Non-cameral coronary artery fistulae after pediatric cardiac transplantation: a multicenter study.
Cameral coronary artery fistulae (C-CAFs) are common after heart transplantation (HTx) and typically drain into the right ventricle. The development of CAFs to non-cameral structures after HTx has not been systematically investigated. We studied the incidence, anatomic distribution, and natural history of non-cameral CAFs (NC-CAFs) in a multicenter pediatric population. Medical records from pediatric HTx patients at 2 centers from January 1, 1999, to August 31, 2009 were reviewed. A classification system for CAF size was developed, and serial angiograms were evaluated for CAF presence, size, and anatomy. Risk factors and outcomes were determined. Identified were 100 patients with a median age at HTx of 8.7 years. Median follow-up was 4.2 years. NC-CAFs occurred in 52 patients, C-CAFs in 20, with both types noted in 11. NC-CAFs originated from coronary arteries and drained predominantly into ipsilateral recipient pulmonary vasculature. Multiple NC-CAFs occurred in 19 patients (19%) for a total of 77 fistulae in 52 patients. Fistulae were classified as small (56%), moderate (36%), and large (8%). NC-CAFs were present at the first post-HTx angiogram in 95% of cases (median 1 year after HTx). Longer donor ischemic time was associated with the development (p = 0.043) and size (p = 0.05) of NC-CAFs. NC-CAFs were not associated with rejection, death, re-transplantation, or coronary revascularization, and none required intervention. Fistulae from donor coronary arteries to recipient pulmonary vasculature develop frequently and early after pediatric HTx. These correlate with graft ischemic time, but are not associated with early graft loss or death.


Activation of Human Mucosal-Associated Invariant T Cells Induces CD40L-Dependent Maturation of Monocyte-Derived and Primary Dendritic Cells.
Mucosal-associated invariant T (MAIT) cells are innate T cells that recognize intermediates of the vitamin B2 biosynthetic pathway presented by the monomorphic MR1 molecule. It remains unclear whether, in addition to their cytolytic activity that is important in antimicrobial defense, MAIT cells have immune-modulatory functions that could enhance dendritic cell (DC) maturation. In this study, we investigated the molecular mechanisms dictating the interactions between human MAIT cells and DCs and demonstrate that human MAIT cells mature monocyte-derived and primary DCs in an MR1- and CD40L-dependent manner. Furthermore, we show that MAIT cell-derived signals synergize with microbial stimuli to induce secretion of bioactive IL-12 by DCs. Activation of human MAIT cells in whole blood leads to MR1- and cytokine-dependent NK cell transactivation. Our results underscore an important property of MAIT cells, which can be of translational relevance to rapidly orchestrate adaptive immunity through DC maturation.


Influences of Biodynamic and Conventional Farming Systems on Quality of Potato (Solanum Tuberosum L.) Crops: Results from Multivariate Analyses of Two Long-Term Field Trials in Sweden.
The aim of this paper was to present results from two long term field experiments comparing potato samples from conventional farming systems with samples from biodynamic farming systems. The principal component analyses (PCA), consistently exhibited differences between potato samples from the two farming systems. According to the PCA, potato samples treated with inorganic fertilizers exhibited a variation positively related to amounts of crude protein, yield, cooking or tissue discoloration and extract decomposition. Potato samples treated according to biodynamic principles, with composted cow manure, were more positively related to traits such as Quality- and EAA-indices, dry matter content, taste quality, relative proportion of pure protein and biocrystallization value. Distinctions between years, crop rotation and cultivars used were sometimes more significant than differences between manuring systems. Grown after barley the potato crop exhibited better quality traits compared to when grown after ley in both the conventional and the biodynamic farming system.


Integrative analysis of DNA methylation and gene expression in butyrate-treated CHO cells.
The cellular mechanisms responsible for the versatile properties of CHO cells as the major production cell line for biopharmaceutical molecules are not entirely understood yet, although several 'omics' data facilitate the understanding of CHO cells and their reactions to environmental conditions. However, genome-wide studies of epigenetic processes such as DNA methylation are still limited. To prove the applicability and usefulness of integrating DNA methylation and gene expression data in a biotechnological context, we exemplarily analyzed the time course of cellular reactions upon butyrate addition in antibody-producing CHO cells by whole-genome bisulfite sequencing and CHO-specific cDNA microarrays. Gene expression and DNA methylation analyses showed that pathways known to be affected by butyrate, including cell cycle and apoptosis, as well as pathways potentially involved in butyrate-induced hyperproductivity such as central energy metabolism and protein biosynthesis were affected. Differentially methylated regions were furthermore found to contain binding-site motifs of specific transcription factors and were hypothesized to represent regulatory regions closely connected to the cellular response to butyrate. Generally, our experiment underlines the benefit of integrating DNA methylation and gene expression data, as it provided potential novel candidate genes for rational cell line development and allowed for new insights into the butyrate effect on CHO cells.


The role of amino acid residues in the active site of L-methionine γ-lyase from Pseudomonas putida.
Cys116, Lys240*, and Asp241* (asterisks indicate residues from the second subunit of the active dimer) at the active site of L-methionine γ-lyase of Pseudomonas putida (MGL_Pp) are highly conserved among heterologous MGLs. In a previous study, we found that substitution of Cys116 for His led to a drastic increase in activity toward L-cysteine and a decrease in that toward L-methionine. In this study, we examined some properties of the C116H mutant by kinetic analysis and 3D structural analysis. We assumed that substitution of Cys116 for His broke the original hydrogen-bond network and that this induced a significant effect of Tyr114 as a general acid catalyst, possibly due to the narrow space in the active site. The C116H mutant acquired a novel β-elimination activity and lead a drastic conformation change in the histidine residue at position 116 by binding the substrate, suggesting that this His residue affects the reaction specificity of C116H. Furthermore, we suggest that Lys240* is important for substrate recognition and structural stability and that Asp241* is also involved in substrate specificity in the elimination reaction. Based on this, we suggest that the hydrogen-bond network among Cys116, Lys240*, and Asp241* contributes to substrate specificity that is, to L-methionine recognition at the active site in MGL_Pp.


Diversity in a hidden world: potential and limitation of next-generation sequencing for surveys of molecular diversity of eukaryotic microorganisms.
With the delivery of millions of sequence reads in a single experiment, next-generation sequencing (NGS) is currently revolutionizing surveys of microorganism diversity. In particular, when applied to Eukaryotes, we are still lacking a rigorous comparison of morphological and NGS-based diversity estimates. In this report, we studied the diversity and the seasonal community turnover of alveolates (Ciliophora and Dinophyceae) in an oligotrophic freshwater lake by SSU amplicon sequencing with NGS as well as by classical morphological analysis. We complemented the morphological analysis by single-cell PCR followed by Sanger sequencing to provide an unambiguous link to the NGS data. We show that NGS and morphological analyses generally capture frequency shifts of abundant taxa over our seasonal samples. The observed incongruencies are probably largely due to rDNA copy number variation among taxa and heterogeneity in the efficiency of cell lysis. Overall, NGS-based amplicon sequencing was superior in detecting rare species. We propose that in the absence of other nuclear markers less susceptible to copy number variation, rDNA-based diversity studies need to be adjusted for confounding effects of copy number variation.


Astaxanthin Supplementation Increases Glutathione Concentrations but Does Not Impact Fat Oxidation During Exercise in Active Young Men.
This study investigated the effects of 6 mg/day of astaxanthin supplementation on markers of oxidative stress and substrate metabolism during a graded exercise test in active young men. A double-blind, randomized, counterbalanced, cross-over design was used. Fourteen men (age = 23 ± 2 years) supplemented with 6 mg/day of astaxanthin and a placebo for 4 weeks, with a 1 week washout period between treatments. Following each supplementation period, a fasting blood sample was obtained to measure markers of oxidative stress: glutathione, hydrogen peroxide, advanced oxidation protein products, and malondialdehyde. Participants also completed a graded exercise test after each treatment to determine substrate utilization during exercise at increasing levels of intensity. Glutathione was ∼7% higher following astaxanthin compared with placebo (1,233 ± 133 vs. 1,156 ± 185 μM, respectively; p = .02, d = 0.48). Plasma hydrogen peroxide and malondialdehyde were not different between treatments (p > .05). Although not statistically significant (p = .45), advanced oxidation protein products were reduced by ∼28%. During the graded exercise test, mean fat oxidation rates were not different between treatments (p > .05); however, fat oxidation decreased from 50 to 120 W (p < .001) and from 85 to 120 W (p = .004) in both conditions. Astaxanthin supplementation of 6 mg/day for 4 weeks increased whole blood levels of the antioxidant glutathione in active young men but did not affect oxidative stress markers or substrate utilization during exercise. Astaxanthin appears to be an effective agent to increase endogenous antioxidant status.


In vitro surfactant structure-toxicity relationships: implications for surfactant use in sexually transmitted infection prophylaxis and contraception.
The need for woman-controlled, cheap, safe, effective, easy-to-use and easy-to-store topical applications for prophylaxis against sexually transmitted infections (STIs) makes surfactant-containing formulations an interesting option that requires a more fundamental knowledge concerning surfactant toxicology and structure-activity relationships. We report in vitro effects of surfactant concentration, exposure time and structure on the viability of mammalian cell types typically encountered in the vagina, namely, fully polarized and confluent epithelial cells, confluent but non-polarized epithelial-like cells, dendritic cells, and human sperm. Representatives of the different families of commercially available surfactants--nonionic (Triton X-100 and monolaurin), zwitterionic (DDPS), anionic (SDS), and cationic (C(n)TAB (n = 10 to 16), C(12)PB, and C(12)BZK)--were examined. Triton X-100, monolaurin, DDPS and SDS were toxic to all cell types at concentrations around their critical micelle concentration (CMC) suggesting a non-selective mode of action involving cell membrane destabilization and/or destruction. All cationic surfactants were toxic at concentrations far below their CMC and showed significant differences in their toxicity toward polarized as compared with non-polarized cells. Their toxicity was also dependent on the chemical nature of the polar head group. Our results suggest an intracellular locus of action for cationic surfactants and show that their structure-activity relationships could be profitably exploited for STI prophylaxis in vaginal gel formulations. The therapeutic indices comparing polarized epithelial cell toxicity to sperm toxicity for all surfactants examined, except C(12)PB and C(12)BZK, does not justify their use as contraceptive agents. C(12)PB and C(12)BZK are shown to have a narrow therapeutic index recommending caution in their use in contraceptive formulations. Our results contribute to understanding the mechanisms involved in surfactant toxicity, have a predictive value with regard to their safety, and may be used to design more effective and less harmful surfactants for use in topical applications for STI prophylaxis.


General practitioners' responsibilities to their patients.
The views of general practitioners about their responsibilities for patient care have not been canvassed. A survey of general practitioners was therefore carried out to determine their views. A postal questionnaire, in which general practitioners were asked what they saw as their responsibilities, was sent to 525 principals in Avon and completed by 424, giving a response rate of 81%. The doctors generally agreed that their responsibilities for patient care included problems related to internal medicine, such as managing diabetes and hypertension. Less consensus was found in the replies to questions about technical procedures, such as resection of ingrowing toenails, and gynaecological, orthopaedic, or psychosocial problems. The results supported the view that general practitioners are gradually abandoning technical aspects of medicine to specialists without a compensating role having been defined. In the light of this trend the responsibilities of general practitioners should be clearly defined by the profession.


Syringe sharing among people who inject drugs in London, Canada.
London, Ontario, is facing an outbreak of HIV among people who inject drugs (PWID), as well as persistently high levels of hepatitis C virus (HCV). Syringe sharing is the primary driver of HIV and HCV transmission risks among PWID, however, little is known about factors contributing to syringe sharing in this setting. Therefore, we sought to characterize syringe sharing and its correlates among London PWID. Between March and April, 2016, PWID participated in a survey administered by peer research associates as part of the Ontario Integrated Supervised Injection Services Feasibility Study. Bivariable and multivariable logistic regression models examined associations with syringe sharing (borrowing or lending previously used syringes) over the previous 6 months. A sub-analysis described patterns of borrowing and lending by self-reported HIV and HCV statuses. Of 198 PWID, 44 (22%) reported syringe sharing in the past 6 months. In the multivariable analysis, selling drugs (adjusted odds ratio; AOR = 1.92, 95% CI = 1.20-3.08), daily crystal methamphetamine injection (AOR = 1.66, 95% CI = 1.07-2.59), and identifying as HIV-positive (AOR = 3.11, 95% CI = 1.61-6.01) were independently associated with increased syringe sharing. While not independently associated with syringe sharing, problems accessing syringes were common (13-50%). Self-reported HIV-positive respondents were more likely to report syringe borrowing (p < 0.001), but not lending (p = 0.26). We observed a high rate of syringe sharing among London PWID, with sharing being associated with high-intensity injection of crystal methamphetamine, as well as with involvement in drug sales. Considering the current HIV outbreak in London, multi-level prevention efforts are urgently needed.


Emergent Properties of Microbial Activity in Heterogeneous Soil Microenvironments: Different Research Approaches Are Slowly Converging, Yet Major Challenges Remain.
Over the last 60 years, soil microbiologists have accumulated a wealth of experimental data showing that the bulk, macroscopic parameters (e.g., granulometry, pH, soil organic matter, and biomass contents) commonly used to characterize soils provide insufficient information to describe quantitatively the activity of soil microorganisms and some of its outcomes, like the emission of greenhouse gasses. Clearly, new, more appropriate macroscopic parameters are needed, which reflect better the spatial heterogeneity of soils at the microscale (i.e., the pore scale) that is commensurate with the habitat of many microorganisms. For a long time, spectroscopic and microscopic tools were lacking to quantify processes at that scale, but major technological advances over the last 15 years have made suitable equipment available to researchers. In this context, the objective of the present article is to review progress achieved to date in the significant research program that has ensued. This program can be rationalized as a sequence of steps, namely the quantification and modeling of the physical-, (bio)chemical-, and microbiological properties of soils, the integration of these different perspectives into a unified theory, its upscaling to the macroscopic scale, and, eventually, the development of new approaches to measure macroscopic soil characteristics. At this stage, significant progress has been achieved on the physical front, and to a lesser extent on the (bio)chemical one as well, both in terms of experiments and modeling. With regard to the microbial aspects, although a lot of work has been devoted to the modeling of bacterial and fungal activity in soils at the pore scale, the appropriateness of model assumptions cannot be readily assessed because of the scarcity of relevant experimental data. For significant progress to be made, it is crucial to make sure that research on the microbial components of soil systems does not keep lagging behind the work on the physical and (bio)chemical characteristics. Concerning the subsequent steps in the program, very little integration of the various disciplinary perspectives has occurred so far, and, as a result, researchers have not yet been able to tackle the scaling up to the macroscopic level. Many challenges, some of them daunting, remain on the path ahead. Fortunately, a number of these challenges may be resolved by brand new measuring equipment that will become commercially available in the very near future.


The problem of rapid variable creation.
Both Marcus (2001) and Jackendoff (2002) have emphasized the importance of finding credible explanations for the occurrence of variables within cognitive representations. Marcus, in particular, has argued that a prevailing form of connectionist modeling, eliminative connectionism, cannot adequately explain crucial forms of human generalization. Eliminative connectionism eschews the use of explicitly represented variables, and the latter, Marcus contends, play an essential role in the forms of generalization that he considers. Recently, van der Velde and de Kamps (2006) proposed a neural blackboard architecture, which they assert to have satisfied the variable representation needs that Marcus and Jackendoff identified. However, this letter argues that closely related variants of Marcus's generalization examples possess variable requirements that are incompatible with the van der Velde and de Kamps approach. Moreover, it is argued here that these newly proposed variants present a severe challenge not only for eliminative connectionism but for all network training methods that require iterative tuning of synaptic strengths. The letter focuses on generalization cases that necessitate either virtually instantaneous creation of variables or very rapid deployment of preexisting variables within highly novel contexts.


Polyfluoride anions, a matrix-isolation and quantum-chemical investigation.
Laser-ablation experiments with metals provide a source of electrons for capture processes, which are codeposited with solid argon and neon containing molecular fluorine. New argon and neon matrix absorptions at 510.6 and 524.7 cm(-1), respectively, are photosensitive upon irradiation at >290 nm, which is consistent with their assignment to an isolated anion. These bands are below the [M](+)[F(3)](-) antisymmetric trifluoride stretching frequency of 550 cm(-1) in an argon matrix, which is the typical relationship for cation-anion complexes and matrix-isolated anions. Thus, we report the isolated [F(3)](-) anion in solid argon and neon environments. Moreover, we have carried out quantum-chemical calculations up to and including the CCSD(T) method to investigate the stabilities of polyfluoride anions higher than the [F(3)](-) anion.


A gripping tale of ribosomal frameshifting: extragenic suppressors of frameshift mutations spotlight P-site realignment.
Mutants of translation components which compensate for both -1 and +1 frameshift mutations showed the first evidence for framing malleability. Those compensatory mutants isolated in bacteria and yeast with altered tRNA or protein factors are reviewed here and are considered to primarily cause altered P-site realignment and not altered translocation. Though the first sequenced tRNA mutant which suppressed a +1 frameshift mutation had an extra base in its anticodon loop and led to a textbook "yardstick" model in which the number of anticodon bases determines codon size, this model has long been discounted, although not by all. Accordingly, the reviewed data suggest that reading frame maintenance and translocation are two distinct features of the ribosome. None of the -1 tRNA suppressors have anticodon loops with fewer than the standard seven nucleotides. Many of the tRNA mutants potentially affect tRNA bending and/or stability and can be used for functional assays, and one has the conserved C74 of the 3' CCA substituted. The effect of tRNA modification deficiencies on framing has been particularly informative. The properties of some mutants suggest the use of alternative tRNA anticodon loop stack conformations by individual tRNAs in one translation cycle. The mutant proteins range from defective release factors with delayed decoding of A-site stop codons facilitating P-site frameshifting to altered EF-Tu/EF1alpha to mutant ribosomal large- and small-subunit proteins L9 and S9. Their study is revealing how mRNA slippage is restrained except where it is programmed to occur and be utilized.


In situ aberration measurement technique based on principal component analysis of aerial image.
We propose a novel in situ aberration measurement technique for lithographic projection lens by use of aerial image based on principal component analysis (AMAI-PCA). The aerial image space, principal component space and Zernike space are introduced to create a transformation model between aerial images and Zernike coefficients. First the aberration-induced aerial images of measurement marks are simulated to form an aerial image space with a statistical Box-Behnken design pattern. The aerial image space is then represented by their principal components based on principal component analysis. The principal component coefficients of the aerial images are finally connected with Zernike coefficients by a regression matrix through regression analysis. Therefore in situ aberration measurement can be achieved based on the regression matrix and the principal component coefficients of the detected aerial images. The measurement performance of the proposed AMAI-PCA technique is demonstrated superior compared to that of the conventional TAMIS technique by using a lithographic simulator tool (Prolith). We also tested the actual performance of AMAI-PCA technique on a prototype wafer exposure tool. The testing results show our proposed technique can rapidly measure the aberrations up to high-order Zernike polynomial term with 1σ repeatability of 0.5 nm to 2.3 nm depending on the aberration type and range.


Bacteria and viruses in the nasopharynx immediately prior to onset of acute lower respiratory infections in Indigenous Australian children.
Acute lower respiratory infection (ALRI) is a major cause of hospitalization for Indigenous children in remote regions of Australia. The associated microbiology remains unclear. Our aim was to determine whether the microbes present in the nasopharynx before an ALRI were associated with its onset. A retrospective case-control/crossover study among Indigenous children aged up to 2 years. ALRI cases identified by medical note review were eligible where nasopharyngeal swabs were available: (1) 0-21 days before ALRI onset (case); (2) 90-180 days before ALRI onset (same child controls); and (3) from time and age-matched children without ALRI (different child controls). PCR assays determined the presence and/or load of selected respiratory pathogens. Among 104 children (182 recorded ALRI episodes), 120 case-same child control and 170 case-different child control swab pairs were identified. Human adenoviruses (HAdV) were more prevalent in cases compared to same child controls (18 vs 7%; OR = 3.08, 95% CI 1.22-7.76, p = 0.017), but this association was not significant in cases versus different child controls (15 vs 10%; OR = 1.93, 95% CI 0.97-3.87 (p = 0.063). No other microbes were more prevalent in cases compared to controls. Streptococcus pneumoniae (74%), Haemophilus influenzae (75%) and Moraxella catarrhalis (88%) were commonly identified across all swabs. In a pediatric population with a high detection rate of nasopharyngeal microbes, HAdV was the only pathogen detected in the period before illness presentation that was significantly associated with ALRI onset. Detection of other potential ALRI pathogens was similar between cases and controls.


Acute calcific tendinitis of the longus colli muscle: case report and review of the literature.
Acute calcific tendinitis of the longus colli muscle (or retropharyngeal tendinitis) is an aseptic inflammatory process characterized by acute posterior neck pain, neck stiffness and dysphagia or odynophagia. Awareness of its existence is crucial in the differential diagnosis, because many other conditions, such as retropharyngeal abscess, meningitis or disc herniation, show similar clinical features. We present a case exhibiting an uncommon symptom (torticollis) and a brief literature review to emphasize the risk of misdiagnosis. A 36-year-old woman presented with neck stiffness and torticollis accompanied by dysphagia and prevertebral space sensitivity on the second day. The diagnosis was established by computed tomography (CT), the gold standard for identifying the presence of prevertebral oedema and calcific deposition associated with retropharyngeal tendinitis. Treatment with NSAIDs and low doses of corticosteroids relieved the symptoms within 48 h. Retropharyngeal tendinitis is an underreported entity in the literature and orthopaedists should become aware of its existence. Misdiagnosis of this important mimicker may lead to unnecessary antibiotics administration and interventions in the retropharyngeal space.


Microfluidics-Based Subretinal Chemical Neuromodulation of Photoreceptor Degenerated Retinas.
Retinal prostheses can restore rudimentary vision in cases of photoreceptor degeneration through electrical stimulation, but face difficulties achieving high spatial resolution because electrical current is an inherently unnatural stimulus. We investigated the therapeutic feasibility of using patterned delivery of the glutamate neurotransmitter, a primary agent of natural synaptic communication of the retina, as a biomimetic chemical alternative to electrical current for neuromodulation of photoreceptor degenerate retina. We injected small quantities of the neurotransmitter glutamate into the subretina of 20 explanted photoreceptor degenerated S334ter-3 rat retinas using glass micropipettes and a prototype multiport microfluidic device to accomplish single- and multisite stimulation in vitro. The effects of chemical stimulation were characterized by recording neural responses from retinal ganglion cells (RGCs) using a multielectrode array. Subretinally injected exogenous glutamate activates RGCs, despite the substantial anatomic and physiologic changes caused by retinal remodeling, eliciting robust neural responses. The presence of excitatory and inhibitory RGC responses provides evidence that exogenous glutamate differentially activated neurons presynaptic to RGCs, likely inner retinal neurons belonging to the OFF and ON pathways. We also demonstrate that glutamate injections can evoke focal RGC responses with spatial resolutions comparable to or better than current generation electrical prostheses and, when applied at multiple sites simultaneously with the multiport microfluidic device, can produce spatially patterned neural responses. These significant results establish that chemical stimulation of degenerated retinas with neurotransmitters is an effective neuromodulation strategy with the potential of restoring high-resolution visual perception in patients rendered blind through photoreceptor degeneration.


Diffuse large B-cell lymphoma in patient after treatment of angioimmunoblastic T-cell lymphoma.
Relatively few cases of Epstein-Barr (EBV)-positive B-cell lymphomas arising in patients with angioimmunoblastic T-cell lymphoma (AITL) have been reported. We report a case of AITL in which diffuse large B-cell lymphoma arose 13 months after the initial diagnosis of AITL. In a 36-year-old female patient, evaluated for moderate leukocytosis, peripheral and abdominal lymphadenopathy AITL was diagnosed in March 2008, based on results of fine-needle aspiration cytology (FNAC) of the enlarged cervical and supraclavicular lymph nodes. The diagnosis was also confirmed by immunophenotyping and histopathology of the cervical lymph nodes. The patient initially recieved FED chemotherapy (fludarabine, cyclophosphamide, dexamethasone) followed by elective autologous hematopoietic stem cell transplantation. In April 2009 the patient was hospitalized because of fever, pancytopenia, hyperbilirubinemia and peripheral lymphadenopathy. The FNAC of the enlarged cervical lymph nodes was performed again, but this time the smears were composed of polymorphous population of lymphocytes with the predomination of large cells, CD20+ on immunocytochemical stains. The immunophenotyping confirmed a predomination of monoclonal mature B-cells. Patient had high number of EBV DNA copies in plasma and serologic testing revealed increased titers of EBV VCA IgG and EBV EBNA IgG. CHOP-R chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab) was then administered, resulting in good partial response of the disease. Reduced intensity allogeneic stem cell transplantation performed thereafter, resulted in complete remission of the disease. AITL is a rare lymphoproliferative disorder in which the neoplastic T-cells represent the minority of the lymph node cell population and almost all cases harbor EBV-infected B-cells. Various authors postulated that immunodeficiency in AITL patients together with immunosuppressive effects of cytotoxic drugs, may be responsible for EBV-induced proliferation of latently or newly EBV-infected B-cells with eventual clonal selection and progression to aggressive B-cell lymphoma.


Surface interpolation and 3D relatability.
Although the role of surface-level processes has been demonstrated, visual interpolation models often emphasize contour relationships. We report two experiments on geometric constraints governing 3D interpolation between surface patches without visible edges. Observers were asked to classify pairs of planar patches specified by random dot disparities and visible through circular apertures (aligned or misaligned) in a frontoparallel occluder. On each trial, surfaces appeared in parallel or converging planes with vertical (in Experiment 1) or horizontal (in Experiment 2) tilt and variable amounts of slant. We expected the classification task to be facilitated when patches were perceived as connected. We found enhanced sensitivity and speed for 3D relatable vs. nonrelatable patches. Here 3D relatability does not involve oriented edges but rather inducing patches' orientations computed from stereoscopic information. Performance was markedly affected by slant anisotropy: both sensitivity and speed were worse for patches with horizontal tilt. We found nearly identical advantages of 3D relatability on performance, suggesting an isotropic unit formation process. Results are interpreted as evidence that inducing slant constrains surface interpolation in the absence of explicit edge information: 3D contour and surface interpolation processes share common geometric constraints as formalized by 3D relatability.


Effects of soluble milk protein or casein supplementation on muscle fatigue following resistance training program: a randomized, double-blind, and placebo-controlled study.
The effects of protein supplementation on muscle thickness, strength and fatigue seem largely dependent on its composition. The current study compared the effects of soluble milk protein, micellar casein, and a placebo on strength and fatigue during and after a resistance training program. Sixty-eight physically active men participated in this randomized controlled trial and underwent 10 weeks of lower-body resistance training. Participants were randomly assigned to the Placebo (PLA), Soluble Milk Protein (SMP, with fast digestion rate) or Micellar Casein (MC, with slow digestion rate) group. During the 10-week training period, participants were instructed to take 30 g of the placebo or protein twice a day, or three times on training days. Tests were performed on quadriceps muscles at inclusion (PRE), after 4 weeks (MID) and after 10 weeks (POST) of training. They included muscle endurance (maximum number of repetitions during leg extensions using 70% of the individual maximal load), fatigue (decrease in muscle power after the endurance test), strength, power and muscle thickness. Muscle fatigue was significantly lower (P < 0.05) in the SMP group at MID and POST (-326.8 ± 114.1 W and -296.6 ± 130.1 W, respectively) as compared with PLA (-439.2 ± 153.9 W and -479.2 ± 138.1 W, respectively) and MC (-415.1 ± 165.1 W and -413.7 ± 139.4 W, respectively). Increases in maximal muscle power, strength, endurance and thickness were not statistically different between groups. The present study demonstrated that protein composition has a large influence on muscular performance after prolonged resistance training. More specifically, as compared with placebo or micellar casein, soluble milk protein (fast digestible) appeared to significantly reduce muscle fatigue induced by intense resistance exercise.


Understanding the meanings of male partner support in the adherence to therapy among HIV-positive women: a gender analysis.
Previous literature reports that low male partner support is a barrier to women's adherence and retention in HIV care programs. This qualitative study explored the relationships between partners to understand what is meant by male partner support in adherence of HIV-positive women in four healthcare facilities in Southern Malawi. We conducted 8 semi-structured focus group discussions (FGDs) with 73 participants (40 men and 33 women) and 10 in-depth interviews (IDIs) between August 2018 to December 2019. Participants were HIV-positive patients, healthcare workers (HCWs), expert patients (EPs), and couples attending the clinic. All data were digitally recorded, transcribed verbatim, and analysed using a gender-responsive grounded theory approach. This study confirms previous literature, which suggests male partner support is expressed by providing access to transport to the clinic and accompaniment to appointments. However, we found that men can also control access to resources and decision-making. Support is more complex than previous literature reported and, in some cases, gender norms significantly limit women's capacity to engage in care independently of male support since women need male partner permission to access the resources to attend clinics. This paper suggests that restrictive male-partner gender norms limit women's power to engage in care. Most importantly, the gender analysis reveals that what previous literature describes as male partner support can sometimes hide male partner control in permitting access to resources to attend health facilities. For this reason, policies enhancing male support should consider the gender power relationship between partners to avoid reinforcing gender inequality.


Sequential Statistical Optimization of Media Components for the Production of Glucoamylase by Thermophilic Fungus Humicola grisea MTCC 352.
Glucoamylase is an industrially important enzyme which converts soluble starch into glucose. The media components for the production of glucoamylase from thermophilic fungus Humicola grisea MTCC 352 have been optimized. Eight media components, namely, soluble starch, yeast extract, KH2PO4, K2HPO4, NaCl, CaCl2, MgSO4 ·7H2O, and Vogel's trace elements solution, were first screened for their effect on the production of glucoamylase and only four components (soluble starch, yeast extract, K2HPO4, and MgSO4 ·7H2O) were identified as statistically significant using Plackett-Burman design. It was fitted into a first-order model (R (2) = 0.9859). Steepest ascent method was performed to identify the location of optimum. Central composite design was employed to determine the optimum values (soluble starch: 28.41 g/L, yeast extract: 9.61 g/L, K2HPO4: 2.42 g/L, and MgSO4 ·7H2O: 1.91 g/L). The experimental activity of 12.27 U/mL obtained was close to the predicted activity of 12.15. High R (2) value (0.9397), low PRESS value (9.47), and AARD values (2.07%) indicate the accuracy of the proposed model. The glucoamylase production was found to increase from 4.57 U/mL to 12.27 U/mL, a 2.68-fold enhancement, as compared to the unoptimized medium.


An ontology for description of drug discovery investigations.
The paper presents an ontology for the description of Drug Discovery Investigation (DDI).This has been developed through the use of a Robot Scientist "Eve", and in consultation with industry. DDI aims to define the principle entities and the relations in the research and development phase of the drug discovery pipeline. DDI is highly transferable and extendable due to its adherence to accepted standards, and compliance with existing ontology resources. This enables DDI to be integrated with such related ontologies as the Vaccine Ontology, the Advancing Clinico-Genomic Trials on Cancer Master Ontology, etc. DDI is available at http://purl.org/ddi/wikipedia or http://purl.org/ddi/home.


Methodological issues in the diagnostic work-up of food allergy: a real challenge.
The standard of reporting in diagnostic studies has generally been low. Fortunately, this issue has begun to be addressed in recent years through the discussion of important methodological issues in educational series, textbooks, and checklists. Double-blind, placebo-controlled, oral food challenges (DBPCFC) are considered to be the gold standard for diagnosis of food allergy. However, there is no consensus regarding how to interpret the outcome and how to define positive and negative provocations in DBPCFC. Furthermore, since most theories on the diagnosis of food allergy rely on the assumption that the DBPCFC has a high accuracy, this accuracy must be formally statistically evaluated. In this review, we discuss essential methodological issues for diagnostic accuracy studies in general and for oral food challenges in particular and discuss the importance of methodological issues as a guide for forthcoming studies of diagnostic procedures.


Anchors weigh more than power: why absolute powerlessness liberates negotiators to achieve better outcomes.
The current research shows that having no power can be better than having a little power. Negotiators prefer having some power (weak negotiation alternatives) to having no power (no alternatives). We challenge this belief that having any alternative is beneficial by demonstrating that weak alternatives create low anchors that reduce the value of first offers. In contrast, having no alternatives is liberating because there is no anchor to weigh down first offers. In our experiments, negotiators with no alternatives felt less powerful but made higher first offers and secured superior outcomes compared with negotiators who had weak alternatives. We established the role of anchoring through mediation by first offers and through moderation by showing that weak alternatives no longer led to worse outcomes when negotiators focused on a countervailing anchor or when negotiators faced an opponent with a strong alternative. These results demonstrate that anchors can have larger effects than feelings of power. Absolute powerlessness can be psychologically liberating.


Positioning of strained islands by interaction with surface nanogrooves.
When strained Stranski-Krastanow islands are used as "self-assembled quantum dots," a key goal is to control the island position. Here we show that nanoscale grooves can control the nucleation of epitaxial Ge islands on Si(001), and can drive lateral motion of existing islands onto the grooves, even when the grooves are very narrow and shallow compared to the islands. A position centered on the groove minimizes energy. We use as prototype grooves the trenches which form naturally around islands. During coarsening, the shrinking islands move laterally to sit directly astride that trench. In subsequent growth, we demonstrate that islands nucleate on the "empty trenches" which remain on the surface after complete dissolution of the original islands.


Amelioration of collagen-induced arthritis and suppression of interferon-gamma, interleukin-12, and tumor necrosis factor alpha production by interferon-beta gene therapy.
To investigate the therapeutic effects and possible mechanisms of action of constitutive expression of interferon-beta (IFNbeta) by syngeneic fibroblasts from DBA/1 mice in the collagen-induced arthritis (CIA) model. Immortalized embryonic DBA/1 fibroblasts were infected with a retrovirus expressing murine IFNbeta. IFNbeta-expressing fibroblasts were then implanted intraperitoneally into mice immunized with bovine type II collagen. The effect of IFNbeta on paw swelling, anticollagen antibody levels, IgG1/IgG2a isotype profiles, arthritis score, histologic joint damage, and cytokine secretion from lymph node cells and from bone marrow-derived macrophages was assessed. A single injection of IFNbeta-secreting fibroblasts was sufficient to prevent arthritis or to ameliorate existing disease. Thus, IFNbeta reduced the clinical score and paw swelling irrespective of whether the injection was administered before or after disease onset in treated mice, compared with that in the untreated control group (P < 0.05). Histologic findings in the IFNbeta-treated mice were markedly less severe than in the control group (P < 0.001). This effect was accompanied by a decrease in total anticollagen IgG levels, a decrease in anticollagen IgG2a, and an increase in IgG1. In vitro, supernatants from these engineered fibroblasts inhibited collagen-induced interferon-gamma secretion from lymph node cells, and reduced the levels of tumor necrosis factor alpha and interleukin-12 produced by lipopolysaccharide/IFNgamma-treated bone marrow-derived macrophages. This effect was specific, since it was reversed with anti-IFNbeta polyclonal antibodies. These results indicate that IFNbeta, which is currently used as a treatment for relapsing, remitting multiple sclerosis, is a potent immunomodulatory and antiinflammatory cytokine in CIA and should be considered for the treatment of rheumatoid arthritis.


A proposal for the addressing the needs of the pediatric pulmonary work force.
Unprecedented opportunities and daunting difficulties are anticipated in the future of pediatric pulmonary medicine. To address these issues and optimize pediatric pulmonary training, a group of faculty from various institutions met in 2019 and proposed specific, long-term solutions to the emerging problems in the field. Input on these ideas was then solicited more broadly from faculty with relevant expertise and from recent trainees. This proposal is a synthesis of these ideas. Pediatric pulmonology was among the first pediatric specialties to be grounded deliberately in science, requiring its fellows to demonstrate expertise in scientific inquiry (1). In the future, we will need more training in science, not less. Specifically, the scope of scientific inquiry will need to be broader. The proposal outlined below is designed to help optimize the practices of current providers and to prepare the next generation to be leaders in pediatric care in the future. We are optimistic that this can be accomplished. Our broad objectives are (a) to meet the pediatric subspecialty workforce demand by increasing interest and participation in pediatric pulmonary training; (b) to modernize training to ensure that future pediatric pulmonologists will be prepared clinically and scientifically for the future of the field; (c) to train pediatric pulmonologists who will add value in the future of pediatric healthcare, complemented by advanced practice providers and artificial intelligence systems that are well-informed to optimize quality healthcare delivery; and (d) to decrease the cost and improve the quality of care provided to children with respiratory diseases.


Association between enhanced soluble CD40 ligand and proinflammatory and prothrombotic states in major depressive disorder: pilot observations on the effects of selective serotonin reuptake inhibitor therapy.
Major depressive disorder (MDD) is associated with low-grade inflammation, and it is considered a risk factor for coronary artery disease (CAD). CD40 ligand (CD40L) plays an important role in inflammation, platelet activation, and clotting system activation. We investigated soluble CD40L (sCD40L) expression in MDD and assessed whether it may represent a molecular mechanism that links inflammation and a prothrombotic state and whether this condition may be modified by selective serotonin reuptake inhibitor (SSRI) therapy. Levels of sCD40L, interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble P-selectin (sP-selectin), activated factor VII (FVIIa), and prothrombin fragment 1+2 (F1+2) were measured in 46 drug-naïve, first-episode MDD patients without conventional CAD risk factors and in 46 matched healthy controls. Participants were screened between March 2002 and November 2005. Twenty of the 46 MDD patients were then randomly assigned to either sertraline 100 mg/day (N = 10) or citalopram 20 mg/day (N = 10); the aforementioned variables were measured at baseline and after 6 weeks of treatment. Compared with control subjects, MDD patients had higher baseline levels of sCD40L, IL-1beta, IL-6, TNF-alpha, sP-selectin, FVIIa, and F1+2. In the clinical group, sCD40L levels, HAM-D total scores, and proinflammatory markers were strongly intercorrelated. In contrast, there were no significant correlations in the control group. Mood improvement achieved with SSRI therapy was associated with significant reduction in sCD40L, proinflammatory markers, and prothrombotic markers expression. (All p values < .0001.) This pilot study shows that CD40/ CD40L pathway up-regulation in MDD patients relates increased levels of sCD40L to a prothrombotic state and, preliminarily, indicates that SSRI therapy may significantly reduce sCD40L and CD40L levels associated with proinflammatory and prothrombotic states.


Parathyroidectomy as a Cure for Calciphylaxis in a Non-Dialysis Chronic Kidney Disease Patient?
BACKGROUND Calciphylaxis is a rare and fatal systemic disease which most commonly occurs in patients with end-stage renal disease. It is a poorly understood vascular calcification with unclear pathology that leads to vascular compromise due to vascular occlusion with endoluminal calcification. CASE REPORT We report a case of a 61-year-old male with chronic kidney disease stage 5 who developed calciphylaxis. The patient was diagnosed with dry gangrene of the second and third digits of the right hand and second, third, and fourth phalanges of the left hand. Despite medical therapy and local wound care, the lesions progressively worsened with time. The patient was found to have secondary hyperparathyroidism (parathyroid hormone was 1028 pg/mL) and underwent subtotal parathyroidectomy. In our patient, the skin lesions due to calciphylaxis completely resolved over the course of 12 months. CONCLUSIONS Parathyroidectomy has been associated with clinical benefit in patients with calciphylaxis. Clinicians should consider parathyroidectomy in the setting of high parathyroid hormone and calciphylaxis. Although parathyroidectomy is an effective treatment option for calciphylaxis it is not a definitive treatment and calciphylaxis can occur, though rarely, even after parathyroidectomy. There is a need to do further studies in order to confirm the efficacy of parathyroidectomy.


Out of America: ancient DNA evidence for a new world origin of late quaternary woolly mammoths.
Although the iconic mammoth of the Late Pleistocene, the woolly mammoth (Mammuthus primigenius), has traditionally been regarded as the end point of a single anagenetically evolving lineage, recent paleontological and molecular studies have shown that successive allopatric speciation events must have occurred within Pleistocene Mammuthus in Asia, with subsequent expansion and hybridization between nominal taxa [1, 2]. However, the role of North American mammoth populations in these events has not been adequately explored from an ancient-DNA standpoint. To undertake this task, we analyzed mtDNA from a large data set consisting of mammoth samples from across Holarctica (n = 160) and representing most of radiocarbon time. Our evidence shows that, during the terminal Pleistocene, haplotypes originating in and characteristic of New World populations replaced or succeeded those endemic to Asia and western Beringia. Also, during the Last Glacial Maximum, mammoth populations do not appear to have suffered an overall decline in diversity, despite differing responses on either side of the Bering land bridge. In summary, the "Out-of-America" hypothesis holds that the dispersal of North American woolly mammoths into other parts of Holarctica created major phylogeographic structuring within Mammuthus primigenius populations, shaping the last phase of their evolutionary history before their demise.


The cobalamin (coenzyme B12) biosynthetic genes of Escherichia coli.
The enteric bacterium Escherichia coli synthesizes cobalamin (coenzyme B12) only when provided with the complex intermediate cobinamide. Three cobalamin biosynthetic genes have been cloned from Escherichia coli K-12, and their nucleotide sequences have been determined. The three genes form an operon (cob) under the control of several promoters and are induced by cobinamide, a precursor of cobalamin. The cob operon of E. coli comprises the cobU gene, encoding the bifunctional cobinamide kinase-guanylyltransferase; the cobS gene, encoding cobalamin synthetase; and the cobT gene, encoding dimethylbenzimidazole phosphoribosyltransferase. The physiological roles of these sequences were verified by the isolation of Tn10 insertion mutations in the cobS and cobT genes. All genes were named after their Salmonella typhimurium homologs and are located at the corresponding positions on the E. coli genetic map. Although the nucleotide sequences of the Salmonella cob genes and the E. coli cob genes are homologous, they are too divergent to have been derived from an operon present in their most recent common ancestor. On the basis of comparisons of G+C content, codon usage bias, dinucleotide frequencies, and patterns of synonymous and nonsynonymous substitutions, we conclude that the cob operon was introduced into the Salmonella genome from an exogenous source. The cob operon of E. coli may be related to cobalamin synthetic genes now found among non-Salmonella enteric bacteria.


Sunscreen abuse for intentional sun exposure.
Skin cancer is caused by exposure to ultraviolet radiation (UV) and the sun is the main source of this radiation. Sunscreens were initially formulated to prevent sunburns; laboratory studies later revealed that in rodents they could reduce UV-induced skin cancer which resembles human squamous cell carcinoma. Three randomized trials in older adults showed the ability of sunscreens to moderately reduce the occurrence of solar keratoses and of squamous cell carcinoma. However, no effect was observed for basal cell carcinoma. There is no animal model for human melanoma and observational studies often found sunscreen use associated with a higher risk of nevus, melanoma and basal cell carcinoma. These higher risks were found when sun exposure appeared to be intentional, that is, with the desire to acquire a tan, a healthy look or simply to spend as long as possible in the sun with as much skin exposed as possible. Three randomized trials showed that sunscreen use by sun sensitive subjects engaging in intentional sun exposure could increase the duration of exposure without decreasing sunburn occurrence. This increased duration could be the reason why melanoma risk is increased when sunscreen is used. Hence, sunscreen abuse may extend sun exposure duration thus allowing sun exposure behaviours that would not be possible otherwise. Advertising for sunscreens and labeling of sunscreen bottles should inform consumers of the carcinogenic hazards associated with sunscreen abuse. It would be good to use a personal UV dosimeter which would give an alert when one's individual sunburn threshold in the absence of sunscreen use is nearing. The combination of sunscreen and a UV dosimeter may be an option for reducing the melanoma risk among sun worshippers.


Facing the Challenges of Developing Fair Risk Scoring Models.
Algorithmic scoring methods are widely used in the finance industry for several decades in order to prevent risk and to automate and optimize decisions. Regulatory requirements as given by the Basel Committee on Banking Supervision (BCBS) or the EU data protection regulations have led to an increasing interest and research activity on understanding black box machine learning models by means of explainable machine learning. Even though this is a step into a right direction, such methods are not able to guarantee for a fair scoring as machine learning models are not necessarily unbiased and may discriminate with respect to certain subpopulations such as a particular race, gender, or sexual orientation-even if the variable itself is not used for modeling. This is also true for white box methods like logistic regression. In this study, a framework is presented that allows analyzing and developing models with regard to fairness. The proposed methodology is based on techniques of causal inference and some of the methods can be linked to methods from explainable machine learning. A definition of counterfactual fairness is given together with an algorithm that results in a fair scoring model. The concepts are illustrated by means of a transparent simulation and a popular real-world example, the German Credit data using traditional scorecard models based on logistic regression and weight of evidence variable pre-transform. In contrast to previous studies in the field for our study, a corrected version of the data is presented and used. With the help of the simulation, the trade-off between fairness and predictive accuracy is analyzed. The results indicate that it is possible to remove unfairness without a strong performance decrease unless the correlation of the discriminative attributes on the other predictor variables in the model is not too strong. In addition, the challenge in explaining the resulting scoring model and the associated fairness implications to users is discussed.


First description of natural Echinococcus multilocularis infections in chinchilla (Chinchilla laniger) and Prevost's squirrel (Callosciurus prevostii borneoensis).
This report describes for the first time the occurrence of alveolar echinococcosis in two exotic rodent species in Europe. A pet chinchilla (Chinchilla laniger) was euthanized due to a painful enlargement of the abdominal cavity, and a Prevost's squirrel (Callosciurus prevostii borneoensis) was found dead in the enclosure of a zoo. At necropsy, extended liver lesions consisting of small vesicles and cysts were observed in the livers of both animals. Histological examination revealed that these cysts were composed of an outer, homogenous, eosinophilic layer and an inner, cellular germinal layer. The cysts from both animals contained numerous protoscolices. The morphological diagnosis of Echinococcus multilocularis metacestode infections was confirmed by molecular means.


The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation.
Mice mutant for granulocyte macrophage colony-stimulating factor (GM-CSF) or the common receptor component (beta c) for GM-CSF, interleukin (IL)-3, and IL-5 exhibit a lung disorder similar to human pulmonary alveolar proteinosis, a rare disease with congenital, infantile, and adult forms. Bone marrow transplantation and hematopoietic reconstitution of beta c mutant mice with wild-type bone marrow reversed the established disease state in the lungs, defining this disease as hematopoietic in nature. It is likely that the disease involves alveolar macrophages, as donor myeloid cell engraftment into the lungs of mutant recipient mice correlated with reverting both the disease and an abnormal macrophage morphology seen in the lungs of affected animals. Recombination Activating Gene-2 mutant donor bone marrow, which lacks the potential to develop lymphocytes, reversed the pathology in the lungs to the same extent as whole bone marrow. These data establish that certain lung disorders, if of cell-autonomous hematopoietic origin, can be manipulated by bone marrow transplantation.


Advantages of the phosphatidylserine-recognizing peptide PSP1 for molecular imaging of tumor apoptosis compared with annexin V.
A number of peptide-based indicators have been identified and reported as potential apoptosis probes, offering great promise for early assessment of therapeutic efficacy in several types of cancer. Direct comparison of the newly developed probes with previously used ones would be an important step in assessing possible applications. Here, we compared the newly identified peptide-based phosphatidylserine (PS) indicator PSP1 (CLSYYPSYC) with annexin V, a common probe for molecular imaging of apoptotic cells, with respect to PS binding kinetics, apoptotic cell-targeting ability, and the efficacy of homing to apoptotic tumor cells in a mouse model after treatment with the anticancer agent camptothecin. Our results indicate that PSP1 efficiently targeted apoptotic cells and generated apoptosis/tumor-specific signals after cancer treatment in the animal model, whereas a similar dose of annexin V showed weak signals. The formation of a stable complex of PSP1 with PS might be one reason for the efficient in vivo targeting. We suggest that PSP1 has potential advantages for in vivo apoptotic cell imaging and could serve as a platform for the development of de novo peptide-based probes for apoptosis.


Adults with a family history of alcohol related problems are more impulsive on measures of response initiation and response inhibition.
Previous studies have found individuals with family histories of alcohol use disorders are more impulsive on some but not all laboratory behavioral measures, suggesting deficits on specific forms of impulse control. However, drawing conclusions is tenuous because these different measures have not been administered together in the same group of participants. In the present study, we compared healthy 21-35 year old adults with family histories of alcohol related problems (FHAP+) or without such histories (FHAP-) on behavioral measures of response inhibition, response initiation, and consequence sensitivity impulsivity. FHAP+ (n=36) and FHAP- (n=36) participants were compared on performance on the Immediate Memory Task (IMT, response initiation), GoStop Impulsivity Paradigm (GoStop, response inhibition), Two Choice Impulsivity Paradigm (TCIP, consequence sensitivity) and Single Key Impulsivity Paradigm (SKIP, consequence sensitivity). FHAP+ individuals were more impulsive on the IMT and GoStop but not on the TCIP or SKIP. These results suggest that response initiation and response inhibition impulsivity are increased in individuals with family histories of alcohol related problems despite not having alcohol or drug use disorders themselves. In contrast, increased consequence sensitivity impulsivity may be associated with additional risk factors such as more severe family histories of alcohol use disorders, or it may be increased as a consequence of heavy drug or alcohol use.


Pharmacodynamics of Metformin in Pregnant Women With Gestational Diabetes Mellitus and Nonpregnant Women With Type 2 Diabetes Mellitus.
Gestational diabetes mellitus is a condition similar to type 2 diabetes mellitus (T2DM) in that patients are unable to compensate for the degree of insulin resistance, and both conditions are often treated with metformin. The comparative pharmacodynamic response to metformin in these 2 populations has not been studied. This study characterized insulin sensitivity, β-cell responsivity, and disposition index following a mixed-meal tolerance test utilizing a minimal model of glucose, insulin, and C-peptide kinetics before and during treatment with metformin. The study included women with gestational diabetes mellitus (n = 34), T2DM (n = 14), and healthy pregnant women (n = 30). Before treatment, the gestational diabetes mellitus group had significantly higher baseline (45%), dynamic (68%), static (71%), and total β-cell responsivity (71%) than the T2DM group. Metformin significantly increased insulin sensitivity (51%) as well as disposition index (97%) and decreased mixed-meal tolerance test peak glucose concentrations (8%) in women with gestational diabetes mellitus after adjustment for gestational age-dependent effects; however, in women with T2DM metformin only significantly affected peak glucose concentrations (22%) and had no significant effect on any other parameters. Metformin had a greater effect on the change in disposition index (Δ disposition index) in women with gestational diabetes mellitus than in those with T2DM (P = .01). In conclusion, response to metformin in women with gestational diabetes mellitus is significantly different from that in women with T2DM, which is likely related to the differences in disease severity.


Risk stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and gene expression markers.
Numerous molecular markers have been recently discovered as potential prognostic factors in acute myeloid leukemia (AML). It has become of critical importance to thoroughly evaluate their interrelationships and relative prognostic importance. Gene expression profiling was conducted in a well-characterized cohort of 439 AML patients (age < 60 years) to determine expression levels of EVI1, WT1, BCL2, ABCB1, BAALC, FLT3, CD34, INDO, ERG and MN1. A variety of AML-specific mutations were evaluated, that is, FLT3, NPM1, N-RAS, K-RAS, IDH1, IDH2, and CEBPA(DM/SM) (double/single). Univariable survival analysis shows that (1) patients with FLT3(ITD) mutations have inferior overall survival (OS) and event-free survival (EFS), whereas CEBPA(DM) and NPM1 mutations indicate favorable OS and EFS in intermediate-risk AML, and (2) high transcript levels of BAALC, CD34, MN1, EVl1, and ERG predict inferior OS and EFS. In multivariable survival analysis, CD34, ERG, and CEBPA(DM) remain significant. Using survival tree and regression methodologies, we show that CEBPA(DM), CD34, and IDH2 mutations are capable of separating the intermediate group into 2 AML subgroups with highly distinctive survival characteristics (OS at 60 months: 51.9% vs 14.9%). The integrated statistical approach demonstrates that from the multitude of biomarkers a greatly condensed subset can be selected for improved stratification of intermediate-risk AML.


Multiview stereo and silhouette consistency via convex functionals over convex domains.
We propose a convex formulation for silhouette and stereo fusion in 3D reconstruction from multiple images. The key idea is to show that the reconstruction problem can be cast as one of minimizing a convex functional, where the exact silhouette consistency is imposed as convex constraints that restrict the domain of feasible functions. As a consequence, we can retain the original stereo-weighted surface area as a cost functional without heuristic modifications of this energy by balloon terms or other strategies, yet still obtain meaningful (non-empty) reconstructions which are guaranteed to be silhouette-consistent. We prove that the proposed convex relaxation approach provides solutions that lie within a bound of the optimal solution. Compared to existing alternatives, the proposed method does not depend on initialization and leads to a simpler and more robust numerical scheme for imposing silhouette consistency obtained by projection onto convex sets. We show that this projection can be solved exactly using an efficient algorithm. We propose a parallel implementation of the resulting convex optimization problem on a graphics card. Given a photo-consistency map and a set of image silhouettes, we are able to compute highly accurate and silhouette-consistent reconstructions for challenging real-world data sets. In particular, experimental results demonstrate that the proposed silhouette constraints help to preserve fine-scale details of the reconstructed shape. Computation times depend on the resolution of the input imagery and vary between a few seconds and a couple of minutes for all experiments in this paper.


Molecular and pharmacological characterization of dominant black coat color in sheep.
Dominant black coat color in sheep is predicted to be caused by an allele ED at the extension locus. Recent studies have shown that this gene encodes the melanocyte stimulating hormone receptor (MC1-R). In mouse and fox, naturally occurring mutations in the coding region of MC1-R produce a constitutively activated receptor that switches the synthesis from phaeomelanin to eumelanin within the melanocyte, explaining the black coat color observed phenotypically. In the sheep, we have identified a Met-->Lys mutation in position 73 (M73K) together with a Asp --> Asn change at position 121 (D121N) showing complete cosegregation with dominant black coat color in a family lineage. Only the M73K mutation showed constitutive activation when introduced into the corresponding mouse receptor (mMC1-R) for pharmacological analysis; however, the position corresponding to D121 in the mouse receptor is required for high affinity ligand binding. The pharmacological profile of the M73K change is unique compared to the constitutively active E92K mutation in the sombre mouse and C123R mutation in the Alaska silver fox, indicating that the M73K change activates the receptor via a mechanism distinct from these previously characterized mutations.


Molecular reorganization in organic field-effect transistors and its effect on two-dimensional charge transport pathways.
Charge transport in organic thin film transistors takes place in the first few molecular layers in contact with the gate dielectric. Here we demonstrate that the charge transport pathways in these devices are extremely sensitive to the orientational defects of the first monolayers, which arise from specific growth conditions. Although these defects partially heal during the growth, they cause depletion of charge carriers in the first monolayer, and drive the current to flow in the monolayers above the first one. Moreover, the residual defects induce lower crystalline order and charge mobility. These results, which are not intuitively explained by electrostatics arguments, have been obtained by combining in situ real time structural and electrical characterization together with ex situ AFM measurements, on thin films of a relevant n-type organic semiconductor, N,N'-bis(n-octyl)-dicyanoperylene-3,4:9,10-bis dicarboximide grown by sublimation in a quasi-layer-by-layer mode at different substrate temperatures.


Sepsis - What's new in 2019?
Sepsis-3 guidelines have implications in a deeper understanding of the biopathology of the disease. Further, the review focuses on timely topics and new literature on fluid resuscitation, the value of steroids in sepsis, and new therapeutic options such as angiotensin II, vitamin C, and thiamine as well as the emerging role of procalcitonin (PCT) in managing antibiotics. Traditional therapies such as type of crystalloid fluid administration and steroid therapy for sepsis are currently under re-evaluation. Angiotensin II is investigated for reversing vasodilatory shock. The role of capillary endothelium leak and cellular metabolism can be affected by vitamin C and thiamine levels. Biomarker level trends, specifically PCT, can aid clinical suspicion of infection. Sepsis-3 shifts the focus from a noninfectious inflammatory process and an emphasis on a dysregulated host response to infection. Hyperchloremic crystalloid resuscitation is associated with poor clinical outcomes. Steroid administration can reverse shock physiology; however, mortality benefits remain uncertain. Angiotensin II, vitamin C, and thiamine are novel treatment options that need further validation. PCT assays can help discern between infectious and noninfectious inflammation.


Neuronal activity in globus pallidus interna can be synchronized to local field potential activity over 3-12 Hz in patients with dystonia.
Pallidal recordings of local field potentials (LFPs) in patients with dystonia have demonstrated semi-oscillatory activity over 3-12 Hz. Although this activity has been hypothesized to contribute to dystonia, it is unclear to what extent these LFP oscillations arise in the globus pallidus interna (GPi) and are synchronous with local neuronal discharge. We therefore recorded LFPs and neuronal activity from microelectrodes inserted into the pallidum on nine sides in six awake patients with primary dystonia during functional neurosurgery. Mean normalized LFP power over 3-12 Hz was higher in GPi than globus pallidus externa. Spike triggered averages were computed, and 11 exhibited significant features in the 3-12 Hz band, indicating that the discharges of local neurons were locked to 3-12 Hz oscillations in the LFP. All but two of these STAs were in GPi. We conclude that pallidal oscillations at 3-12 Hz are maximal in GPi, the surgical target, in patients with dystonia and that they can be synchronized to activity in local neurons. This lends support to a pathophysiological relationship between LFP activity at 3-12 Hz and dystonia.


High-resolution genetic map for understanding the effect of genome-wide recombination rate on nucleotide diversity in watermelon.
We used genotyping by sequencing to identify a set of 10,480 single nucleotide polymorphism (SNP) markers for constructing a high-resolution genetic map of 1096 cM for watermelon. We assessed the genome-wide variation in recombination rate (GWRR) across the map and found an association between GWRR and genome-wide nucleotide diversity. Collinearity between the map and the genome-wide reference sequence for watermelon was studied to identify inconsistency and chromosome rearrangements. We assessed genome-wide nucleotide diversity, linkage disequilibrium (LD), and selective sweep for wild, semi-wild, and domesticated accessions of Citrullus lanatus var. lanatus to track signals of domestication. Principal component analysis combined with chromosome-wide phylogenetic study based on 1563 SNPs obtained after LD pruning with minor allele frequency of 0.05 resolved the differences between semi-wild and wild accessions as well as relationships among worldwide sweet watermelon. Population structure analysis revealed predominant ancestries for wild, semi-wild, and domesticated watermelons as well as admixture of various ancestries that were important for domestication. Sliding window analysis of Tajima's D across various chromosomes was used to resolve selective sweep. LD decay was estimated for various chromosomes. We identified a strong selective sweep on chromosome 3 consisting of important genes that might have had a role in sweet watermelon domestication.


Resting sympathetic baroreflex sensitivity in subjects with low and high tolerance to central hypovolemia induced by lower body negative pressure.
Central hypovolemia elicited by orthostasis or hemorrhage triggers sympathetically-mediated baroreflex responses to maintain organ perfusion; these reflexes are less sensitive in patients with orthostatic intolerance, and during conditions of severe blood loss, may result in cardiovascular collapse (decompensatory or circulatory shock). The ability to tolerate central hypovolemia is variable and physiological factors contributing to tolerance are emerging. We tested the hypothesis that resting muscle sympathetic nerve activity (MSNA) and sympathetic baroreflex sensitivity (BRS) are attenuated in male and female subjects who have low tolerance (LT) to central hypovolemia induced by lower body negative pressure (LBNP). MSNA and diastolic arterial pressure (DAP) were recorded in 47 human subjects who subsequently underwent LBNP to tolerance (onset of presyncopal symptoms). LT subjects experienced presyncopal symptoms prior to completing LBNP of -60 mm Hg, and subjects with high tolerance (HT) experienced presyncopal symptoms after completing LBNP of -60 mm Hg. Contrary to our hypothesis, resting MSNA burst incidence was not different between LT and HT subjects, and was not related to time to presyncope. BRS was assessed as the slope of the relationship between spontaneous fluctuations in DAP and MSNA during 5 min of supine rest. MSNA burst incidence/DAP correlations were greater than or equal to 0.5 in 37 subjects (LT: n = 9; HT: n = 28), and BRS was not different between LT and HT (-1.8 ± 0.3 vs. -2.2 ± 0.2 bursts·(100 beats)(-1) ·mm Hg(-1), p = 0.29). We conclude that tolerance to central hypovolemia is not related to either resting MSNA or sympathetic BRS.


Associations between hyperopia and other vision and refractive error characteristics.
To investigate the association of hyperopia greater than +3.25 diopters (D) with amblyopia, strabismus, anisometropia, astigmatism, and reduced stereoacuity in preschoolers. Three- to five-year-old Head Start preschoolers (N = 4040) underwent vision examination including monocular visual acuity (VA), cover testing, and cycloplegic refraction during the Vision in Preschoolers Study. Visual acuity was tested with habitual correction and was retested with full cycloplegic correction when VA was reduced below age norms in the presence of significant refractive error. Stereoacuity testing (Stereo Smile II) was performed on 2898 children during study years 2 and 3. Hyperopia was classified into three levels of severity (based on the most positive meridian on cycloplegic refraction): group 1: greater than or equal to +5.00 D, group 2: greater than +3.25 D to less than +5.00 D with interocular difference in spherical equivalent greater than or equal to 0.50 D, and group 3: greater than +3.25 D to less than +5.00 D with interocular difference in spherical equivalent less than 0.50 D. "Without" hyperopia was defined as refractive error of +3.25 D or less in the most positive meridian in both eyes. Standard definitions were applied for amblyopia, strabismus, anisometropia, and astigmatism. Relative to children without hyperopia, children with hyperopia greater than +3.25 D (n = 472, groups 1, 2, and 3) had a higher proportion of amblyopia (34.5 vs. 2.8%, p < 0.0001) and strabismus (17.0 vs. 2.2%, p < 0.0001). More severe levels of hyperopia were associated with higher proportions of amblyopia (51.5% in group 1 vs. 13.2% in group 3) and strabismus (32.9% in group 1 vs. 8.4% in group 3; trend p < 0.0001 for both). The presence of hyperopia greater than +3.25 D was also associated with a higher proportion of anisometropia (26.9 vs. 5.1%, p < 0.0001) and astigmatism (29.4 vs. 10.3%, p < 0.0001). Median stereoacuity of nonstrabismic, nonamblyopic children with hyperopia (n = 206) (120 arcsec) was worse than that of children without hyperopia (60 arcsec) (p < 0.0001), and more severe levels of hyperopia were associated with worse stereoacuity (480 arcsec for group 1 and 120 arcsec for groups 2 and 3, p < 0.0001). The presence and magnitude of hyperopia among preschoolers were associated with higher proportions of amblyopia, strabismus, anisometropia, and astigmatism and with worse stereoacuity even among nonstrabismic, nonamblyopic children.


Efficient delivery of RNA Interference to peripheral neurons in vivo using herpes simplex virus.
Considerable interest has been focused on inducing RNA interference (RNAi) in neurons to study gene function and identify new targets for disease intervention. Although small interfering RNAs (siRNAs) have been used to silence genes in neurons, in vivo delivery of RNAi remains a major challenge limiting its applications. We have developed a highly efficient method for in vivo gene silencing in dorsal root ganglia (DRG) using replication-defective herpes simplex viral (HSV-1) vectors. HSV-mediated delivery of short-hairpin RNA (shRNA) targeting reporter genes resulted in highly effective and specific silencing in neuronal and non-neuronal cells in culture and in the DRG of mice in vivo including in a transgenic mouse model. We further establish proof of concept by demonstrating in vivo silencing of the endogenous trpv1 gene. These data are the first to show silencing in DRG neurons in vivo by vector-mediated delivery of shRNA. Our results support the utility of HSV vectors for gene silencing in peripheral neurons and the potential application of this technology to the study of nociceptive processes and in pain gene target validation studies.


A genetically encoded tag for correlated light and electron microscopy of intact cells, tissues, and organisms.
Electron microscopy (EM) achieves the highest spatial resolution in protein localization, but specific protein EM labeling has lacked generally applicable genetically encoded tags for in situ visualization in cells and tissues. Here we introduce "miniSOG" (for mini Singlet Oxygen Generator), a fluorescent flavoprotein engineered from Arabidopsis phototropin 2. MiniSOG contains 106 amino acids, less than half the size of Green Fluorescent Protein. Illumination of miniSOG generates sufficient singlet oxygen to locally catalyze the polymerization of diaminobenzidine into an osmiophilic reaction product resolvable by EM. MiniSOG fusions to many well-characterized proteins localize correctly in mammalian cells, intact nematodes, and rodents, enabling correlated fluorescence and EM from large volumes of tissue after strong aldehyde fixation, without the need for exogenous ligands, probes, or destructive permeabilizing detergents. MiniSOG permits high quality ultrastructural preservation and 3-dimensional protein localization via electron tomography or serial section block face scanning electron microscopy. EM shows that miniSOG-tagged SynCAM1 is presynaptic in cultured cortical neurons, whereas miniSOG-tagged SynCAM2 is postsynaptic in culture and in intact mice. Thus SynCAM1 and SynCAM2 could be heterophilic partners. MiniSOG may do for EM what Green Fluorescent Protein did for fluorescence microscopy.


Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus.
Hepatitis C virus (HCV) infection causes liver cancer and cirrhosis and may also increase the risk of other tumors, particularly hematopoietic malignancies and thyroid cancer. Previous studies have been too small to adequately assess these risks. To test the hypothesis that HCV infection is associated with increased risk for hematological malignancies, related lymphoproliferative disorders, and thyroid cancer. A retrospective cohort study of users of US Veterans Affairs health care facilities from 1997-2004, which included 146,394 patients infected with HCV who had at least 2 visits with a diagnostic code for HCV infection, and 572,293 patients uninfected with HCV. To assemble the HCV-uninfected cohort, we randomly selected up to 4 patients per patient infected with HCV from all veterans who matched on age, sex, and baseline visit date and type (inpatient or outpatient). Individuals with human immunodeficiency virus were excluded. Risks of hematopoietic malignancies, related lymphoproliferative precursor diseases, and thyroid cancer, adjusting for selection factors, race, era of military service, and use of medical services. The mean (SD) age of the patients was 52 (8) years, and 97% were men. Risks for non-Hodgkin lymphoma (n = 1359), Waldenström macroglobulinemia (n = 165), and cryoglobulinemia (n = 551) were increased with HCV infection (adjusted hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.12-1.45; adjusted HR, 2.76; 95% CI, 2.01-3.79; and adjusted HR, 3.98; 95% CI, 3.36-4.72; respectively). We found no significantly increased risk for other hematological malignancies. Although thyroiditis risk was slightly increased, risk for thyroid cancer (n = 320) was not (adjusted HR, 0.72; 95% CI, 0.52-0.99). Adjusted P values for non-Hodgkin lymphoma, Waldenström macroglobulinemia, cryoglobulinemia, and thyroiditis were all <.0038, the Bonferroni threshold for statistical significance considering multiple comparisons. Hepatitis C virus infection confers a 20% to 30% increased risk of non-Hodgkin lymphoma overall, and a 3-fold higher risk of Waldenström macroglobulinemia, a low-grade lymphoma. Risks were also increased for cryoglobulinemia. These results support an etiological role for HCV in causing lymphoproliferation and causing non-Hodgkin lymphoma.


Burn patients' experience of peripherally inserted central catheter insertion: Analysis of focus group interviews from a South Korean burn center.
Although the use of peripherally inserted central catheters (PICCs) has increased in burn patient treatment, little is known about the subjective experiences of these patients with PICCs. These experiences may be similar to those of other patients, particularly cancer patients receiving long term care but it is not clear if this is the case. Burn patients' exposure to skin injury may result in pain and apprehension similar but different from that felt by cancer patients. The aim of this study was to explore the subjective experiences of PICC insertion procedures among burn patients treated and managed in a burn center in South Korea. A qualitative descriptive study was conducted using focus group interviews. Twenty-two participants who experienced of PICC insertion procedures participated in audio-taped focus groups sessions. Qualitative content analysis was used to identify categories of discussion depicting participants' subjective experience with PICC procedures. Three categories of PICC subjective experience were identified: (a) distress: painful burn treatments and repeated venipunctures, (b) PICC insertion: short and endurable, and (c) use of PICC: lots of pros and a few cons. The major findings from our focus group interviews were that frequent venipunctures are a significant sources of distress for burn patients. However, most participants reported that PICC provided a very convenient route for venous infiltration and for that they were generally positive about the procedure. This knowledge may enable clinicians to better the needs of their patients when undergoing PICC insertion and management.


A single transgene locus triggers both transcriptional and post-transcriptional silencing through double-stranded RNA production.
Silencing of a target locus by an unlinked silencing locus can result from transcription inhibition (transcriptional gene silencing; TGS) or mRNA degradation (post-transcriptional gene silencing; PTGS), owing to the production of double-stranded RNA (dsRNA) corresponding to promoter or transcribed sequences, respectively. The involvement of distinct cellular components in each process suggests that dsRNA-induced TGS and PTGS likely result from the diversification of an ancient common mechanism. However, a strict comparison of TGS and PTGS has been difficult to achieve because it generally relies on the analysis of distinct silencing loci. We describe a single transgene locus that triggers both TGS and PTGS, owing to the production of dsRNA corresponding to promoter and transcribed sequences of different target genes. We describe mutants and epigenetic variants derived from this locus and propose a model for the production of dsRNA. Also, we show that PTGS, but not TGS, is graft-transmissible, which together with the sensitivity of PTGS, but not TGS, to RNA viruses that replicate in the cytoplasm, suggest that the nuclear compartmentalization of TGS is responsible for cell-autonomy. In contrast, we contribute local and systemic trafficking of silencing signals and sensitivity to viruses to the cytoplasmic steps of PTGS and to amplification steps that require high levels of target mRNAs.


Outcome After Surgical Repair of Proximal Hamstring Avulsions: A Systematic Review.
At the present time, no systematic review, including a quality assessment, has been published about the outcome after proximal hamstring avulsion repair. To determine the outcome after surgical repair of proximal hamstring avulsions, to compare the outcome after acute (≤4 weeks) and delayed repairs (>4 weeks), and to compare the outcome after different surgical techniques. Systematic review and best-evidence synthesis. PubMed, CINAHL, SPORTdiscus, Cochrane library, EMBASE, and Web of Science were searched (up to December 2013) for eligible studies. Two authors screened the search results separately, while quality assessment was performed by 2 authors independently using the Physiotherapy Evidence Database (PEDro) scale. A best-evidence synthesis was subsequently used. Thirteen studies (387 participants) were included in this review. There were no studies with control groups of nonoperatively treated proximal hamstring avulsions. All studies had a low methodological quality. After surgical repair of proximal hamstring avulsion, 76% to 100% returned to sports, 55% to 100% returned to preinjury activity level, and 88% to 100% were satisfied with surgery. Mean hamstring strength varied between reporting studies (78%-101%), and hamstring endurance and flexibility were fully restored compared with the unaffected side. Symptoms of residual pain were reported by 8% to 61%, and reported risk of major complications was low (3% rerupture rate). No to minimal difference in outcome was found between acute and delayed repair in terms of return to sports, patient satisfaction, hamstring strength, and pain. Achilles allograft reconstruction and primary repair with suture anchors led to comparable results. The quality of studies included is low. Surgical repair of proximal hamstring avulsions appears to result in a subjective highly satisfying outcome. However, decreased strength, residual pain, and decreased activity level were reported by a relevant number of patients. Minimal to no differences in outcome of acute and delayed repairs were found. Limited evidence suggests that an Achilles allograft reconstruction yields results comparable with primary repair in delayed cases where primary repair is not possible. High-level studies are required to confirm these findings.


Structural basis for alcohol modulation of a pentameric ligand-gated ion channel.
Despite its long history of use and abuse in human culture, the molecular basis for alcohol action in the brain is poorly understood. The recent determination of the atomic-scale structure of GLIC, a prokaryotic member of the pentameric ligand-gated ion channel (pLGIC) family, provides a unique opportunity to characterize the structural basis for modulation of these channels, many of which are alcohol targets in brain. We observed that GLIC recapitulates bimodal modulation by n-alcohols, similar to some eukaryotic pLGICs: methanol and ethanol weakly potentiated proton-activated currents in GLIC, whereas n-alcohols larger than ethanol inhibited them. Mapping of residues important to alcohol modulation of ionotropic receptors for glycine, γ-aminobutyric acid, and acetylcholine onto GLIC revealed their proximity to transmembrane cavities that may accommodate one or more alcohol molecules. Site-directed mutations in the pore-lining M2 helix allowed the identification of four residues that influence alcohol potentiation, with the direction of their effects reflecting α-helical structure. At one of the potentiation-enhancing residues, decreased side chain volume converted GLIC into a highly ethanol-sensitive channel, comparable to its eukaryotic relatives. Covalent labeling of M2 positions with an alcohol analog, a methanethiosulfonate reagent, further implicated residues at the extracellular end of the helix in alcohol binding. Molecular dynamics simulations elucidated the structural consequences of a potentiation-enhancing mutation and suggested a structural mechanism for alcohol potentiation via interaction with a transmembrane cavity previously termed the "linking tunnel." These results provide a unique structural model for independent potentiating and inhibitory interactions of n-alcohols with a pLGIC family member.


Cardiac surgeons' concerns, perceptions, and responses during the COVID-19 pandemic.
The coronavirus disease 2019 (COVID-19) pandemic has had an unprecedented impact on health care and cardiac surgery. We report cardiac surgeons' concerns, perceptions, and responses during the COVID-19 pandemic. A detailed survey was sent to recruit participating adult cardiac surgery centers in North America. Data regarding cardiac surgeons' perceptions and changes in practice were analyzed. Our study comprises 67 institutions with diverse geographic distribution across North America. Nurses were most likely to be redeployed (88%), followed by advanced care practitioners (69%), trainees (28%), and surgeons (25%). Examining surgeon concerns in regard to COVID-19, they were most worried with exposing their family to COVID-19 (81%), followed by contracting COVID-19 (68%), running out of personal protective equipment (PPE) (28%), and hospital resources (28%). In terms of PPE conservation strategies among users of N95 respirators, nearly half were recycling via decontamination with ultraviolet light (49%), followed by sterilization with heat (13%) and at home or with other modalities (13%). Reuse of N95 respirators for 1 day (22%), 1 week (21%) or 1 month (6%) was reported. There were differences in adoption of methods to conserve N95 respirators based on institutional pandemic phase and COVID-19 burden, with higher COVID-19 burden institutions more likely to resort to PPE conservation strategies. The present study demonstrates the impact of COVID-19 on North American cardiac surgeons. Our study should stimulate further discussions to identify optimal solutions to improve workforce preparedness for subsequent surges, as well as facilitate the navigation of future healthcare crises.


A 10,000-year record of Arctic Ocean sea-ice variability--view from the beach.
We present a sea-ice record from northern Greenland covering the past 10,000 years. Multiyear sea ice reached a minimum between ~8500 and 6000 years ago, when the limit of year-round sea ice at the coast of Greenland was located ~1000 kilometers to the north of its present position. The subsequent increase in multiyear sea ice culminated during the past 2500 years and is linked to an increase in ice export from the western Arctic and higher variability of ice-drift routes. When the ice was at its minimum in northern Greenland, it greatly increased at Ellesmere Island to the west. The lack of uniformity in past sea-ice changes, which is probably related to large-scale atmospheric anomalies such as the Arctic Oscillation, is not well reproduced in models. This needs to be further explored, as it is likely to have an impact on predictions of future sea-ice distribution.


In vivo fast variable focus photoacoustic microscopy using an electrically tunable lens.
Fast focusing scan over a large depth range is challenging in photoacoustic microscopic imaging. In this paper, a fast variable focus photoacoustic microscopy (VF-PAM) with a large range of imaging depth was presented by using an electrically tunable lens (ETL). The ETL controlled the divergence angle of the laser beam for fast and continuous focus-shifting in depth direction with the shifting time of 15 ms, and 2.82 mm focus-shifting range with a 1 µm shifting accuracy was achieved by combining the ETL with a 0.3 NA plan microscope objective lens. Carbon fibers imaging verified the depth imaging ability of the system, in vivo microvasculature of mouse ear and brain tissues of the mouse imaging further demonstrated the focusing scan ability in biomedical application. The fast VF-PAM system allows substantial shortening of the focus-shifting time, which will be more conducive to studying living biological tissue, and will promote the development of in vivo noninvasive PA depth imaging without mechanical scan.


Effect of Gua Sha therapy on patients with diabetic peripheral neuropathy: A randomized controlled trial.
To examine the effect of Gua Sha therapy in the treatment of diabetic peripheral neuropathy (DNP). An open-label randomized controlled study was conducted with usual care as the control (60 subjects in Gua Sha group and 59 subjects in usual care group). Outcome measures included Toronto Clinical Scoring System (TCSS), Vibration Perception Threshold (VPT), Ankle Brachial Index (ABI), and fasting plasma glucose (FPG). There were 12 consecutive sessions of Gua Sha, one session per week. After the first cycle of Gua Sha intervention, only performance of sensory function measured by the VPT, and peripheral artery disease symptoms by the ABI were statistically significant differences between the two groups (both P values < 0.01), and the total TCSS score and the FPG level were no group differences (P = 0.14, and 0.25, respectively). At the eight-week and 12-week post intervention assessment, Gua Sha therapy significantly reduced severity of neuropathy symptoms, improved performance of sensory function, reduced peripheral artery disease, and better controlled plasma glucose by comparing with the control group (all P values < 0.01). The changes of mean scores of TCSS, VPT, ABI and the plasma glucose levels in the Gua Sha group showed a significant change from baseline to week 12, indicating that Gua Sha therapy induced progressive improvement in the management of DPN symptoms, sensory function, peripheral artery disease and glucose levels. No serious adverse events were reported in either arm. Gua Sha therapy in this study was effective, safe and well tolerated by patients. Gua Sha therapy appears to be effective at reducing the severity of DPN in a clinically relevant dimension, and at improving other health outcomes in patients with DPN. While this study found that Gua Sha therapy is a promising treatment in reducing the symptoms of patients with DPN, further, larger sample studies are required to confirm the effects of Gua Sha therapy in patients with DPN.


Cortactin is necessary for E-cadherin-mediated contact formation and actin reorganization.
Classical cadherin adhesion molecules are key determinants of cell-cell recognition during development and in post-embryonic life. A decisive step in productive cadherin-based recognition is the conversion of nascent adhesions into stable zones of contact. It is increasingly clear that such contact zone extension entails active cooperation between cadherin adhesion and the force-generating capacity of the actin cytoskeleton. Cortactin has recently emerged as an important regulator of actin dynamics in several forms of cell motility. We now report that cortactin is recruited to cell-cell adhesive contacts in response to homophilic cadherin ligation. Notably, cortactin accumulates preferentially, with Arp2/3, at cell margins where adhesive contacts are being extended. Recruitment of cortactin is accompanied by a ligation-dependent biochemical interaction between cortactin and the cadherin adhesive complex. Inhibition of cortactin activity in cells blocked Arp2/3-dependent actin assembly at cadherin adhesive contacts, significantly reduced cadherin adhesive contact zone extension, and perturbed both cell morphology and junctional accumulation of cadherins in polarized epithelia. Together, our findings identify a necessary role for cortactin in the cadherin-actin cooperation that supports productive contact formation.


Effects of ecological flooding on the temporal and spatial dynamics of carabid beetles (Coleoptera, Carabidae) and springtails (Collembola) in a polder habitat.
Within the scope of the Integrated Rhine Program an ecological flood gate and channel was inserted into the polder "Ingelheim" to enhance animal and plant diversity. In 2008, carabid beetles and springtails were collected, using pitfall traps, to measure the effects of ecological flooding and a strong precipitation event at a flood-disturbed and a dry location in this area. At both localities, xerophilic and mesophilic carabid beetle species were dominant throughout the study period. The total number of individuals of hygrophilic species was comparatively constant, while species number increased, partly due to the changed moisture conditions caused by ecological flooding and strong precipitation. Carabid beetle diversity and evenness decreased marginally when ecological flooding was absent. Springtails represent a less mobile arthropod order, and as such the impact of ecological flooding was stronger. An increase in both numbers of species and individuals of hygrophilic and hygrotolerant species occurred in the flood-disturbed location after ecological flooding. After the sites at both locations had dried, the number of individuals belonging to these species declined rapidly. In contrast to carabid species, the strong precipitation event showed no influence on hygrophilic springtail species. Thus, collembolan diversity and evenness decreased markedly in the absence of flooding. We showed that ecological flooding has an influence on the spatial and temporal dynamics of different arthropod groups that inhabit the polder "Ingelheim". These findings demonstrate the importance of using different arthropod groups as bioindicators in determining the ecological value of a particular polder design.