One of the most cost-effective and environmentally sound methods of developing hydropower is through the uprating of hydroelectric turbines. In many countries hydroelectric dams have turbines that ...are approaching their expected service life, with plans underway to install replacement turbines that are expected to improve fish passage survival. To validate these improvements, there is a need to develop a baseline hydraulic characterization of existing Kaplan turbines. An autonomous sensor device known as the Sensor Fish was deployed at Ice Harbor Dam to characterize the hydraulics under different operating conditions. Nadir pressures varied by operating condition, with values decreasing with operating power (144–106 kPaA). Pressure changes during turbine passage varied by operating condition, with values increasing with operating power (311–344 kPa). There were slightly more significant events (acceleration ≥95G) in the stay vane/wicket gate region than the runner region. Rotational velocity data were similar between operating conditions. Sensor Fish data amassed during field studies in similar turbines were used for comparison. This study offers critical insights into the biological performance of large Kaplan turbines and provides vital information that can be used to make informed decisions that lead to additional design or operational improvements.
•Sensor Fish data collected in a large Kaplan turbine at Ice Harbor Dam.•Nadir pressure and rotational velocity were lowest among turbines compared.•Severe acceleration events were similar among the turbines compared.•Data provides insight into the biological performance of large Kaplan turbines.•Data provides information that can lead to further design/operational improvements.
Objective:
To formulate clinical practice guidelines for the use of continuous glucose monitoring and continuous subcutaneous insulin infusion in adults with diabetes.
Participants:
The participants ...include an Endocrine Society-appointed Task Force of seven experts, a methodologist, and a medical writer. The American Association for Clinical Chemistry, the American Association of Diabetes Educators, and the European Society of Endocrinology co-sponsored this guideline.
Evidence:
The Task Force developed this evidence-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned one systematic review and used the best available evidence from other published systematic reviews and individual studies.
Consensus Process:
One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society, the American Association for Clinical Chemistry, the American Association of Diabetes Educators, and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines.
Conclusions:
Continuous subcutaneous insulin infusion and continuous glucose monitoring have an important role in the treatment of diabetes. Data from randomized controlled trials are limited on the use of medical devices, but existing studies support the use of diabetes technology for a wide variety of indications. This guideline presents a review of the literature and practice recommendations for appropriate device use.
The objective is to formulate clinical practice guidelines for the use of continuous glucose monitoring and continuous subcutaneous insulin infusion in adults with diabetes.
The cellular inhibitors of apoptosis (cIAP) 1 and 2 are amplified in about 3% of cancers and have been identified in multiple malignancies as being potential therapeutic targets as a result of their ...role in the evasion of apoptosis. Consequently, small-molecule IAP antagonists, such as LCL161, have entered clinical trials for their ability to induce tumor necrosis factor (TNF)-mediated apoptosis of cancer cells. However, cIAP1 and cIAP2 are recurrently homozygously deleted in multiple myeloma (MM), resulting in constitutive activation of the noncanonical nuclear factor (NF)-κB pathway. To our surprise, we observed robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and in patients with relapsed-refractory MM, where the addition of cyclophosphamide resulted in a median progression-free-survival of 10 months. This effect was not a result of direct induction of tumor cell death, but rather of upregulation of tumor-cell-autonomous type I interferon (IFN) signaling and a strong inflammatory response that resulted in the activation of macrophages and dendritic cells, leading to phagocytosis of tumor cells. Treatment of a MM mouse model with LCL161 established long-term anti-tumor protection and induced regression in a fraction of the mice. Notably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all of the treated mice.
To assess the frequency of continuous glucose monitoring (CGM) device use, factors associated with its use, and the relationship of CGM with diabetes outcomes (HbA1c, severe hypoglycemia SH, and ...diabetic ketoacidosis DKA).
Survey questions related to CGM device use 1 year after enrollment in the T1D Exchange clinic registry were completed by 17,317 participants. Participants were defined as CGM users if they indicated using real-time CGM during the prior 30 days.
Nine percent of participants used CGM (6% of children <13 years old, 4% of adolescents 13 to <18 years, 6% of young adults 18 to <26 years, and 21% of adults ≥26 years). CGM use was more likely with higher education, higher household income, private health insurance, longer duration of diabetes, and use of insulin pump (P < 0.01 all factors). CGM use was associated with lower HbA1c in children (8.3% vs. 8.6%, P < 0.001) and adults (7.7% vs. 7.9%, P < 0.001). In adults, more frequent use of CGM (≥6 days/week) was associated with lower mean HbA1c. Only 27% of users downloaded data from their device at least once per month, and ≤15% of users reported downloading their device at least weekly. Among participants who used CGM at baseline, 41% had discontinued within 1 year.
CGM use is uncommon but associated with lower HbA1c in some age-groups, especially when used more frequently. Factors associated with discontinuation and infrequent use of retrospective analysis of CGM data should be considered in developing next-generation devices and education on CGM use.
Patients with multiple myeloma (MM) with mutated RAS are less likely to respond to chemotherapy and have a shortened survival. Therefore, targeting RAS farnesylation may be a novel approach to ...treatment of MM. We evaluated the activity and tolerability of the farnesyltransferase (FTase) inhibitor tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit protein farnesylation and oncogenic pathways in patients with relapsed MM. Forty-three patients (median age, 62 years range, 33-82 years) with a median of 4 (range, 1-6) chemotherapy regimens entered the study. Tipifarnib, 300 mg orally twice daily, was administered for 3 weeks every 4 weeks. The most common toxicity was fatigue occurring in 66% of patients. Other toxicities included diarrhea, nausea, neuropathy, anemia, and thrombocytopenia. Sixty-four percent of the patients had disease stabilization. Treatment with tipifarnib suppressed FTase (but not geranylgeranyltransferase I) in bone marrow and peripheral blood mononuclear cells and also inhibited the farnesylation of HDJ-2 in unfractionated mononuclear cells and purified myeloma cells. Inhibition of farnesylation did not correlate with disease stabilization. Finally, tipifarnib decreased the levels of phosphorylated Akt and STAT3 (signal transducer and activator of transcription 3) but not Erk1/2 (extracellular signal regulated kinase 1 and 2) in bone marrow cells. We conclude that tipifarnib is tolerable, can induce disease stabilization, and can inhibit farnesylation and oncogenic/tumor survival pathways. (Blood. 2004;103:3271-3277)
It is generally accepted that complete β-cell destruction eventually occurs in individuals with type 1 diabetes, which has implications for treatment approaches and insurance coverage. The frequency ...of residual insulin secretion in a large cohort of individuals at varying ages of diagnosis and type 1 diabetes duration is unknown.
The frequency of residual insulin secretion was determined by measurement of nonfasting serum C-peptide concentration in 919 individuals with type 1 diabetes according to prespecified groups based on age at diagnosis and duration of disease (from 3 to 81 years' duration). Stimulated C-peptide was measured in those with detectable nonfasting values and a group of those with undetectable values as control.
The overall frequency of detectable nonfasting C-peptide was 29%, decreasing with time from diagnosis regardless of age at diagnosis. In all duration groups, the frequency of C-peptide was higher with diagnosis age >18 years compared with ≤18 years. Nineteen percent of those with undetectable nonfasting C-peptide were C-peptide positive upon stimulation testing.
The American Diabetes Association's definition of type 1 diabetes as "usually leading to absolute insulin deficiency" results in clinicians often considering the presence of residual insulin secretion as unexpected in this population. However, our data suggest that residual secretion is present in almost one out of three individuals 3 or more years from type 1 diabetes diagnosis. The frequency of residual C-peptide decreases with time from diagnosis regardless of age at diagnosis, yet at all durations of disease, diagnosis during adulthood is associated with greater frequency and higher values of C-peptide.
Fish passing downstream through hydroelectric facilities may pass through turbines where they experience a rapid decrease in pressure, which can lead to barotraumas including swim bladder rupture, ...exopthalmia, emboli, and hemorrhaging. In juvenile Chinook salmon, the main mechanism for injury is thought to be expansion of existing gases (particularly those present in the swim bladder) and the rupture of the swim bladder ultimately leading to exopthalmia, emboli and hemorrhaging. In fish lacking a swim bladder, such as lamprey, barotraumas due to rapid decompression may be reduced, however this has yet to be extensively studied. Another mechanism for barotrauma can be gases coming out of solution and the rate of this occurrence may vary among species. In this study, juvenile brook and Pacific lamprey acclimated to 146.2kPa (equivalent to a depth of 4.6m) were subjected to rapid (<1s) or sustained decompression (17min) to a very low pressure (13.8kPa) using a protocol previously applied to juvenile salmon. No mortality or evidence of barotraumas was observed following rapid decompression, nor up to 120h after sustained decompression. In contrast, mortality or injury would be expected for 97.5% of juvenile Chinook salmon exposed to a similar rapid decompression to these very low pressures. Additionally, juvenile Chinook salmon experiencing sustained decompression died within 7min. Thus, juvenile lamprey may not be susceptible to barotraumas associated with turbine passage to the same degree as juvenile salmonids.
Abstract Background: Elevated levels of cortisol have been implicated in the development of type 2 diabetes mellitus and the metabolic syndrome. Modulation of cortisol levels and activity may be ...useful in the treatment of type 2 diabetes and its comorbidities. Objective: The purpose of this study was to evaluate the safety profile and pharmacodynamic effects of DIO-902 (2 S ,4 R -ketoconazole), an inhibitor of cortisol synthesis. Methods: Subjects with type 2 diabetes who were between the ages of 18 and 70 years and were drug naive or receiving metformin at a stable dose were randomized to receive one of the following once daily at bedtime for 14 days: ketoconazole 400 mg; DIO-902 200, 400, or 600 mg; or placebo. Tolerability was assessed based on adverse events reported by subjects and the results of physical examinations and standard hematology, chemistry, and urinalysis tests performed on days 8 and 15. Glycosylated hemoglobin (HbA1c ) and levels of fructosamine, fasting glucose, lipoproteins, and C-reactive protein were measured at baseline and the end of treatment. The Jonckheere-Terpstra test was used to test for an ordinal dose-response trend between the DIO-902 doses and placebo. Morning (7:30 am) salivary cortisol levels were measured and overnight plasma cortisol levels were analyzed as a 12-hour AUC at baseline and the end of treatment. Adrenocorticotropic hormone (ACTH) levels were measured and an ACTH stimulation test was used to assess adrenal reserve at baseline and the end of treatment. Results: The study enrolled 21 women (58.3%) and 15 (41.7%) men. Their mean (SD) age was 55.4 (8.5) years; mean HbA1c , 8.1% (1.3%); and mean duration of diabetes, 4.8 (3.7) years. White subjects were in the majority (86.1%), with black subjects constituting 11.1% of the population and those of other racial backgrounds constituting 2.8%; 47.2% of subjects were of Hispanic ethnicity. The proportions of subjects experiencing any adverse event were 62.5% in the ketoconazole group; 60.0%, 83.3%, and 100% in the DIO-902 200-, 400-, and 600-mg groups, respectively; and 50.0% in the placebo group. Gastrointestinal disorders were the most common adverse event, reported in 12.5% of the ketoconazole group, 35.0% of the combined DIO-902 treatment group, and 16.7% of the placebo group. Headache, the second most commonly reported adverse event, was reported in 12.5% of the ketoconazole group, 30.0% of the overall DIO-902 group, and none of the placebo group. DIO-902 treatment was not associated with any significant differences in measures of glycemic control relative to placebo or any significant decreases in mean morning salivary cortisol levels or mean overnight cortisol exposure. Dose-dependent reductions from baseline were seen in mean levels of low-density lipoprotein cholesterol (mean percent reductions: −11.39, −23.38, and −42.10 with DIO-902 200, 400, and 600 mg, respectively; P < 0.001), as well as in total cholesterol (P < 0.001) and high-density lipoprotein cholesterol ( P = 0.034). Mean levels of C-reactive protein were significantly reduced relative to placebo at all doses of DIO-902 ( P = 0.027); no reductions in either of these parameters were seen in the placebo group. Conclusion: In this small, short-term study in subjects with type 2 diabetes, DIO-902 was generally well tolerated, although it was associated with an increased incidence of gastrointestinal disorders and headache. Levels of low-density lipoprotein cholesterol were significantly decreased in subjects treated with DIO-902.
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