Early experiences of nusinersen for the treatment of spinal muscular atrophy: Results from a large survey of patients and caregivers.

BACKGROUND: This study aimed to examine the early experience of nusinersen for spinal muscular atrophy (SMA) from the patient and caregiver perspective. METHODS: A 54-item online survey was administered to adult patients and caregivers of pediatric patients diagnosed with SMA. RESULTS: Overall, respondents (56 patients and 45 caregivers) were satisfied with nusinersen. Satisfaction was highest on changes in energy, stamina, and motor function and lowest on treatment administration and overall time commitment. Differences were noted for treatment effect sustained over time as reported by adult patients vs caregivers reporting on behalf of pediatric patients. Respondents reported insurance approval as a key barrier to access, particularly among adult patients. CONCLUSIONS: Despite therapeutic advances, there remain significant unmet needs for SMA. Challenges with administration and barriers to access potentially limit the number of patients treated or delay treatment. Continued efforts are needed to develop more treatment options and to improve access to treatments.

Assessment of 2,4-Dinitroanisole Transformation Using Compound-Specific Isotope Analysis after In Situ Chemical Reduction of Iron Oxides.

Ferrous iron-bearing minerals are important reductants in the contaminated subsurface, but their availability for the reduction of anthropogenic pollutants is often limited by competition with other electron acceptors including microorganisms and poor accessibility to Fe(II) in complex hydrogeologic settings. The supply of external electron donors through in situ chemical reduction (ISCR) has been proposed as one remediation approach, but the quantification of pollutant transformation is complicated by the perturbations introduced to the subsurface by ISCR. Here, we evaluate the application of compound specific isotope analysis (CSIA) for monitoring the reduction of 2,4-dinitroanisole (DNAN), a component of insensitive munitions formulations, by mineral-bound Fe(II) generated through ISCR of subsurface material from two field sites. Electron balances from laboratory experiments in batch and column reactors showed that 3.6% to 11% of the total Fe in the sediments was available for the reduction of DNAN and its partially reduced intermediates after dithionite treatment. The extent of DNAN reduction was successfully quantified from its N isotope fractionation measured in the column effluent based on the derivation of a N isotope enrichment factor, εN, derived from a comprehensive series of isotope fractionation experiments with numerous Fe(II)-bearing minerals as well as dithionite-reduced subsurface materials. Our observations illustrate the utility of CSIA as a robust approach to evaluate the success of in situ remediation through abiotic contaminant reduction.

Assessment of the chlorine demand and disinfection byproduct formation potential of surface waters via satellite remote sensing.

The ability of satellites to assess surface water quality indicators such as colored dissolved organic matter (CDOM) suggests that remote sensing could be a useful tool for evaluating water treatability metrics in considering potential drinking water supplies. To explore this possibility, 24 surface water samples were collected throughout Minnesota, USA with wide ranging values of CDOM (a440; 0.41-27.9 m-1), dissolved organic carbon (DOC; 5.5-47.6 mg/L) and specific ultraviolet absorbance at 254 nm (SUVA254; 1.3-5.1 L/mg-M). Laboratory experiments were performed to quantify chlorine demand and the formation of two classes of halogenated disinfection byproducts (DBPs), trihalomethanes (THMs) and haloacetic acids (HAAs), using the uniform formation conditions (UFC) test. Chlorine demand and THMUFC were linearly correlated with CDOM (R2 = 0.97 and 0.91, respectively), indicating that CDOM is a useful predictor of these parameters. On the other hand, data comparing di- and tri-HAAUFC with CDOM were better fit by a logarithmic relationship (R2 = 0.73 and 0.87, respectively), while mono-HAAUFC was linearly correlated with CDOM (R2 = 0.46) but only for low-to moderately-colored waters (a440 ≤ 11 m-1). The correlations relating chlorine demand and DBPUFC values with CDOM were coupled with satellite CDOM assessments to estimate chlorine demand and DBPUFC values for all surface waters larger than 0.05 km2 in the state of Minnesota, USA. The resulting maps suggest that only 21.8% of Minnesota lakes would meet both the THM and HAA maximum contaminant levels, but only when pre-disinfection treatment removes 75% of DBP precursors. There are limitations to determining CDOM using satellites for high color surface waters (a440 > 11 m-1), however, leading to underpredicted values for CDOM, chlorine demand, and DBPUFC. Overall, the results demonstrate the potential benefits of satellite remote sensing for assessing potential drinking water sources and water treatability metrics.

Color, chlorophyll a, and suspended solids effects on Secchi depth in lakes: implications for trophic state assessment.

Secchi depth (SD), a primary metric to assess trophic state, is controlled in many lakes by algal densities, measured as chlorophyll-a (chl-a) concentration. Two other optically related water quality variables also directly affect SD: non-algal suspended solids (SSNA ) and colored dissolved organic matter (CDOM, expressed as the absorption coefficient at 440 nm, a440 ). Using a database of ~1,460 samples from ~625 inland lake basins in Minnesota and two other Upper Midwest states, Wisconsin and Michigan, we analyzed relationships among these variables, with special focus on CDOM levels that influence SD values and the Minnesota SD standards used to assess eutrophication impairment of lakes. Log-transformed chl-a, total suspended solids (TSS), and SD were strongly correlated with each other; log(a440 ) had major effects on log(SD) but was only weakly correlated with log(chl-a) and log(TSS). Multiple regression models for log(SD) and 1/SD based on the three driving variables (chl-a, SSNA , and CDOM) explained ~80% of the variance in SD in the whole data set, but substantial differences in the form of the best-fit relationships were found between major ecoregions. High chl-a concentrations (> 50 µg/L) and TSS (> 20 mg/L) rarely occurred in lakes with high CDOM (a440  > ~4 m-1 ), and all lakes with a440  > 8 m-1 had SD ≤ 2.0 m despite low chl-a values (<10 µg/L) in most lakes. Further statistical analyses revealed that CDOM has significant effects on SD at a440 values > ~ 4 m-1 . Thus, SD is not an accurate trophic state metric in moderately to highly colored lakes, and Minnesota's 2-m SD criterion should not be the sole metric to assess eutrophication impairment in warm/cool-water lakes of the Northern Lakes and Forest ecoregion. More generally, trophic state assessments using SD in regions with large landscape sources of CDOM need to account for effects of CDOM on SD.

Rapid and Economic Synthesis of a Li7PS6 Solid Electrolyte from a Liquid Approach.

Solid electrolytes are the key to realize future solid-state batteries that show the advantages of high energy density and intrinsic safety. However, most solid electrolytes require long time and energy-consuming synthesis conditions of either extended ball milling or high-temperature solid-state reactions, impeding practical applications of solid electrolytes for large-scale systems. Here, we report a new and rapid liquid-based synthetic method for preparing a high-purity Li7PS6 solid electrolyte through the stoichemical reaction of Li3PS4 and Li2S. This method relies on facile and low-cost solution-based soft chemistry to complete chemical reaction in extensively short time (2 h). The prepared Li7PS6 solid electrolyte shows a high phase purity, an impressive ionic conductivity (0.11 mS cm-1), and a reasonable electrochemical stability with a metallic lithium anode. Our results highlight the use of an economic and nontoxic solvent to quickly synthesize a Li7PS6 solid electrolyte, which would promote the development of solid-state batteries for next-generation energy storage systems.

A comparison of three electrophysiological methods for the assessment of disease status in a mild spinal muscular atrophy mouse model.

OBJECTIVES: There is a need for better, noninvasive quantitative biomarkers for assessing the rate of progression and possible response to therapy in spinal muscular atrophy (SMA). In this study, we compared three electrophysiological measures: compound muscle action potential (CMAP) amplitude, motor unit number estimate (MUNE), and electrical impedance myography (EIM) 50 kHz phase values in a mild mouse model of spinal muscular atrophy, the Smn1c/c mouse. METHODS: Smn1c/c mice (N = 11) and wild type (WT) animals (-/-, N = 13) were measured on average triweekly until approximately 1 year of age. Measurements included CMAP, EIM, and MUNE of the gastrocnemius muscle as well as weight and front paw grip strength. At the time of sacrifice at one year, additional analyses were performed on the animals including serum survival motor neuron (SMN) protein levels and muscle fiber size. RESULTS: Both EIM 50 kHz phase and CMAP showed strong differences between WT and SMA animals (repeated measures 2-way ANOVA, P<0.0001 for both) whereas MUNE did not. Both body weight and EIM showed differences in the trajectory over time (p<0.001 and p = 0.005, respectively). At the time of sacrifice at one year, EIM values correlated to motor neuron counts in the spinal cord and SMN levels across both groups of animals (r = 0.41, p = 0.047 and r = 0.57, p  = 0.003, respectively), while CMAP did not. Motor neuron number in Smn1c/c mice was not significantly reduced compared to WT animals. CONCLUSIONS: EIM appears sensitive to muscle status in this mild animal model of SMA. The lack of a reduction in MUNE or motor neuron number but reduced EIM and CMAP values support that much of the pathology in these animals is distal to the cell body, likely at the neuromuscular junction or the muscle itself.

Correlations between in situ sensor measurements and trace organic pollutants in urban streams.

Quantification of organic and microbial pollutant loading is expensive and labor-intensive because collection and analysis of grab samples are needed. Instruments are available, however, for in situ analysis of basic water quality parameters at high temporal resolution. Throughout the late summer and fall of 2008 a two-node water quality monitoring network was deployed to measure turbidity, specific conductance, pH, depth, temperature, dissolved oxygen, and nitrate at high frequencies in two urban streams in the Minneapolis, MN metropolitan area. Grab samples also were collected at 2 h intervals for 22 h during two dry periods and five rain events and analyzed for organic and microbial pollutants. This study investigated the viability of using in situ near real-time sensors to predict fecal coliforms, prometon (a residential herbicide), atrazine (an agricultural herbicide), and caffeine (a wastewater indicator) concentrations. Such pollutants can be used as indicators of sources that contribute to what is often termed "urban stream syndrome." At one stream, linear correlations were observed between nitrate and caffeine (R(2) = 0.66), turbidity and prometon (R(2) = 0.91), and discharge and prometon (R(2) = 0.92). At another location, caffeine linearly correlated with specific conductance (R(2) = 0.64). A lack of correlation with sensed water quality parameters was also observed with some of the pollutants. When one considers that error is estimated to be as high as 200% when using monthly grab samples to estimate pollutant loading in streams, even moderate correlations, such as the ones found in this study, can provide better loading estimates if frequently sensed parameters can be used for load estimation. Therefore, such site-specific relationships can be used to estimate the loading of specific pollutants in near real-time until robust low-cost technologies to analyze these pollutants in situ become available.

Role of environmental surveillance in determining the risk of hospital-acquired legionellosis: a national surveillance study with clinical correlations.

OBJECTIVE: Hospital-acquired Legionella pneumonia has a fatality rate of 28%, and the source is the water distribution system. Two prevention strategies have been advocated. One approach to prevention is clinical surveillance for disease without routine environmental monitoring. Another approach recommends environmental monitoring even in the absence of known cases of Legionella pneumonia. We determined the Legionella colonization status of water systems in hospitals to establish whether the results of environmental surveillance correlated with discovery of disease. None of these hospitals had previously experienced endemic hospital-acquired Legionella pneumonia. DESIGN: Cohort study. SETTING: Twenty US hospitals in 13 states. INTERVENTIONS: Hospitals performed clinical and environmental surveillance for Legionella from 2000 through 2002. All specimens were shipped to the Special Pathogens Laboratory at the Veterans Affairs Pittsburgh Medical Center. RESULTS: Legionella pneumophila and Legionella anisa were isolated from 14 (70%) of 20 hospital water systems. Of 676 environmental samples, 198 (29%) were positive for Legionella species. High-level colonization of the water system (30% or more of the distal outlets were positive for L. pneumophila) was demonstrated for 6 (43%) of the 14 hospitals with positive findings. L. pneumophila serogroup 1 was detected in 5 of these 6 hospitals, whereas 1 hospital was colonized with L. pneumophila serogroup 5. A total of 633 patients were evaluated for Legionella pneumonia from 12 (60%) of the 20 hospitals: 377 by urinary antigen testing and 577 by sputum culture. Hospital-acquired Legionella pneumonia was identified in 4 hospitals, all of which were hospitals with L. pneumophila serogroup 1 found in 30% or more of the distal outlets. No cases of disease due to other serogroups or species (L. anisa) were identified. CONCLUSION: Environmental monitoring followed by clinical surveillance was successful in uncovering previously unrecognized cases of hospital-acquired Legionella pneumonia.

Viscosupplementation: managed care issues for osteoarthritis of the knee.

BACKGROUND: Osteoarthritis (OA) affects an estimated 49 million adults in North America, or nearly 1 of every 6 adults. More than 8 million North Americans have limited mobility to some extent because of OA. By 2030, an estimated 71 million North Americans will be diagnosed with OA, an increase of 45% over current figures. For one group-model health maintenance organization (HMO), the average cost of care for patients with OA was $543 per member, a total annual cost to the HMO of $4,728,425. Of this total amount, 46% was for inpatient care, 32% was for medication, and 22% was for ambulatory care. OBJECTIVE: To determine the impact of OA on managed care and discuss treatment options available to those with OA, particularly of the knee. SUMMARY: OA represents an advanced stage of an active, progressive disease process. We know from medical research that OA is the endpoint of a progression in tissue degradation that results in loss of cartilage structure and function. Relief of pain and preservation of joint tissue must evolve to encompass treatments that interfere with cartilage-degrading mechanisms that follow acute or chronic injury, restore normal cartilage and joint homeostasis, and arrest the progression of disease. Optimal future treatments will also reverse existing damage and restore normal cartilage structure and function. Viscosupplementation with an elastoviscous fluid containing polymers of hylan derivatives of the natural glycosaminoglycan hyaluronan is indicated for treating pain of OA of the knee that has not responded to or is contraindicated for conservative nonpharmacologic therapy and traditional analgesics. These analgesics include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors. Clinicians in the managed care setting may consider using viscosupplementation in patients (1) who have persistent pain despite their use of conservative nonpharmacologic and pharmacologic therapy (e.g., exercise, weight loss, physician therapy, bracing/orthotics, NSAIDs, COX-2 inhibitors, and intra-articular glucocorticoids); (2) who have compromised gastrointestinal (GI) function or who are at risk for GI bleeding due to the adverse events of NSAIDs; (3) who are taking concomitant anticoagulant therapy for any condition; (4) who have cardiovascular or renal risk factors that preclude use of COX-2 inhibitors; and (5) for whom surgery is not appropriate. Further study should be conducted with larger numbers of patients to help identify a subgroup of patients with OA in whom viscosupplementation may have even greater effects. Additional research should also concentrate on assessing the risks and benefits of extended treatments, because limited data are available concerning the effectiveness of multiple courses of therapy. CONCLUSION: OA is an important public health issue as the leading cause of disability in North America. As populations age, socioeconomic costs of OA will dramatically increase. Among available treatment options, viscosupplementation is a valuable alternative to more conservative therapy and has the benefit of circumventing the possible side effects of systemically administered pharmacologic agents. Viscosupplementation demonstrated efficacy in OA of the knee, and its use in the managed care arena may generate savings in hospitalizations and other costs.

A quality rating scale for aesthetic surgical procedures.

BACKGROUND: Cosmetic dermatologic procedures offer the promise of visible aesthetic enhancement with minimal risk. While in recent years the number of available procedures has proliferated, there are few objective methods for evaluating the relative quality of these procedures for particular indications or specific patients. OBJECTIVE: (A) To develop a simple, easy-to-use numerical rating scale to assess the quality of cosmetic surgical procedures on a range of parameters pertaining to clinical efficacy and patient satisfaction; (B) to statistically validate the discriminative value of this rating scale. METHODS: (A) Patient and physician interviews were performed to elicit a list of factors that may collectively characterize the clinical efficacy and patient tolerability of cosmetic dermatologic procedures. A 0-100 point rating scale was developed based on these factors, with the face-validity of this scale checked by a group of patients and physicians; (B) Statistical analysis of the questionnaire was performed by asking 15 expert cosmetic dermatologic surgeons to use it to rate 23 common cosmetic dermatologic procedures, and analyzing the results. RESULTS: (A) An easy-to-use scale was constructed to assess the quality of cosmetic dermatologic procedures by rating the associated cost, risk, time (procedure and recovery), discomfort, results, and longevity of benefit. A "physician adjustment factor" was used to further increase the relevance of this 0-100 point scale for specific patients; (B) Repeated-measures analysis of variations (ANOVAs) performed on the data from the survey of experts demonstrated that this scale can be used to discriminate between common dermatologic procedures. The differences in mean subscores and total scores among procedures grouped by anatomic site and target lesion-type were significant at the level of P < .05. LIMITATIONS: Patient preferences exogenous to the rating scale may increase or decrease the suitability of specific procedures. CONCLUSIONS: Common cosmetic dermatologic procedures are of uniformly high quality, as per expert ratings on a systematic measure. This quality rating scale appears statistically valid and robust, given that expert raters assigned similar ratings to the same procedures but mean ratings were different across procedures. In the future, this quality rating scale can be used to assess novel interventions, and to help dermatologic surgeons faced with patient concern to optimally select among alternative procedures for a given indication.