Long-term incidence of cervical cancer in women with human immunodeficiency virus.
The objective of this study was to estimate the incidence of invasive cervical cancer (ICC) in women with human immunodeficiency virus (HIV) and compare it with the incidence in HIV-uninfected women. In a cohort study of HIV-infected and uninfected women who had Papanicolaou tests obtained every 6 months, pathology reports were retrieved for women who had biopsy results or a self-report of ICC. Histology was reviewed when reports confirmed ICC. Incidence rates were calculated and compared with those in HIV-negative women. After a median follow-up of 10.3 years, 3 ICCs were confirmed in HIV-seropositive women, and none were confirmed in HIV-seronegative women. The ICC incidence rate was not found to be associated significantly with HIV status (HIV-negative women [0 of 100,000 person-years] vs HIV-positive women [21.4 of 100,000 person-years]; P = .59). A calculated incidence rate ratio standardized to expected results from the Surveillance Epidemiology and End Results database that was restricted to HIV-infected Women's Interagency HIV Study participants was 1.32 (95% confidence interval, 0.27-3.85; P = 0.80). Among women with HIV in a prospective study that incorporated cervical cancer prevention measures, the incidence of ICC was not significantly higher than that in a comparison group of HIV-negative women.


Cyathea cranhamii sp. nov. (Cyatheaceae), anatomically preserved tree fern sori from the Lower Cretaceous of Vancouver Island, British Columbia.
Permineralized cyatheaceous sori occur among remains of conifers, fungi, and other plants in newly discovered calcareous concretions from Early Cretaceous (Barremian) marine sediments of Vancouver Island, British Columbia, Canada. Sori are superficially attached in two rows to narrow pinnules and display a globose sphaeropteroid indusium. Annulate sporangia with multicellular stalks diverge from a basal, vascularized receptacle. The nearly vertical uniseriate annulus is not interrupted by the stalk. The sporangia bear 64 trilete spores with perispore sculpturing that ranges from irregular granulate/echinate to prominent rodlets. These specimens, described as Cyathea cranhamii sp. nov., are the first anatomically preserved tree fern sori from the fossil record. They represent the most ancient evidence for fertile structures of the Cyatheaceae and demonstrate that essentially modern species of cyatheaceous tree ferns had evolved by the Early Cretaceous.


The in-vivo use of superparamagnetic iron oxide nanoparticles to detect inflammation elicits a cytokine response but does not aggravate experimental arthritis.
Superparamagnetic Iron Oxide Nanoparticles (SPION) are used in diagnostic imaging of a variety of different diseases. For such in-vivo application, an additional coating with a polymer, for example polyvinyl alcohol (PVA), is needed to stabilize the SPION and prevent aggregation. As the particles are foreign to the body, reaction against the SPION could occur. In this study we investigated the effects that SPION may have on experimental arthritis after intra-articular (i.a.) or intravenous (i.v.) injection. PVA-coated SPION were injected either i.a. (6 or 24 μg iron) or i.v. (100 μg or 1 mg iron) into naïve Toll-like receptor-4 deficient (TLR4-/-) or wild-type C57Bl/6 mice, or C57Bl/6 mice with antigen-induced arthritis. As control, some mice were injected with PVA or PBS. MR imaging was performed at 1 and 7 days after injection. Mice were sacrificed 2 hours and 1, 2, 7, 10 and 14 days after injection of the SPION, and RNA from synovium and liver was isolated for pro-inflammatory gene expression analysis. Serum cytokine measurements and whole knee joint histology were also performed. Injection of a high dose of SPION or PVA into naïve knee joints resulted in an immediate upregulation of pro-inflammatory gene expression in the synovium. A similar gene expression profile was observed after SPION or PVA injection into knee joints of TLR4-/- mice, indicating that this effect is not due to LPS contamination. Histological analysis of the knee joints also revealed synovial inflammation after SPION injection. Two hours after i.v. injection of SPION or PVA into naïve mice, an upregulation of pro-inflammatory gene expression was detected in the liver. Administration of SPION or PVA into arthritic mice via i.a. injection did not result in an upregulation in gene expression and also no additional effects were observed on histology. MR imaging and histology showed long-term retention of SPION in the inflamed joint. However, 14 days after the injections no long-term effects were evident for gene expression, histology or serum cytokine concentrations. Injection of SPION, either locally or systemically, gives an acute inflammatory response. In the long term, up to 14 days after the injection, while the SPION reside in the joint, no further activating effects of SPION were observed. Hence, we conclude that SPION do not aggravate arthritis and can therefore be used safely to detect joint inflammation by MR imaging.


Sinonasal symptom-related sleep disorders before and after surgery for nasal polyposis.
Patients with nasal polyposis (NP) complain of several sinonasal symptoms that impact their sleep and quality of life. However, data on sleep disorders related to NP symptoms, before and after surgery, is poor. The aim of the present study was to analyze sleep complaints related to each NP symptom, before and after surgery, using the Dynachron questionnaire. 63 patients operated for NP were included in this prospective study. They filled the DyNaChron questionnaire one day before surgery (V0), 6 weeks (V1) and 7 months (V2) after surgery. The self-ratings (0-10 point visual analog scale) of nasal obstruction, anterior rhinorrhea, postnasal discharge, cough and 5 items related to sleep disturbances, due to each symptom of chronic nasal dysfunction, were extracted from the questionnaire and analyzed. There was significant improvement of symptoms and symptom-related sleep disturbance scores at V1 and V2 compared to baseline scores. Before surgery, moderate/severe sleep disorders that patients attributed to nasal obstruction (the patient thinks it is due to nasal obstruction rather than a clinical test to show nasal obstruction) or anterior rhinorrhea were reported in two thirds of patients, postnasal discharge in one half, and chronic cough in one third. After surgery, less than 10% of patients reported moderate/severe sleep disorders at V1. There was a mild increase of patients who rated moderate/severe sleep disorders at V2 in comparison to V1. The correlation between scores of nasal obstruction and its impacts on sleep quality was weak before surgery and strong afterwards. Nasalization improved sleep quality significantly at 6 weeks and at 7 months after surgery. However, there was a mild increase of complaints related to postnasal discharge and cough at 7 months after surgery.


Mathematical modelling of competitive LDL/VLDL binding and uptake by hepatocytes.
Elevated levels of low-density-lipoprotein cholesterol (LDL-C) in the plasma are a well-established risk factor for the development of coronary heart disease. Plasma LDL-C levels are in part determined by the rate at which LDL particles are removed from the bloodstream by hepatic uptake. The uptake of LDL by mammalian liver cells occurs mainly via receptor-mediated endocytosis, a process which entails the binding of these particles to specific receptors in specialised areas of the cell surface, the subsequent internalization of the receptor-lipoprotein complex, and ultimately the degradation and release of the ingested lipoproteins' constituent parts. We formulate a mathematical model to study the binding and internalization (endocytosis) of LDL and VLDL particles by hepatocytes in culture. The system of ordinary differential equations, which includes a cholesterol-dependent pit production term representing feedback regulation of surface receptors in response to intracellular cholesterol levels, is analysed using numerical simulations and steady-state analysis. Our numerical results show good agreement with in vitro experimental data describing LDL uptake by cultured hepatocytes following delivery of a single bolus of lipoprotein. Our model is adapted in order to reflect the in vivo situation, in which lipoproteins are continuously delivered to the hepatocyte. In this case, our model suggests that the competition between the LDL and VLDL particles for binding to the pits on the cell surface affects the intracellular cholesterol concentration. In particular, we predict that when there is continuous delivery of low levels of lipoproteins to the cell surface, more VLDL than LDL occupies the pit, since VLDL are better competitors for receptor binding. VLDL have a cholesterol content comparable to LDL particles; however, due to the larger size of VLDL, one pit-bound VLDL particle blocks binding of several LDLs, and there is a resultant drop in the intracellular cholesterol level. When there is continuous delivery of lipoprotein at high levels to the hepatocytes, VLDL particles still out-compete LDL particles for receptor binding, and consequently more VLDL than LDL particles occupy the pit. Although the maximum intracellular cholesterol level is similar for high and low levels of lipoprotein delivery, the maximum is reached more rapidly when the lipoprotein delivery rates are high. The implications of these results for the design of in vitro experiments is discussed.


Hemophagocytic Lymphohistiocytosis Secondary to PD-1 and IDO Inhibition in a Patient with Refractory Glioblastoma.
Immune checkpoint inhibition (ICI)-based approaches have transformed the treatment landscape of numerous solid tumors. Glioblastoma (GBM) is an aggressive and almost universally fatal disease which is in need of novel treatment options, and combinations of immune checkpoint inhibitors, including dual agent therapy, are starting to be explored in refractory GBM. Growing adoption of ICI-based approaches in solid tumors has been met with improved understanding of immune-related adverse events (IRAEs), including primary hematologic adverse events. Although management guidelines for multiple hematologic IRAEs have been established, the emergence of hemophagocytic lymphohistiocytosis (HLH) secondary to ICI therapy has only rarely been described, and its pathogenesis and optimal management are incompletely understood. We present the case of a 74-year-old male with a history of refractory GBM treated with PD-1 and indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibition who experienced acute liver injury, followed by progressive fevers, altered mental status, and cytopenias. Serum studies and examination of spleen and bone marrow pathology were consistent with HLH, which was refractory to steroids and ultimately resulted in his rapid clinical decline. Here, we review prior cases of HLH secondary to ICI therapy across solid tumors, and explore potential mechanisms contributing to the rapid onset and refractory nature of our patient's HLH syndrome. We hope to further highlight HLH as an emerging hematologic IRAE secondary to ICI therapy, and suggest that new practice guidelines begin to recognize HLH as a characteristic hematologic IRAE in patients treated with PD-1 and other immune checkpoint inhibitors.


Quantitative description of the state of awareness of patients in vegetative and minimally conscious state.
Clinical scales represent the golden standard in characterizing awareness for patients in vegetative or in a minimally conscious state. Clinical scales suffer from problems of sensitivity, specificity, subjectivity, and inter-rater reliability. This leads to a misdiagnosis rate of up to 40% and consequences associated with inappropriate treatment decisions. In this study, objective measures including physiological and neurological signals are used to quantify the patient status. Using linear backward regression analysis, 13 variables (based on frequency analysis of the electrocardiogram, heart rate variability, amplitude and latency of the P300, skin conductance responses, changes in the blood pressure and respiration signal) were found to be sufficient to describe 74.7% of the variability of the scores. In this regression model, the P300, electrocardiogram and the blood pressure signal account for most of the variability. More patient data and additional measures will enable refinement of the methods. This new objective-measurement based model of the state of awareness will complement the clinical scales in order to increase the quality of diagnosis.


Endoscopic transnasal odontoidectomy to treat basilar invagination with congenital osseous malformations.
Transoral resection of the odontoid has been accepted as a standard procedure to decompress the cervicomedullary junction during the past several decades. The endoscopic transnasal odontoidectomy is emerging as a feasible surgical alternative to conventional microscopic transoral approach. In this article, we describe several operative nuances and pearls from our experience about this approach, which provided successful decompression. From September 2009 to April 2010, three consecutive patients with basilar invagination, of which the etiology was congenital osseous malformations, underwent endoscopic transnasal odontoidectomy. All patients presented with myelopathy. The last two cases also received occipitocervical fixation and bone fusion during the same surgical episode to ensure stability. All the patients were extubated after recovery from anesthesia and allowed oral food intake the next day. Cerebrospinal fluid rhinorrhea was found in the second case and cured by continuous lumber drainage of cerebrospinal fluid. No infection was noted. The average follow-up time was more than 24 months. Remarkable neurological recovery was observed postoperative in all patients. The endoscopic transnasal odontoidectomy is a feasible approach for anterior decompression of pathology at the cervicomedullary junction. The advantages over the standard transoral odontoidectomy include elimination of risk of tongue swelling and teeth damaging, improvement of visualization, alleviation of prolonged intubation, reduction of need for enteral tube feeding and less risk of affecting phonation. The minimally invasive access and faster recovery associated with this technique make it a valid alternative for decompression of the ventral side of the cervicomedullary junction.


A systematic review of hepatitis B virus (HBV) drug and vaccine escape mutations in Africa: A call for urgent action.
International sustainable development goals for the elimination of viral hepatitis as a public health problem by 2030 highlight the pressing need to optimize strategies for prevention, diagnosis and treatment. Selected or transmitted resistance associated mutations (RAMs) and vaccine escape mutations (VEMs) in hepatitis B virus (HBV) may reduce the success of existing treatment and prevention strategies. These issues are particularly pertinent for many settings in Africa where there is high HBV prevalence and co-endemic HIV infection, but lack of robust epidemiological data and limited education, diagnostics and clinical care. The prevalence, distribution and impact of RAMs and VEMs in these populations are neglected in the current literature. We therefore set out to assimilate data for sub-Saharan Africa through a systematic literature review and analysis of published sequence data, and present these in an on-line database (https://livedataoxford.shinyapps.io/1510659619-3Xkoe2NKkKJ7Drg/). The majority of the data were from HIV/HBV coinfected cohorts. The commonest RAM was rtM204I/V, either alone or in combination with associated mutations, and identified in both reportedly treatment-naïve and treatment-experienced adults. We also identified the suite of mutations rtM204V/I + rtL180M + rtV173L, that has been associated with vaccine escape, in over 1/3 of cohorts. Although tenofovir has a high genetic barrier to resistance, it is of concern that emerging data suggest polymorphisms that may be associated with resistance, although the precise clinical impact of these is unknown. Overall, there is an urgent need for improved diagnostic screening, enhanced laboratory assessment of HBV before and during therapy, and sustained roll out of tenofovir in preference to lamivudine alone. Further data are needed in order to inform population and individual approaches to HBV diagnosis, monitoring and therapy in these highly vulnerable settings.


Development of the pulmonary vein and the systemic venous sinus: an interactive 3D overview.
Knowledge of the normal formation of the heart is crucial for the understanding of cardiac pathologies and congenital malformations. The understanding of early cardiac development, however, is complicated because it is inseparably associated with other developmental processes such as embryonic folding, formation of the coelomic cavity, and vascular development. Because of this, it is necessary to integrate morphological and experimental analyses. Morphological insights, however, are limited by the difficulty in communication of complex 3D-processes. Most controversies, in consequence, result from differences in interpretation, rather than observation. An example of such a continuing debate is the development of the pulmonary vein and the systemic venous sinus, or "sinus venosus". To facilitate understanding, we present a 3D study of the developing venous pole in the chicken embryo, showing our results in a novel interactive fashion, which permits the reader to form an independent opinion. We clarify how the pulmonary vein separates from a greater vascular plexus within the splanchnic mesoderm. The systemic venous sinus, in contrast, develops at the junction between the splanchnic and somatic mesoderm. We discuss our model with respect to normal formation of the heart, congenital cardiac malformations, and the phylogeny of the venous tributaries.


Cryptic epitopes induce high-titer humoral immune response in patients with cancer.
In search of novel markers for diagnosis, prognosis, and therapy of cancer, screening of rcDNA expression libraries with patient's sera has been established as a valuable tool for identification of cancer-specific Ags. Interestingly, besides the expected humoral responses to annotated proteins, patients with cancer were frequently found to have serum Abs that bind to peptides without homology to known proteins. So far, the nature of these unconventional epitopes and their possible significance in tumor immunology have never been thoroughly investigated. In our study, we specifically analyzed humoral immune response toward such peptides in patients with pancreatic or breast cancer using yeast-displayed cDNA expression libraries derived from tumor tissue. A detailed analysis of the identified peptides revealed that they originated from translation of sequences outside annotated open reading frames and may derive from the use of alternative start codons or from DNA indel mutations. In several cases, the corresponding mRNA templates have a known association with cancer. In a final analysis, we were able to detect one of these tumor Ags in cancer tissue arrays by a selected Fab-Ab. We conclude that cryptic epitopes may elicit specific humoral immune responses in patients with cancer and thus play a role in immunologic surveillance. Due to the high prevalence of immune responses against some of the peptides, they may also be valuable markers for cancer diagnosis, prognosis, or therapy monitoring.


TGFβ-induced deptor suppression recruits mTORC1 and not mTORC2 to enhance collagen I (α2) gene expression.
Enhanced TGFβ activity contributes to the accumulation of matrix proteins including collagen I (α2) by proximal tubular epithelial cells in progressive kidney disease. Although TGFβ rapidly activates its canonical Smad signaling pathway, it also recruits noncanonical pathway involving mTOR kinase to regulate renal matrix expansion. The mechanism by which chronic TGFβ treatment maintains increased mTOR activity to induce the matrix protein collagen I (α2) expression is not known. Deptor is an mTOR interacting protein that suppresses mTOR activity in both mTORC1 and mTORC2. In proximal tubular epithelial cells, TGFβ reduced deptor levels in a time-dependent manner with concomitant increase in both mTORC1 and mTORC2 activities. Expression of deptor abrogated activity of mTORC1 and mTORC2, resulting in inhibition of collagen I (α2) mRNA and protein expression via transcriptional mechanism. In contrast, neutralization of endogenous deptor by shRNAs increased activity of both mTOR complexes and expression of collagen I (α2) similar to TGFβ treatment. Importantly, downregulation of deptor by TGFβ increased the expression of Hif1α by increasing translation of its mRNA. TGFβ-induced deptor downregulation promotes Hif1α binding to its cognate hypoxia responsive element in the collagen I (α2) gene to control its protein expression via direct transcriptional mechanism. Interestingly, knockdown of raptor to specifically block mTORC1 activity significantly inhibited expression of collagen I (α2) and Hif1α while inhibition of rictor to prevent selectively mTORC2 activation did not have any effect. Critically, our data provide evidence for the requirement of TGFβ-activated mTORC1 only by deptor downregulation, which dominates upon the bystander mTORC2 activity for enhanced expression of collagen I (α2). Our results also suggest the presence of a safeguard mechanism involving deptor-mediated suppression of mTORC1 activity against developing TGFβ-induced renal fibrosis.


[Microhistory or biography? On the meaning of the life of Joannes Groenevelt].
The main goal of the microstoria, a genre that was coined by Carlo Ginzburg in his book about the world view of a sixteenth-century Italian heretic, seems to be to criticize the grand narratives of history. By zooming in on the life of atypical persons, microhistory sets out to show that historiography has a tendency to blur the complexities of the past by reducing it to a set of sweeping statements about kings, generals, and geniuses. Recently, Harold Cook has written a book about Joannes Groenevelt, an 'ordinary doctor' who lived at the end of the seventeenth century, who moved in the circles of the Royal Society and who was found guilty of malpractice by the London College of Physicians. Although Cook claims his book to be a microhistory, Groenvelt was far from 'atypical'. Instead, he is being presented as an exponent of that important watershed in the history of science labelled 'Scientific Revolution'. It is argued that Cook's book - which is a traditional biography rather than a microhistory -- is important for at least two reasons. First, because it shows how the life of an ordinary physician can shed light on the nature of medicine and its workings in society; and second, by playing with dormant notions about the period, it shows the heuristic value of period labels like the Scientific Revolution.


A genomewide scan identifies two novel loci involved in specific language impairment.
Approximately 4% of English-speaking children are affected by specific language impairment (SLI), a disorder in the development of language skills despite adequate opportunity and normal intelligence. Several studies have indicated the importance of genetic factors in SLI; a positive family history confers an increased risk of development, and concordance in monozygotic twins consistently exceeds that in dizygotic twins. However, like many behavioral traits, SLI is assumed to be genetically complex, with several loci contributing to the overall risk. We have compiled 98 families drawn from epidemiological and clinical populations, all with probands whose standard language scores fall > or =1.5 SD below the mean for their age. Systematic genomewide quantitative-trait-locus analysis of three language-related measures (i.e., the Clinical Evaluation of Language Fundamentals-Revised [CELF-R] receptive and expressive scales and the nonword repetition [NWR] test) yielded two regions, one on chromosome 16 and one on 19, that both had maximum LOD scores of 3.55. Simulations suggest that, of these two multipoint results, the NWR linkage to chromosome 16q is the most significant, with empirical P values reaching 10(-5), under both Haseman-Elston (HE) analysis (LOD score 3.55; P=.00003) and variance-components (VC) analysis (LOD score 2.57; P=.00008). Single-point analyses provided further support for involvement of this locus, with three markers, under the peak of linkage, yielding LOD scores >1.9. The 19q locus was linked to the CELF-R expressive-language score and exceeds the threshold for suggestive linkage under all types of analysis performed-multipoint HE analysis (LOD score 3.55; empirical P=.00004) and VC (LOD score 2.84; empirical P=.00027) and single-point HE analysis (LOD score 2.49) and VC (LOD score 2.22). Furthermore, both the clinical and epidemiological samples showed independent evidence of linkage on both chromosome 16q and chromosome 19q, indicating that these may represent universally important loci in SLI and, thus, general risk factors for language impairment.


Mechanisms and time course of neuronal degeneration in experimental autoimmune encephalomyelitis.
Neuronal and axonal damage is considered to be the main cause for long-term disability in multiple sclerosis. We analyzed the mechanism and kinetics of neuronal cell death in experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG) by combining an electrophysiological in vivo assessment of the optic pathway with the investigation of retinal ganglion cell (RGC) counts. In accordance with our previous findings in this animal model, neuritis of the optic nerve (ON) leads to apoptotic RGC death. By further investigating the time course of RGC apoptosis in the present study, we found that neuronal cell death together with decreased visual acuity values occurred before the onset of clinical symptoms. Simultaneously with the time course of RGC apoptosis, we found a down-regulation of phospho-Akt as well as a shift in the relation of 2 proteins of the Bcl-2 family, Bax and Bcl-2, towards a more proapoptotic ratio in these cells. Comparing the kinetics and mechanisms of RGC death during MOG-EAE with those following complete surgical transection of the ON, we found significant agreement. We hypothesize that the main reason for RGC loss in MOG-EAE is the inflammatory attack but RGC death also occurs independently of histopathological ON changes.


Infection of Drosophila melanogaster by Tubulinosema kingi: stage-specific susceptibility and within-host proliferation.
Despite its importance as a model organism very little is known about the interaction between Drosophila and its microsporidian pathogens. Here we report on the relative susceptibility of Drosophila melanogaster life history stages to infection by Tubulinosema kingi, and on patterns of pathogen proliferation. We find that only larvae can be infected, and that this susceptibility decreases with larval age. Following infection, the pathogen shows little subsequent proliferation in larvae, a limited amount in pupae while it replicates greatly in adults. We present evidence that the host launches a cellular immune response after infection with the pathogen, although its effectiveness remains to be demonstrated.


The alcohol dehydrogenase polymorphism in Drosophila melanogaster: fitness measurements and predictions under conditions with no alcohol stress.
The relative fitnesses of the different Adh genotypes under normal laboratory conditions and in the absence of alcohol stress were estimated in Drosophila melanogaster according to Prout's method. The larval component (viability) did not reveal fitness differences between the genotypes but for the adult component significant differences were observed. The female adult component (fecundity) showed an overdominant pattern: both homozygous genotypes showed a relative fitness significantly lower than the heterozygous genotype. For the male adult component (virility) also differences were observed. The homozygous SS genotype showed a lower relative fitness than the other two genotypes. Predictions for gene frequency changes based on the estimated fitness values do show a reasonably good correspondence with frequency changes actually observed in a number of experimental cage populations and indicate a globally stable equilibrium around a frequency of the F allele of 0.40-0.70. The relevance of these fitness estimates, obtained under conditions with no alcohol stress, for the explanation of the Adh polymorphisms observed in nature is discussed.


Occurrence and Timing of Subsequent SARS-CoV-2 RT-PCR Positivity Among Initially Negative Patients.
SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) testing remains the cornerstone of laboratory-based identification of patients with COVID-19. As the availability and speed of SARS-CoV-2 testing platforms improve, results are increasingly relied upon to inform critical decisions related to therapy, use of personal protective equipment, and workforce readiness. However, early reports of RT-PCR test performance have left clinicians and the public with concerns regarding the reliability of this predominant testing modality and the interpretation of negative results. In this work, two independent research teams report the frequency of discordant SARS-CoV-2 test results among initially negative, repeatedly tested patients in regions of the United States with early community transmission and access to testing. All patients at the University of Washington (UW) and Stanford Health Care undergoing initial testing by nasopharyngeal (NP) swab between March 2nd and April 7th, 2020 were included. SARS-CoV-2 RT-PCR was performed targeting the N, RdRp, S, and E genes and ORF1ab, using a combination of Emergency Use Authorization laboratory-developed tests and commercial assays. Results through April 14th were extracted to allow for a complete 7-day observation period and an additional day for reporting. A total of 23,126 SARS-CoV-2 RT-PCR tests (10,583 UW, 12,543 Stanford) were performed in 20,912 eligible patients (8,977 UW, 11,935 Stanford) undergoing initial testing by NP swab; 626 initially test-negative patients were re-tested within 7 days. Among this group, repeat testing within 7 days yielded a positive result in 3.5% (4.3% UW, 2.8% Stanford) of cases, suggesting an initial false negative RT-PCR result; the majority (96.5%) of patients with an initial negative result who warranted reevaluation for any reason remained negative on all subsequent tests performed within this window. Two independent research teams report the similar finding that, among initially negative patients subjected to repeat SARS-CoV-2 RT-PCR testing, the occurrence of a newly positive result within 7 days is uncommon. These observations suggest that false negative results at the time of initial presentation do occur, but potentially at a lower frequency than is currently believed. Although it is not possible to infer the clinical sensitivity of NP SARS-CoV-2 RT-PCR testing using these data, they may be used in combination with other reports to guide the use and interpretation of this common testing modality.


Standardized classification and reporting of glomerulonephritis.
A kidney biopsy is done to determine the etiology of the glomerulonephritis (GN) and the severity of the lesion, to identify whether other lesions, related to or not related to the GN, are present on the kidney biopsy and finally to ascertain the extent of chronicity of the GN. The etiology of GN is based on the classification of GN into five groups: immune complex-mediated GN, antineutrophil cytoplasmic antibody (ANCA)-associated GN, anti-glomerular basement membrane (GBM) GN, monoclonal immunoglobulin-mediated GN and C3 glomerulopathy. Immune complex GN includes multiple specific diseases such as lupus nephritis, IgA nephropathy, infection-related GN and fibrillary GN. ANCA GN, anti-GBM GN and C3 glomerulopathy are specific diseases in themselves, while monoclonal Ig GN includes proliferative GN with monoclonal Ig deposits and monoclonal Ig deposition disease. Thus identification of the class of GN and within it the specific disease determines the etiology of GN. Ancillary studies may be required to confirm the etiology of GN. The severity of the GN is revealed by the pattern of injury, such as crescentic, necrotizing, diffuse proliferative, exudative, membranoproliferative, mesangial proliferative or a sclerosing GN. Secondary diagnosis either related or unrelated to the GN, such as diabetic glomerulosclerosis, acute tubular necrosis or thrombotic microangiopathy, may also be present. The secondary diagnosis may sometimes be the reason for the kidney biopsy. The chronicity of GN is determined by evaluating the extent of glomerulosclerosis, tubular atrophy and interstitial fibrosis and vascular sclerosis present on the biopsy. This review summarizes the approach to standardizing a kidney biopsy report that includes these components in a logical and sequential manner.


Linkage of organic anion transporter-1 to metabolic pathways through integrated "omics"-driven network and functional analysis.
The main kidney transporter of many commonly prescribed drugs (e.g. penicillins, diuretics, antivirals, methotrexate, and non-steroidal anti-inflammatory drugs) is organic anion transporter-1 (OAT1), originally identified as NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478). Targeted metabolomics in knockouts have shown that OAT1 mediates the secretion or reabsorption of many important metabolites, including intermediates in carbohydrate, fatty acid, and amino acid metabolism. This observation raises the possibility that OAT1 helps regulate broader metabolic activities. We therefore examined the potential roles of OAT1 in metabolic pathways using Recon 1, a functionally tested genome-scale reconstruction of human metabolism. A computational approach was used to analyze in vivo metabolomic as well as transcriptomic data from wild-type and OAT1 knock-out animals, resulting in the implication of several metabolic pathways, including the citric acid cycle, polyamine, and fatty acid metabolism. Validation by in vitro and ex vivo analysis using Xenopus oocyte, cell culture, and kidney tissue assays demonstrated interactions between OAT1 and key intermediates in these metabolic pathways, including previously unknown substrates, such as polyamines (e.g. spermine and spermidine). A genome-scale metabolic network reconstruction generated some experimentally supported predictions for metabolic pathways linked to OAT1-related transport. The data support the possibility that the SLC22 and other families of transporters, known to be expressed in many tissues and primarily known for drug and toxin clearance, are integral to a number of endogenous pathways and may be involved in a larger remote sensing and signaling system (Ahn, S. Y., and Nigam, S. K. (2009) Mol. Pharmacol. 76, 481-490, and Wu, W., Dnyanmote, A. V., and Nigam, S. K. (2011) Mol. Pharmacol. 79, 795-805). Drugs may alter metabolism by competing for OAT1 binding of metabolites.


Variable levels of normal RNA in different fetal organs carrying a cystic fibrosis transmembrane conductance regulator splicing mutation.
Disease severity varies among cystic fibrosis (CF) patients carrying the same cystic fibrosis transmembrane conductance regulator (CFTR) genotype and among organs of the same individual. It has been shown that the class V splicing mutation 3849 + 10 kb C--> T produces both normal and aberrantly spliced CFTR transcripts. We analyzed the levels of normal CFTR messenger RNA (mRNA) in different organs of an aborted fetus carrying the 3849 + 10 kb C--> T mutation, and found that they correlated with the histopathologic changes observed in these organs. We performed semiquantitative nondifferential reverse transcription-polymerase chain reaction on several organs from a 22-wk aborted CF fetus carrying the 3849 + 10 kb C--> T mutation. A very low level (1%) of normal CFTR mRNA was detected in the severely affected ileum of this fetus. Higher levels were found in the histopathologically unaffected trachea (17%), colon (19%), and lung (26%). Thus, as early as in utero, the regulation of alternative splice-site selection is an important mechanism underlying variable CF severity. Understanding of the mechanisms regulating alternative splicing in different tissues will contribute to potential therapy for patients carrying splicing mutations in CF and other human disease genes.


Black silicon with self-cleaning surface prepared by wetting processes.
This paper reports on a simple method to prepare a hydrophobic surface on black silicon, which is fabricated by metal-assisted wet etching. To increase the reaction rate, the reaction device was placed in a heat collection-constant temperature type magnetic stirrer and set at room temperature. It was demonstrated that the micro- and nanoscale spikes on the black silicon made the surface become hydrophobic. As the reaction rate increases, the surface hydrophobicity becomes more outstanding and presents self-cleaning until the very end. The reflectance of the black silicon is drastically suppressed over a broad spectral range due to the unique geometry, which is effective for the enhancement of absorption.


Inspiratory muscle strength training improves weaning outcome in failure to wean patients: a randomized trial.
Most patients are readily liberated from mechanical ventilation (MV) support, however, 10% - 15% of patients experience failure to wean (FTW). FTW patients account for approximately 40% of all MV days and have significantly worse clinical outcomes. MV induced inspiratory muscle weakness has been implicated as a contributor to FTW and recent work has documented inspiratory muscle weakness in humans supported with MV. We conducted a single center, single-blind, randomized controlled trial to test whether inspiratory muscle strength training (IMST) would improve weaning outcome in FTW patients. Of 129 patients evaluated for participation, 69 were enrolled and studied. 35 subjects were randomly assigned to the IMST condition and 34 to the SHAM treatment. IMST was performed with a threshold inspiratory device, set at the highest pressure tolerated and progressed daily. SHAM training provided a constant, low inspiratory pressure load. Subjects completed 4 sets of 6-10 training breaths, 5 days per week. Subjects also performed progressively longer breathing trials daily per protocol. The weaning criterion was 72 consecutive hours without MV support. Subjects were blinded to group assignment, and were treated until weaned or 28 days. Groups were comparable on demographic and clinical variables at baseline. The IMST and SHAM groups respectively received 41.9 ± 25.5 vs. 47.3 ± 33.0 days of MV support prior to starting intervention, P = 0.36. The IMST and SHAM groups participated in 9.7 ± 4.0 and 11.0 ± 4.8 training sessions, respectively, P = 0.09. The SHAM group's pre to post-training maximal inspiratory pressure (MIP) change was not significant (-43.5 ± 17.8 vs. -45.1 ± 19.5 cm H2O, P = 0.39), while the IMST group's MIP increased (-44.4 ± 18.4 vs. -54.1 ± 17.8 cm H2O, P < 0.0001). There were no adverse events observed during IMST or SHAM treatments. Twenty-five of 35 IMST subjects weaned (71%, 95% confidence interval (CI) = 55% to 84%), while 16 of 34 (47%, 95% CI = 31% to 63%) SHAM subjects weaned, P = .039. The number of patients needed to be treated for effect was 4 (95% CI = 2 to 80). An IMST program can lead to increased MIP and improved weaning outcome in FTW patients compared to SHAM treatment. ClinicalTrials.gov: NCT00419458.


A case control study of HIV seroconversion in gay men, 1988-1993: what are the current risk factors?
To investigate current risk factors for HIV seroconversion among homo/bisexual men. Matched case control study in a large STD clinic in central London. Data on risk factors were obtained by case note review. Fifty-six cases who had at least one negative HIV test followed by a positive test between June 1988 and July 1993, and two homo/bisexual controls (having two or more negative HIV tests) matched to each case on age, total number of HIV tests and test interval period were identified. Univariate and multivariate odds ratio were calculated for acute STD, ano-genital intercourse, condom use and HIV status of sexual partners. Adjusted odds ratios (95% confidence intervals) for HIV seroconversion were 4.1 (1.3-13.3) for having an acute interval STD and 4.6 (1.4-15.4) for having a known HIV infected sexual partner. Compared with men who always used condoms, odds ratios for men who sometimes or never used condoms were 7.9 (2.2-28.9) and 16.2 (3.0-86.0) respectively. Unprotected ano-genital intercourse was commonly reported by both cases and controls, and reported condom use was no greater with a known HIV infected partner than with a partner of unknown HIV status. HIV seroconversion among homo/bisexual men attending STD clinics is strongly related to having an acute STD, a known HIV infected partner and not using condoms. Although consistent use of condoms is highly protective, knowing that a partner is HIV infected does not ensure condom use between serodiscordant men. More effective, well-evaluated interventions are needed to reduce sexual risk-taking in this population.


High prevalence of asthma in patients with bronchiectasis in Hong Kong.
Eighty five Chinese patients with diffuse or localized bronchiectasis (non-cystic fibrosis) were studied regarding the prevalence of asthma. Twenty three of the 85 had concomitant asthma, diagnosed by history and reversibility on lung function testing either spontaneously or after bronchodilator. None fulfilled the diagnostic criteria of allergic bronchopulmonary aspergillosis (ABPA). Asthma preceded the onset of bronchiectasis in 13 patients and developed after long duration of bronchiectasis in seven, while the temporal onset could not be differentiated in three patients. Patients with both asthma and bronchiectasis had inferior spirometric values, higher prevalence of bronchial hyperresponsiveness to methacholine, higher prevalence of skin atopy, elevated serum immunoglobulin E (IgE), and more sputum eosinophilia, compared with their non-asthmatic counterparts. Possible mechanisms by which asthma and bronchiectasis predispose to each other include asthmatic obstruction contributing to development of bronchiectasis, and sensitization of airways with increased lability due to microbial colonization of the ectatic bronchial tree.


Manuka honey modulates the release profile of a dHL-60 neutrophil model under anti-inflammatory stimulation.
Manuka honey, a wound treatment used to eradicate bacteria, resolve inflammation, and promote wound healing, is a current focus in the tissue engineering community as a tissue template additive. However, Manuka honey's effect on neutrophils during the inflammation-resolving phase has yet to be examined. This study investigates the effect of 0.5% and 3% Manuka honey on the release of cytokines, chemokines, and matrix-degrading enzymes from a dHL-60 neutrophil model in the presence of anti-inflammatory stimuli (TGF-β, IL-4, IL-4 +IL-13). We hypothesized that Manuka honey would reduce the output of pro-inflammatory signals and increase the release of anti-inflammatory signals. The results of this study indicate that 0.5% honey significantly increases the release of CXCL8/IL-8, CCL2/MCP-1, CCL4/MIP-1β, CCL20/MIP-3α, IL-4, IL-1ra, and FGF-13 while reducing Proteinase 3 release in the anti-inflammatory-stimulated models. However, 3% honey significantly increased the release of TNF-α and CXCL8/IL-8 while reducing the release of all other analytes. We replicated a subset of the most notable findings in primary human neutrophils, and the consistent results indicate that the HL-60 data are relevant to the performance of primary cells. These findings demonstrate the variable effects of Manuka honey on the release of cytokines, chemokines, and matrix-degrading enzymes of this model of neutrophil anti-inflammatory activity. This study reinforces the importance of tailoring the concentration of Manuka honey in a wound or tissue template to elicit the desired effects during the inflammation-resolving phase of wound healing. Future in vivo investigation should be undertaken to translate these results to a physiologically-relevant wound environment.


The complete mitochondrial genome sequence of the spider Habronattus oregonensis reveals rearranged and extremely truncated tRNAs.
We sequenced the entire mitochondrial genome of the jumping spider Habronattus oregonensis of the arachnid order Araneae (Arthropoda: Chelicerata). A number of unusual features distinguish this genome from other chelicerate and arthropod mitochondrial genomes. Most of the transfer RNA (tRNA) gene sequences are greatly reduced in size and cannot be folded into typical cloverleaf-shaped secondary structures. At least nine of the tRNA sequences lack the potential to form TPsiC arm stem pairings and instead are inferred to have TV-replacement loops. Furthermore, sequences that could encode the 3' aminoacyl acceptor stems in at least 10 tRNAs appear to be lacking, because fully paired acceptor stems are not possible and because the downstream sequences instead encode adjacent genes. Hence, these appear to be among the smallest known tRNA genes. We postulate that an RNA editing mechanism must exist to restore the 3' aminoacyl acceptor stems to allow the tRNAs to function. At least seven tRNAs are rearranged with respect to the chelicerate Limulus polyphemus, although the arrangement of the protein-coding genes is identical. Most mitochondrial protein-coding genes of H. oregonensis have ATN as initiation codons, as commonly found in arthropod mtDNAs, but cytochrome oxidase subunits 2 and 3 genes apparently use TTG as an initiation codon. Finally, many of the gene sequences overlap one another and are truncated. This 14,381-bp genome, the first mitochondrial genome of a spider yet sequenced, is one of the smallest arthropod mitochondrial genomes known. We suggest that posttranscriptional RNA editing can likely maintain function of the tRNAs, while permitting the accumulation of mutations that would otherwise be deleterious. Such mechanisms may have allowed for the minimization of the spider mitochondrial genome.


Boryllithium: isolation, characterization, and reactivity as a boryl anion.
Nucleophilic, anionic boryl compounds are long-sought but elusive species. We report that reductive cleavage of the boron-bromine bond in N,N'-bis(2,6-diisopropylphenyl)-2-bromo-2,3-dihydro-1H-1,3,2-diazaborole by lithium naphthalenide afforded the corresponding boryllithium, which is isoelectronic with an N-heterocyclic carbene. The structure of the boryllithium determined by x-ray crystallography was consistent with sp(2) boron hybridization and revealed a boron-lithium bond length of 2.291 +/- 0.006 angstroms. The structural similarity between this compound and the calculated free boryl anion suggests that the boron atom has an anionic charge. The (11)B nuclear magnetic resonance spectrum also supports the boryl anion character. Moreover, the compound behaves as an efficient base and nucleophile in its reactions with electrophiles such as water, methyl trifluoromethanesulfonate, 1-chlorobutane, and benzaldehyde.


Effectiveness of the Epley manoeuvre in posterior canal benign paroxysmal positional vertigo: a randomised clinical trial in primary care.
Evidence on the effectiveness of the Epley manoeuvre in primary care is scarce. To evaluate effectiveness at 1 week, 1 month, and 1 year of a single Epley manoeuvre versus a sham manoeuvre in primary care. Multicentre, double-blind randomised controlled trial in two primary care practices in Spain from November 2012 to January 2015. Patients were ≥18 years diagnosed with subjective or objective posterior benign paroxysmal positional vertigo (vertigo only, or vertigo and nystagmus after a Dix-Hallpike test [DHT]). The intervention group received the Epley manoeuvre, and the control group received a sham manoeuvre. Betahistine was prescribed following the same regimen in both groups. The main outcome measures were the DHT result classified as negative (neither vertigo nor nystagmus) or positive. Positive results were further divided into a positive result for both vertigo and nystagmus (positive DHT with nystagmus), and a positive result for vertigo only (positive DHT without nystagmus); self-reported resolution of vertigo; and self-reported severity of vertigo evaluated on a 10-point Likert scale (10 = worst imaginable vertigo). In total, 134 patients were randomised to either the intervention group (n = 66) or the sham group (n = 68). The intervention group showed better results in the unadjusted analyses at 1 week, with a lower rate of positive DHT with nystagmus (P = 0.022). A positive baseline DHT with nystagmus was associated with a reduction in vertigo severity (marginal effect for 10-point Likert-like question -1.73, 95% confidence interval [CI] = -2.95 to -0.51) and better positive DHT rates in the intervention group (adjusted odds ratio 0.09, 95% CI = 0.01 to 0.92) in the multivariate analyses. A single Epley manoeuvre performed in primary care is an effective treatment for reversing a positive DHT and reducing vertigo severity in patients with baseline nystagmus in the DHT.


Prioritizing areas for quality marker development in children in UK general practice: extending the use of the nominal group technique.
There is a deficiency in the ability to measure the quality of care of children in primary care and there is no professional consensus in UK general practice regarding which quality markers should be used. To prioritize clinical areas on which to focus quality marker development in paediatric primary care and to describe the challenges in generating professional consensus. We convened an expert panel of GPs with a special interest in child health and using the nominal group technique (NGT), a well-established structured, multistep facilitated group meeting technique, we generated consensus around the key clinical areas to focus quality marker development. Twelve GPs participated in the expert panel. The eight items agreed by panellists as most important were early recognition of serious illness, whole practice involvement in safeguarding, health promotion, mental health, evidence-based management of common conditions, child and carer friendliness and safe and cost-effective prescribing. Panel members struggled to balance the broad clinical areas while attempting to focus on specific areas that are important. The main challenges included managing panel uncertainty, effective organization, presentation of items for review and group inclination to 'include everything'. This is the first consensus study of UK GPs to identify key areas to target quality marker development in children. By using the NGT, we have highlighted front-line health care professionals' priorities to improve the quality of care of children and identified the benefits and challenges of developing consensus in a broad topic area.


An audit of restorative proctocolectomy.
A total of 168 restorative proctocolectomies have been performed without mortality during the past nine years. Morbidity from pelvic sepsis (12%), ileoanal stricture (15%), and pouch related fistulas (16%) have become less with increasing experience of the operation. Pouch excision, which occurred in 30% of the first 50 patients was undertaken in only 4% in the last 68 patients. Despite this, intestinal obstruction (18%) continues to complicate the operation. We have abandoned restorative proctocolectomy after failed ileorectal anastomosis in patients with slow transit constipation as half have now requested pouch excision because of poor results. Failure to identify Crohn's disease continues to influence the outcome: in 10 patients now known to have Crohn's disease six developed post operative fistulas, three have required pouch excision. Sexual impairment has occurred in three male patients (4%). Ten women had children after operation, eight uncomplicated vaginal deliveries occurred without impaired continence. Seven of nine patients over 60 years of age have had a successful outcome. Our data also indicate that the operation may be justified in distal disease if urgency is socially inconvenient. Frequency of defecation is usually less than three per 24 hours in patients with familial adenomatous polyposis but remains variable in those with ulcerative colitis.


The projection of a test genome onto a reference population and applications to humans and archaic hominins.
We introduce a method for comparing a test genome with numerous genomes from a reference population. Sites in the test genome are given a weight, w, that depends on the allele frequency, x, in the reference population. The projection of the test genome onto the reference population is the average weight for each x, [Formula: see text]. The weight is assigned in such a way that, if the test genome is a random sample from the reference population, then [Formula: see text]. Using analytic theory, numerical analysis, and simulations, we show how the projection depends on the time of population splitting, the history of admixture, and changes in past population size. The projection is sensitive to small amounts of past admixture, the direction of admixture, and admixture from a population not sampled (a ghost population). We compute the projections of several human and two archaic genomes onto three reference populations from the 1000 Genomes project-Europeans, Han Chinese, and Yoruba-and discuss the consistency of our analysis with previously published results for European and Yoruba demographic history. Including higher amounts of admixture between Europeans and Yoruba soon after their separation and low amounts of admixture more recently can resolve discrepancies between the projections and demographic inferences from some previous studies.


Effect of the phase volume ratio on the potential of a liquid-membrane ion-selective electrode.
Two-phase liquid system IA(w)|IX(o) comprising the interface between the aqueous solution (w) of uni-univalent electrolyte IA and an organic solvent solution (o) of a uni-univalent electrolyte IX with the common cation I(+) is considered as a simple model of a liquid-membrane ion-selective electrode (ISE). Taking into account the electroneutrality and mass balance conditions, the equilibrium Galvani potential difference (pd) between the aqueous and organic phases, phi = phi(w) - phi(o), is calculated numerically as a function of the ratio of the initial electrolyte concentrations, x = / = 10(-)(4)-10(4), for the selected values of the phase volume ratio r = V(o)/V(w) = 10(-)(3), 1, and 10(3), and the standard ion transfer potentials of the present ions ranging from -0.5 to 0.5 V. Numeric results corroborate the symbolic expressions derived for the cases when X(-) and A(-) are extremely lipophilic and hydrophilic ions, respectively, or when the concentration ratio x is extremely large or small. In contrast to the extraction system, where both electrolytes are initially present in the aqueous phase, the effect of the phase volume ratio on the equilibrium pd in the ISE model is rather weak, unless the counterions X(-) and A(-) differ little in their lipophilicity from the target ion I(+). It is shown that both the ISE and extraction model exhibit the Nernstian behavior only in a limited range of the concentration ratio x depending on the value of the standard ion transfer potentials of the counterions. When this ratio is extremely large or small, equilibrium pd approaches the limiting value given by the distribution potential of the electrolyte IA or IX, respectively. Similar conclusions can be drawn for the two-phase liquid system AI(w)|XI(o) with the common anion I(-).


Three-dimensional high-resolution particle tracking for optical tweezers by forward scattered light.
A quadrant photodiode placed in the back-focal plane of the microscope of a laser trap provides a high-resolution position sensor. We show that in addition to the lateral displacement of a trapped sphere, its axial position can be measured by the ratio of the intensity of scattered laser light to the total amount of the light reaching the detector. The addition of the axial information offers true three-dimensional position detection in solution, creating, together with a position control, a photonic force microscope with nanometer spatial and microsecond temporal resolution. The measured position signals are explained as interference of the unscattered trapping laser beam with the laser light scattered by the trapped bead. Our model explains experimental data for trapped particles in the Rayleigh regime (radius a <0.2lambda) for displacements up to the focal dimensions. The cross-talk between the signals in the three directions is explained and it is shown that this cross-talk can be neglected for lateral displacements smaller than 75 nm and axial displacements below 150 nm. The advantages of three-dimensional single-particle tracking over conventional video-tracking are shown through the example of the diffusion of the GPI-anchored membrane protein Thy1.1 on a neurite.


The reduction of selenium(IV) by boreal Pseudomonas sp. strain T5-6-I - Effects on selenium(IV) uptake in Brassica oleracea.
Selenium (Se) is an essential micronutrient but toxic when taken in excessive amounts. Therefore, understanding the metabolic processes related to selenium uptake and bacteria-plant interactions coupled with selenium metabolism are of high importance. We cultivated Brassica oleracea with the previously isolated heterotrophic aerobic Se(IV)-reducing Pseudomonas sp. T5-6-I strain to better understand the phenomena of bacteria-mediated Se(IV) reduction on selenium availability to the plants. B. oleracea grown on Murashige and Skoog medium (MS-salt agar) with and without of Pseudomonas sp. were amended with Se(IV)/75Se(IV), and selenium transfer into plants was studied using autoradiography and gamma spectroscopy. XANES was in addition used to study the speciation of selenium in the B. oleracea plants. In addition, the effects of Se(IV) on the protein expression in B. oleracea was studied using HPLC-SEC. TEM and confocal microscopy were used to follow the bacterial/Se-aggregate accumulation in plants and the effects of bacterial inoculation on root-hair growth. In the tests using 75Se(IV) on average 130% more selenium was translocated to the B. oleracea plants grown with Pseudomonas sp. compared to the plants grown with selenium, but without Pseudomonas sp.. In addition, these bacteria notably increased root hair density. Changes in the protein expression of B. oleracea were observed on the ∼30-58 kDa regions in the Se(IV) treated samples, probably connected e.g. to the oxidative stress induced by Se(IV) or expression of proteins connected to the Se(IV) metabolism. Based on the XANES measurements, selenium appears to accumulate in B. oleracea mainly in organic C-Se-H and C-Se-C bonds with and without bacteria inoculation. We conclude that the Pseudomonas sp. T5-6-I strain seems to contribute positively to the selenium accumulation in plants, establishing the high potential of Se0-producing bacteria in the use of phytoremediation and biofortification of selenium.


Diabetes in rural towns: effectiveness of continuing education and feedback for healthcare providers in altering diabetes outcomes at a population level: protocol for a cluster randomised controlled trial.
Type 2 diabetes is one of the fastest growing chronic diseases internationally. The health complications associated with type 2 diabetes can be prevented, delayed, or improved via early diagnosis and effective management. This research aims to examine the impact of a primarily web-based educational intervention on the diabetes care provided by general practitioners (GPs) in rural areas, and subsequent patient outcomes. A population-level approach to outcome assessment is used, via whole-town de-identified pathology records. The study uses a cluster randomised controlled trial with rural communities as the unit of analysis. Towns from four Australian states were selected and matched on factors including rurality, population size, proportion of the population who were Indigenous Australians, and socio-economic status. Eleven pairs of towns from two states were suitable for the trial, and one town from each pair was randomised to the experimental group. GPs in the towns allocated to the experimental group are offered an intervention package comprising education on best practice diabetes care via an on-line active learning module, a moderated discussion forum, access to targeted and specialist advice through an on-line request form, and town-based performance feedback on diabetes monitoring and outcomes. The package is offered via repeated direct mail. The benefits of the outcomes of the trial are described along with the challenges and limitations associated with the methodology. Australian New Zealand Clinical Trials Registry: ACTRN12611000553976.


Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.
To assess the clinical and cost-effectiveness of continuous subcutaneous insulin infusion (CSII) compared with multiple daily injections (MDI) in the delivery of intensive insulin therapy for the treatment of diabetes mellitus. Electronic databases, references of retrieved articles and manufacturer submissions. Experts in the field were consulted. For the systematic review of clinical and cost-effectiveness, studies were assessed for inclusion according to predefined criteria by two reviewers. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Data on clinical effectiveness were synthesised through a narrative review with full tabulation of all eligible studies, with meta-analysis performed where appropriate. Twenty studies comparing CSII with MDI were identified. Quality was generally poor. In adults with Type 1 diabetes, glycated haemoglobin improved by 0.61% (95% CI -1.29 to 0.07) in longer term studies, although this improvement was smaller when a study using bovine ultralente was excluded. A reduction in insulin dose with CSII of about 12 units per day (-11.90, 95% CI -18.16 to 5.63) was found in short-term studies, with smaller differences in longer term studies. Body weight and cholesterol levels were similar between treatments. Hypoglycaemic events did not differ significantly between CSII and MDI in most trials, but some found fewer events with CSII and one found more hypoglycaemia and hypoglycaemic coma with CSII. There was no consistency between the studies in patient preference, but progress has been made both with insulin pumps and injector pens since the publication of many of the older studies. No difference in glycated haemoglobin between CSII and MDI was found in pregnancy; one study found less insulin was required by patients with CSII, but two other studies found no significant difference. One study of adolescents found lower glycated haemoglobin and insulin dose with CSII whereas a second study found no significant difference. In CSII analogue insulin was associated with lower glycated haemoglobin levels than soluble insulin. No economic evaluations comparing CSII with MDI were identified. The estimated additional cost of CSII compared to MDI varies from GBP1091 per annum to GBP1680 per annum, according to the make of the insulin pump and the estimated life of the device. These estimates include the costs for the insulin pump, the consumables associated with delivery of CSII, and an allowance for the initial education required when patients switch from MDI to CSII. The largest component of the annual cost for CSII is the cost of consumable items (e.g. infusion sets). When compared with optimised MDI, CSII results in a modest but worthwhile improvement in glycated haemoglobin in adults with Type 1 diabetes. It has not been possible to establish the longer term benefits of such a difference in glycated haemoglobin, although there is an expectation that it would be reflected in a reduction in long-term complications. More immediate primary benefits from CSII may be associated with an impact on the incidence of hypoglycaemic events and the dawn phenomenon, and greater flexibility of lifestyle. However, there is limited evidence on this, and information presented to offer context on quality-of-life is based on testimonies from those patients who have had a positive experience of CSII. The estimated cost to the NHS per year for CSII would be around GBP3.5 million in England and Wales if 1% of people with Type 1 diabetes used CSII, GBP10.5 million for 3%, and GBP17.5 million for 5%. Further research should focus on wider benefits of CSII, such as flexibility of lifestyle and quality of life, and on the psychological impact of wearing a device for 24 hours every day. Research into the use of CSII in children of different ages is also needed.


Poor impulse control predicts inelastic demand for nicotine but not alcohol in rats.
Tobacco and alcohol dependence are characterized by continued use despite deleterious health, social and occupational consequences, implying that addicted individuals pay a high price for their use. In behavioral economic terms, such persistent consumption despite increased costs can be conceptualized as inelastic demand. Recent animal studies demonstrated that high-impulsive individuals are more willing to work for nicotine or cocaine infusions than their low-impulsive counterparts, indicating that this trait might be causally related to inelastic drug demand. By employing progressive ratio schedules of reinforcement combined with a behavioral economics approach of analysis, we determined whether trait impulsivity is associated with an insensitivity of nicotine or alcohol consumption to price increments. Rats were trained on a delayed discounting task, measuring impulsive choice. Hereafter, high- and low-impulsive rats were selected and trained to nose poke for intravenous nicotine or oral alcohol. Upon stable self-administration on a continuous reinforcement schedule, the price (i.e. response requirement) was increased. Demand curves, depicting the relationship between price and consumption, were produced using Hursh's exponential demand equation. Similar to human observations, nicotine and alcohol consumption in rats fitted this equation, thereby demonstrating the validity of our model. Moreover, high-impulsive rats displayed inelastic nicotine demand, as their nicotine consumption was less sensitive to price increments as compared with that in low-impulsive rats. Impulsive choice was not related to differences in alcohol demand elasticity. Our model seems well suited for studying nicotine and alcohol demand in rats and, as such, might contribute to our understanding of tobacco and alcohol dependence.


Trinucleotide repeats and other microsatellites in yeasts.
Microsatellites are direct tandem DNA repeats found in all genomes. A particular class of microsatellites, called trinucleotide repeats, is responsible for a number of neurological disorders in humans. We review here our current state of knowledge on trinucleotide repeat instability, and discuss the molecular mechanisms that may be involved in trinucleotide repeat expansions leading to fatal diseases in humans. We also present original data on microsatellite distribution in several microbial genomes, and on the use of microsatellites as physical markers to accurately and easily genotype yeast strains.


Visualization and measurement of the cortical surface.
Much of the human cortical surface is obscured from view by the complex pattern of folds, making the spatial relationship between different surface locations hard to interpret. Methods for viewing large portions of the brain's surface in a single flattened representation are described. The flattened representation preserves several key spatial relationships between regions on the cortical surface. The principles used in the implementations and evaluations of these implementations using artificial test surfaces are provided. Results of applying the methods to structural magnetic resonance measurements of the human brain are also shown. The implementation details are available in the source code, which is freely available on the Internet.


The Competition-Day Preparation Strategies of Strongman Athletes.
Winwood, PW, Pritchard, HJ, Wilson, D, Dudson, M, and Keogh, JWL. The competition-day preparation strategies of strongman athletes. J Strength Cond Res 33(9): 2308-2320, 2019-This study provides the first empirical evidence of the competition-day preparation strategies used by strongman athletes. Strongman athletes (n = 132) (mean ± SD: 33.7 ± 8.1 years, 178.2 ± 11.1 cm, 107.0 ± 28.6 kg, 12.8 ± 8.0 years general resistance training, 5.9 ± 4.8 years strongman implement training) completed a self-reported 4-page internet survey on their usual competition-day preparation strategies. Analysis of the overall group and by sex, age, body mass, and competitive standard was conducted. Ninety-four percent of strongman athletes used warm-ups in competition, which were generally self-directed. The typical warm-up length was 16.0 ± 8.9 minutes, and 8.5 ± 4.3 minutes was the perceived optimal rest time before the start of an event. The main reasons for warming up were injury prevention, to increase activation, and increase blood flow/circulation, temperature, and heart rate. Athletes generally stated that competition warm-ups were practiced in training. Dynamic stretching, foam rolling, and myofascial release work were performed during warm-ups. Warm-up intensity was monitored using the rate of perceived exertion, perceived speed of movement, and training load (as a percentage of 1 repetition maximum). Cognitive strategies were used to improve competition performance, and psychological arousal levels needed to increase or be maintained in competition. Electrolyte drinks, caffeine, and preworkout supplements were the commonly used supplements. These data will provide strongman athletes and coaches some insight into common competition-day preparation strategies, which may enhance competition performances. Future research could compare different competition-day preparation strategies in an attempt to further improve strongman competition performance and injury prevention.


State-space models of mental processes from fMRI.
In addition to functional localization and integration, the problem of determining whether the data encode some information about the mental state of the subject, and if so, how this information is represented has become an important research agenda in functional neuroimaging. Multivariate classifiers, commonly used for brain state decoding, are restricted to simple experimental paradigms with a fixed number of alternatives and are limited in their representation of the temporal dimension of the task. Moreover, they learn a mapping from the data to experimental conditions and therefore do not explain the intrinsic patterns in the data. In this paper, we present a data-driven approach to building a spatio-temporal representation of mental processes using a state-space formalism, without reference to experimental conditions. Efficient Monte Carlo algorithms for estimating the parameters of the model along with a method for model-size selection are developed. The advantages of such a model in determining the mental-state of the subject over pattern classifiers are demonstrated using an fMRI study of mental arithmetic.


The urban brain: analysing outdoor physical activity with mobile EEG.
Researchers in environmental psychology, health studies and urban design are interested in the relationship between the environment, behaviour settings and emotions. In particular, happiness, or the presence of positive emotional mindsets, broadens an individual's thought-action repertoire with positive benefits to physical and intellectual activities, and to social and psychological resources. This occurs through play, exploration or similar activities. In addition, a body of restorative literature focuses on the potential benefits to emotional recovery from stress offered by green space and 'soft fascination'. However, access to the cortical correlates of emotional states of a person actively engaged within an environment has not been possible until recently. This study investigates the use of mobile electroencephalography (EEG) as a method to record and analyse the emotional experience of a group of walkers in three types of urban environment including a green space setting. Using Emotiv EPOC, a low-cost mobile EEG recorder, participants took part in a 25 min walk through three different areas of Edinburgh. The areas (of approximately equal length) were labelled zone 1 (urban shopping street), zone 2 (path through green space) and zone 3 (street in a busy commercial district). The equipment provided continuous recordings from five channels, labelled excitement (short-term), frustration, engagement, long-term excitement (or arousal) and meditation. A new form of high-dimensional correlated component logistic regression analysis showed evidence of lower frustration, engagement and arousal, and higher meditation when moving into the green space zone; and higher engagement when moving out of it. Systematic differences in EEG recordings were found between three urban areas in line with restoration theory. This has implications for promoting urban green space as a mood-enhancing environment for walking or for other forms of physical or reflective activity.


ESPEN Guidelines on Parenteral Nutrition: central venous catheters (access, care, diagnosis and therapy of complications).
When planning parenteral nutrition (PN), the proper choice, insertion, and nursing of the venous access are of paramount importance. In hospitalized patients, PN can be delivered through short-term, non-tunneled central venous catheters, through peripherally inserted central catheters (PICC), or - for limited period of time and with limitation in the osmolarity and composition of the solution - through peripheral venous access devices (short cannulas and midline catheters). Home PN usually requires PICCs or - if planned for an extended or unlimited time - long-term venous access devices (tunneled catheters and totally implantable ports). The most appropriate site for central venous access will take into account many factors, including the patient's conditions and the relative risk of infective and non-infective complications associated with each site. Ultrasound-guided venepuncture is strongly recommended for access to all central veins. For parenteral nutrition, the ideal position of the catheter tip is between the lower third of the superior cava vein and the upper third of the right atrium; this should preferably be checked during the procedure. Catheter-related bloodstream infection is an important and still too common complication of parenteral nutrition. The risk of infection can be reduced by adopting cost-effective, evidence-based interventions such as proper education and specific training of the staff, an adequate hand washing policy, proper choices of the type of device and the site of insertion, use of maximal barrier protection during insertion, use of chlorhexidine as antiseptic prior to insertion and for disinfecting the exit site thereafter, appropriate policies for the dressing of the exit site, routine changes of administration sets, and removal of central lines as soon as they are no longer necessary. Most non-infective complications of central venous access devices can also be prevented by appropriate, standardized protocols for line insertion and maintenance. These too depend on appropriate choice of device, skilled implantation and correct positioning of the catheter, adequate stabilization of the device (preferably avoiding stitches), and the use of infusion pumps, as well as adequate policies for flushing and locking lines which are not in use.


Taking behavioralism seriously: some evidence of market manipulation.
Over the last ten to fifteen years, economists and legal scholars have become increasingly interested in and sensitive to behavioralist insights. In a companion article, Jon Hanson and Douglas Kysar argued that those scholars have nevertheless given short shrift to what is, at least for policymaking purposes, perhaps the most important lesson of the behavioralist research: individuals' perceptions and preferences are highly manipulable. According to Hanson and Kysar, one theoretical implication of that insight for products liability law is that manufacturers and marketers will manipulate the risk perceptions of consumers. Indeed, to survive in a competitive market, manufacturers and marketers must do so. In this Article, Hanson and Kysar present empirical evidence of market manipulation--a previously unrecognized source of market failure. The Article begins by surveying the extensive qualitative and quantitative marketing research and consumer behavioral studies that discern and influence consumer perceptions. It then provides evidence of market manipulation by reviewing common practices in everyday market settings, such as gas stations and supermarkets, and by examining familiar marketing approaches, such as environmentally oriented and fear-based advertising. Although consumers may be well-aware of those practices and approaches, they appear to be generally unaware of the extent to which those tactics are manipulative. The Article then focuses on the industry that has most depended upon market manipulation: the cigarette industry. Through decades of sophisticated marketing and public relations efforts, cigarette manufacturers have heightened consumer demand and lowered consumer risk perceptions. Because consumers are aware that smoking may pose significant health risks, the tobacco industry's success in manipulating risk perceptions constitutes especially strong evidence of the power of market manipulation. The Article concludes by arguing that the evidence of market manipulation may justify moving to a regime of enterprise liability. Indeed, according to Hanson and Kysar, the evidence of market manipulation confirms the intuitions of the first generation of product liability scholars, who worried about manufacturers' power to manipulate and called for just such a regime.


Stroke Prevention for High-Risk Atrial Fibrillation in the Emergency Setting: The Emergency Physician Perspective.
Atrial fibrillation is a frequent reason for presentation to an emergency department (ED), and the number of these visits are increasing. This creates an opportunity to improve the suboptimal rate of oral anticoagulation (OAC) use in patients with atrial fibrillation who are at high risk of stroke. However, there are very few data on whether OAC initiation in the ED, compared with referral to the longitudinal health care provider to initiate it, results in better long-term use. Moreover, for ethical and medicolegal reasons, physicians who initiate a chronic medication are obliged to reassess the patient at a later date, to check for medication side effects and the need for dose adjustment. More research is needed to determine whether OAC should be prescribed in the ED, by a physician who will never see the patient again. Patients who are cardioverted in the ED might be an exception, secondary to the increased risk of stroke after cardioversion. If ED OAC prescribing is associated with better outcomes, these results must be placed into context with the care and outcomes of the other patients in the ED. If there is a net benefit, the findings should be disseminated to practicing emergency physicians, preferably via emergency physician opinion leaders. An implementation science-based approach, which addresses the barriers to ED OAC prescribing (eg, the competing demands of running an ED and lack of guaranteed follow-up care after discharge from an ED), should be used to support prescribing of OAC in the ED. Potential solutions are described.


Genomic Variants Among Threatened Acropora Corals.
Genomic sequence data for non-model organisms are increasingly available requiring the development of efficient and reproducible workflows. Here, we develop the first genomic resources and reproducible workflows for two threatened members of the reef-building coral genus Acropora We generated genomic sequence data from multiple samples of the Caribbean A. cervicornis (staghorn coral) and A. palmata (elkhorn coral), and predicted millions of nucleotide variants among these two species and the Pacific A. digitifera A subset of predicted nucleotide variants were verified using restriction length polymorphism assays and proved useful in distinguishing the two Caribbean acroporids and the hybrid they form ("A. prolifera"). Nucleotide variants are freely available from the Galaxy server (usegalaxy.org), and can be analyzed there with computational tools and stored workflows that require only an internet browser. We describe these data and some of the analysis tools, concentrating on fixed differences between A. cervicornis and A. palmata In particular, we found that fixed amino acid differences between these two species were enriched in proteins associated with development, cellular stress response, and the host's interactions with associated microbes, for instance in the ABC transporters and superoxide dismutase. Identified candidate genes may underlie functional differences in how these threatened species respond to changing environments. Users can expand the presented analyses easily by adding genomic data from additional species, as they become available.


An outbreak of Salmonella Typhimurium 9 at a school camp linked to contamination of rainwater tanks.
In March 2007, an outbreak of gastroenteritis was identified at a school camp in rural Victoria, Australia, affecting about half of a group of 55 students. A comprehensive investigation was initiated to identify the source. Twenty-seven attendees were found to have abdominal pain, diarrhoea and nausea (attack rate 49%). Of 11 faecal specimens tested all were positive for Salmonella Typhimurium definitive phage type 9 (DT9). Of four samples taken from the untreated private water supply, two were positive for DT9. Drinking water from containers filled from rainwater tanks [relative risk (RR) 3.2, P=0.039] and participation in two recreational activities - flying fox (RR 5.3, P=0.011), and beam-balance (RR 3.9, P=0.050) - were indicative of a link with illness. Environmental and epidemiological investigations suggested rainwater collection tanks contaminated with DT9 as being the cause of the outbreak. Increased use of rainwater tanks may heighten the risk of waterborne disease outbreaks unless appropriate preventative measures are undertaken.


Study to prospectively evaluate reamed intramedually nails in patients with tibial fractures (S.P.R.I.N.T.): study rationale and design.
Surgeons agree on the benefits of operative treatment of tibial fractures - the most common of long bone fractures - with an intramedullary rod or nail. Rates of re-operation remain high - between 23% and 60% in prior trials - and the two alternative nailing approaches, reamed or non-reamed, each have a compelling biological rationale and strong proponents, resulting in ongoing controversy regarding which is better. The objective of this trial was to assess the impact of reamed versus non-reamed intramedullary nailing on rates of re-operation in patients with open and closed fractures of the tibial shaft. The study to prospectively evaluate reamed intramedullary nails in tibial fractures (S.P.R.I.N.T) was a multi-center, randomized trial including 29 clinical sites in Canada, the United States and the Netherlands which enrolled 1200 skeletally mature patients with open (Gustilo Types I-IIIB) or closed (Tscherne Types 0-3) fractures of the tibial shaft amenable to surgical treatment with an intramedullary nail. Patients received a statically locked intramedullary nail with either reamed or non-reamed insertion. The first strategy involved fixation of the fracture with an intramedullary nail following reaming to enlarge the intramedullary canal (Reamed Group). The second treatment strategy involved fixation of the fracture with an intramedullary nail without prior reaming of the intramedullary canal (Non-Reamed Group). Patients, outcome assessors, and data analysts were blinded to treatment allocation. Peri-operative care was standardized, and re-operations before 6 months were proscribed. Patients were followed at discharge, 2 weeks post-discharge, and at 6 weeks, 3, 6, 9, and 12 months post surgery. A committee, blinded to allocation, adjudicated all outcomes. The primary outcome was re-operation to promote healing, treat infection, or preserve the limb (fasciotomy for compartment syndrome after nailing). The primary outcome was a composite comprising the following re-operations: bone grafts, implant exchanges, and dynamizations, in patients with fracture gaps less than 1 cm post intramedullary nail insertion. Infections and fasciotomies were considered events irrespective of the fracture gap. We planned a priori to conduct a subgroup analysis of outcomes in patients with open and closed fractures. S.P.R.I.N.T is the largest collaborative trial evaluating alternative orthopaedic surgical interventions in patients with tibial shaft fractures. The methodological rigor will set new benchmarks for future trials in the field and its results will have important impact on patient care. The S.P.R.I.N.T trial was registered [ID NCT00038129] and received research ethics approval (REB#99-077).


SVBRDF-Invariant Shape and Reflectance Estimation from a Light-Field Camera.
Light-field cameras have recently emerged as a powerful tool for one-shot passive 3D shape capture. However, obtaining the shape of glossy objects like metals or plastics remains challenging, since standard Lambertian cues like photo-consistency cannot be easily applied. In this paper, we derive a spatially-varying (SV)BRDF-invariant theory for recovering 3D shape and reflectance from light-field cameras. Our key theoretical insight is a novel analysis of diffuse plus single-lobe SVBRDFs under a light-field setup. We show that, although direct shape recovery is not possible, an equation relating depths and normals can still be derived. Using this equation, we then propose using a polynomial (quadratic) shape prior to resolve the shape ambiguity. Once shape is estimated, we also recover the reflectance. We present extensive synthetic data on the entire MERL BRDF dataset, as well as a number of real examples to validate the theory, where we simultaneously recover shape and BRDFs from a single image taken with a Lytro Illum camera.


Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study.
The prevalence of comorbid alcohol, other drug, and mental disorders in the US total community and institutional population was determined from 20,291 persons interviewed in the National Institute of Mental Health Epidemiologic Catchment Area Program. Estimated US population lifetime prevalence rates were 22.5% for any non-substance abuse mental disorder, 13.5% for alcohol dependence-abuse, and 6.1% for other drug dependence-abuse. Among those with a mental disorder, the odds ratio of having some addictive disorder was 2.7, with a lifetime prevalence of about 29% (including an overlapping 22% with an alcohol and 15% with another drug disorder). For those with either an alcohol or other drug disorder, the odds of having the other addictive disorder were seven times greater than in the rest of the population. Among those with an alcohol disorder, 37% had a comorbid mental disorder. The highest mental-addictive disorder comorbidity rate was found for those with drug (other than alcohol) disorders, among whom more than half (53%) were found to have a mental disorder with an odds ratio of 4.5. Individuals treated in specialty mental health and addictive disorder clinical settings have significantly higher odds of having comorbid disorders. Among the institutional settings, comorbidity of addictive and severe mental disorders was highest in the prison population, most notably with antisocial personality, schizophrenia, and bipolar disorders.


Cloning, sequence and mRNA expression of bovine interleukin-16.
A lambda gt11 cDNA library was constructed using mRNA isolated from Theileria parva-infected bovine lymphocytes. Sequencing of random clones of this library resulted in the identification of a cDNA encoding bovine interleukin-16 (IL-16). The cDNA has an open reading frame of 1134 bp, and a 3' untranslated region of 275 nucleotides with a polyadenylation signal 16 bases upstream from the poly (A) tail. The protein predicted by the cDNA sequence contains 378 amino acids and the level of amino acid homology with the corresponding part of human precursor IL-16 is 79 %. No information is available about the tissue distribution of IL-16 in cattle, therefore we investigated the expression of IL-16 mRNA in bovine lymphoid tissues by reverse-transcription polymerase chain reaction assays. To investigate the potential of IL-16 as an immunoregulatory molecule we also analysed IL-16 mRNA expression in CD4+ and CD8+T-cell clones derived from T. parva-immunised cattle.


Multicellular microorganisms: laboratory versus nature.
Our present in-depth knowledge of the physiology and regulatory mechanisms of microorganisms has arisen from our ability to remove them from their natural, complex ecosystems into pure liquid cultures. These cultures are grown under optimized laboratory conditions and allow us to study microorganisms as individuals. However, microorganisms naturally grow in conditions that are far from optimal, which causes them to become organized into multicellular communities that are better protected against the harmful environment. Moreover, this multicellular existence allows individual cells to differentiate and acquire specific properties, such as forming resistant spores, which benefit the whole population. The relocation of natural microorganisms to the laboratory can result in their adaptation to these favourable conditions, which is accompanied by complex changes that include the repression of some protective mechanisms that are essential in nature. Laboratory microorganisms that have been cultured for long periods under optimized conditions might therefore differ markedly from those that exist in natural ecosystems.


Effects of sodium status on the venous response to noradrenaline infusion in pre-ascitic cirrhosis.
1. This study assesses the effects of sodium status on venous responsiveness to noradrenaline and the neurohumoral profile in pre-ascitic cirrhotic patients. Eight cirrhotic patients and ten control subjects were studied after both a low (20 mmol/day) and a high (200 mmol/day) sodium diet. Venous responsiveness to increasing doses of noradrenaline in a dorsal hand vein and various plasma hormone levels were measured. Maximal response (Rmax.) and the dose of noradrenaline that yielded 50% of Rmax. (ED50) were then calculated. 2. A significantly smaller dorsal hand vein diameter was observed in the control subjects on a low sodium (2.23 +/- 0.14 mm) compared with a high sodium (2.57 +/- 0.15 mm; P = 0.04) diet, but not in the cirrhotic patients. Rmax. was not significantly different in either group on both diets. With low sodium intake, ED50 was similar in the two groups. However, on high sodium intake, control subjects had a significantly higher ED50 (34.4 +/- 7.4 ng/min) than the cirrhotic patients (5.03 +/- 0.86 ng/min; P < 0.003). Plasma noradrenaline in the control subjects fell significantly with the change from a low (1.29 +/- 0.11 nmol/l) to a high (0.68 +/- 0.09 nmol/l; P < 0.001) sodium diet, but remained elevated in the cirrhotic patients. Cirrhotic patients had significantly higher atrial natriuretic factor levels and lower plasma renin activity than the control subjects on both diets. 3. In conclusion, pre-ascitic cirrhotic patients show no evidence of venodilatation. Their sympathetic nervous activity is not suppressible by volume expansion. Relative hyper-responsiveness of the peripheral venous circulation to adrenergic stimulation with high sodium intake is present.


Association of patient-provider communication domains with lung cancer treatment.
Patient-physician communication is critical for helping patients understand and complete the complex steps needed to diagnose stage and treat lung cancer. We assessed which domains of patient-physician communication about lung cancer and its treatment are associated with receipt of disease-directed, stage-appropriate treatment. Patients with recently diagnosed lung cancer were recruited from four medical centers in New York City from 2008 to 2011. Participants were surveyed about discussions with physicians regarding treatment, symptoms, and needs. Multiple regression analysis and structural equation modeling were used to assess which communication factors were associated with disease treatment. Of the 352 participants, 191 (54%) received disease-directed, stage-appropriate treatment. Unadjusted associations between communication items and treatment found that participants who felt that their physicians explained the risks and disadvantages of lung cancer treatment (p < 0.01), discussed their chances of cure (p = 0.02), discussed goals of treatment (p < 0.01), or who were warm and friendly (p = 0.04) were more likely to undergo treatment. Three communication domains were identified: treatment information, physician support, and patient symptoms/needs. After adjusting for known determinants of lung cancer treatment, increased treatment information was associated with higher probability of cancer-directed treatment (p = 0.003). Other communication domains (physician support or patient symptoms/needs) were not independent predictors of treatment (p > 0.05 for both comparisons). These data suggest that treatment information is particularly important for increasing the probability of cancer-directed therapy among lung cancer patients. Clinicians should ensure that they clearly discuss treatment goals and options with patients while maintaining empathy, supporting patient needs, and addressing symptoms.


Fiber-optic extrinsic Fabry-Perot interferometer sensors with three-wavelength digital phase demodulation.
A three-wavelength-based passive quadrature digital phase-demodulation scheme has been developed for readout of fiber-optic extrinsic Fabry-Perot interferometer vibration, acoustic, and strain sensors. This scheme uses a superluminescent diode light source with interference filters in front of the photodiodes and real-time arctan calculation. Quasi-static strain and dynamic vibration sensing with up to an 80-kHz sampling rate is demonstrated. Periodic nonlinearities owing to dephasing with increasing fringe number are corrected for with a suitable algorithm, resulting in significant improvement of the linearity of the sensor characteristics.


Adverse Oncologic Impact of New-Onset Diabetes Mellitus on Recurrence in Resected Pancreatic Ductal Adenocarcinoma: A Comparison With Long-standing and Non-Diabetes Mellitus Patients.
Diabetes mellitus (DM) is prevalent with pancreatic ductal adenocarcinoma (PDAC). Importantly, new-onset DM is characteristic of the disease and could be an early sign of PDAC. The clinical outcome of PDAC with new-onset DM may differ from that in patients without DM or long-standing DM. We retrospectively reviewed medical records of PDAC patients who underwent curative resection between 2006 and 2014. New-onset DM was defined as a diagnosis of DM within 24 months before the diagnosis of PDAC. Survival analysis and Cox regression were performed to evaluate oncologic outcomes. No significant differences in clinical characteristics were found in 3 groups. Overall survival of patients with new-onset DM was worse than non-DM (22 vs 33 months, P = 0.039). New-onset DM was highly associated with early recurrence (hazard ratio, 1.451; 95% confidence interval, 1.054-1.999; P = 0.022). Poor oncologic outcome of new-onset DM was more pronounced in low T stage patients (overall survival in low vs high T stage, 33 vs 18 months; P = 0.129). Pancreatic ductal adenocarcinoma with new-onset DM has worse oncologic outcomes than non-DM or long-standing DM. These results suggest that new-onset DM represents aggressive tumor biology, especially in the early stage of PDAC.


The effects of endurance training in persons with a hereditary myosin myopathy.
To evaluate muscle performance and its consequences in eight individuals with a hereditary myopathy and the effects of an 8-week endurance training program. Handgrip, muscle strength and endurance and oxygen consumption by breath-by-breath analysis during a stepless bicycle ergonometer test were evaluated. Walking, balance test and activities of daily living (ADL) were assessed, and a questionnaire for activity level and perceived symptoms was used. The design was a before-after trial in comparison with data from a control population, bicycling at 70% of maximal workload, 30 min/day, 5 days/week for 8 weeks. The subjects were weaker than age-matched controls. After training, the peak watt increased by almost 20% (P < 0.05). Muscle strength (flexion/extension) and isometric endurance (40% of maximum at 60 degrees ) did not change significantly. The average self-selected walking speed increased significantly (P < 0.05) from 1.25 to 1.45 m/s. Compliance was excellent and no serious adverse events occurred. Endurance training seems to function for this myopathy.