Increasing precision in the measurement of change in pediatric neurodegenerative disease.

Due to the surge in new brain-directed treatments, metrics to detect the alteration in developmental trajectories in cognition and adaptive behavior have become increasingly important. We propose Growth Scale Values (GSVs) as a solution to monitoring children with severe neurologic/neurodegenerative conditions. This report stems from a panel of experts presenting at the Gorlin symposium (WORLD Symposium) and a subsequent open Webinar sponsored by the National MPS Society. Because norm-referenced scores (Standard Scores or Intelligence Quotient, i.e., IQ) do not yield information about gain, stability, or loss of skills, they are not suitable for natural history studies or clinical trials. Age-equivalent (AE) scores have been the standard metric used in natural history studies. While AEs are familiar and interpretable to clinicians and parents, they are imprecise due to lack of standard deviations, standard errors of measurement, and equal intervals between scores. Raw scores also have unequal intervals and are not comparable between ages or ability levels. The GSV, a nonlinear transformation of raw scores using item calibration to make an interval scale score, can be used for accurate measures of within-person change. GSVs have been identified as a useful metric for longitudinal measurement of other conditions involving neurodiversity. These growth scores circumvent inaccurate AEs in infants, are not limited by age and can be used for impaired patients who are chronologically above the normative age range. GSVs have interval properties (a given difference between GSV values represents the same difference in ability at all score levels) and each GSV value has a known standard error of measurement (SEM). GSVs are recommended to measure change in cognitive and adaptive behavior in natural history studies and in clinical trials for children with neurologic disease.

Assessing sociodemographic differences in human papillomavirus vaccine impact studies in the United States: a systematic review using narrative synthesis.

OBJECTIVES: Sociodemographic disparities in the incidence and mortality of human papillomavirus (HPV)-associated conditions have been well documented in the pre-HPV vaccine era. It is still unknown if the introduction of routine vaccination has been effective in reducing these prevaccine era inequalities. The purpose of this review was to determine the utilization of sociodemographic variables to assess for disparities in population-level HPV vaccine impact research and to evaluate the current evidence for disparities in the reduction of HPV-associated conditions after vaccine introduction in the United States (US). STUDY DESIGN: A systematic review of the literature from January 2007 through March 2018 was carried out to identify studies evaluating the impact HPV vaccines have had on the rates of HPV infection, genital warts, and cervical dysplasia (cervical intraepithelial neoplasia grades 1+) in the US. An in-depth review was then performed to synthesize these data and to assess the way prior studies have reported and evaluated for potential disparities in the vaccine's impact within various racial, ethnic, and/or socio-economic subgroups of the population. METHODS: Vaccine impact studies measure the change in the population-level burden of disease prelicensure versus postlicensure of the vaccine. We systematically searched PubMed/Medline and Embase, combining search terms related to the HPV vaccine, sentinel surveillance, and HPV-associated conditions. Eligible studies were those with population-level, postvaccine introduction data that were conducted in the US. Finally, a cited reference search was conducted for all included articles using the Web of Science platform that accesses three major citation indexes: Science Citation Index, Social Sciences Citation Index, and Arts and Humanities Citation Index. This allowed us to screen not only the articles that were cited by our final collection of studies but also the articles that used our selected studies as one of their references. The study protocol is registered in PROSPERO (#CRD42018107579). RESULTS: Overall, 23 of the 4139 references retrieved assessed the population-level impact of HPV vaccines between January 1, 2007, and March 29, 2018. Among these, 13 (57%) reported sociodemographic data. Only two articles reported stratified results by sociodemographic factors, thereby allowing assessment for potential disparate impact. One of these studies described differences in the impact of the vaccine by race, ethnicity, and income. CONCLUSION: Although approximately half of the studies that assessed the impact of the HPV vaccine measured sociodemographic characteristics, few presented results in a way that allowed for the identification of potential differences in impact between the relevant subgroups of the population. Determining to what extent, if any, vaccines are reducing known sociodemographic disparities is an important public health priority and an essential step in developing immunization strategies that are beneficial for all.

Method for computing the optimal signal distribution and channel capacity.

An iterative method for computing the channel capacity of both discrete and continuous input, continuous output channels is proposed. The efficiency of new method is demonstrated in comparison with the classical Blahut - Arimoto algorithm for several known channels. Moreover, we also present a hybrid method combining advantages of both the Blahut - Arimoto algorithm and our iterative approach. The new method is especially efficient for the channels with a priory unknown discrete input alphabet.

Research challenges in central nervous system manifestations of inborn errors of metabolism.

The Research Challenges in CNS Manifestations of Inborn Errors of Metabolism workshop was designed to address challenges in translating potential therapies for these rare disorders, and to highlight novel therapeutic strategies and innovative approaches to CNS delivery, assessment of effects and directions for the future in the treatment of these diseases. Therapies for the brain in inborn errors represent some of the greatest challenges to translational research due to the special properties of the brain, and of inborn errors themselves. This review covers the proceedings of this workshop as submitted by participants. Scientific, ethical and regulatory issues are discussed, along with ways to measure outcomes and the conduct of clinical trials. Participants included regulatory and funding agencies, clinicians, scientists, industry and advocacy groups.

Early psychological interventions for prevention and treatment of post-traumatic stress disorder (PTSD) and post-traumatic stress symptoms in post-partum women: A systematic review and meta-analysis.

BACKGROUND: Pre-term or full-term childbirth can be experienced as physically or psychologically traumatic. Cumulative and trans-generational effects of traumatic stress on both psychological and physical health indicate the ethical requirement to investigate appropriate preventative treatment for stress symptoms in women following a routine traumatic experience such as childbirth. OBJECTIVE: The objective of this review was to investigate the effectiveness of early psychological interventions in reducing or preventing post-traumatic stress symptoms and post-traumatic stress disorder in post-partum women within twelve weeks of a traumatic birth. METHODS: Randomised controlled trials and pilot studies of psychological interventions preventing or reducing post-traumatic stress symptoms or PTSD, that included women who had experienced a traumatic birth, were identified in a search of Cochrane Central Register of Randomised Controlled Trials, MEDLINE, Embase, Psychinfo, PILOTS, CINAHL and Proquest Dissertations databases. One author performed database searches, verified results with a subject librarian, extracted study details and data. Five authors appraised extracted data and agreed upon risk of bias. Analysis was completed with Rev Man 5 software and quality of findings were rated according to Grading of Recommendation, Assessment, Development, and Evaluation. RESULTS: Eleven studies were identified that evaluated the effectiveness of a range of early psychological interventions. There was firm evidence to suggest that midwifery or clinician led early psychological interventions administered within 72 hours following traumatic childbirth are more effective than usual care in reducing traumatic stress symptoms in women at 4-6 weeks. Further studies of high methodological quality that include longer follow up of 6-12 months are required in order to substantiate the evidence of the effectiveness of specific face to face and online early psychological intervention modalities in preventing the effects of stress symptoms and PTSD in women following a traumatic birth before introduction to routine care and practice. PROSPERO REGISTRATION: CRD42020202576, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=202576.

Renal insufficiency is an independent risk factor for complications after partial nephrectomy.

PURPOSE: We identify and describe the postoperative outcomes of a single surgeon partial nephrectomy cohort. We performed univariate and multivariate analysis on preoperative patient characteristics, and their association with increased length of stay and postoperative complication rates. MATERIALS AND METHODS: Perioperative characteristics of 146 consecutive patients undergoing partial nephrectomy were recorded. Postoperative complications were defined as those occurring within 30 days using the Clavien postoperative complication scale. We conducted logistic regression analysis to evaluate the development of complications and linear regression analysis to determine the effect on length of stay. RESULTS: In a linear regression model patients with renal insufficiency had a mean of 1.7 +/- 0.6 days longer length of stay compared to those with normal renal function (p = 0.006). Complications occurred in 48.5% in the renal insufficiency group compared with 16.8% in the other cohort (p = 0.0004). There were no mortalities. On univariable analysis 4 factors were significantly associated with the development of complications including race (p = 0.03), preoperative Modification of Diet in Renal Disease less than 60 (p <0.0001), tumor size greater than 4 cm (p = 0.03) and estimated blood loss (p = 0.04). On multivariable analysis the 2 factors of Modification of Diet in Renal Disease less than 60 (p = 0.003) and race (p = 0.03) remained significant. The odds ratio for complications comparing patients with renal insufficiency to the normal cohort, adjusting for confounding factors, was 4.58 (95% CI 1.65-12.65). CONCLUSIONS: Preoperative renal insufficiency defined as Modification of Diet in Renal Disease less than 60 and non African-American race, which may be related to Modification of Diet in Renal Disease, are predictive of complications after partial nephrectomy. Decreased Modification of Diet in Renal Disease is an independent risk factor for increased length of hospital stay and increased complication rate in partial nephrectomy.

The nature and impact of neurobehavioral symptoms in neuronopathic Hunter syndrome.

In neuronopathic Hunter syndrome, neurobehavioral symptoms are known to be serious but have been incompletely described. While families face significant stress stemming from this complex and far-reaching array of symptoms, neither caregiver burden nor the neurobehavioral symptoms have been measured comprehensively. We delineated these neurobehavioral characteristics and their impact on the caregiver using multiple approaches. Methods: As part of the initial phase of developing a Hunter-specific behavioral assessment tool, we used multiple methods to obtain data on patient behaviors and caregiver burden, with the intention of drafting item sets for the tool. We utilized 1) caregiver descriptions from focus groups and individual interviews, 2) observations from video-recorded play of affected children, 3) descriptions from historic chart review, 4) consultation with patient advocacy groups and international experts, 5) reports from a caregiver advisory board, and 6) literature review. Results: Neurobehavioral symptoms were diverse and categorized as focus/attention, impulsivity/heightened activity, sensation seeking, emotional/behavioral function, social interaction, and sleep. A significant reported challenge was susceptibility to misinterpretation of some behaviors as defiant or aggressive, particularly if physical. Caregiver burden involved social isolation, exhaustion, stress, and financial and vocational strain. These new descriptions will aid in developing quantitative measures of change in neurobehavioral symptoms and family burden. These descriptions will be the foundation of a neurobehavioral rating scale, which is very much needed to aid in patient management and assess interventions for individuals with neuronopathic Hunter syndrome.

Initial evaluation of the use of USPIO cell labeling and noninvasive MR monitoring of human tissue-engineered vascular grafts in vivo.

This pilot study examines noninvasive MR monitoring of tissue-engineered vascular grafts (TEVGs) in vivo using cells labeled with iron oxide nanoparticles. Human aortic smooth muscle cells (hASMCs) were labeled with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles. The labeled hASMCs, along with human aortic endothelial cells, were incorporated into eight TEVGs and were then surgically implanted as aortic interposition grafts in a C.B-17 SCID/bg mouse host. USPIO-labeled hASMCs persisted in the grafts throughout a 3 wk observation period and allowed noninvasive MR imaging of the human TEVGs for real-time, serial monitoring of hASMC retention. This study demonstrates the feasibility of applying noninvasive imaging techniques for evaluation of in vivo TEVG performance.

Ablation of uroplakin III gene results in small urothelial plaques, urothelial leakage, and vesicoureteral reflux.

Urothelium synthesizes a group of integral membrane proteins called uroplakins, which form two-dimensional crystals (urothelial plaques) covering >90% of the apical urothelial surface. We show that the ablation of the mouse uroplakin III (UPIII) gene leads to overexpression, defective glycosylation, and abnormal targeting of uroplakin Ib, the presumed partner of UPIII. The UPIII-depleted urothelium features small plaques, becomes leaky, and has enlarged ureteral orifices resulting in the back flow of urine, hydronephrosis, and altered renal function indicators. Thus, UPIII is an integral subunit of the urothelial plaque and contributes to the permeability barrier function of the urothelium, and UPIII deficiency can lead to global anomalies in the urinary tract. The ablation of a single urothelial-specific gene can therefore cause primary vesicoureteral reflux (VUR), a hereditary disease affecting approximately 1% of pregnancies and representing a leading cause of renal failure in infants. The fact that VUR caused by UPIII deletion seems distinct from that caused by the deletion of angiotensin receptor II gene suggests the existence of VUR subtypes. Mutations in multiple gene, including some that are urothelial specific, may therefore cause different subtypes of primary reflux. Studies of VUR in animal models caused by well-defined genetic defects should lead to improved molecular classification, prenatal diagnosis, and therapy of this important hereditary problem.

Identification of a peptide specific for Aplysia sensory neurons by PCR-based differential screening.

In order to identify genes specific for the sensory neurons of Aplysia, a miniaturized differential screening method based on the polymerase chain reaction and applicable to small amounts of tissue was used. One messenger RNA was isolated that is expressed in every mechanoreceptor sensory cluster of the Aplysia central nervous system. This messenger RNA encodes a peptide that seems to function as an inhibitory cotransmitter. The peptide selectively inhibits certain postsynaptic cells but not others and thereby allows the sensory neurons to achieve target-specific synaptic actions.

Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome.

Hurler syndrome (mucopolysaccharidosis type I, MPS IH) is characterized by a deficiency of alpha-L-iduronidase resulting in progressive multiorgan dysfunction. We sought to determine whether enzyme replacement therapy (ERT) with iduronidase in the peritransplant period affects outcome of hematopoietic stem cell transplantation (HSCT) for MPS IH. Seven children with MPS IH at a median age of 1.5 years at the time of myeloablative HSCT were eligible. All patients had null mutations in IDUA gene. Iduronidase (0.58 mg/kg per dose) was administered intravenously in 11-14 weekly doses before HSCT and 8 weekly doses after HSCT. The infusions were well tolerated. All patients developed antibodies to iduronidase but all engrafted with >90% donor hematopoiesis. A majority of patients had significant pulmonary complications before ERT and HSCT but all are alive and well with a median follow-up of more than 1 year after HSCT. This suggests that ERT prior to HSCT is unlikely to alter engraftment. In addition, morbidity was acceptable, despite a previous history of pulmonary difficulties that suggested that these patients were high risk for these complications. Therefore, we recommend treatment of MPS IH patients with combination of ERT and HSCT therapy to further investigate its potential to enhance outcomes with HSCT.

Local tissue water changes assessed by tissue dielectric constant: single measurements versus averaging of multiple measurements.

Previous reports describe the use of average tissue dielectric constant (TDC) measurements to assess local tissue water and its change. Our goal was to determine if a single TDC measurement could be used in place of the average of multiple measurements. The comparison criteria used to test this was the extent to which single and averaged measurements yielded similar TDC values in both normal and lymphedematous tissue. Measurements were made on both ventral forearms to a depth of 2.5 mm in 10 women with unilateral arm lymphedema. The main results showed that the 95% confidence interval for differences between single and averaged TDC values was less than +/- 1 TDC unit for both normal and lymphedematous arms. This finding strongly suggests that for most, if not all, clinical evaluations, suitable assessments can be made using a single TDC measurement.

Localized tissue water changes accompanying one manual lymphatic drainage (MLD) therapy session assessed by changes in tissue dielectric constant inpatients with lower extremity lymphedema.

Previous reports described the utility of assessing local tissue water via tissue dielectric constant (TDC) measurements. Our goal was to determine the suitability of this method to evaluate lymphedema changes. For this purpose, we measured changes in TDC produced by one MLD treatment in 27 legs of 18 patients with lower extremity lymphedema. TDC values were measured to a depth of 2.5 mm at the greatest leg swelling site before and after one MLD treatment. Girth at the target site was measured with a calibrated tape measure. TDC values, which range from 1 for zero water to 78.5 for all water within the sampled volume, were measured four times and the average used to estimate local changes. Results showed that in every case the posttreatment TDC was reduced from its pretreatment value with percentage reductions (mean SD) of -9.8 +/- 5.64% (p < 0.0001). Girth changes were smaller being -1.5 +/- 1.93% (p < 0.01). We conclude that since TDC measurements reflect changes to a depth of about 2.5 mm whereas girth measurements reflect conditions of the entire cross-section, TDC assessment may be more sensitive to localized lymphedema changes. This finding suggests that TDC measurements are useful as complementary and perhaps as independent assessment methods of edema/lymphedema and treatment-related changes.

Tumor hypoglycemia: relationship to high molecular weight insulin-like growth factor-II.

The mechanism of tumor-associated hypoglycemia was examined in 11 patients with hepatocellular carcinoma, 6 of whom presented with severe hypoglycemia and 5 in whom plasma glucose was persistently normal. Serum insulin levels in the hypoglycemic patients were low. Although total serum insulin-like growth factor II (IGF-II) levels in both groups of tumor patients were lower than normal, tumor tissue from hypoglycemic patients contained levels of IGF-II mRNA that were 10-20-fold higher than those present in normal liver. IGF-II immunoreactivity consisted in all cases of a mixture of both higher molecular weight forms and material having the character of IGF-II itself. The former comprised a greater proportion of total IGF-II, in patients with hypoglycemia. Studies to characterize the interactions of IGF-II with serum proteins showed that (a) the radiolabeled peptide bound to an approximately 40,000-D protein in sera from both hypoglycemic patients and normal subjects, (b) sera from hypoglycemic patients and normal subjects had similar capacity to bind the radiolabeled peptide, and (c) the apparent affinities of serum binding proteins for IGF-II were the same for both hypoglycemic patients and normal subjects. Whereas, acid extracted, tumor-derived IGF-II immunoreactive peptides with low or intermediate molecular weights bound to serum proteins in a manner indistinguishable from that of IGF-II itself, the highest molecular weight IGF-II immunoreactive peptide exhibited negligible ability to compete for radiolabeled ligand binding to serum proteins. The low affinity of serum binding proteins for this component suggests that high molecular weight IGF-II immunoreactivity might circulate free and be available for interaction with cell-surface receptors.

Quantitative study of insulin secretion and clearance in normal and obese subjects.

The secretion and hepatic extraction of insulin were compared in 14 normal volunteers and 15 obese subjects using a previously validated mathematical model of insulin secretion and rate constants for C-peptide derived from analysis of individual decay curves after intravenous bolus injections of biosynthetic human C-peptide. Insulin secretion rates were substantially higher than normal in the obese subjects after an overnight fast (86.7 +/- 7.1 vs. 50.9 +/- 4.8 pmol/m2 per min, P less than 0.001, mean +/- SEM), over a 24-h period on a mixed diet (279.6 +/- 24.2 vs. 145.8 +/- 8.8 nmol/m2 per 24 h, P less than 0.001), and during a hyperglycemic intravenous glucose infusion (102.2 +/- 10.8 vs. 57.2 +/- 2.8 nmol/m2 per 180 min, P less than 0.001). Linear regression analysis revealed a highly significant relationship between insulin secretion and body mass index. Basal hepatic insulin extraction was not significantly different in the normal and obese subjects (53.1 +/- 3.8 vs. 51.6 +/- 4.0%). In the normal subjects, fasting insulin did not correlate with basal hepatic insulin extraction, but a significant negative correlation between fasting insulin and hepatic insulin extraction was seen in obesity (r = -0.63, P less than 0.02). This finding reflected a higher extraction in the six obese subjects with fasting insulin levels within the range of the normal subjects than in the nine subjects with elevated fasting insulin concentrations (61 +/- 3 vs. 45 +/- 6%, P less than 0.05). During the hyperglycemic clamp, the insulin secretion rate increased to an average maximum of 6.2-fold over baseline in the normal subjects and 5.8-fold in the obese subjects. Over the same time, the peripheral insulin concentration increased 14.1-fold over baseline in the normals and 16.6-fold over baseline in the obese, indicating a reduction in the clearance of endogenously secreted insulin. Although the fall in insulin clearance tended to be greater in the obese subjects, the differences between the two groups were not statistically significant. Thus, under basal, fasting conditions and during ingestion of a mixed diet, the hyperinsulinemia of obesity results predominantly from increased insulin secretion. In patients with more marked basal hyperinsulinemia and during intense stimulation of insulin secretion, a reduction in insulin clearance may contribute to the greater increase in peripheral insulin concentrations that are characteristic of the obese state.+

N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy.

Hematopoietic stem cell transplantation as a treatment for childhood cerebral adrenoleukodystrophy (ALD) has historically only been successful in early disease. As ALD is associated with oxidative damage, we reasoned that adjunctive therapy with an antioxidant agent, N-acetyl-L-cysteine (NAC), may provide protection from rapid neurologic decline in boys with advanced cerebral disease. We report three boys with advanced ALD, whose neurologic status and brain radiographic findings were stabilized by treatment including NAC 8-11 months after hematopoietic stem cell transplantation. These results contrast with previous survival data in cerebral ALD patients who had a similar degree of brain involvement, all of whom died within 1 year of stem cell infusion despite a full donor engraftment. Thus, NAC merits investigation as a therapeutic strategy for patients with advanced ALD as an intervention that could change this lethal disease to a condition amendable to treatment with hematopoietic stem cell transplantation.

The American Academy of Pediatrics Workforce Survey for the Section on Urology 2015.

INTRODUCTION: In 2013, the American Academy of Pediatrics (AAP) Division of Workforce and Medical Education Policy assumed the task of organizing the updated AAP Workforce Survey, which was modeled after the Future of Pediatric Education II study. OBJECTIVE: The objective of the present study was to evaluate changes in practice patterns of all pediatric medical and surgical specialists over time, to facilitate advocacy work by the Academy at federal and state levels. STUDY DESIGN: The survey was sent to members of the AAP Section on Urology and the Society for Pediatric Urology between June and November 2014. The survey included general and sub-specialty-specific questions. Data analysis was performed using SPSS 18.0. Descriptive statistics, including frequency distributions and measures of central tendency, were used to summarize all responses. RESULTS: A total of 255 pediatric urologists returned the survey, giving a response rate of 56.4%. The specialty remained vibrant, and members remained content in their career choice. About two-thirds practiced in a full-time clinical setting, and had research, teaching, and/or administrative duties. About 75% reported no change in clinical volume or case complexity, although 50% reported an increase in their referral base. A 50% increase in minor cases and a 43.3% decrease in open cases were reported. Only 13% planned to retire within the next 3-6 years. The current job market for fellows was unrestricted for 51.3%, significantly restricted for location for 23.1%, and restricted with regard to practice type for 25.6%. Overall, 51%, 37%, and 13% of the respondents expressed the opinions that over the next 5 years, too many specialists in pediatric urology were currently being trained, just the right number, and too few, respectively. Medical student interest remained encouraging. DISCUSSION: One of the primary objectives of the survey was to gain insights into whether there was concordance between the number of trainees and the current and future job opportunities. Unfortunately, the main limitations of the survey were the questions on retirement and adding a partner. Since the survey was anonymous, there was a missed opportunity to direct fellows to specific job openings. In addition, every member of a large group may have individually responded, inflating the responses or, in some cases, negating the responses if the partners did not agree. CONCLUSION: Pediatric urologists have an overall sense of contentment of career choice, despite shifts in complex open surgical volume and increasing competition. Surveys that are not anonymous would provide specific geographical manpower needs.

Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma.

Although many genetic alterations are known to be associated with human transitional cell carcinoma (TCC) of the urinary bladder, relatively little is known about the roles of these molecular defects, singular or in combination, in bladder tumorigenesis. We have developed a transgenic mouse model of bladder tumorigenesis using a 3.6-kb promoter of uroplakin II gene to drive the urotheliums-specific expression of oncogenes. In this study, we demonstrate that transgenic mice bearing a low copy number of SV40T transgene developed bladder carcinoma in situ (CIS), whereas those bearing high copies developed CIS as well as invasive and metastatic TCCs. These results indicate that the SV40T inactivation of p53 and retinoblastoma gene products, defects frequently found in human bladder CIS and invasive TCCs, can cause the aggressive form of TCC. Our results also provide experimental proof that CIS is a precursor of invasive TCCs, thus supporting the concept of two distinct pathways of bladder tumorigenesis (papillary versus CIS/invasive TCC). This transgenic system can be used for the systematic dissection of the roles of individual or combinations of specific molecular events in bladder tumorigenesis.

Mucopolysaccharidosis (MPS) Physical Symptom Score: Development, Reliability, and Validity.

OBJECTIVES: We quantified medical signs and symptoms to construct the Physical Symptom Score (PSS) for use in research to assess somatic disease burden in mucopolysaccharidoses (MPS) to track disease and monitor treatments. We examined scoring reliability, its concurrent validity with other measures, and relationship to age in MPS type I. METHODS: Fifty-four patients with MPS I (36 with Hurler syndrome treated with hematopoietic cell transplant and 18 with attenuated MPS I treated with enzyme replacement therapy), ages 5 to 18 years, were seen longitudinally over 5 years. The summation of frequency and severity of signs of specific organ involvement, surgeries, and hydrocephalus drawn from medical histories comprise the PSS. We examined relationship to age and to daily living skills (DLS) from the Vineland Adaptive Behavior Scale and physical quality of life from the Child Health Questionnaire (CHQ) for each group. RESULTS: The PSS was associated with age in both groups, indicating increase in disease burden over time. The PSS was significantly negatively associated with DLS (r = -0.48) and CHQ (r = -0.55) in the attenuated MPS I but not in the Hurler group. CONCLUSIONS: The association of somatic disease burden with physical quality of life and ability to carry out daily living skills suggests that the PSS will be useful in the measurement of disease and treatment effects in the attenuated MPS I group. Earlier treatment with transplant and differing parental expectations are possible explanations for its lack of association with other outcomes necessitating an adaptation for Hurler syndrome in the future.