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Therapeutic development and monitoring require demonstration of effects on disease phenotype. However, due to the complexity of measuring clinically-relevant effects in rare multisystem diseases, robust biomarkers are essential. For the mucopolysaccharidoses (MPS), the measurement of glycosaminoglycan levels is relevant as glycosaminoglycan accumulation is the primary event that occurs due to reduced lysosomal enzyme activity. Traditional dye-based assays that measure total glycosaminoglycan levels have a high background, due to a normal, baseline glycosaminoglycan content in unaffected individuals. An assay that selectively detects the disease-specific non-reducing ends of heparan sulfate glycosaminoglycans that remain undegraded due to deficiency of a specific enzyme in the catabolic pathway avoids the normal background, increasing sensitivity and specificity. We evaluated glycosaminoglycan content by dye-based and non-reducing end methods using urine, serum, and cerebrospinal fluid from MPS I human samples before and after treatment with intravenous recombinant human alpha-l-iduronidase. We found that both urine total glycosaminoglycans and serum heparan sulfate derived non-reducing end levels were markedly decreased compared to baseline after 26 weeks and 52 weeks of therapy, with a significantly greater percentage reduction in serum non-reducing end (89.8% at 26 weeks and 81.3% at 52 weeks) compared to urine total glycosaminoglycans (68.3% at 26 weeks and 62.4% at 52 weeks, p

Five subjects with mucopolysaccharidosis type I and symptomatic cervical spinal stenosis received intrathecal laronidase in a 4-month pilot study and/or a 12-month extension study [1]. Clinical descriptions of study subjects, nonserious adverse events, individual data tables, and scoring system methods are provided. There were ten nonserious adverse events that occurred in more than one study subject. Somatosensory evoked potentials were absent in two subjects and normal in two subjects, limiting their utility as an endpoint. There were no significant changes in magnetic resonance imaging of cervical spinal cord or brain, pulmonary function tests, or cerebrospinal fluid opening pressure. These data are presented along with the scoring methods used in evaluation of the study subjects.

Enzyme replacement therapy with laronidase (recombinant human alpha-l-iduronidase) is successfully used to treat patients with mucopolysaccharidosis type I (MPS I). However, the intravenously-administered enzyme is not expected to treat or prevent neurological deterioration. As MPS I patients suffer from spinal cord compression due in part to thickened spinal meninges, we undertook a phase I clinical trial of lumbar intrathecal laronidase in MPS I subjects age 8 years and older with symptomatic (primarily cervical) spinal cord compression. The study faced significant challenges, including a heterogeneous patient population, difficulty recruiting subjects despite an international collaborative effort, and an inability to include a placebo-controlled design due to ethical concerns. Nine serious adverse events occurred in the subjects. All subjects reported improvement in symptomatology and showed improved neurological examinations, but objective outcome measures did not demonstrate change. Despite limitations, we demonstrated the safety of this approach to treating neurological disease due to MPS I.

To determine the association between all-cause mortality and dietary protein intake in patients with chronic kidney disease, we performed a large-scale, 8-y prospective cohort study in 98,489 maintenance hemodialysis patients from a multicenter dialysis care provider. Compared with the reference level (60 to

The Navigation Program is a health department-community agency collaboration to reengage lost HIV clinic patients in Los Angeles County using best practices from disease investigator services locator activities and the Antiretroviral Treatment Access Study (ARTAS), a CDC-recommended intervention. Clinic databases were reviewed to identify HIV patients who: (1) had no HIV care visits in 6-12 months and last viral load was greater than 200 copies per milliliter; (2) had no HIV care visits in >12 months; (3) were newly diagnosed and never in care; or (4) were recently released from jail/prison/other institution with no regular HIV medical provider. Patients were contacted by trained Navigators using locator information from clinic medical records, HIV/sexually transmitted disease surveillance, and people-finder databases and offered enrollment in a modified ARTAS intervention. Among the 1139 lost clinic patients identified, 36% were in care elsewhere, 29% could not be located, 8% returned to the clinic independently, 4% declined enrollment, and 7% (n = 78) were located and enrolled in the intervention. Participants received an average of 4.5 Navigator sessions over 11.6 hours. Among reengaged patients, 68% linked within 3 months, 85% linked within 6 months, and 94% linked within 12 months, and 82% of linked patients were retained in care 12 months after study enrollment. The percentage of linked patients virally suppressed was compared at time of linkage by the Navigators (52%) with a second viral load measure after linkage to care (63%) (χ(2) = 11.8; P = 0.01). The combined disease investigator services/ARTAS model of reengagement was effective for locating and reengaging lost HIV clinic patients. Access to HIV surveillance data is critical for the efficient identification of persons truly in need of reengagement.

Decreased dietary protein intake may be associated with increased mortality risk in individuals undergoing maintenance hemodialysis (MHD). We examined 8−year all-cause mortality in 100,088 MHD patients from DaVita dialysis clinics in the US (2001–2009) and hypothesized that survival is better across higher levels of nPNA, (nPCR, a dietary protein intake surrogate) with consistent trends across race and in hypoalbuminemic patients. Time-averaged Cox models were used to estimate death hazard ratios for quarterly averaged nPNA categories controlled for case-mix, comorbidity, dialysis dose, and available markers of malnutrition-inflammation-complex syndrome (MICS). In all patients, both low (

Low serum albumin level is the strongest mortality-predictor in maintenance hemodialysis (MHD) patients. It is not known whether this association is consistent across all age groups, especially in the elderly. We examined the association of serum albumin and all–cause mortality in 105,523 MHD patients across different age groups using Cox models to estimate death hazard ratios for quarterly averaged serum albumin increments controlled for case–mix, comorbidity, dialysis dose, and available markers of malnutrition–inflammation–complex syndrome (MICS) in all age groups. In those 4.0 g/dL continues to provide incremental survival advantage (Panel A), whereas in patients >65 yr old, no additional survival gain is observed beyond 4.0−g/dL (Panels B-D). High albumin levels are linearly associated with greater survival in all MHD patients although in the elderly gain stops at albumin >4.0 g/dL. Figure options Download full-size image Download as PowerPoint slide