Predictors and rates of treatment-resistant tumor growth in acromegaly

Background: Multimodal therapy for acromegaly affords adequate disease control for many patients; however, there remains a subset of individuals that exhibit treatment-resistant disease. The issue of treatment-resistant pituitary tumor growth remains relatively under-explored. Methods: We assessed the literature for relevant data regarding the surgical, medical and radio-therapeutic treatment of acromegaly in order to identify the factors that were predictive of aggressive or treatment-resistant pituitary tumor behavior in acromegaly and undertook an assessment of the rates of failure to control tumor progression with available treatment modalities. Results: Young age at diagnosis, large tumor size, high growth hormone secretion and certain histological markers are predictors of future aggressive tumor behavior in acromegaly. Significant tumor regrowth occurs in less than 10% of cases thought to be cured surgically, whereas failure to control tumor growth is seen in less than 1% of patients receiving radiotherapy. Somatostatin analogs induce a variable degree of tumor shrinkage in acromegaly but up to 2.2% of somatostatin analog-treated tumors continue to grow. Relative to other therapies, limited data are available for pegvisomant, but these indicate that persistent tumor growth occurs in 1.6-2.9% of cases followed up regularly with serial magnetic resonance imaging scans. Conclusions: Treatment-resistant tumor progression occurs in a small minority of patients with acromegaly, regardless of treatment modality. Young patients with large tumors or those with high pre-treatment levels of growth hormone particularly warrant close monitoring for continued tumor progression during treatment for acromegaly

Direct oral anticoagulants‐Remove versus Taipan snake venom time for detection of a lupus anticoagulant in patients taking oral direct factor Xa inhibitors

Background: The optimal method of detecting a lupus anticoagulant (LA) for patients taking direct factor Xa inhibitor (DFXaI) direct oral anticoagulants (DOACs) remains controversial. Methods include charcoal adsorption of the DOACs to allow testing with the activated partial thromboplastin time (APTT) and dilute Russell viper venom time (dRVVT), or use of the DFXaI‐insensitive Taipan snake venom time (TSVT) and Ecarin time (ET) assays on neat plasma. Objectives: The objective was to compare the utility of APTT and dRVVT analysis following DOAC Remove against TSVT/ET on untreated plasma for LA detection in spiked plasmas and routine clinical samples for patients on DFXaIs. Patients/methods: Various LA‐negative and LA‐positive samples were assayed by APTT, dRVVT, and TSVT/ET, and then separately spiked with rivaroxaban, apixaban, and edoxaban calibrators to a concentration of ~190 ng/ml and the assays repeated on spiked plasma before and after DOAC Remove treatment. Testing of 284 consecutive samples from DFXaI‐anticoagulated patients by APTT/dRVVT and TSVT/ET before and after DOAC Remove treatment was undertaken. Results: In the spiking model, we found that both TSVT/ET and DOAC Remove strategies generally distinguished LA‐negative and LA‐positive samples, but some false‐positive LA results occurred. In the investigation of 284 consecutive patient samples on DFXaIs, the percentage agreement for LA detection in neat samples tested by TSVT/ET versus APTT and dRVVT after DOAC Remove treatment was 90% (Cohen kappa 0.12). Conclusion: Our data highlight uncertainty and disagreement for testing LA in patients on DFXaI. Further studies are required

On Conceptually Simple Algorithms for Variants of Online Bipartite Matching

We present a series of results regarding conceptually simple algorithms for bipartite matching in various online and related models. We first consider a deterministic adversarial model. The best approximation ratio possible for a one-pass deterministic online algorithm is $1/2$, which is achieved by any greedy algorithm. D\"urr et al. recently presented a $2$-pass algorithm called Category-Advice that achieves approximation ratio $3/5$. We extend their algorithm to multiple passes. We prove the exact approximation ratio for the $k$-pass Category-Advice algorithm for all $k \ge 1$, and show that the approximation ratio converges to the inverse of the golden ratio $2/(1+\sqrt{5}) \approx 0.618$ as $k$ goes to infinity. The convergence is extremely fast --- the $5$-pass Category-Advice algorithm is already within $0.01\%$ of the inverse of the golden ratio. We then consider a natural greedy algorithm in the online stochastic IID model---MinDegree. This algorithm is an online version of a well-known and extensively studied offline algorithm MinGreedy. We show that MinDegree cannot achieve an approximation ratio better than $1-1/e$, which is guaranteed by any consistent greedy algorithm in the known IID model. Finally, following the work in Besser and Poloczek, we depart from an adversarial or stochastic ordering and investigate a natural randomized algorithm (MinRanking) in the priority model. Although the priority model allows the algorithm to choose the input ordering in a general but well defined way, this natural algorithm cannot obtain the approximation of the Ranking algorithm in the ROM model

Concentrations of Metals in Aquatic Invertebrates from the Ozark National Scenic Riverways, Missouri

This report summarizes the findings of a study conducted as a pilot for part of a park-wide monitoring program being developed for the Ozark National Scenic Riverways (ONSR) of southeastern Missouri. The objective was to evaluate using crayfish (Orconectes spp.) and Asian clam (Corbicula fluminea) for monitoring concentrations of metals associated with lead-zinc mining. Lead-zinc mining presently (2007) occurs near the ONSR and additional mining has been proposed. Three composite samples of each type (crayfish and Asian clam), each comprising ten animals of approximately the same size, were collected during late summer and early fall of 2005 from five sites on the Current River and Jacks Fork within the ONSR and from one site on the Eleven Point River and the Big River, which are outside the ONSR. The Big River has been contaminated by mine tailings from historical leadzinc mining. Samples were analyzed by inductively coupled plasma mass spectrometry for lead, zinc, cadmium, cobalt, and nickel concentrations. All five metals were detected in all samples; concentrations were greatest in samples of both types from the Big River, and lowest in samples from sites within the ONSR. Concentrations of zinc and cadmium typically were greater in Asian clams than in crayfish, but differences were less evident for the other metals. In addition, differences among sites were small for cobalt in Asian clams and for zinc in crayfish, indicating that these metals are internally regulated to some extent. Consequently, both sample types are recommended for monitoring. Concentrations of metals in crayfish and Asian clams were consistent with those reported by other studies and programs that sampled streams in southeast Missouri

Concentrations of Metals in Aquatic Invertebrates from the Ozark National Scenic Riverways, Missouri

This report summarizes the findings of a study conducted as a pilot for part of a park-wide monitoring program being developed for the Ozark National Scenic Riverways (ONSR) of southeastern Missouri. The objective was to evaluate using crayfish (Orconectes spp.) and Asian clam (Corbicula fluminea) for monitoring concentrations of metals associated with lead-zinc mining. Lead-zinc mining presently (2007) occurs near the ONSR and additional mining has been proposed. Three composite samples of each type (crayfish and Asian clam), each comprising ten animals of approximately the same size, were collected during late summer and early fall of 2005 from five sites on the Current River and Jacks Fork within the ONSR and from one site on the Eleven Point River and the Big River, which are outside the ONSR. The Big River has been contaminated by mine tailings from historical leadzinc mining. Samples were analyzed by inductively coupled plasma mass spectrometry for lead, zinc, cadmium, cobalt, and nickel concentrations. All five metals were detected in all samples; concentrations were greatest in samples of both types from the Big River, and lowest in samples from sites within the ONSR. Concentrations of zinc and cadmium typically were greater in Asian clams than in crayfish, but differences were less evident for the other metals. In addition, differences among sites were small for cobalt in Asian clams and for zinc in crayfish, indicating that these metals are internally regulated to some extent. Consequently, both sample types are recommended for monitoring. Concentrations of metals in crayfish and Asian clams were consistent with those reported by other studies and programs that sampled streams in southeast Missouri

Biomonitoring of Lead, Zinc, and Cadmium in Streams Draining Lead-Mining and Non-Mining Areas, Southeast Missouri, USA

We evaluated exposure of aquatic biota to lead (Pb), zinc (Zn), and cadmium (Cd) in streams draining a Pb-mining district in southeast Missouri. Samples of plant biomass (detritus, periphyton, and filamentous algae), invertebrates (snails, crayfish, and riffle benthos), and two taxa of fish were collected from seven sites closest to mining areas (mining sites), four sites further downstream from mining (downstream sites), and eight reference sites in fall 2001. Samples of plant biomass from mining sites had highest metal concentrations, with means 10- to 60- times greater than those for reference sites. Mean metal concentrations in over 90% of samples of plant biomass from mining sites were significantly greater than those from reference sites. Mean concentrations of Pb, Zn, and Cd in most invertebrate samples from mining sites, and mean Pb concentrations in most fish samples from mining sites, were also significantly greater than those from reference sites. Concentrations of all three metals were lower in samples from downstream sites, but several samples of plant biomass from downstream sites had metal concentrations significantly greater than those from reference sites. Analysis of supplemental samples collected in the fall of 2002, a year of above-average stream discharge, had lower Pb concentrations and higher Cd concentrations than samples collected in 2001, near the end of a multi-year drought. Concentrations of Pb measured in fish and invertebrates collected from mining sites during 2001 and 2002 were similar to those measured at nearby sites in the 1970s, during the early years of mining in the Viburnum Trend. Results of this study demonstrate that long-term Pb mining activity in southeast Missouri has resulted in significantly elevated concentrations of Pb, Cd, and Zn in biota of receiving streams, compared to biota of similar streams without direct influence of mining. Our results also demonstrate that metal exposure in the study area differed significantly among sample types, habitats, and years, and that these factors should be carefully considered in the design of biomonitoring studies

Assessment of Elemental Concentrations in Streams of the New Lead Belt in Southeastern Missouri, 2002–05

Concerns about possible effects of lead-mining activities on the water quality of federally protected streams located in southeastern Missouri prompted a suite of multidisciplinary studies to be conducted by the U.S. Geological Survey. As part of this investigation, a series of biological studies were initiated in 2001 for streams in the current mining region and the prospecting area. In this report, results are examined for trace elements and other selected chemical measurements in sediment, surface water, and sediment interstitial (pore) water sampled between 2002 and 2005 in association with these biological studies. Compared to reference sites, fine sediments collected downstream from mining areas were enriched in metals by factors as large as 75 for cadmium, 62 for cobalt, 171 for nickel, 95 for lead, and 150 for zinc. Greatest metal concentrations in sediments collected in 2002 were from sites downstream from mines on Strother Creek, Courtois Creek, and the West Fork Black River. Sediments from sites on Bee Fork, Logan Creek, and Sweetwater Creek also were noticeably enriched in lead. Sediments in Clearwater Lake, at least 75 kilometers downstream from mining activity, had metal concentrations that were 1.5 to 2.1 times greater than sediments in an area of the lake with no upstream mining activity. Longitudinal sampling along three streams in 2004 indicated that sediment metal concentrations decreased considerably a few kilometers downstream from mining activities; however, in Strother Creek some metals were still enriched by a factor of five or more as far as 13 kilometers downstream from the Buick tailings impoundment. Compared with 2002 samples, metals concentrations were dramatically lower in sediments collected in 2004 at an upper West Fork Black River site, presumably because beneficiation operations at the West Fork mill ceased in 2000. Concentrations of metals and sulfate in sediment interstitial (pore) waters generally tracked closely with metal concentrations in sediments. Metals, including cobalt, nickel, lead, and zinc, were elevated substantially in laboratory-produced pore waters of fine sediments collected near mining operations in 2002 and 2004. Passive diffusion samplers (peepers) buried 4 to 6 centimeters deep in riffle-run stream sediments during 2003 and 2005 had much lower pore-water metal concentrations than the laboratory-produced pore waters of fine sediments collected in 2002 and 2004, but each sampling method produced similar patterns among sites. The combined mean concentration of lead in peeper samples from selected sites located downstream from mining activities for six streams was about 10-fold greater than the mean of the reference sites. In most instances, metals concentrations in surface water and peeper water were not greatly different, indicating considerable exchange between the surface water and pore water at the depths and locations where peepers were situated. Passive sampling probes used to assess metal lability in pore waters of selected samples during 2004 sediment toxicity tests indicated that most of the filterable lead in the laboratory-prepared pore water was relatively non-labile, presumably because lead was complexed by organic matter, or was present as colloidal species. In contrast, large percentages of cobalt and nickel in pore water appeared to be labile. Passive integrative samplers deployed in surface water for up to 3 weeks at three sites in July 2005 confirmed the presence of elevated concentrations of labile metals downstream from mining operations on Strother Creek and, to a lesser extent, Bee Fork. These samplers also indicated a considerable increase in metal loadings occurred for a few days at the Strother Creek site, which coincided with moderate increases in stream discharges in the area

A macroinvertebrate assessment of Ozark streams located in lead–zinc mining areas of the Viburnum Trend in southeastern Missouri, USA

The Viburnum Trend lead–zinc mining subdistrict is located in the southeast Missouri portion of the Ozark Plateau. In 2003 and 2004, we assessed the ecological effects of mining in several watersheds in the region. We included macroinvertebrate surveys, habitat assessments, and analysis of metals in sediment, pore water, and aquatic biota. Macroinvertebrates were sampled at 21 sites to determine aquatic life impairment status (full, partial, or nonsupport) and relative biotic condition scores. Macroinvertebrate biotic condition scores were significantly correlated with cadmium, nickel, lead, zinc, and specific conductance in 2003 (r = −0.61 to −0.68) and with cadmium, lead, and pore water toxic units in 2004 (r = −0.55 to −0.57). Reference sites were fully supporting of aquatic life and had the lowest metals concentrations and among the highest biotic condition scores in both years. Sites directly downstream from mining and related activities were partially supporting, with biotic condition scores 10% to 58% lower than reference sites. Sites located greater distances downstream from mining activities had intermediate scores and concentrations of metals. Results indicate that elevated concentrations of metals originating from mining activities were the underlying cause of aquatic life impairment in several of the streams studied. There was a general concurrence among the adversely affected sites in how the various indicators responded to the mining activities during the overall study

The Graz seismo-electromagnetic VLF facility

Abstract. In this paper we describe the Graz seismo-electromagnetic very low frequency (VLF) facility, as part of the European VLF receiver network, together with the scientific objectives and results from two years operation. After a brief technical summary of the present system – with heritage from a predecessor facility – i.e. hardware, software, operational modes and environmental influences, we discuss results from statistical data and scientific events related to terrestrial VLF propagation over Europe

GABA-glycine cotransmitting neurons in the ventrolateral medulla: development and functional relevance for breathing

Inhibitory neurons crucially contribute to shaping the breathing rhythm in the brain stem. These neurons use GABA or glycine as neurotransmitter; or co-release GABA and glycine. However, the developmental relationship between GABAergic, glycinergic and cotransmitting neurons, and the functional relevance of cotransmitting neurons has remained enigmatic. Transgenic mice expressing fluorescent markers or the split-Cre system in inhibitory neurons were developed to track the three different interneuron phenotypes. During late embryonic development, the majority of inhibitory neurons in the ventrolateral medulla are cotransmitting cells, most of which differentiate into GABAergic and glycinergic neurons around birth and around postnatal day 4, respectively. Functional inactivation of cotransmitting neurons revealed an increase of the number of respiratory pauses, the cycle-by-cycle variability, and the overall variability of breathing. In summary, the majority of cotransmitting neurons differentiate into GABAergic or glycinergic neurons within the first 2 weeks after birth and these neurons contribute to fine-tuning of the breathing pattern