Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

Low Dissolved Oxygen in an Estuarine Channel (San Joaquin River, California): Mechanisms and Models Based on Long-term Time Series

The Stockton Deep Water Ship Channel, a stretch of the tidal San Joaquin River, is frequently subject to low dissolved oxygen conditions and annually violates regional water quality objectives. Underlying mechanisms are examined here using the long-term water quality data, and the efficacy of possible solutions using time-series regression models. Hypoxia is most common during June-September, immediately downstream of where the river enters the Ship Channel. At the annual scale, ammonium loading from the Regional Wastewater Control Facility has the largest identifiable effect on year-to-year variability. The longer-term upward trend in ammonium loads, which have been increasing over 10% per year, also corresponds to a longer-term downward trend in dissolved oxygen during summer. At the monthly scale, river flow, loading of wastewater ammonium and river phytoplankton, Ship Channel temperature, and Ship Channel phytoplankton are all significant in determining hypoxia. Over the recent historical range (1983–2003), wastewater ammonium and river phytoplankton have played a similar role in the monthly variability of the dissolved oxygen deficit, but river discharge has the strongest effect. Model scenarios imply that control of either river phytoplankton or wastewater ammonium load alone would be insufficient to eliminate hypoxia. Both must be strongly reduced, or reduction of one must be combined with increases in net discharge to the Ship Channel. Model scenarios imply that preventing discharge down Old River with a barrier markedly reduces hypoxia in the Ship Channel. With the Old River barrier in place, unimpaired or full natural flow at Vernalis would have led to about the same frequency of hypoxia that has occurred with actual flows since the early 1980s

Low Dissolved Oxygen in an Estuarine Channel (San Joaquin River, California): Mechanisms and Models Based on Long-term Time Series

The Stockton Deep Water Ship Channel, a stretch of the tidal San Joaquin River, is frequently subject to low dissolved oxygen conditions and annually violates regional water quality objectives. Underlying mechanisms are examined here using the long-term water quality data, and the efficacy of possible solutions using time-series regression models. Hypoxia is most common during June-September, immediately downstream of where the river enters the Ship Channel. At the annual scale, ammonium loading from the Regional Wastewater Control Facility has the largest identifiable effect on year-to-year variability. The longer-term upward trend in ammonium loads, which have been increasing over 10% per year, also corresponds to a longer-term downward trend in dissolved oxygen during summer. At the monthly scale, river flow, loading of wastewater ammonium and river phytoplankton, Ship Channel temperature, and Ship Channel phytoplankton are all significant in determining hypoxia. Over the recent historical range (1983–2003), wastewater ammonium and river phytoplankton have played a similar role in the monthly variability of the dissolved oxygen deficit, but river discharge has the strongest effect. Model scenarios imply that control of either river phytoplankton or wastewater ammonium load alone would be insufficient to eliminate hypoxia. Both must be strongly reduced, or reduction of one must be combined with increases in net discharge to the Ship Channel. Model scenarios imply that preventing discharge down Old River with a barrier markedly reduces hypoxia in the Ship Channel. With the Old River barrier in place, unimpaired or full natural flow at Vernalis would have led to about the same frequency of hypoxia that has occurred with actual flows since the early 1980s.</p

Low Dissolved Oxygen in an Estuarine Channel (San Joaquin River, California): Mechanisms and Models Based on Long-term Time Series

The Stockton Deep Water Ship Channel, a stretch of the tidal San Joaquin River, is frequently subject to low dissolved oxygen conditions and annually violates regional water quality objectives. Underlying mechanisms are examined here using the long-term water quality data, and the efficacy of possible solutions using time-series regression models. Hypoxia is most common during June-September, immediately downstream of where the river enters the Ship Channel. At the annual scale, ammonium loading from the Regional Wastewater Control Facility has the largest identifiable effect on year-to-year variability. The longer-term upward trend in ammonium loads, which have been increasing over 10% per year, also corresponds to a longer-term downward trend in dissolved oxygen during summer. At the monthly scale, river flow, loading of wastewater ammonium and river phytoplankton, Ship Channel temperature, and Ship Channel phytoplankton are all significant in determining hypoxia. Over the recent historical range (1983–2003), wastewater ammonium and river phytoplankton have played a similar role in the monthly variability of the dissolved oxygen deficit, but river discharge has the strongest effect. Model scenarios imply that control of either river phytoplankton or wastewater ammonium load alone would be insufficient to eliminate hypoxia. Both must be strongly reduced, or reduction of one must be combined with increases in net discharge to the Ship Channel. Model scenarios imply that preventing discharge down Old River with a barrier markedly reduces hypoxia in the Ship Channel. With the Old River barrier in place, unimpaired or full natural flow at Vernalis would have led to about the same frequency of hypoxia that has occurred with actual flows since the early 1980s

Transparency tube provides reliable water-quality measurements

We examined the efficacy of using transparency-tube measurements to estimate turbidity, total suspended solids (TSS) and particulate nitrogen and phosphorus concentrations in several California waterways. Just as lowering a black-and-white disk (Secchi disk) into a lake provides a convenient way to measure its water clarity, a transparency tube offers a practical alternative for measuring water clarity and suspended solids concentrations in California streams and waterways. While transparency relationships with turbidity and TSS are strongest within a given sampling location, these relationships are relatively robust across a wide range of water bodies displaying contrasting conditions. However, transparency-tube measurements appear to have limited value in predicting particulate nutrient concentrations, even at a given sampling site. The low cost, ease of use and excellent repeatability of measurement make the transparency tube a potentially valuable tool for anyone interested in monitoring water quality, including farmers, ranchers, citizen volunteer groups, schools and local governments seeking to get involved in watershed monitoring programs

Transparency tube provides reliable water-quality measurements

We examined the efficacy of using transparency-tube measurements to estimate turbidity, total suspended solids (TSS) and particulate nitrogen and phosphorus concentrations in several California waterways. Just as lowering a black-and-white disk (Secchi disk) into a lake provides a convenient way to measure its water clarity, a transparency tube offers a practical alternative for measuring water clarity and suspended solids concentrations in California streams and waterways. While transparency relationships with turbidity and TSS are strongest within a given sampling location, these relationships are relatively robust across a wide range of water bodies displaying contrasting conditions. However, transparency-tube measurements appear to have limited value in predicting particulate nutrient concentrations, even at a given sampling site. The low cost, ease of use and excellent repeatability of measurement make the transparency tube a potentially valuable tool for anyone interested in monitoring water quality, including farmers, ranchers, citizen volunteer groups, schools and local governments seeking to get involved in watershed monitoring programs

Reservoir-derived subsidies provide a potential management opportunity for novel river ecosystems

Aquatic ecosystems world-wide are being irreversibly altered, suggesting that new and innovative management strategies are necessary to improve ecosystem function and sustainability. In river ecosystems degraded by dams environmental flows and selective withdrawal (SWD) infrastructure have been used to improve habitat for native species. Yet, few studies have quantified nutrient and food web export subsidies from upstream reservoirs, despite their potential to subsidize downstream riverine food webs. We sampled nutrient, phytoplankton, and zooplankton concentrations in outflows from the Shasta-Keswick reservoir complex in Northern California over a 12-month period to understand how SWD operation and internal reservoir conditions interact to influence subsidies to the Sacramento River. We found that nutrients, phytoplankton, and zooplankton were continuously exported from Shasta Reservoir to the Sacramento River and that gate operations at Shasta Dam were important in controlling exports. Further, our results indicate that gate operations and water-export depth strongly correlated with zooplankton community exports, whereas internal reservoir conditions (mixing and residence time) controlled concentrations of exported zooplankton biomass and chlorophyll a. These results demonstrate that reservoirs can be an important source of nutrient and food web subsidies and that selective withdrawal infrastructure may provide a valuable management tool to control ecosystem-level productivity downstream of dams