the precursor in the droplet, which enables the large-scale fabrication of SC arrays with minimal residue. Direct on-chip fabrication of 3D and 2D perovskite photodetector devices with outstanding performance is demonstrated. The approach shows that any MHP SC can now be manufactured on substrates using precision printing and scalable, high-throughput coating methods., (© 2022 Wiley-VCH GmbH.)

The choice of interfacial materials and their properties play a critical role in determining solar cell performance and stability. For compatibility with roll-to-roll printing, it is desirable to develop stable cathode interface layers (CILs) that can be processed over the photoactive layer using orthogonal solvents. In this study, an n -type naphthalene diimide core and oligo (ethylene glycol) side-chain-based conjugated polymer is reported as a universal, efficient CIL for organic and perovskite photovoltaics. Besides good thermal stability and easy processing in alcohol/water, the new CIL is found to possess electron transport properties with an electrical conductivity of 2.3 × 10 -6 S cm -1 , enabling its use as a CIL with a film thickness of up to ∼35(±2) nm. Utilizing the new CIL, 16% power conversion efficiency (PCE) is achieved for organic solar cells (OSCs) based on the PM6-Y6 photoactive layer (8.9% PCE for no CIL and 15.1% with state-of-the-art CIL, PDINO), and perovskite solar cells from methylammonium lead iodide yielded a PCE of 17.6%. Compared to the reference devices, the new CIL reduced trap-assisted carrier recombination and increased the built-in potential by 80 mV, simultaneously enhancing all photovoltaic parameters. Moreover, new CIL based devices had better photostability with no burn-in losses., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Context: SJX-653 is a novel neurokinin 3 receptor (NK3R) antagonist. The NK3 pathway is a central regulator of gonadotropin releasing hormone (GnRH) secretion and has also been implicated in the generation of hot flashes. Therefore, decreases of luteinizing hormone (LH) and testosterone in men serve as sensitive pharmacodynamic (PD) markers of central NK3 antagonism., Objective: To characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of SJX-653 in healthy men., Design: A randomized, placebo-controlled, double-blind, single ascending dose study., Setting: Phase 1 unit., Patients or Other Participants: Seven cohorts of 6 healthy men 18-45 years of age (4:2 randomization to SJX-653/placebo per cohort)., Intervention(s): Single oral doses of 0.5-90 mg SJX-653., Main Outcome Measure(s): Safety assessments and serial pharmacokinetic (PK)/PD measurements., Results: SJX-653 was well tolerated at all dose levels. Cmax and AUC0-24 increased in a dose-proportional manner. The terminal elimination half-life ranged between 9.8 and 12.5 hours independent of dose. A statistically significant, dose-dependent, reversible reduction of LH and testosterone was observed with near maximal effect after 15 mg and little to no effect at 4.5 mg. Maximal LH reduction was 70 ± 7% (mean ± sd) at 6 hours after 30 mg SJX-653 versus 10 ± 43% for placebo (P = 0.0006); maximal T reduction was of 68 ± 5% at 8 hours after 60 mg SJX-653 versus 18 ± 11% for placebo (P < 0.0001). The plasma IC50 for LH reduction was 33 ng/mL., Conclusions: These data demonstrate clinical proof-of-mechanism for SJX-653 as a potent centrally-acting NK3R antagonist., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Co-transcriptional imprinting of mRNA by Rpb4 and Rpb7 subunits of RNA polymerase II (RNAPII) and by the Ccr4-Not complex conditions its post-transcriptional fate. In turn, mRNA degradation factors like Xrn1 are able to influence RNAPII-dependent transcription, making a feedback loop that contributes to mRNA homeostasis. In this work, we have used repressible yeast GAL genes to perform accurate measurements of transcription and mRNA degradation in a set of mutants. This genetic analysis uncovered a link from mRNA decay to transcription elongation. We combined this experimental approach with computational multi-agent modelling and tested different possibilities of Xrn1 and Ccr4 action in gene transcription. This double strategy brought us to conclude that both Xrn1-decaysome and Ccr4-Not regulate RNAPII elongation, and that they do it in parallel. We validated this conclusion measuring TFIIS genome-wide recruitment to elongating RNAPII. We found that xrn1Δ and ccr4Δ exhibited very different patterns of TFIIS versus RNAPII occupancy, which confirmed their distinct role in controlling transcription elongation. We also found that the relative influence of Xrn1 and Ccr4 is different in the genes encoding ribosomal proteins as compared to the rest of the genome., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The fields of photovoltaics, photodetection and light emission have seen tremendous activity in recent years with the advent of hybrid organic-inorganic perovskites. Yet, there have been far fewer reports of perovskite-based field-effect transistors. The lateral and interfacial transport requirements of transistors make them particularly vulnerable to surface contamination and defects rife in polycrystalline films and bulk single crystals. Here, we demonstrate a spatially-confined inverse temperature crystallization strategy which synthesizes micrometre-thin single crystals of methylammonium lead halide perovskites MAPbX 3 (X = Cl, Br, I) with sub-nanometer surface roughness and very low surface contamination. These benefit the integration of MAPbX 3 crystals into ambipolar transistors and yield record, room-temperature field-effect mobility up to 4.7 and 1.5 cm 2  V -1  s -1 in p and n channel devices respectively, with 10 4 to 10 5 on-off ratio and low turn-on voltages. This work paves the way for integrating hybrid perovskite crystals into printed, flexible and transparent electronics.

Alipogene tiparvovec (Glybera) is a gene therapy product approved in Europe under the "exceptional circumstances" pathway as a treatment for lipoprotein lipase deficiency (LPLD), a rare genetic disease resulting in chylomicronemia and a concomitantly increased risk of acute and recurrent pancreatitis, with potentially lethal outcome. This retrospective study analyzed the frequency and severity of pancreatitis in 19 patients with LPLD up to 6 years after a single treatment with alipogene tiparvovec. An independent adjudication board of three pancreas experts, blinded to patient identification and to pre- or post-gene therapy period, performed a retrospective review of data extracted from the patients' medical records and categorized LPLD-related acute abdominal pain events requiring hospital visits and/or hospitalizations based on the adapted 2012 Atlanta diagnostic criteria for pancreatitis. Both entire disease time period data and data from an equal time period before and after gene therapy were analyzed. Events with available medical record information meeting the Atlanta diagnostic criteria were categorized as definite pancreatitis; events treated as pancreatitis but with variable levels of laboratory and imaging data were categorized as probable pancreatitis or acute abdominal pain events. A reduction of approximately 50% was observed in all three categories of the adjudicated post-gene therapy events. Notably, no severe pancreatitis and only one intensive care unit admission was observed in the post-alipogene tiparvovec period. However, important inter- and intraindividual variations in the pre- and post-gene therapy incidence of events were observed. There was no relationship between the posttreatment incidence of events and the number of LPL gene copies injected, the administration of immunosuppressive regimen or the percent triglyceride decrease achieved at 12 weeks (primary end point in the prospective clinical studies). Although a causal relationship cannot be established and despite the limited number of individuals evaluated, results from this long-term analysis suggest that alipogene tiparvovec was associated with a lower frequency and severity of pancreatitis events, and a consequent overall reduction in health care resource use up to 6 years posttreatment.

Background: Lipoprotein lipase (LPL) deficiency is a serious lipid disorder of severe hypertriglyceridemia (SHTG) with chylomicronemia. A large number of variants in the LPL gene have been reported but their influence on LPL activity and SHTG has not been completely analyzed. Gaining insight into the deleterious effect of the mutations is clinically essential., Methods: We used gene sequencing followed by in-vivo/in-vitro and in-silico tools for classification. We classified 125 rare LPL mutations in 33 subjects thought to have LPL deficiency and in 314 subjects selected for very SHTG., Results: Of the 33 patients thought to have LPL deficiency, only 13 were homozygous or compound heterozygous for deleterious mutations in the LPL gene. Among the 314 very SHTG patients, 3 were compound heterozygous for pathogenic mutants. In a third group of 51,467 subjects, from a general population, carriers of common variants, Asp9Asn and Asn291Ser, were associated with mild increase in triglyceride levels (11%-35%)., Conclusion: In total, 39% of patients clinically diagnosed as LPL deficient had 2 deleterious variants. Three patients selected for very SHTG had LPL deficiency. The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: nab-Paclitaxel is an albumin-bound formulation of paclitaxel approved for the treatment of metastatic breast cancer (MBC). This analysis was designed to characterize the treatment patterns, efficacy, and safety of nab-paclitaxel for MBC treatment using health claims data from US health plans associated with Optum., Methods: Women aged ≥ 18 years who initiated nab-paclitaxel for MBC treatment from January 1, 2005, to September 30, 2012, and who met eligibility criteria were selected from the Optum Research Database for this analysis. Patients were required to have complete medical coverage and pharmacy benefits, ≥ 6 months of continuous enrollment, and a diagnosis of MBC prior to nab-paclitaxel initiation. The pattern of use for nab-paclitaxel (eg, regimen, schedule, duration, and administration) and claims-captured toxicities were characterized by line of therapy. Overall survival (OS) and time to next therapy or death (TNTD) were described by line of therapy, regimen, and schedule., Results: Of the 664 nab-paclitaxel patients, 172 (25.9%) received it as first-line therapy, 211 (31.8%) as second-line therapy, and 281 (42.3%) as third-line or later therapy. Overall, the majority of patients received monotherapy (61%) and followed a weekly (71%) rather than an every 3 weeks treatment schedule. nab-Paclitaxel was often (31.7%) combined with targeted therapy (57.5% with bevacizumab and 23.9% with trastuzumab or lapatinib). The median duration of therapy was 128 days (4.2 months). For the overall population, median OS was 17.4 months (22.7, 17.4, and 15.1 months in first-, second-, and third-line or later therapy, respectively). Median TNTD was 6.1 months (7.1, 6.6, and 5.3 months in first-, second-, and third-line or later therapy, respectively). For patients aged ≤ 50 years or with ≥ 3 metastatic sites, median OS was 15.6 months. No new safety signal was identified., Conclusions: In this US healthcare system, the majority of patients received nab-paclitaxel as second-line or later therapy, monotherapy, and weekly treatment. The efficacy and safety outcomes of nab-paclitaxel observed in this real-world setting appear consistent with those from clinical trial data.

Background: Different dosages-schedules of nab-paclitaxel have been assessed in trials of metastatic breast cancer (MBC). However, there is limited information on nab-paclitaxel dosing-scheduling in the community setting., Objective: To report on experience with nab-paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative MBC and identify patient characteristics affecting nab-paclitaxel treatment patterns in the community practice setting., Methods: From September 6-October 21, 2013, a 35-question, web-based survey on nab-paclitaxel dosing, toxicities leading to dose modifications, management, and treatment duration was sent to US Oncology network oncologists. Respondents were categorized by percentage of their patients with HER2-negative MBC who received nab-paclitaxel., Results: 104 of 428 oncologists responded; 84% were from large practices (≥16 oncologists), and 56% had a high level of experience using nab-paclitaxel. For first- and second-line treatment, 100 mg/m² weekly was the most common starting dosage-schedule, followed by 125 mg/m² weekly and 260 mg/m² every 3 weeks (q3w); 150 mg/m² weekly was used least frequently. Several factors, including select aggressive disease characteristics, were found to affect nab-paclitaxel dose selection. Weekly dosing was preferred in patients with select aggressive disease characteristics, whereas q3w dosing was commonly used in patients aged ≤50 years and those with good performance status. Differences in management styles among oncologists with high compared with infrequent nab-paclitaxel experience were also observed. Peripheral neuropathy and neutropenia were common dose-limiting toxicities., Limitations: Recall and response bias may be limitations of this study., Conclusions: In the community setting, nab-paclitaxel 100 mg/m² weekly was the most commonly used starting dose for patients with HER2-negative MBC, including those with aggressive disease characteristics., (©2015 Frontline Medical Communications.)

Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (<400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-of-function for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.

The outlook for transplant-ineligible multiple myeloma patients has improved enormously over recent years with the incorporation of new agents into standard regimens. Novel regimens combine melphalan and prednisone (MP) with bortezomib (VMP), with thalidomide (MPT), and with lenalidomide with (MPR-R) and without (MPR) lenalidomide maintenance. The efficacy, safety, and cost-effectiveness of these regimens have not yet been compared; therefore, we conducted a pharmacoeconomic analysis using data from randomized controlled trials versus MP. Using a Markov model developed from a U.S. payer's perspective, we compared VMP with MPT and MPR-R over a lifetime horizon. MPT and MPR-R were chosen because, like VMP, they are superior to MP in response and outcomes. Data from the Velcade as Initial Standard Therapy in Multiple Myeloma (VISTA; VMP), Intergroupe Francophone du Myelome (IFM) 99-06 (MPT), and MM-015 (MPR-R) trials were used. The IFM 99-06 study was selected because of the superior activity in this study compared with other MPT studies. Using patient-level (VMP) and published (MPT, MPR-R) data, we estimated the health-state transition and adverse event probabilities for each regimen, related costs, and state-specific utility estimates. Costs (in 2010 U.S. dollars) and health outcomes were discounted at 3%. Discounted lifetime direct medical costs were lowest with VMP at $119,102. MPT cost $142,452 whereas MPR-R cost $248,358. Incremental cost-effectiveness ratio calculations projected that VMP would confer cost savings and better health outcomes relative to MPT and MPR-R. We conclude that VMP is highly likely to be cost-effective compared with MP, MPT, and MPR-R.

Objective. Patient-reported outcomes (PROs) have become an essential part of the assessment of patients with rheumatoid arthritis (RA). We aimed to evaluate the agreement and correlation between PROs and the physician's measurements. Methods. This was a cross-sectional analytical study in which 135 patients with RA were clinically evaluated during two different sessions of focus group interviews. Rheumatologist recorded 28 swollen (SJCs) and tender joint counts (TJCs). The patients filled out the PROs instruments (MDHAQ, RADAI, RAPID3, 4, and 5 and self-report articular index (SAI) diagram for pain and joint swelling). DAS28 was calculated (C-reactive protein). An adjusted multiple lineal regression model was done (DAS28 as dependent variable). Results. Highly significant agreements were found between SJC and TJC registered by the physician and patient. There was moderate correlation between DAS28 with patient SJC (r = 0.52), patient TJC (r = 0.55), RADAI (r = 0.56), RAPID3 (r = 0.52), RAPID4 (r = 0.56), RAPID5 (r = 0.66), and VAS-Global (r = 0.51). Likewise, we found moderate to high correlations between CDAI and SDAI with all variable measurements done by the patients. The resulting predictive equation was DAS28(CRP) = 2.02 + 0.037 × RAPID4 + 0.042× patient SJC. Conclusion. PROs applied in focus groups interview are a useful tool for managing patients with RA regardless of gender, educational level, and duration of disease.

Objective: To identify and estimate the common effect size of HLA-Class II contributing to susceptibility on T1D in Latin America (LA) through a meta-analysis., Methods: A systematic review of the literature searching for all HLA-Class II alleles and susceptibility for T1D case-control studies performed in LA was made up to October 2009. Effect summary ORs and 95% CI were obtained by means of the random effect model. A prediction model that identifies peptides binding to HLA-DR alleles that were significantly associated with T1D throughout the meta-analysis was done., Results: 21 studies were included (1138 cases and 1920 controls). DRB1*0301 (OR: 9.65; 95% CI: 5.69-16.36; p<0.0001), DRB1*1201 (OR: 4.84; 95% CI: 1.97-11.91; p=0.001), DQB1*0302 (OR: 4.58; 95% CI: 3.36-6.26; p<0.0001), DQA1*0301(OR: 3.02; 95% CI: 1.37-6.65; p=0.0059) and DQB1*0602 (OR: 0.19; 95% CI: 0.11-0.33; p<0.0001), DRB1*14 (OR: 0.18; 95% CI: 0.06-0.55; p=0.0024), and DQB1*0501 (OR: 0.47; 95% CI: 0.26-0.83; p=0.0097) were the most significant alleles associated with T1D. DRB1*0301-DQA1*0501-DQB1*0201 (OR: 13.50; 95% CI: 3.85-47.28; p<0.0001) and DRB1*1301-DQB1*0603 (OR: 0.25; 95% CI: 0.1-0.65; p=0.004) were the most significant risk and protective haplotypes associated, respectively. There were peptides binding to significantly HLA-DRB1 alleles and haplotypes found through the meta-analysis from islet cell protein tyrosine phosphatase and glutamic acid decarboxylase., Conclusions: These results strengthen the effect of HLA-Class II on T1D in LA similar to Caucasians regardless of the latitudinal gradient and admixture. The shared chemical characteristics in critical pockets could explain the predisposition to present a "diabetogenic peptide" to T cells in this population., (2010 Elsevier B.V. All rights reserved.)

Background: Pompe's disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe's disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe's disease., Methods: Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC)., Results: At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients)., Conclusions: In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.), (Massachusetts Medical Society)

In a previous 52-wk trial, treatment with alglucosidase alpha markedly improved cardiomyopathy, ventilatory function, and overall survival among 18 children <7 mo old with infantile-onset Pompe disease. Sixteen of the 18 patients enrolled in an extension study, where they continued to receive alglucosidase alpha at either 20 mg/kg biweekly (n = 8) or 40 mg/kg biweekly (n = 8), for up to a total of 3 y. These children continued to exhibit the benefits of alglucosidase alpha at the age of 36 mo. Cox regression analyses showed that over the entire study period, alglucosidase alpha treatment reduced the risk of death by 95%, reduced the risk of invasive ventilation or death by 91%, and reduced the risk of any type of ventilation or death by 87%, compared with an untreated historical control group. Cardiomyopathy continued to improve and 11 patients learned and sustained substantial motor skills. No significant differences in either safety or efficacy parameters were observed between the 20 and 40 mg/kg biweekly doses. Overall, long-term alglucosidase alpha treatment markedly extended survival as well as ventilation-free survival and improved cardiomyopathy.

Purpose: To investigate the correlation of the urinary glucose tetrasaccharide, Glcalpha1-6Glcalpha1-4Glcalpha1-4Glc, (Glc4) with skeletal muscle glycogen content and the long-term clinical response to enzyme replacement therapy with recombinant human acid alpha glucosidase in infantile Pompe disease., Methods: Eighteen patients, < or =6 months old, were enrolled in a clinical trial of enzyme replacement therapy for up to 142 weeks. Urinary Glc4, skeletal muscle glycogen, and other clinical and laboratory assessments were made at baseline and at regular intervals. Urinary Glc4 was determined using an isotope-dilution tandem mass spectrometric assay. The clinical response to treatment was defined according to the motor function response. Trends in urinary Glc4 were correlated with the clinical response and compared with serum enzyme markers of skeletal muscle damage, creatine kinase, aspartate aminotransferase, and alanine aminotransferase., Results: Urinary Glc4, in contrast to the serum markers, correlated closely with skeletal muscle glycogen content and with the clinical response. Patients with the best response to treatment maintained the lowest levels of Glc4 throughout the trial., Conclusion: The results from this study support the use of urinary Glc4 for monitoring patients with infantile-onset Pompe disease on therapy.

Purpose: A clinical trial was conducted to evaluate the safety and efficacy of alglucosidase alfa in infants and children with advanced Pompe disease., Methods: Open-label, multicenter study of IV alglucosidase alfa treatment in 21 infants 3-43 months old (median 13 months) with minimal acid alpha-glucosidase activity and abnormal left ventricular mass index by echocardiography. Patients received IV alglucosidase alfa every 2 weeks for up to 168 weeks (median 120 weeks). Survival results were compared with an untreated reference cohort., Results: At study end, 71% (15/21) of patients were alive and 44% (7/16) of invasive-ventilator free patients remained so. Compared with the untreated reference cohort, alglucosidase alfa reduced the risk of death by 79% (P < 0.001) and the risk of invasive ventilation by 58% (P = 0.02). Left ventricular mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Five patients were walking independently at the end of the study and 86% (18/21) gained functional independence skills. Overall, 52% (11/21) of patients experienced infusion-associated reactions; 95% (19/20) developed IgG antibodies to recombinant human lysosomal acid alpha-glucosidase; no patients withdrew from the study because of safety concerns., Conclusions: In this population of infants with advanced disease, biweekly infusions with alglucosidase alfa prolonged survival and invasive ventilation-free survival. Treatment also improved indices of cardiomyopathy, motor skills, and functional independence.