Stream Nitrogen and Phosphorus Loads Are Differentially Affected by Storm Events and the Difference May Be Exacerbated by Conservation Tillage.

Storm events disproportionately mobilize dissolved phosphorus (P) compared to nitrogen (N), contributing to reduction in load N:P. In agricultural watersheds, conservation tillage may lead to even further declines in load N:P due to dissolved P accumulation in the top soil layers. Due to an increase in this management activity, we were interested in the impacts of conservation tillage on N and P loads during storm events. Using a 20 year data set of nutrient loads to a hypereutrophic reservoir, we observed disproportionately increasing P loads relative to base flow during storm events, whereas N loads were proportional to discharge. We also observed a change in that relationship, i.e., even greater P load relative to base flow with more conservation tillage in the watershed. This suggests conservation tillage may contribute to significantly reduced N:P loads during storms with potential implications for the water quality of receiving water bodies.

Stream Nitrogen, Phosphorus, and Sediment Concentrations Show Contrasting Long-term Trends Associated with Agricultural Change.

Stream water quality can be greatly influenced by changes in agricultural practices, but studies of long-term dynamics are scarce. Here we describe trends over 21 yr (1994-2014) in nutrients and suspended sediments in three streams in a Midwestern US agricultural watershed. During this time, the watershed experienced substantial changes in agricultural practices, most importantly a pronounced shift from conventional to conservation tillage. In the 1990s and early 2000s, NH, soluble reactive P, and suspended sediment concentrations (standardized for discharge and season) each declined significantly (>4-12% per year) in at least two of the three streams ( < 0.01), whereas NO changed relatively little. However, since the early 2000s, declines in NH and sediment concentrations have slowed, soluble reactive P concentrations have not declined and may actually have increased, and NO concentrations have declined sharply. The more recent lack of decline in soluble reactive P coincides with a plateau in the prevalence of conservation tillage and may be because of increased soil P stratification due to long-term reduced tillage. The more recent decline in NO may be due to improved efficiency of N fertilizer use, increased soil denitrification, and/or declines in atmospheric N deposition. Our study shows that stream concentrations of N, P, and sediment can respond in contrasting ways to changes in agriculture, and that temporal trends can moderate, accelerate, or reverse over decadal timescales. Management strategies must consider contrasting temporal responses of water quality indicators and may need to be adaptively adjusted at scales of years to decades.

Assessing uncertainty in annual nitrogen, phosphorus, and suspended sediment load estimates in three agricultural streams using a 21-year dataset.

Accurate estimation of constituent loads is important for studies of ecosystem mass balance or total maximum daily loads. In response, there has been an effort to develop methods to increase both accuracy and precision of constituent load estimates. The relationship between constituent concentration and stream discharge is often complicated, potentially leading to high uncertainty in load estimates for certain constituents, especially at longer-term (annual) scales. We used the loadflex R package to compare uncertainty in annual load estimates from concentration vs. discharge relationships in constituents of interest in agricultural systems, including ammonium as nitrogen (NH4-N), nitrate as nitrogen (NO3-N), soluble reactive phosphorus (SRP), and suspended sediments (SS). We predicted that uncertainty would be greatest in NO3-N and SS due to complex relationships between constituent concentration and discharge. We also predicted lower uncertainty with a composite method compared to regression or interpolation methods. Contrary to predictions, we observed the lowest uncertainty in annual NO3-N load estimates (relative error 1.5-23%); however, uncertainty was greatest in SS load estimates, consistent with predictions (relative error 19-96%). For all constituents, we also generally observed reductions in uncertainty by up to 34% using the composite method compared to regression and interpolation approaches, as predicted. These results highlight differences in uncertainty among different constituents and will aid in model selection for future studies requiring accurate and precise estimates of constituent load.

Early treatment intensification with R-ICE and 90Y-ibritumomab tiuxetan (Zevalin)-BEAM stem cell transplantation in patients with high-risk diffuse large B-cell lymphoma patients and positive interim PET after 4 cycles of R-CHOP-14.

In the treatment of diffuse large B-cell lymphoma, a persistently positive [18F]fluorodeoxyglucose positron emission tomography (PET) scan typically carries a poor prognosis. In this prospective multi-center phase II study, we sought to establish whether treatment intensification with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemotherapy followed by 90Y-ibritumomab tiuxetan-BEAM (BCNU, etoposide, cytarabine, and melphalan) for high-risk diffuse large B-cell lymphoma patients who are positive on interim PET scan after 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, and prednisone) can improve 2-year progression-free survival from a historically unfavorable rate of 40% to a rate of 65%. Patients received 4 cycles of R-CHOP-14, followed by a centrally-reviewed PET performed at day 17-20 of cycle 4 and assessed according to International Harmonisation Project criteria. Median age of the 151 evaluable patients was 57 years, with 79% stages 3-4, 54% bulk, and 54% International Prognostic Index 3-5. Among the 143 patients undergoing interim PET, 101 (71%) were PET-negative (96 of whom completed R-CHOP), 42 (29%) were PET-positive (32 of whom completed R-ICE and 90Y-ibritumomab tiuxetan-BEAM). At a median follow up of 35 months, the 2-year progression-free survival for PET-positive patients was 67%, a rate similar to that for PET-negative patients treated with R-CHOP-14 (74%, P=0.11); overall survival was 78% and 88% (P=0.11), respectively. In an exploratory analysis, progression-free and overall survival were markedly superior for PET-positive Deauville score 4 versus score 5 (P=0.0002 and P=0.001, respectively). Therefore, diffuse large B-cell lymphoma patients who are PET-positive after 4 cycles of R-CHOP-14 and who switched to R-ICE and 90Y-ibritumomab tiuxetan-BEAM achieved favorable survival outcomes similar to those for PET-negative R-CHOP-14-treated patients. Further studies are warranted to confirm these promising results. (Registered at: ACTRN12609001077257).

Climate and land use interactively affect lake phytoplankton nutrient limitation status.

Climate-change models predict more frequent and intense summer droughts for many areas, including the midwestern United States. Precipitation quantity and intensity in turn drive the rates and ratios at which nitrogen (N) and phosphorus (P) are exported from watersheds into lakes, but these rates and ratios are also modulated by watershed land use. This led us to ask the question, is the effect of precipitation on phytoplankton nutrient limitation dependent on watershed land use? Across 42 lakes, we found that phytoplankton in lakes in agricultural landscapes were usually P limited but shifted to strong N limitation under increased drought intensity, and that droughts promoted N-fixing cyanobacteria. In contrast, phytoplankton in lakes with forested watersheds were consistently N limited, regardless of drought status. This climate-land use interaction suggests that droughts may increase the incidence of N limitation in agriculturally impacted lakes. N limitation would likely impair valuable ecosystem services such as drinking water, fisheries, and recreation by promoting the occurrence and severity of cyanobacterial blooms.

Immune priming with avelumab and rituximab prior to R-CHOP in diffuse large B-cell lymphoma: the phase II AvR-CHOP study.

Immune evasion, due to abnormal expression of programmed-death ligands 1 and 2 (PD-L1/PD-L2), predicts poor outcomes with chemoimmunotherapy in diffuse large B-cell lymphoma (DLBCL). Immune checkpoint inhibition (ICI) has limited efficacy at relapse but may sensitise relapsed lymphoma to subsequent chemotherapy. ICI delivery to immunologically intact patients may thus be the optimal use of this therapy. In the phase II AvR-CHOP study, 28 patients with treatment-naive stage II-IV DLBCL received sequential avelumab and rituximab priming ("AvRp;" avelumab 10 mg/kg and rituximab 375 mg/m2 2-weekly for 2 cycles), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone for 6 cycles) and avelumab consolidation (10 mg/kg 2-weekly for 6 cycles). Grade 3/4 immune-related adverse events occurred in 11%, meeting the primary endpoint of a grade ≥3 irAE rate of <30%. R-CHOP delivery was not compromised but one patient ceased avelumab. Overall response rates (ORR) after AvRp and R-CHOP were 57% (18% CR) and 89% (all CR). High ORR to AvRp was observed in primary mediastinal B-cell lymphoma (67%; 4/6) and molecularly-defined EBV-positive DLBCL (100%; 3/3). Progression during AvRp was associated with chemorefractory disease. Two-year failure-free and overall survival were 82% and 89%. An immune priming strategy with AvRp, R-CHOP and avelumab consolidation shows acceptable toxicity with encouraging efficacy.

A simplified frailty scale predicts outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma treated in the FIRST (MM-020) trial.

Patients with multiple myeloma are generally older and vary in fitness levels, which may influence the clinical benefit of treatment. Patients from the large, phase 3 FIRST trial in newly diagnosed multiple myeloma (NDMM) were retrospectively investigated to determine outcomes based on frailty using scores for age, Charlson Comorbidity Index (CCI), and Eastern Cooperative Oncology Group performance status (ECOG PS), instead of the EQ-5D quality-of-life questionnaire, as previously reported. ECOG PS (n = 1618) was investigated in frailty groups: frail (49%) and nonfrail (51%). Frail patients experienced worse progression-free and overall survival vs nonfrail patients. Prognostic assessment was improved when combining frailty and International Staging System stage (I/II vs III). Frail patients had a higher risk of developing grade 3/4 treatment-emergent adverse events. Treatment effects observed in the FIRST trial were confirmed per frailty group and per frailty and ISS group. The use of this ECOG PS-containing frailty scale as a predictive measure of clinical outcomes in patients with transplant-ineligible NDMM is supported by data from the FIRST trial. This score, based on age, CCI, and ECOG PS, can be easily replicated and may help design future myeloma studies in frail or nonfrail elderly patients.

Water quality trends and changing agricultural practices in a midwest U.S. watershed, 1994-2006.

Sediment and nutrient concentrations in surface water in agricultural regions are strongly influenced by agricultural activities. In the Corn Belt, recent changes in farm management practices are likely to affect water quality, yet there are few data on these linkages at the landscape scale. We report on trends in concentrations of N as ammonium (NH(4)) and nitrate (NO(3)), soluble reactive phosphorus (SRP), and suspended sediment (SS) in three Corn Belt streams with drainage areas of 12 to 129 km(2) for 1994 through 2006. During this period, there has been an increase in conservation tillage, a decline in fertilizer use, and consolidation of animal feeding operations in our study watersheds and throughout the Corn Belt. We use an autoregressive moving average model to include the effects of discharge and season on concentrations, LOWESS plots, and analyses of changes in the relation between discharge and concentration. We found significant declines in mean monthly concentrations of NH(4) at all three streams over the 13-yr period, declines in SRP and SS in two of the three streams, and a decline in NO(3) in one stream. When trend coefficients are converted to percent per year and weighted by drainage, area changes in concentration are -8.5% for NH(4), -5.9% for SRP, -6.8% for SS, and -0.8% for NO(3). Trends in total N and P are strongly tied to trends in NO(3), SRP, and SS and indicate that total P is declining, whereas total N is not.

Nutrient cycling by fish supports relatively more primary production as lake productivity increases.

Animals can be important in nutrient cycling in particular ecosystems, but few studies have examined how this importance varies along environmental gradients. In this study we quantified the nutrient cycling role of an abundant detritivorous fish species, the gizzard shad (Dorosoma cepedianum), in reservoir ecosystems along a gradient of ecosystem productivity. Gizzard shad feed mostly on sediment detritus and excrete sediment-derived nutrients into the water column, thereby mediating a cross-habitat translocation of nutrients to phytoplankton. We quantified nitrogen and phosphorus cycling (excretion) rates of gizzard shad, as well as nutrient demand by phytoplankton, in seven lakes over a four-year period (16 lake-years). The lakes span a gradient of watershed land use (the relative amounts of land used for agriculture vs. forest) and productivity. As the watersheds of these lakes became increasingly dominated by agricultural land, primary production rates, lake trophic state indicators (total phosphorus and chlorophyll concentrations), and nutrient flux through gizzard shad populations all increased. Nutrient cycling by gizzard shad supported a substantial proportion of primary production in these ecosystems, and this proportion increased as watershed agriculture (and ecosystem productivity) increased. In the four productive lakes with agricultural watersheds (>78% agricultural land), gizzard shad supported on average 51% of phytoplankton primary production (range 27-67%). In contrast, in the three relatively unproductive lakes in forested or mixed-land-use watersheds (>47% forest, <52% agricultural land), gizzard shad supported 18% of primary production (range 14-23%). Thus, along a gradient of forested to agricultural landscapes, both watershed nutrient inputs and nutrient translocation by gizzard shad increase, but our data indicate that the importance of nutrient translocation by gizzard shad increases more rapidly. Our results therefore support the hypothesis that watersheds and gizzard shad jointly regulate primary production in reservoir ecosystems.

Endobronchial ultrasound-guided transbronchial needle aspiration for the evaluation of suspected lymphoma.

BACKGROUND: Evidence regarding the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the assessment of isolated mediastinal lymphadenopathy (IMLN) is evolving. Its diagnostic accuracy in the evaluation of suspected lymphoma remains uncertain. METHODS: We reviewed a prospectively recorded database of consecutive patients with suspected lymphoma who underwent EBUSTBNA to evaluate IMLN. Patients in whom EBUS-TBNA was nondiagnostic subsequently underwent surgical biopsy or a minimum of 6 months radiologic surveillance. RESULTS: Ninety-eight patients underwent EBUS-TBNA for evaluation of IMLN. Clinicoradiologic features suggested sarcoidosis as the likely diagnosis in 43 patients. In the remaining 55 patients, EBUS-TBNA achieved definitive diagnosis in 42 patients (76%; 95% confidence interval [CI] 55-90). Lymphoma was ultimately diagnosed in 21 of 55 patients (38%). EBUS-TBNA demonstrated lymphoma in 16 (76%) patients; however, four patients required further surgical biopsy to completely characterize lymphoma subtypes. Surgical biopsy was required to diagnose specific lymphoma subtypes not readily amenable to diagnosis with low volume specimens. Sensitivity and specificity for definitive diagnosis of lymphoma were 57% (95% CI 37-76) and 100% (95% CI 91-100), respectively. CONCLUSIONS: Although the diagnostic accuracy of EBUS-TBNA for lymphoma is lower than that for the lung cancer staging, the procedure is an appropriate investigative technique for the patients with IMLN because of the low incidence of lymphoma in this population, and the significant proportion of such patients (76%) in whom surgical biopsy is obviated.

Use of filgrastim and pegfilgrastim to support delivery of chemotherapy: twenty years of clinical experience.

Neutropenia is a serious hematologic toxicity of myelosuppressive chemotherapy. The discovery that granulocyte colony-stimulating factor (G-CSF) could stimulate the production of neutrophils was followed by the purification and molecular cloning of filgrastim (Neupogen), the human recombinant form of the protein, between 1984 and 1986. In this article, we review 20 years of clinical literature with filgrastim and the more recent experience with pegfilgrastim (Neulasta) to support the delivery of chemotherapy. The earliest clinical studies of filgrastim showed that it produces immediate transient leukopenia followed by a sustained, dose-dependent increase in circulating neutrophils. In the two registrational studies of filgrastim, the cumulative incidence of febrile neutropenia (FN) was reduced by about 50% compared with placebo. Subsequent clinical trials and meta-analyses established that primary prophylaxis with filgrastim (beginning in the first cycle of chemotherapy) reduced the incidence of FN, FN-related hospitalizations, intravenous anti-infective use, infection-related mortality, and the need for chemotherapy dose modification, compared with placebo or no treatment, in many tumor types. Pegfilgrastim, formed by the addition of a polyethylene glycol molecule to filgrastim, has comparable efficacy to filgrastim when administered only once per chemotherapy cycle. High-level evidence indicates that both filgrastim and pegfilgrastim improve the likelihood of completing dose-dense and dose-intense chemotherapy. The most recent guidelines from three international cancer organizations, the European Organization for Research and Treatment of Cancer, the American Society of Clinical Oncology, and the US National Comprehensive Cancer Network, are in agreement that filgrastim or pegfilgrastim should be given prophylactically when the risk of FN with a chemotherapy regimen is > or =20%, or when the risk is 10-20% and the patient has other risk factors for FN. The development of filgrastim and pegfilgrastim has revolutionized oncology practice. Prophylactic use of these agents has enabled development of more aggressive chemotherapy regimens, including dose-dense chemotherapy, and treatment of a broader range of patients.

Quantifying sample biases of inland lake sampling programs in relation to lake surface area and land use/cover.

We quantified potential biases associated with lakes monitored using non-probability based sampling by six state agencies in the USA (Michigan, Wisconsin, Iowa, Ohio, Maine, and New Hampshire). To identify biases, we compared state-monitored lakes to a census population of lakes derived from the National Hydrography Dataset. We then estimated the probability of lakes being sampled using generalized linear mixed models. Our two research questions were: (1) are there systematic differences in lake area and land use/land cover (LULC) surrounding lakes monitored by state agencies when compared to the entire population of lakes? and (2) after controlling for the effects of lake size, does the probability of sampling vary depending on the surrounding LULC features? We examined the biases associated with surrounding LULC because of the established links between LULC and lake water quality. For all states, we found that larger lakes had a higher probability of being sampled compared to smaller lakes. Significant interactions between lake size and LULC prohibit us from drawing conclusions about the main effects of LULC; however, in general lakes that are most likely to be sampled have either high urban use, high agricultural use, high forest cover, or low wetland cover. Our analyses support the assertion that data derived from non-probability-based surveys must be used with caution when attempting to make generalizations to the entire population of interest, and that probability-based surveys are needed to ensure unbiased, accurate estimates of lake status and trends at regional to national scales.

Recombinant activated factor VII: treating postoperative hemorrhage in cardiac surgery.

BACKGROUND: The purpose of this study is to review the effect of recombinant activated factor VII (rFVIIa) as rescue therapy in continuing severe postoperative hemorrhage, despite conventional measures in a series of cardiac patients at our institution. METHODS: A series of all patients who received rFVIIa as rescue therapy for uncontrollable postoperative hemorrhage after cardiac surgery over a 2-year period was analyzed. We assessed and compared the use of blood products, coagulation indicators (international normalized ratio [INR], activated partial thromboplastin [APTT], and fibrinogen), and platelet levels immediately before and after the rFVIIa was given. RESULTS: Twelve patients received rFVIIa. Eight patients (75%) had thoracic aortic surgery. Bleeding stopped in all cases. Prior to the administration of rFVIIa, mean blood product usage was the following: fresh frozen plasma (FFP) 18.7 units (range, 10-40); packed cells 7.7U (range, 0-18); cryoprecipitate 19.5U (range, 8-32); and platelets 22.5U (range, 10-40). The mean coagulation results immediately prior to rFVIIa were the following: INR 2.0 (range, 1.3-8.5); APTT 60 seconds (range, 30-220); fibrinogen 3.2 gm/L (range, 1.6-6.4), and platelet count was 174,000 (range, 78,000-257,000). After rFVIIa administration the mean blood product usage was the following: FFP 0U (range, 0-2); red cells 0U (range, 0-1); cryoprecipitate 0 (range, 0); and platelets 0 (range, 0); p less than 0.0005. The mean INR was 0.9 (range, 0.7-1.5), p less than 0.001; mean APTT was 42 seconds (range, 30-87), mean fibrinogen was 3.1 (range, 1.7-4.5), and the mean platelet count was 170,000 (range, 93,000-289,000); p values not significant. There were no thrombotic complications, no cardiac ischemic events, and no deaths. CONCLUSIONS: Our results support the use of rFVIIa as rescue therapy in severe, uncontrollable, nonsurgical, postoperative hemorrhage after cardiac surgery as efficacious and safe.