Calibration approaches for distributed hydrologic models in poorly gaged basins: implication for streamflow projections under climate change

Abstract. This study tests the performance and uncertainty of calibration strategies for a spatially distributed hydrologic model in order to improve model simulation accuracy and understand prediction uncertainty at interior ungaged sites of a sparsely gaged watershed. The study is conducted using a distributed version of the HYMOD hydrologic model (HY-MOD_DS) applied to the Kabul River basin. Several calibration experiments are conducted to understand the benefits and costs associated with different calibration choices, including (1) whether multisite gaged data should be used simultaneously or in a stepwise manner during model fitting, (2) the effects of increasing parameter complexity, and (3) the potential to estimate interior watershed flows using only gaged data at the basin outlet. The implications of the different calibration strategies are considered in the context of hydrologic projections under climate change. To address the research questions, high-performance computing is utilized to manage the computational burden that results from high-dimensional optimization problems. Several interesting results emerge from the study. The simultaneous use of multisite data is shown to improve the calibration over a stepwise approach, and both multisite approaches far exceed a calibration based on only the basin outlet. The basin outlet calibration can lead to projections of mid-21st century streamflow that deviate substantially from projections under multisite calibration strategies, supporting the use of caution when using distributed models in data-scarce regions for climate change impact assessments. Surprisingly, increased parameter complexity does not substantially increase the uncertainty in streamflow projections, even though parameter equifinality does emerge. The results suggest that increased (excessive) parameter complexity does not always lead to increased predictive uncertainty if structural uncertainties are present. The largest uncertainty in future streamflow results from variations in projected climate between climate models, which substantially outweighs the calibration uncertainty

Massive benign pericardial cyst presenting with simultaneous superior vena cava and middle lobe syndromes

A 66 year old woman presented in extremis with symptoms and clinical and radiological signs of simultaneous obstruction of superior vena cava and middle lobe of right lung secondary to compression by a massive benign anterior mediastinal cyst. Excision of the cyst at median sternotomy resulted in complete resolution of all symptoms. This report is unusual on account of a) the concomitant presence of superior vena cava and middle lobe syndromes caused by a benign cyst because of its sheer size producing obstruction of these structures and b) the complete resolution of all symptoms and signs after removal of the cyst. Benign anterior mediastinal cysts are unknown to cause either of the two syndromes. To our knowledge, it is the first report of a benign anterior mediastinal cyst causing either superior vena cava syndrome or middle lobe syndrome or both simultaneously. Etiologies of both superior vena cava and middle lobe syndromes are discussed in detail

Weinberg like sum rules revisited

The generalized Weinberg sum rules containing the difference of isovector vector and axial-vector spectral functions saturated by both finite and infinite number of narrow resonances are considered. We summarize the status of these sum rules and analyze their overall agreement with phenomenological Lagrangians, low-energy relations, parity doubling, hadron string models, and experimental data.Comment: 31 pages, noticed misprints are corrected, references are added, and other minor corrections are mad

HMM-FRAME: accurate protein domain classification for metagenomic sequences containing frameshift errors

<p>Abstract</p> <p>Background</p> <p>Protein domain classification is an important step in metagenomic annotation. The state-of-the-art method for protein domain classification is profile HMM-based alignment. However, the relatively high rates of insertions and deletions in homopolymer regions of pyrosequencing reads create frameshifts, causing conventional profile HMM alignment tools to generate alignments with marginal scores. This makes error-containing gene fragments unclassifiable with conventional tools. Thus, there is a need for an accurate domain classification tool that can detect and correct sequencing errors.</p> <p>Results</p> <p>We introduce HMM-FRAME, a protein domain classification tool based on an augmented Viterbi algorithm that can incorporate error models from different sequencing platforms. HMM-FRAME corrects sequencing errors and classifies putative gene fragments into domain families. It achieved high error detection sensitivity and specificity in a data set with annotated errors. We applied HMM-FRAME in Targeted Metagenomics and a published metagenomic data set. The results showed that our tool can correct frameshifts in error-containing sequences, generate much longer alignments with significantly smaller E-values, and classify more sequences into their native families.</p> <p>Conclusions</p> <p>HMM-FRAME provides a complementary protein domain classification tool to conventional profile HMM-based methods for data sets containing frameshifts. Its current implementation is best used for small-scale metagenomic data sets. The source code of HMM-FRAME can be downloaded at <url>http://www.cse.msu.edu/~zhangy72/hmmframe/</url> and at <url>https://sourceforge.net/projects/hmm-frame/</url>.</p

The complete inventory of receptors encoded by the rat natural killer cell gene complex

The natural killer cell gene complex (NKC) encodes receptors belonging to the C-type lectin superfamily expressed primarily by NK cells and other leukocytes. In the rat, the chromosomal region that starts with the Nkrp1a locus and ends with the Ly49i8 locus is predicted to contain 67 group V C-type lectin superfamily genes, making it one of the largest congregation of paralogous genes in vertebrates. Based on physical proximity and phylogenetic relationships between these genes, the rat NKC can be divided into four major parts. We have previously reported the cDNA cloning of the majority of the genes belonging to the centromeric Nkrp1/Clr cluster and the two telomeric groups, the Klre1–Klri2 and the Ly49 clusters. Here, we close the gap between the Nkrp1/Clr and the Klre1–Klri2 clusters by presenting the cDNA cloning and transcription patterns of eight genes spanning from Cd69 to Dectin1, including the novel Clec2m gene. The definition, organization, and evolution of the rat NKC are discussed

Estimation of the incidence of genital warts and the cost of illness in Germany: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Human papillomavirus (HPV) is a necessary cause of cervical cancer. HPV is also responsible for benign <it>condylomata acuminata</it>, also known as genital warts. We assessed the incidence of genital warts in Germany and collected information on their management to estimate the annual cost of disease.</p> <p>Methods</p> <p>This was a multi-centre observational (cross-sectional) study of genital warts in Germany. Data were collected from gynecologists, dermatologists, and urologists seeing patients with genital warts between February and April 2005. The number of patients with new and recurrent genital warts was used to estimate the incidence in Germany. We assessed resource use for patients with genital warts seen during a two-month period as well as retrospective resource use twelve months prior to the inclusion visit through a chart review. The mean costs of treatment of patients with genital warts from third-party payer and societal perspectives were estimated, and the total annual cost of genital warts was then calculated.</p> <p>Results</p> <p>For the incidence calculation 217 specialists provided information on 848 patients and 214 specialists provided resource use data for 617 patients to assess resource consumption. The incidence of new and recurrent cases of genital warts was 113.7 and 34.7 per 100 000, respectively, for women aged 14–65 years consulting gynecologists. The highest incidence was observed in women aged 14–25 years (171.0 per 100 000) for new cases and in women aged 26–45 years (53.1 per 100 000) for recurrent cases. The sample size for males was too small to allow a meaningful estimate of the incidence. The mean direct cost per patient with new genital warts was estimated at 378 euros (95% CI: 310.8–444.9); for recurrent genital warts at 603 euros (95% CI: 436.5–814.5), and for resistant genital warts at 1,142 euros (95% CI: 639.6–1752.3). The overall cost to third-party payers was estimated at 49.0 million euros, and the total societal cost at 54.1 million euros, corresponding to an average cost per patient of 550 euros and 607 euros, respectively.</p> <p>Conclusion</p> <p>The societal burden and costs of managing and treating genital warts in Germany are considerable. A vaccination programme using the quadrivalent human papillomavirus vaccine could provide a substantial health benefit and reduce the costs associated with genital warts in Germany.</p

Effect of crystalline disorder on quantum tunneling in the single-molecule magnet Mn12 benzoate

10 páginas, 9 figuras, 1 tabla.-- PACS number(s): 75.45.+j, 75.50.Xx, 75.60.Jk, 75.50.Kj.-- et al.We report a detailed study of the effects that crystalline disorder has on the magnetic relaxation and quantum tunneling of Mn12 benzoate clusters. Thanks to the absence of interstitial molecules in the crystal structure of this molecular compound, we have been able to isolate the influence of long-range crystalline disorder. For this, we compare results obtained under two extreme situations: a crystalline sample and a nearly amorphous material. The results show that crystalline disorder affects little the anisotropy, magnetic relaxation, and quantum tunneling of these materials. It follows that disorder is not a necessary ingredient for the existence of magnetic quantum tunneling. The results unveil, however, a subtle influence of crystallinity via the modification of the symmetry of dipole-dipole interactions. The faster tunneling rates measured for the amorphous material are accounted for by a narrower distribution of dipolar bias in this material, as compared with the crystalline sample.This work has been partly funded by Grants No. MAT2009-13977-C03, No. MAT2008-06542- C04, and No. CSD2007-00010 from the Spanish Ministerio de Ciencia e Innovación, and NABISUP from DGA. We acknowledge funding from Acción Integrada under Grant No. HA2006-0051 and the Network of Excellence MAGMANet. J.v.S and S.D. acknowledge the financial support of the Deutsche Forschungsgemeinschaft (DFG) and the DAAD. Ch.C. and I.I. acknowledge the Spanish Ministerio de Ciencia e Innovación.Peer reviewe

A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity.

Background AKT, a critical effector of the phosphoinositide 3-kinase (PI3K) signalling cascade, is an intensely pursued therapeutic target in oncology. Two distinct classes of AKT inhibitors have been in clinical development, ATP-competitive and allosteric. Class-specific differences in drug activity are likely the result of differential structural and conformational requirements governing efficient target binding, which ultimately determine isoform-specific potency, selectivity profiles and activity against clinically relevant AKT mutant variants.Methods We have carried out a systematic evaluation of clinical AKT inhibitors using in vitro pharmacology, molecular profiling and biochemical assays together with structural modelling to better understand the context of drug-specific and drug-class-specific cell-killing activity.Results Our data demonstrate clear differences between ATP-competitive and allosteric AKT inhibitors, including differential effects on non-catalytic activity as measured by a novel functional readout. Surprisingly, we found that some mutations can cause drug resistance in an isoform-selective manner despite high structural conservation across AKT isoforms. Finally, we have derived drug-class-specific phosphoproteomic signatures and used them to identify effective drug combinations.Conclusions These findings illustrate the utility of individual AKT inhibitors, both as drugs and as chemical probes, and the benefit of AKT inhibitor pharmacological diversity in providing a repertoire of context-specific therapeutic options

The Familial Intracranial Aneurysm (FIA) study protocol

BACKGROUND: Subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms (IAs) occurs in about 20,000 people per year in the U.S. annually and nearly half of the affected persons are dead within the first 30 days. Survivors of ruptured IAs are often left with substantial disability. Thus, primary prevention of aneurysm formation and rupture is of paramount importance. Prior studies indicate that genetic factors are important in the formation and rupture of IAs. The long-term goal of the Familial Intracranial Aneurysm (FIA) Study is to identify genes that underlie the development and rupture of intracranial aneurysms (IA). METHODS/DESIGN: The FIA Study includes 26 clinical centers which have extensive experience in the clinical management and imaging of intracerebral aneurysms. 475 families with affected sib pairs or with multiple affected relatives will be enrolled through retrospective and prospective screening of potential subjects with an IA. After giving informed consent, the proband or their spokesperson invites other family members to participate. Each participant is interviewed using a standardized questionnaire which covers medical history, social history and demographic information. In addition blood is drawn from each participant for DNA isolation and immortalization of lymphocytes. High- risk family members without a previously diagnosed IA undergo magnetic resonance angiography (MRA) to identify asymptomatic unruptured aneurysms. A 10 cM genome screen will be performed to identify FIA susceptibility loci. Due to the significant mortality of affected individuals, novel approaches are employed to reconstruct the genotype of critical deceased individuals. These include the intensive recruitment of the spouse and children of deceased, affected individuals. DISCUSSION: A successful, adequately-powered genetic linkage study of IA is challenging given the very high, early mortality of ruptured IA. Design features in the FIA Study that address this challenge include recruitment at a large number of highly active clinical centers, comprehensive screening and recruitment techniques, non-invasive vascular imaging of high-risk subjects, genome reconstruction of dead affected individuals using marker data from closely related family members, and inclusion of environmental covariates in the statistical analysis

Impact of point-of-care pre-procedure creatinine and eGFR testing in patients with ST segment elevation myocardial infarction undergoing primary PCI: The pilot STATCREAT study

Background: Contrast-induced acute kidney injury (CI-AKI) is a recognised complication during primary PCI that affects short and long term prognosis. The aim of this study was to assess the impact of point-of-care (POC) pre-PPCI creatinine and eGFR testing in STEMI patients. Methods 160 STEMI patients (STATCREAT group) with pre-procedure POC testing of Cr and eGFR were compared with 294 consecutive retrospective STEMI patients (control group). Patients were further divided into subjects with or without pre-existing CKD. Results: The incidence of CI-AKI in the whole population was 14.5% and not different between the two overall groups. For patients with pre-procedure CKD, contrast dose was significantly reduced in the STATCREAT group (124.6 ml vs. 152.3 ml, p = 0.015). The incidence of CI-AKI was 5.9% (n = 2) in the STATCREAT group compared with 17.9% (n = 10) in the control group (p = 0.12). There was no difference in the number of lesions treated (1.118 vs. 1.196, p = 0.643) or stents used (1.176 vs. 1.250, p = 0.78). For non-CKD patients, there was no significant difference in contrast dose (172.4 ml vs. 158.4 ml, p = 0.067), CI-AKI incidence (16.7% vs. 13.4%, p = 0.4), treated lesions (1.167 vs. 1.164, p = 1.0) or stents used (1.214 vs. 1.168, p = 0.611) between the two groups. Conclusions: Pre-PPCI point-of-care renal function testing did not reduce the incidence of CI-AKI in the overall group of STEMI patients. In patients with CKD, contrast dose was significantly reduced, but a numerical reduction in CI-AKI was not found to be statistically significant. No significant differences were found in the non-CKD group