Channelling of substrate promiscuity of the skeletal-muscle ADP-ribosyl cyclase isoform.
The novel Ca2+-mobilizing second messengers cADPr (cyclic ADP-ribose) and NAADP (nicotinic acid-adenine dinucleotide phosphate) are both synthesized by ADP-ribosyl cyclases. Using HSR (heavy sarcoplasmic reticulum) fractions from rabbit skeletal muscle, NAADP-induced Ca2+ release was observed. In the present paper, we show in HSR membranes the formation of authentic cADPr, cGDPr (cyclic GDP-ribose) and NAADP. The cyclization reaction to form cADPr and cGDPr as well as the base-exchange reaction to form NAADP were strictly dependent on pH. Although the formation of cGDPr is optimized at pH 6, the synthesis of NAADP was most pronounced at a pH below 5. A novel regulation mechanism is provided for nicotinic acid, the co-substrate for NAADP synthesis. Nicotinic acid had virtually no influence on the cyclization reaction, but increased the affinity of NADP at an acidic pH and had the opposite effect at alkaline pH. Nicotinamide, the side product of cADPr synthesis, is an inhibitor of the cyclization reaction (IC50, 0.7+/-0.1 mM) and was 30-fold more potent at suppressing the base-exchange reaction. Although the synthesis of NAADP was highly sensitive to nicotinamide inhibition, this was not via a competition with the nicotinic-acid-binding site. In contrast with the ecto-ADP-ribosyl cyclase (CD38), the cyclization and base-exchange reaction of the skeletal muscle isoform was inhibited by Cu2+ and Zn2+, while other bivalent cations such as Ca2+, Mg2+ and Mn2+ had virtually no effect. These findings allow for the prediction of a novel ADP-ribosyl cyclase isoform in skeletal muscle HSR, other than CD38. Hence the enzymic prerequisite for cADPr- and NAADP-mediated Ca2+ signalling is present.


Deficiency of autophagy in dendritic cells protects against experimental autoimmune encephalomyelitis.
Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) in the immune system. DCs present antigens to CD8 and CD4 T cells in the context of class I or II MHC. Recent evidence suggests that autophagy, a conserved intracellular degradation pathway, regulates class II antigen presentation. In vitro studies have shown that deletion of autophagy-related genes reduced antigen presentation by APCs to CD4 T cells. In vivo studies confirmed these findings in the context of infectious diseases. However, the relevance of autophagy-mediated antigen presentation in autoimmunity remains to be elucidated. Here, we report that loss of autophagy-related gene 7 (Atg7) in DCs ameliorated experimental autoimmune encephalomyelitis (EAE), a CD4 T cell-mediated mouse model of multiple sclerosis, by reducing in vivo priming of T cells. In contrast, severity of hapten-induced contact hypersensitivity, in which CD8 T cells and NK cells play major roles, was unaffected. Administration of the autophagy-lysosomal inhibitor chloroquine, before EAE onset, delayed disease progression and, when administered after the onset, reduced disease severity. Our data show that autophagy is required in DCs for induction of EAE and suggest that autophagy might be a potential target for treating CD4 T cell-mediated autoimmune conditions.


The physiological function of drug-transporting P-glycoproteins.
The mammalian drug-transporting or mdr1-type P-glycoproteins can extrude a range of structurally diverse, toxic xenobiotic compounds from cells. Our analysis of knockout mice lacking one or both of the mdr1-type P-glycoproteins indicates that a major function of these proteins is the protection of organisms against many of the toxic xenobiotics to which they can potentially be exposed in nature. P-glycoprotein confers protection by limiting the uptake of compounds from the gastrointestinal tract, and by stimulating excretion of compounds in the liver, kidney, and intestine. Moreover, P-glycoprotein in the blood-brain barrier and other blood-tissue barriers protects sensitive organs from exposure to toxic compounds that may have entered the bloodstream. Although we cannot exclude additional physiological functions for mdr1-type P-glycoproteins, these are not vital, since the mdr1-deficient mice are viable and fertile, and do not display obvious phenotypic abnormalities other than hypersensitivity to drugs.


Light sintering of ultra-smooth and robust silver nanowire networks embedded in poly(vinyl-butyral) for flexible OLED.
A conductive, uniform, and ultra-smooth flexible transparent composite film is produced by embedding silver nanowires (AgNWs) into poly(vinyl-butyral) (PVB) without pressure or high-temperature annealing. The adhesion of AgNWs was greatly improved by embedding them in PVB, and surface roughness and sheet resistance (Rs) improvements were achieved through the use of the intense pulsed light (IPL) method, which welds the interconnections among AgNWs in a short time without heat or pressure treatment. The sheet resistance of PVB/AgNWs with the IPL(PAI) composite film reaches 12.6 ohm/sq with a transmittance of 85.7% (at 550 nm); no clear changes in the sheet resistance are observed after a substrate bending and tape test, suggesting excellent flexibility. In the case of PAI, the change in sheet resistance was only 2.6% after a 2,000-bend test, and the resulting bending radius was less than 1 mm. When IPL was exposed to PVB/AgNWs, the figure of merit was 2.36 times higher than that without exposure. Finally, flexible OLEDs using PAI exhibited comparable or higher electroluminescent characteristics than other devices with well-known flexible electrodes-including indium-zinc-oxide on polymer plastic-which is a promising discovery for flexible optoelectronic applications.


[Relation between characteristics of pregnant adolescents and resistance to drugs use].
This is a qualitative study. We interviewed 20 pregnant adolescents, who agreed to participate in this research about the relation between the characteristics of pregnant adolescents and resistance to drugs use. We observed that they had contact will legal and illegal drugs, as well as their decision to reject them, give up or decrease substance use; we also identified a lack of knowledge about reproductive health and body changes. It is important for this population to be able to count on their partner and child, as a support not using addictive toxic substances.


cis-Selective synthesis of 1,3-disubstituted tetrahydro-β-carbolines from N-sulfonyl N,S-acetals.
Nucleophilic addition of Grignard reagents to tetrahydro-β-carboline (THC) N-sulfonyl N,S-acetal generates exclusively cis-1,3-disubstituted THCs with a unique 1,3-diaxial conformation. The stereochemical relationship of the 1,3-substituents was confirmed by 2-dimensional NMR spectroscopy and X-ray crystallography. The mechanism of the reaction is proposed based on crystal structures and molecular orbital calculations.


Characterisation of TRIM46 autoantibody-associated paraneoplastic neurological syndrome.
To report the expanded neurological presentations and oncological associations of tripartite motif-containing protein 46 (TRIM46)-IgG seropositive patients. Archived sera/cerebrospinal fluid (CSF) were evaluated by tissue-based immunofluorescence assay to identify patients with identical axon initial segment (AIS)-specific staining pattern. Phage immunoprecipitation sequencing (PhIP-Seq) was used to identify the putative autoantigen. IgG in serum (17) and/or CSF (16) from 25 patients yielded unique AIS-specific staining on murine central nervous system (CNS) tissue. An autoantibody specific for TRIM46 was identified by PhIP-Seq, and autoantigen specificity was confirmed by transfected COS7 cell-based assay. Clinical information was available for 22 TRIM46-IgG seropositive patients. Fifteen were female (68%). Median age was 67 years (range 25-87). Fifteen (68%) patients presented with subacute cerebellar syndrome (six isolated; nine with CNS accompaniments: encephalopathy (three), brainstem signs (two), myelopathy (two), parkinsonism (one)). Other phenotypes included limbic encephalitis (three), encephalopathy with/without seizures (two), myelopathy (two). Eighteen (82%) had cancer: neuroendocrine carcinomas (9; pancreatic (3), small-cell lung (4), oesophagus (1), endometrium (1)), adenocarcinomas (6; lung (2), ovarian (2), endometrial (1), breast (1)), sarcoma (2) and gastrointestinal tumour (1). Neurological symptoms in three followed immune checkpoint inhibitor (ICI) administration. This study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.


Measurement of the Prompt D^{0} Nuclear Modification Factor in p-Pb Collisions at sqrt[s_{NN}]=8.16 TeV.
The production of prompt D^{0} mesons in proton-lead collisions in both the forward and backward rapidity regions at a center-of-mass energy per nucleon pair of sqrt[s_{NN}]=8.16 TeV is measured by the LHCb experiment. The nuclear modification factor of prompt D^{0} mesons is determined as a function of the transverse momentum p_{T}, and the rapidity in the nucleon-nucleon center-of-mass frame y^{*}. In the forward rapidity region, significantly suppressed production with respect to pp collisions is measured, which provides significant constraints on models of nuclear parton distributions and hadron production down to the very low Bjorken-x region of ∼10^{-5}. In the backward rapidity region, a suppression with a significance of 2.0-3.8 standard deviations compared to parton distribution functions in a nuclear environment expectations is found in the kinematic region of p_{T}>6 GeV/c and -3.25<y^{*}<-2.5, corresponding to x∼0.01.


Interventions to Improve Medication Adherence: A Review.
Among adults with chronic illness, 30% to 50% of medications are not taken as prescribed. In the United States, it is estimated that medication nonadherence is associated with 125 000 deaths, 10% of hospitalizations, and $100 billion in health care services annually. PubMed was searched from January 1, 2000, to September 6, 2018, for English-language randomized clinical trials of interventions to improve medication adherence. Trials of patients younger than 18 years, trials that used self-report as the primary adherence outcome, and trials with follow-up periods less than 6 months were excluded; 49 trials were included. The most common methods of identifying patients at risk for nonadherence were patient self-report, electronic drug monitors (pill bottles), or pharmacy claims data to measure gaps in supply. Patient self-report is the most practical method of identifying nonadherent patients in the context of clinical care but may overestimate adherence compared with objective methods such as electronic drug monitors and pharmacy claims data. Six categories of interventions, and characteristics of successful interventions within each category, were identified: patient education (eg, recurrent and personalized telephone counseling sessions with health educators); medication regimen management (using combination pills to reduce the number of pills patients take daily); clinical pharmacist consultation for chronic disease co-management (including education, increased frequency of disease monitoring via telephone or in-person follow-up visits, and refill reminders); cognitive behavioral therapies (such as motivational interviewing by trained counselors); medication-taking reminders (such as refill reminder calls or use of electronic drug monitors for real-time monitoring and reminding); and incentives to promote adherence (such as reducing co-payments and paying patients and clinicians for achieving disease management goals). The choice of intervention to promote adherence will depend on feasibility and availability within a practice or health system. Successful interventions that are also clinically practical include using combination pills to reduce daily pill burden, clinical pharmacist consultation for disease co-management, and medication-taking reminders such as telephone calls to prompt refills (maximum observed absolute improvements in adherence of 10%, 15%, and 33%, respectively). Adherence can be assessed and improved within the context of usual clinical care, but more intensive and costly interventions that have demonstrated success will require additional investments by health systems.


Transition metal-free direct C-H functionalization of quinones and naphthoquinones with diaryliodonium salts: synthesis of aryl naphthoquinones as β-secretase inhibitors.
A novel ligand-free, transition metal-free direct C-H functionalization of quinones with diaryliodonium salts has been developed for the first time. The transformation was promoted only through the use of a base and gave aryl quinone derivatives in moderate to good yields. This methodology provided an effective and easy way to synthesize β-secretase inhibitors. The radical trapping experiments showed that this progress was the radical mechanism.


Practice Patterns for Prevention of Chemotherapy-Induced Nausea and Vomiting and Antiemetic Guideline Adherence Based on Real-World Prescribing Data.
Guideline-recommended antiemetic prophylaxis improves nausea and vomiting control in most patients undergoing chemotherapy. Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology (MASCC/ESMO) antiemetic guidelines recommend prophylaxis with a neurokinin-1 receptor antagonist (NK1 RA), a 5-hydroxytryptamine-3 receptor antagonist (5-HT3 RA), and dexamethasone for patients receiving highly emetogenic chemotherapy (HEC), including anthracycline-cyclophosphamide (AC)- and carboplatin (considered moderately emetogenic chemotherapy)-based chemotherapy. Here, we analyze the use of NK1 RA-5-HT3 RA-dexamethasone for antiemetic prophylaxis associated with HEC and carboplatin. The data source was the Global Oncology Monitor (Ipsos Healthcare). Geographically representative physicians from France, Germany, Italy, Spain, and the U.K. were screened for treatment involvement and number of patients treated per month. Patients' data from January to December 2018 were collected from medical charts and extrapolated on the basis of the total number of physicians who prescribe chemotherapy. The emetic risk of chemotherapy was classified per MASCC/ESMO guidelines. Data from 45,324 chemotherapy-treated patients were collected, representing a total extrapolated prevalence of 1,394,848 chemotherapy treatments included in the analysis. NK1 RAs were used in 45%, 42%, and 19% of patients receiving cisplatin-, AC-, and carboplatin-based chemotherapy, respectively; 18%, 24%, and 7% received the guideline-recommended NK1 RA-5-HT3 RA-dexamethasone combination; no antiemetics were prescribed for 12% of the treatments. Often, physicians' perception of the emetic risk of chemotherapy did not follow MASCC/ESMO guideline classification. Low adherence to antiemetic guidelines was revealed in clinical practice in five European countries, with 15% of all HEC-/carboplatin-based treatments receiving guideline-recommended NK1 RA-5-HT3 RA-dexamethasone prophylaxis and 12% of them receiving no antiemetics. New strategies for improving guideline adherence are urgently needed. Despite recent advances in antiemetic therapy, a substantial proportion of patients experience nausea and vomiting associated with chemotherapy in daily clinical practice. Antiemetic guidelines aim at prevention of chemotherapy-induced nausea and vomiting (CINV), and guideline-consistent antiemetic therapy can effectively prevent vomiting and, to a lesser extent, nausea in most patients with cancer. This study reports low adherence to antiemetic guidelines in the highly emetogenic chemotherapy setting in daily clinical practice across five European countries. Opportunity exists to increase adherence to antiemetic guideline recommendations. Implementation of strategies to facilitate guideline adherence can potentially improve CINV control.


Modified Hongyu Decoction promotes wound healing by activating the VEGF/PI3K/Akt signaling pathway.
Wound healing is a considerable problem for clinicians. Ever greater attention has been paid to the role of Chinese herbal monomers and compounds on wound healing. This study aims to elucidate the wound healing mechanism of Modified Hongyu Decoction (MHD) in vivo and in vitro. MHD wound healing activity in vivo was evaluated using an excision rat model. H and E staining, Masson's staining and immunofluorescence of wound tissue on days 7 and 14 were performed to evaluate the efficacy of MHD on wound healing. Subsequently, human umbilical vein endothelial cells (HUVECs) were used to evaluate wound healing characteristics in vitro. Cell Counting Kit-8 (CCK-8) and scratch assays were conducted to assess the effects of MHD on the proliferation and migration of HUVECs. The involvement of the VEGF/PI3K/Akt signaling pathway was assessed by western blotting. The rats in the MHD group displayed more neovascularization and collagen fibers. Western blotting of wound tissue showed that VEGF, PI3K, p-Akt and p-eNOS expression were significantly increased (p<0.05) in the MHD group. Cell Counting Kit-8 and scratch assays demonstrated that MHD promoted HUVECs proliferation and migration. MHD treatment significantly increased VEGF, PI3K, p-Akt and p-eNOS expression in HUVECs (p<0.05), which was inhibited by LY294002. Both in vivo and in vitro data indicated that MHD promotes wound healing by regulating the VEGF/PI3K/Akt signaling pathway.


[Reliability of the thyroid stimulating hormone receptor antibodies level determination in diagnosing and prognosing of autoimmune hyperthyroidism].
Graves disease (GD) is defined as hyperthyroidism with diffuse goiter caused by immunogenic disturbances. Antibodies to the thyroid stimulating hormone (TSH) receptors of thyroid gland (TRAb) have crucial pathogenetic importance in the development and maintenance of autoimmune hyperthyroidism. The aim of this study was to identify sensitivity, specificity, positive an negative predictive velue of TRAb level in sera of patients with GD as well as to estimate significance of TRAb level for remission and GD relapses occurrence. We studied prospectively and partly retrospectively 149 patients, 109 female and 40 male patients, 5-78 years old, in the period 1982-2007. There were 96 patients with GD. The control group consisted of 53 patients, 21 with hyperthyroidism of second etiology and 32 patients on amiodarone therapy, with or without thyroid dysfunction TRAb was measured by radioreceptor assay (TRAK Assay and DYNO Test TRAK Human Brahms Diagnostica GMBH). According to the results the sensitivity (Sn) of TRAb test was 80%, specificity (Sp) 100%, positive predictive value (PP) 100% and negative predictive value (NP) 83%. Also, the Sn of hTRAb test was 94%, Sp 100%, PP 100% and NP 94%. Our results show that an increased level of TRAb/hTRAb at the beginning of the disease and the level at the end of medical therapy is associated with an increased number of GD relapses and a shorter remission duration. Detection and measurement of TRAb in serum is a very sensitive method for diagnosing GD and very highly specific in vitro method for differential diagnosis of various forms of hyperthyroidism. Clinical significance of differentiating various forms of hyperthyroidism, using this in vitro assay, lays in adequate therapeutic choice for these entities.


Suppression of Nippostrongylus brasiliensis (Nematoda)-induced lysophospholipase activity and peripheral eosinophilia by Eimeria nieschulzi (Apicomplexa).
Interspecific interactions between Nippostrongylus brasiliensis and Eimeria nieschulzi were studied by measuring fecal lysophospholipase (LYPH) activity and relative numbers of peripheral eosinophils in rats singly or concurrently infected with one or both parasite species. Three groups of 10 rats each were inoculated with 2 X 10(3) N. brasiliensis L3 larvae and/or 5 X 10(5) E. nieschulzi sporulated oocysts. Groups 1 and 2 were infected with E. nieschulzi or N. brasiliensis, respectively. Group 3 rats were infected first with N. brasiliensis, followed on day 8 postinoculation (PI) with E. nieschulzi. Each rat served as its own control. Results revealed LYPH levels rose steadily in Group 2 rats, reaching significant peaks on days 10 and 12 PI before decreasing to control levels. Lysophospholipase activity in Groups 1 and 3, however, did not differ from control values. Group 2 rats also demonstrated peripheral eosinophilia, with peak values occurring on days 10, 12, 14, and 16 PI, while rats in Groups 1 and 3 exhibited no eosinophilia. These results demonstrate that E. nieschulzi suppressed intestinal LYPH activity and relative peripheral eosinophilia and demonstrate that a host's immune response to a single parasite may be significantly altered when a second parasite species is present.


Affect and Sexual Responsivity in Men With and Without a History of Sexual Aggression.
Despite increased attention to understanding risk factors for sexual aggression, knowledge regarding the emotional and sexual arousal patterns of sexually aggressive men remains limited. The current study examined whether sexually aggressive men exhibit unique profiles of affective responsivity, in particular to negatively valenced stimuli, as well as sexual arousal patterns that differentiate them from nonaggressive men. We presented 78 young men (38 sexually aggressive; 40 nonaggressive) with a series of videos designed to induce positive, sad, or anxious affect. Affect and subjective sexual arousal were assessed following each film and erectile responses were measured continuously. Sexually aggressive men reported significantly higher levels of sexual arousal following both the positive and negative conditions as compared to nonaggressive men. Erectile responses of sexually aggressive men were significantly greater than nonaggressive men's following the positive affect induction. Self-reported positive affect, but not negative affect, was a significant predictor of subjective sexual arousal for both groups of men. Compared to nonaggressive men, sexually aggressive men showed significantly weaker correlations between subjective and physiological sexual arousal. Findings suggest that generalized heightened propensity for sexual arousal may be a risk factor for sexually aggressive behavior.


[Trends in prevalence of cardiovascular risk factors and their treatment in coronary heart disease: the Euroaspire-project].
To determine the prevalence of cardiovascular risk factors and their treatment in Dutch patients with coronary heart disease (the 'Euroaspire'-project) and to compare these data with those from 4 and 10 years previously. Retrospective. The study included consecutive patients under 71 years of age, who had already been admitted for coronary revascularization or with myocardial infarction. Data were collected > 6 months after discharge. The prevalence of risk factors and their treatment were compared during the period May 1995-February 2006. In this third part of the study almost 80% of the patients were overweight (BMI >or= 25 kg/m2). 21% had diabetes mellitus. The average cholesterol level was 4.3 mmol/l. The percentage of smokers decreased significantly, from approximately 30% to 15%. More than 60% of subjects were hypertensive. More than 95% of the patients were on antiplatelet therapy or oral anticoagulants, 92% on cholesterol-reducing medication and 94% on antihypertensive medication. A sharp increase in medication was noted in comparison with earlier studies. Treatment of the most important cardiovascular risk factors has intensified over the past few years. Almost all patients were treated with antiplatelets, statins and antihypertensive medication. Overweight, hypertension and diabetes have become more important in the past decade. Care of cardiac patients will continue to be characterized by long-term and intensive care.


Low-dose divalproex in agitated patients with Alzheimer's disease.
Adequate treatment of behavioral disturbances in Alzheimer's disease is both important and difficult. This report describes a case series that examined the effectiveness and safety of low-dose divalproex in the treatment of agitated patients with Alzheimer's disease who were admitted to an inpatient geriatric psychiatry unit over a 1-year period. All patients had agitation due to probable Alzheimer's disease or mixed dementia and were prescribed divalproex monotherapy at low and completely flexible doses. Patients and nursing staff were blind to study enrollment. Clinical global impression scale scores, divalproex serum levels, and a variety of medical chart data were collected. Twenty patients met selection criteria and were included in the study. Of those, 13 patients (65%) were considered responders, while 4 patients (20%) required augmentation with other psychotropic medications; divalproex was discontinued in 1 patient. Adverse events occurred in 25% of patients. This case series suggests that low-dose divalproex may offer behavioral improvement and a reduced risk of side effects for some patients with agitation in Alzheimer's disease.


Analysis of laser speckle reduction utilizing microlens-array-based projection screen.
This paper focuses on the theoretical analyzation of laser speckle reduction by utilizing a microlens array (MLA). A theoretical model was established to describe the screen effect on speckle reduction, taking into account MLA cell size and on-screen projection/detection resolution area size. The relationship between the speckle contrast ratio (SCR) of a projection system and the cell size of an MLA was studied and investigated. A guideline for choosing an MLA that is able to suppress SCR below the threshold of human perception is proposed from the obtained results.


Evaluating interest in narrative therapy for decision making about pectus excavatum treatment.
The decision to proceed with surgical treatment for pectus excavatum (PE) is rarely clear-cut. Patients interested in treatment are referred for evaluation by numerous different specialists, but psychosocial counselling is currently not included in this process. Our objective was to assess whether PE patients would be interested in formal assistance with the decision-making process surrounding PE surgery using narrative therapy principles. Ninety-seven untreated PE patients at 5 different institutions in 4 countries completed a questionnaire consisting of 13 questions, with 3 questions specifically evaluating interest in narrative therapy. Eighty-two percent of participants were interested in narrative therapy to assist with the decision-making process surrounding PE surgery. Individuals most interested in narrative therapy tend to be more interested in correction (P < 0.05) to improve the way they feel about their body (P < 0.05). The majority of PE patients are interested in narrative therapy to aid the decision-making process about treatment. We propose that narrative therapy should be offered to PE patients during the treatment evaluation process to address the psychosocial difficulties associated with PE and the surgical decision-making process overall. Future studies should assess the effectiveness of this interdisciplinary model.


Fractionation of Magnetic Microspheres in a Microfluidic Spiral: Interplay between Magnetic and Hydrodynamic Forces.
Magnetic forces and curvature-induced hydrodynamic drag have both been studied and employed in continuous microfluidic particle separation and enrichment schemes. Here we combine the two. We investigate consequences of applying an outwardly directed magnetic force to a dilute suspension of magnetic microspheres circulating in a spiral microfluidic channel. This force is realized with an array of permanent magnets arranged to produce a magnetic field with octupolar symmetry about the spiral axis. At low flow rates particles cluster around an apparent streamline of the flow near the outer wall of the turn. At high flow rates this equilibrium is disrupted by the induced secondary (Dean) flow and a new equilibrium is established near the inner wall of the turn. A model incorporating key forces involved in establishing these equilibria is described, and is used to extract quantitative information about the magnitude of local Dean drag forces from experimental data. Steady-state fractionation of suspensions by particle size under the combined influence of magnetic and hydrodynamic forces is demonstrated. Extensions of this work could lead to new continuous microscale particle sorting and enrichment processes with improved fidelity and specificity.


Increasing the spatial and temporal impact of ecological research: A roadmap for integrating a novel terrestrial process into an Earth system model.
Terrestrial ecosystems regulate Earth's climate through water, energy, and biogeochemical transformations. Despite a key role in regulating the Earth system, terrestrial ecology has historically been underrepresented in the Earth system models (ESMs) that are used to understand and project global environmental change. Ecology and Earth system modeling must be integrated for scientists to fully comprehend the role of ecological systems in driving and responding to global change. Ecological insights can improve ESM realism and reduce process uncertainty, while ESMs offer ecologists an opportunity to broadly test ecological theory and increase the impact of their work by scaling concepts through time and space. Despite this mutualism, meaningfully integrating the two remains a persistent challenge, in part because of logistical obstacles in translating processes into mathematical formulas and identifying ways to integrate new theories and code into large, complex model structures. To help overcome this interdisciplinary challenge, we present a framework consisting of a series of interconnected stages for integrating a new ecological process or insight into an ESM. First, we highlight the multiple ways that ecological observations and modeling iteratively strengthen one another, dispelling the illusion that the ecologist's role ends with initial provision of data. Second, we show that many valuable insights, products, and theoretical developments are produced through sustained interdisciplinary collaborations between empiricists and modelers, regardless of eventual inclusion of a process in an ESM. Finally, we provide concrete actions and resources to facilitate learning and collaboration at every stage of data-model integration. This framework will create synergies that will transform our understanding of ecology within the Earth system, ultimately improving our understanding of global environmental change, and broadening the impact of ecological research.


Pandemic economics: optimal dynamic confinement under uncertainty and learning.
Most integrated models of the covid pandemic have been developed under the assumption that the policy-sensitive reproduction number is certain. The decision to exit from the lockdown has been made in most countries without knowing the reproduction number that would prevail after the deconfinement. In this paper, I explore the role of uncertainty and learning on the optimal dynamic lockdown policy. I limit the analysis to suppression strategies where the SIR dynamics can be approximated by an exponential infection decay. In the absence of uncertainty, the optimal confinement policy is to impose a constant rate of lockdown until the suppression of the virus in the population. I show that introducing uncertainty about the reproduction number of deconfined people reduces the optimal initial rate of confinement.


A Simple Overview of Pancreatic Cancer Treatment for Clinical Oncologists.
Pancreatic cancer (PDAC) is one of the most aggressive solid tumors and is showing increasing incidence. The aim of our review is to provide practical help for all clinical oncologists and to summarize the current management of PDAC using a simple "ABC method" (A-anatomical resectability, B-biological resectability and C-clinical conditions). For anatomically resectable PDAC without any high-risk factors (biological or conditional), the actual standard of care is represented by surgery followed by adjuvant chemotherapy. The remaining PDAC patients should all be treated with initial systemic therapy, though the intent for each is different: for borderline resectable patients, the intent is neoadjuvant; for locally advanced patients, the intent is conversion; and for metastatic PDAC patients, the intent remains just palliative. The actual standard of care in first-line therapy is represented by two regimens: FOLFIRINOX and gemcitabine/nab-paclitaxel. Recently, NALIRIFOX showed positive results over gemcitabine/nab-paclitaxel. There are limited data for maintenance therapy after first-line treatment, though 5-FU or FOLFIRI after initial FOLFIRINOX, and gemcitabine, after initial gemcitabine/nab-paclitaxel, might be considered. We also dedicate space to special rare conditions, such as PDAC with germline BRCA mutations, pancreatic acinar cell carcinoma and adenosquamous carcinoma of the pancreas, with few clinically relevant remarks.


A comprehensive overview of the medicinal chemistry of antifungal drugs: perspectives and promise.
The emergence of new fungal pathogens makes the development of new antifungal drugs a medical imperative that in recent years motivates the talents of numerous investigators across the world. Understanding not only the structural families of these drugs but also their biological targets provides a rational means for evaluating the merits and selectivity of new agents for fungal pathogens and normal cells. An equally important aspect of modern antifungal drug development takes a balanced look at the problems of drug potency and drug resistance. The future development of new antifungal agents will rest with those who employ synthetic and semisynthetic methodology as well as natural product isolation to tackle these problems and with those who possess a clear understanding of fungal cell architecture and drug resistance mechanisms. This review endeavors to provide an introduction to a growing and increasingly important literature, including coverage of the new developments in medicinal chemistry since 2015, and also endeavors to spark the curiosity of investigators who might enter this fascinatingly complex fungal landscape.


A comparative study of microbial diversity and community structure in marine sediments using poly(A) tailing and reverse transcription-PCR.
To obtain a better understanding of metabolically active microbial communities, we tested a molecular ecological approach using poly(A) tailing of environmental 16S rRNA, followed by full-length complementary DNA (cDNA) synthesis and sequencing to eliminate potential biases caused by mismatching of polymerase chain reaction (PCR) primer sequences. The RNA pool tested was extracted from marine sediments of the Yonaguni Knoll IV hydrothermal field in the southern Okinawa Trough. The sequences obtained using the poly(A) tailing method were compared statistically and phylogenetically with those obtained using conventional reverse transcription-PCR (RT-PCR) with published domain-specific primers. Both methods indicated that Deltaproteobacteria are predominant in sediment (>85% of the total sequence read). The poly(A) tailing method indicated that Desulfobacterales were the predominant Deltaproteobacteria, while most of the sequences in libraries constructed using RT-PCR were derived from Desulfuromonadales. This discrepancy may have been due to low coverage of Desulfobacterales by the primers used. A comparison of library diversity indices indicated that the poly(A) tailing method retrieves more phylogenetically diverse sequences from the environment. The four archaeal 16S rRNA sequences that were obtained using the poly(A) tailing method formed deeply branching lineages that were related to Candidatus "Parvarchaeum" and the ancient archaeal group. These results clearly demonstrate that poly(A) tailing followed by cDNA sequencing is a powerful and less biased molecular ecological approach for the study of metabolically active microbial communities.


Doppler imaging using spectrally-encoded endoscopy.
The capability to image tissue motion such as blood flow through an endoscope could have many applications in medicine. Spectrally encoded endoscopy (SEE) is a recently introduced technique that utilizes a single optical fiber and miniature diffractive optics to obtain endoscopic images through small diameter probes. Using spectral-domain interferometry, SEE is furthermore capable of three-dimensional volume imaging at video rates. Here we show that by measuring relative spectral phases, this technology can additionally measure Doppler shifts. Doppler SEE is demonstrated in flowing Intralipid phantoms and vibrating middle ear ossicles.


Absorption spectra and linear dichroism of some amphibian photoreceptors.
Absorption spectra and linear dichroism of dark-adapted, isolated photoreceptors of mudpuppies, larval and adult tiger salamanders, and tropical toads were measured microspectrophotometrically. Spectral half-band width, dichroic ratio, and transverse specific density were determined using averaged polarized absorptance spectra and photomicrographs of seven types of rod outer segments. Two classes of cells were found, one with higher specific density and dichroic ratio, associable with the presence of rhodopsins, the other, lower in both quantities, associable with porphyropsins. Relationships were derived to calculate the product of molar concentration and extinction coefficient (CEmax) from specific density and dichroic ratio. By utilizing the hypothesis of invariance of oscillator strengths and measured half-band widths, Emax values were independently determined, permitting the calculation of C. The pigment concentration for all cells tested was about 3.5 mM. The broadness of green rod pigment spectra is correlated with reduced molar absorptivity and reduced cellular specific density. Estimation of physiological spectral sensitivities is discussed. Based on dichroic ratio considerations, a model is proposed for the orientation of retinals in situ which could account for the apparent degree of alignment of transition moments. In the chosen orientation, the ring portion of conjugation becomes primarily responsible for axial extinction. Reduced dichroism of dehydroretinal-bearing cells can thus result from the extended ring conjugation of chromophores. Some inferences derivable from the model are discussed.


Parental preferences toward genomic sequencing for non-medically actionable conditions in children: a discrete-choice experiment.
PurposeApplication of whole-exome and whole-genome sequencing is likely to increase in clinical practice, public health contexts, and research. We investigated how parental preference for acquiring information from genome-scale testing is influenced by the characteristics of non-medically actionable genetic disorders in children, as well as whether the preferences differed by gender and between African-American and white respondents.MethodsWe conducted a Web-based discrete-choice experiment with 1,289 parents of young children. Participants completed "choice tasks" based on pairs of profiles describing sequencing results for hypothetical genetic disorders, selected the profile in each pair that they believed represented the information that would be more important to know, and answered questions that measured their level of distress.ResultsKnowing the likelihood that the disorder would develop given a true-positive test result was most important to parents. Parents showed greater interest in learning sequencing results for disease profiles with more severe manifestations. This was associated with greater distress. Differences by gender and race reflected small differences in magnitude, but not direction.ConclusionParents preferred to learn results about genetic disorders with more severe manifestations, even when this knowledge was associated with increased distress. These results may help clinicians support parental decision making by revealing which types of sequencing results parents are interested in learning.


A diverse assemblage of indole-3-acetic acid producing bacteria associate with unicellular green algae.
Microalgae have tremendous potential as a renewable feedstock for the production of liquid transportation fuels. In natural waters, the importance of physical associations and biochemical interactions between microalgae and bacteria is generally well appreciated, but the significance of these interactions to algal biofuels production have not been investigated. Here, we provide a preliminary report on the frequency of co-occurrence between indole-3-acetic acid (IAA)-producing bacteria and green algae in natural and engineered ecosystems. Growth experiments with unicellular algae, Chlorella and Scenedesmus, revealed IAA concentration-dependent responses in chlorophyll content and dry weight. Importantly, discrete concentrations of IAA resulted in cell culture synchronization, suggesting that biochemical priming of cellular metabolism could vastly improve the reliability of high density cultivation. Bacterial interactions may have an important influence on algal growth and development; thus, the preservation or engineered construction of the algal-bacterial assembly could serve as a control point for achieving low input, reliable production of algal biofuels.


Impulsivity and compulsivity as parallel mediators of emotion dysregulation in eating-related addictive-like behaviors, alcohol use, and compulsive exercise.
Transdiagnostically relevant psychological traits associated with psychiatric disorders are increasingly being researched, notably in substance use and addictive behaviors. We investigated whether emotion dysregulation mediated by impulsivity and/or compulsivity could explain variance in binge eating, food addiction, self-starvation, and compulsive exercise, as well as alcohol use (addictive-like behaviors relevant to the obesity and eating disorder fields). A general population sample of adults (N = 500, mean age = 32.5 years), females (n = 376) and males (n = 124), completed the Difficulties in Emotion Regulation Scale-16, the Trait Rash Impulsivity Scale, the Obsessive-Compulsive Inventory-Revised, the Eating Disorders Examination Questionnaire, the Self-Starvation Scale, the Exercise Dependence Scale, the Yale Food Addiction Scale, and the Alcohol Use Disorders Identification Test online. Besides gender comparisons and intercorrelations between measures, we used predefined multiple mediation models with emotion dysregulation as independent variable, impulsivity and compulsivity as parallel mediators, to investigate whether these factors contributed explanatory power to each addictive-like behavior as outcome, also using age and body mass index as covariates. Females scored higher than males on emotion dysregulation and the eating-related addictive-like behaviors food addiction, self-starvation, and binge eating. Intercorrelations between measures showed that emotion dysregulation and compulsivity were associated with all outcome variables, impulsivity with all except compulsive exercise, and the eating-related behaviors intercorrelated strongly. Mediation models showed full or partial mediation of emotion dysregulation for all behaviors, especially via compulsivity, suggesting a behavior-specific pattern. Mediation models were not affected by age or gender. Addictive-like behaviors seemed to be maintained by trait levels of emotion dysregulation, albeit channeled via trait levels of compulsivity and/or impulsivity. The role of emotion dysregulation may help us to understand why addictive-like behaviors can be difficult to change in both clinical and nonclinical groups, and may be informative for treatment-planning in patients where these behaviors are present. Our findings support adopting a more dimensional approach to psychiatric classification by focusing psychological facets such as those studied.


Effects of day length- and temperature-regulated genes on annual transcriptome dynamics in Japanese cedar (Cryptomeria japonica D. Don), a gymnosperm indeterminate species.
Seasonal phenomena in plants are primarily affected by day length and temperature. The shoot transcriptomes of trees grown in the field and a controlled-environment chamber were compared to characterize genes that control annual rhythms and the effects of day length- and temperature-regulated genes in the gymnosperm Japanese cedar (Cryptomeria japonica D. Don), which exhibits seasonally indeterminate growth. Annual transcriptome dynamics were clearly demonstrated by principal component analysis using microarray data obtained under field-grown conditions. Analysis of microarray data from trees grown in a controlled chamber identified 2,314 targets exhibiting significantly different expression patterns under short-day (SD) and long-day conditions, and 2,045 targets exhibited significantly different expression patterns at 15°C (LT; low temperature) versus 25°C. Interestingly, although growth was suppressed under both SD and LT conditions, approximately 80% of the SD- and LT-regulated targets differed, suggesting that each factor plays a unique role in the annual cycle. The top 1,000 up-regulated targets in the growth/dormant period in the field coincided with more than 50% of the SD- and LT-regulated targets, and gene co-expression network analysis of the annual transcriptome indicated a close relationship between the SD- and LT-regulated targets. These results indicate that the respective effects of day length and temperature interact to control annual transcriptome dynamics. Well-known upstream genes of signaling pathways responsive to environmental conditions, such as the core clock (LHY/CjLHYb and CCA1/CjLHYa) and PEBP family (MFT) genes, exhibited unique expression patterns in Japanese cedar compared with previous reports in other species, suggesting that these genes control differences in seasonal regulation mechanisms between species. The results of this study provide new insights into seasonal regulation of transcription in Japanese cedar.


Mental healthcare in primary and community-based settings: evidence beyond the WHO Mental Health Gap Action Programme (mhGAP) Intervention Guide.
The WHO's Mental Health Gap Action Programme Intervention Guide (mhGAP-IG) has been widely used in low and middle-income countries. We reviewed literature describing interventions and training programmes beyond the mhGAP-IG, in primary healthcare (PHC) and community-based healthcare (CBH). We searched studies excluded from our updated mhGAP-IG systematic review, and included in other relevant systematic reviews, for evidence and experience of initiatives integrating mental health into PHC and CBH. Our 24 November 2020 mhGAP-IG search encompassed MEDLINE, Embase, PsycINFO, Web of Knowledge, Scopus, CINAHL, LILACS, ScieELO, Cochrane, PubMed databases, 3ie and Google Scholar. Although heterogeneity prevented meta-analysis, we descriptively summarised the evidence-base. Out of 1827 results, we identified 208 relevant records. They described randomised controlled trials of mental health interventions (98 studies, n=55 523 participants), non-randomised studies measuring clinical outcomes (22 studies, n=7405), training outcomes (36 studies, n=12 280) and implementation outcomes (21 studies, n=1090), plus descriptive accounts (18 studies, n=2526), baseline surveys and exploratory studies (6 studies, n=17 093) and commentaries (7 studies). Most (40%) were conducted in the African region, region of the Americas (16%), and South-East Asia (13%). Randomised and non-randomised studies reported improved symptoms, substance use, functioning, parenting and child outcomes. Non-randomised studies reported improved clinical knowledge, confidence and skills following training. The literature beyond the mhGAP-IG is extensive and shares common findings. Future priorities are less-studied regions, interventions for severe mental illness, exploring ways that mhGAP-IG and alternative approaches complement each other in different contexts and scaling-up mental health integration.PROSPERO registration numberCRD42017068459.


Simultaneous and direct determination of glyphosate and AMPA in water samples from the hydroponic cultivation of eucalyptus seedlings using HPLC-ICP-MS/MS.
Glyphosate is the main herbicide currently used in the world due to wide applicability and efficiency in controlling weeds in many crops. However, its overuse may lead to undesirable impacts on the environment and to human health in the long run. This present study aimed to optimize and validate solid phase extraction (SPE) using an anionic resin for the simultaneous and direct determination of glyphosate and aminomethylphosphonic acid (AMPA) in water samples using high-performance liquid chromatography combined with inductively coupled plasma with triple quadrupole mass spectrometer (HPLC-ICP-MS/MS). The results showed that recovery percentage and relative standard deviation were 103.9 ± 7.9 and 99.40 ± 9.9% for glyphosate and AMPA, respectively. The validation certified that the method was precise, accurate, linear, and selective, with a limit of quantification of 1.09 and 0.29 μg L-1 for glyphosate and AMPA, respectively. The optimized methodology reached the concentration factor of 250 times and was successfully applied to analyze water samples from hydroponic cultivation of the eucalyptus seedlings. The results showed that the exudation process occurs at glyphosate doses starting from 2 L ha-1.


A voltage-clamp study of the effects of Joro spider toxin and zinc on excitatory synaptic transmission in CA1 pyramidal cells of the guinea pig hippocampal slice.
Using the single-electrode voltage-clamp technique, we have examined the effects of a non-N-methyl-D-aspartate (NMDA) antagonist. Joro spider toxin (JSTX), and of an NMDA antagonist, zinc, on excitatory postsynaptic currents (EPSCs) evoked by stimulation of stratum radiatum in CA1 pyramidal cells of the guinea-pig hippocampal slice. Pressure application of a synthesized JSTX (JSTX-3) at 10-200 microM greatly reduced the EPSCs (14/19 cells). The block by JSTX-3 was observed in pyramidal cells where the EPSCs showed linear peak current-voltage (I-V) relations in the control. EPSCs remaining after JSTX-3 application showed non-linear peak I-V relationships (10/14 cells), and were blocked by puff application of the selective NMDA receptor antagonist DL-2-amino-5-phosphonovalerate (APV) at 200 microM (6/10 cells). In the presence of JSTX-3, the decay time constant of the EPSC was increased and was less affected by membrane potential. JSTX-3 had no detectable effects on EPSCs apparently mediated solely by NMDA receptor. These observations suggest that JSTX-3 blocks excitatory synaptic transmission mainly by suppressing non-NMDA-receptor-mediated EPSCs, and that the JSTX-3-insensitive component is mediated at least in part by NMDA receptors in the hippocampal slice. Zinc (100-200 microM) reversibly attenuated EPSCs (6/9 cells) and appeared to block a slower component of the EPSCs, suggesting that mainly NMDA receptor-mediated currents were affected.


[The dynamics of oligophrenia from the forensic psychiatric aspect].
Clinical-catamnestic examination of patients with oligophrenia (71 subjects) who performed socially dangerous acts and were brought to the Research Institute of General and Forensic Psychiatry named after V. P. Serbskiĭ for in-patient forensic psychiatric expertise was carried out. All the individuals examined are people who at least once were recognized irresponsible with diagnosis "oligophrenia at debility level". Presence of dynamic shifts both in main symptomatology of illness and in concomitant emotional-volitional manifestations were detected; prognostic variants of disease development and social adaptation of oligophrenics were noted. Group of patients with mental deficiency, who needs introduction of "limited sanity" term was singled out.


Turkish Version of the Multidimensional Measure of Emotional Abuse: Preliminary Psychometrics in College Students.
The aim of the current study was to investigate the basic psychometrics of the Multidimensional Measure of Emotional Abuse (MMEA; Murphy & Hoover, 1999) in a Turkish sample. Two hundred and fifty-four college students participated and completed the Turkish version of the MMEA (MMEA-TR) along with the Physical Assault of Conflict Tactics Scale-Revised, Experiences in Close Relationships Inventory, Relationship Assessment Scale, and Social Desirability Questionnaire. Confirmatory factor analysis supported the four-factor structure of the MMEA-TR for both victimization and perpetration reports. This factor structure was cross-validated with an independent older sample of 328 dating college students for perpetration reports. Satisfactory criterion validity and internal consistency reliability results were obtained as well. Based on the preliminary investigation, the MMEA-TR appears to be a psychometrically sound measure of psychological dating aggression perpetration and victimization among college students in Turkey. The results, limitations, and recommendations for future studies were discussed.


Prediction of difficult laryngoscopy in obstetric patients scheduled for Caesarean delivery.
Failed intubation is an important cause of anaesthetic-related maternal mortality. The purpose of this study was to determine the ability to predict difficult visualization of the larynx from the following preoperative airway predictive indices, in isolation and combination: modified Mallampati test, the ratio of height to thyromental distance and the Upper-Lip-Bite test. We collected data on 400 consecutive parturients scheduled for elective Caesarean delivery under general anaesthesia requiring endotracheal intubation and then assessed all three factors before surgery. An experienced anaesthesiologist, not apprised of the recorded preoperative airway assessment, performed the laryngoscopy and grading (as per Cormack and Lehane's classification). Sensitivity, specificity and positive predictive value for each airway predictor in isolation and in combination were determined. Difficult laryngoscopy (Grade 3 or 4) occurred in 35 patients (8.75%). The ratio of height to thyromental distance had a higher sensitivity, positive predictive value and fewer false negatives than the other variables tested. The ratio of height to thyromental distance of 21.24 provided the best cut-off point for predicting subsequent difficult laryngoscopy. The odds ratio (95% CI) of the ratio of height to thyromental distance, Mallampati class and the Upper-Lip-Bite test were 127.8 (44.8-364.5), 49.8 (20.3-121.8) and 6.6 (2.29-19.30), respectively. The ratio of height to thyromental distance may prove a useful screening test for predicting difficult laryngoscopy in obstetric population.


Evaluation of the use of low-molecular-weight heparin in neonates: a retrospective, single-center study.
Controversies exist over the currently recommended guidelines for the use of low-molecular-weight heparin (LMWH) in neonates. We retrospectively studied 30 neonates treated with LMWH and found a poor therapeutic response to recommended doses as measured by anti-Xa levels. Sixty percent of the study participants required their doses to be increased because of subtherapeutic anti-Xa levels during the initial course of their treatment. The mean starting enoxaparin dose was 1.53 ± 0.38 mg/kg. The mean enoxaparin dose, once therapeutic anti-Xa levels had been achieved, was 1.86 ± 0.50 mg/kg. Preterm and term infants required doses of 2.06 ± 0.61 mg/kg and 1.67 ± 0.26 mg/kg, respectively, to achieve therapeutic anti-Xa levels. In summary, our results suggest that higher initial doses are required to achieve therapeutic anticoagulation in neonates.


Correlative micro-diffraction and differential phase contrast study of mean inner potential and subtle beam-specimen interaction.
We present a correlative micro-diffraction and differential phase contrast (DPC) study within scanning transmission electron microscopy (STEM) on the determination of mean inner potential (MIP) and explain the origin of subtle beam-specimen interactions at the edge of wedge-shaped crystals using both experiment and simulation. Our measurement of MIP of Si and GaAs resulted in 12.48 ± 0.22 V and 14.15 ± 0.22 V, respectively, from directly evaluating beam refraction in micro-diffraction mode. DPC-STEM measurements gave very similar values. Fresnel fringes within the diffraction disk resulting from interaction of the highly coherent electron beam with the aperture are observed and a numerical simulation scheme is implemented to reproduce the effect of the specimen on the fringe pattern. Perfect agreement between experiment and simulation has been achieved in terms of subtle displacements of the fringes upon approaching the sample edge with the electron probe. The existence of the fringes has minor effect on the DPC-STEM signal, which is well below the noise level of our setup at practically reasonable acquisition times. We suggest the possibility to perform pseudo-contactless probing of weak potential differences in beam sensitive samples by evaluating the subtle displacements of Fresnel fringes quantitatively.


The Glaucoma Laser Trial. I. Acute effects of argon laser trabeculoplasty on intraocular pressure. Glaucoma Laser Trial Research Group.
The Glaucoma Laser Trial Research Group has examined the acute effects of argon laser trabeculoplasty on immediate change in intraocular pressure and the formation of peripheral anterior synechiae among the 271 eyes assigned to argon laser trabeculoplasty as initial treatment for primary open angle glaucoma. Argon laser trabeculoplasty was administered in two sessions. Intraocular pressure rises of greater than 5 mm Hg occurred in 34% of eyes after one or both of the treatment sessions; intraocular pressure rises of greater than 10 mm Hg occurred in 12%. Eyes that had an intraocular pressure rise after the first session were more likely to have a rise after the second session than eyes with no rise after the first session. Among the many patient, eye, and treatment characteristics examined, only pigmentation of the trabecular meshwork was strongly associated with intraocular pressure rises. Forty-six percent of eyes developed greater than or equal to 1 degree of peripheral anterior synechiae. Brown iris color and posterior placement of laser burns were associated with higher rates of peripheral anterior synechiae formation.


Clinical and therapeutical follow-up of HIV-associated pulmonary hypertension: prospective study of 10 patients.
To determine the clinical course and prognosis of pulmonary hypertension (PH) in HIV-infected patients in comparison with a group of PH patients without HIV infection. The secondary objective was to ascertain whether more powerful antiretroviral treatments (highly active antiretroviral therapy) could modify the course of PH in HIV-infected patients. Patients with PH and HIV (HIV-PH, group 1) and patients without HIV (PPH, group 2) were prospectively followed. A tertiary care institution. Group 1 included 10 patients, and group 2 included 25 patients. In group 1, HIV infection was staged according to Centers for Disease Control and Prevention (CDC) classification when patients entered the study, and was re-staged every fourth month. In both groups, PH functional classes and right heart catheterization (RHC) were determined at baseline. In group 1, one of 10 patients was assigned to New York Heart Association (NYHA) class II, seven patients to NYHA class III, and two patients to NYHA class IV. CDC stages ranged from A1 (three patients) to C3 (one patient). No patient showed progression of HIV disease during follow-up. By May 2001, six patients had died. The median survival by the time of RHC was 15.1 months. Causes of death were heart failure in three cases, sepsis in two, and suicide in one case. In seven patients, epoprostenol was started; three patients survived and four died. The cause of death was heart failure in one patient, suicide in one, non-catheter-related sepsis in one patient and catheter-related sepsis in the last patient. In group 2, 11 patients out of 25 were assigned to NYHA class II, 11 patients to NYHA class III, and three patients to NYHA class IV. RHC was not statistically different in the two groups. By May 2001, nine of 25 patients died and one underwent a double-lung transplant. The median survival from the time of RHC was 6.86 months. Cumulative survival rates by RHC were not statistically different (hazard ratio close to 1). In HIV-infected patients, the onset of PH adversely affects the prognosis at any stage of infection. Clinically adverse progression of PH is not correlated with HIV initial stage and evolution. Moreover, prognosis in patients with sporadic or familial PPH and in patients with HIV-PH with similar RHC is so similar as to strengthen the concept that pulmonary vascular disease overshadows the overall clinical problem in HIV-infected patients.


Targeted antibiotic delivery using low temperature-sensitive liposomes and magnetic resonance-guided high-intensity focused ultrasound hyperthermia.
Chronic non-healing wound infections require long duration antibiotic therapy, and are associated with significant morbidity and health-care costs. Novel approaches for efficient, readily-translatable targeted and localised antimicrobial delivery are needed. The objectives of this study were to 1) develop low temperature-sensitive liposomes (LTSLs) containing an antimicrobial agent (ciprofloxacin) for induced release at mild hyperthermia (∼42 °C), 2) characterise in vitro ciprofloxacin release, and efficacy against Staphylococcus aureus plankton and biofilms, and 3) determine the feasibility of localised ciprofloxacin delivery in combination with MR-HIFU hyperthermia in a rat model. LTSLs were loaded actively with ciprofloxacin and their efficacy was determined using a disc diffusion method, MBEC biofilm device, and scanning electron microscopy (SEM). Ciprofloxacin release from LTSLs was assessed in a physiological buffer by fluorescence spectroscopy, and in vivo in a rat model using MR-HIFU. Results indicated that < 5% ciprofloxacin was released from the LTSL at body temperature (37 °C), while >95% was released at 42 °C. Precise hyperthermia exposures in the thigh of rats using MR-HIFU during intravenous (i.v.) administration of the LTSLs resulted in a four fold greater local concentration of ciprofloxacin compared to controls (free ciprofloxacin + MR-HIFU or LTSL alone). The biodistribution of ciprofloxacin in unheated tissues was fairly similar between treatment groups. Triggered release at 42 °C from LTSL achieved significantly greater S. aureus killing and induced membrane deformation and changes in biofilm matrix compared to free ciprofloxacin or LTSL at 37 °C. This technique has potential as a method to deliver high concentration antimicrobials to chronic wounds.


Body weight influences pharmacokinetics of levodopa in Parkinson's disease.
Changes in body weight may induce substantial variations in peripheral pharmacokinetics of drugs, but the relation between body weight and levodopa (LD) pharmacokinetics has never been investigated in Parkinson's disease. To address this issue, we conducted a pharmacokinetic study with 164 patients with sporadic Parkinson's disease. Patients underwent an oral acute LD test with 250 mg of LD, and pharmacokinetic variables were assessed at baseline and at 30, 60, 120, and 240 minutes after LD administration. Plasmatic-LD areas under the curve and body weight were significantly and inversely correlated as well as the elimination of the half-life of LD and body weight. In our sample, women were significantly lighter and had a significantly greater area under the curve than men. Moreover, a greater percentage of women showed LD peak-dose dyskinesias compared with men. Our findings suggest that lighter patients with Parkinson's disease probably receive a greater cumulative dosage of LD per kilogram of body weight during long-term treatment, because in clinical practice, LD is administered without any adjustment of the dose to body weight. This could explain gender differences for the development of LD-induced peak-dose dyskinesias observed during the course of the disease.


Pilot study of a novel tool for input-free automated identification of transition zone prostate tumors using T2- and diffusion-weighted signal and textural features.
To present results of a pilot study to develop software that identifies regions suspicious for prostate transition zone (TZ) tumor, free of user input. Eight patients with TZ tumors were used to develop the model by training a Naïve Bayes classifier to detect tumors based on selection of most accurate predictors among various signal and textural features on T2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC) maps. Features tested as inputs were: average signal, signal standard deviation, energy, contrast, correlation, homogeneity and entropy (all defined on T2WI); and average ADC. A forward selection scheme was used on the remaining 20% of training set supervoxels to identify important inputs. The trained model was tested on a different set of ten patients, half with TZ tumors. In training cases, the software tiled the TZ with 4 × 4-voxel "supervoxels," 80% of which were used to train the classifier. Each of 100 iterations selected T2WI energy and average ADC, which therefore were deemed the optimal model input. The two-feature model was applied blindly to the separate set of test patients, again without operator input of suspicious foci. The software correctly predicted presence or absence of TZ tumor in all test patients. Furthermore, locations of predicted tumors corresponded spatially with locations of biopsies that had confirmed their presence. Preliminary findings suggest that this tool has potential to accurately predict TZ tumor presence and location, without operator input.


Survival and mortality analysis in two nephrology centers: A prospective observational study.
The prevalence of chronic kidney disease (CKD) requiring dialysis therapy is increasing globally. Survival and mortality data of these patients in Germany are fragmentary since the nationwide registry was terminated in 2006. The objective of this study was to analyze the survival, causes of death, and co-morbidities of dialysis patients in a German population cohort as well as to assess the factors influencing mortality in these patients. We included adult, prevalent chronic dialysis patients from the German population who underwent hemodialysis and peritoneal dialysis at our centers between 2014 and 2018. We compared the characteristics of living and deceased patients and assessed survival. Patients with and without diabetes mellitus were also examined, and their co-morbidities were analyzed. Of the 425 patients included in our study (m/f: 235/190), 182 died within the observation period. Mean survival of patients with coronary artery disease (CAD) (n = 217), peripheral artery disease (PAD) (n = 128), and cardiorenal syndrome (CRS) (n = 99) was significantly reduced compared to patients without the disease (CAD: 4.2 vs. 6.4 years; PAD: 4.3 vs. 6.5 years; CRS: 3.7 vs. 7.3 years, p < 0.001, respectively). Patients with diabetes mellitus (n = 110) showed no reduced survival compared to patients without the disease (n = 315) (4.8 vs. 4.9 years, p = 0.421). Diastolic blood pressure (DBP) and C-reactive protein (CRP) levels were associated with dialysis time in linear regression analysis (DBP: R = 0.029, p < 0,001; CRP: R = 0.085, p < 0.001). Our results provide novel data regarding German CKD patients requiring dialysis and factors influencing mortality, which could serve as a useful reference for further studies.


Remote Patient Monitoring and Telemedicine in Neonatal and Pediatric Settings: Scoping Literature Review.
Telemedicine and telehealth solutions are emerging rapidly in health care and have the potential to decrease costs for insurers, providers, and patients in various settings. Pediatric populations that require specialty care are disadvantaged socially or economically or have chronic health conditions that will greatly benefit from results of studies utilizing telemedicine technologies. This paper examines the emerging trends in pediatric populations as part of a systematic literature review and provides a scoping review of the type, extent, and quantity of research available. This paper aims to examine the role of remote patient monitoring (RPM) and telemedicine in neonatal and pediatric settings. Findings can be used to identify strengths, weaknesses, and gaps in the field. The identification of gaps will allow for interventions or research to improve health care quality and costs. A systematic literature review is being conducted to gather an adequate amount of relevant research for telehealth in pediatric populations. The fields of RPM and telemedicine are not yet very well established by the health care services sector, and definitions vary across health care systems; thus, the terms are not always defined similarly throughout the literature. Three databases were scoped for information for this specific review, and 56 papers were included for review. Three major telemedicine trends emerged from the review of 45 relevant papers-RPM, teleconsultation, and monitoring patients within the hospital, but without contact-thus, decreasing the likelihood of infection or other adverse health effects. While the current telemedicine approaches show promise, limited studied conditions and small sample sizes affect generalizability, therefore, warranting further research. The information presented can inform health care providers of the most widely implemented, studied, and effective forms of telemedicine for patients and their families and the telemedicine initiatives that are most cost efficient for health systems. While the focus of this review is to summarize some telehealth applications in pediatrics, we have also presented research studies that can inform providers about the importance of data sharing of remote monitoring data between hospitals. Further reports will be developed to inform health systems as the systematic literature review continues.


Dignity and Respect: Why Therapeutic Assent Matters.
During therapeutic treatment and research in psychology and related fields, informed consent by the client or participant is required when they are over the age of 18; assent is required when a client or participant is under the age of 18 or a conserved adult. During both research and treatment, behavior analysts often work with neurodiverse individuals who have language deficits, and these clients may require unique assent procedures. This article will outline reasons behavior-analytic research and therapy require field-specific assent procedures. Furthermore, the goals of research and therapy are different and therefore assent may need to differ as well. This article will also argue that therapeutic assent during behavior-analytic treatment requires a unique set of guidelines and procedures that may differ from the behavior-analytic research.


The effect of molded and unmolded orthotics on balance and pain while jogging following inversion ankle sprain.
During this study, we examined the effects of using molded orthotics on persons who had suffered an inversion ankle sprain. We assessed standing balance with a digital balance evaluator for a group of 15 subjects who had no history of ankle sprains and for a group of nine subjects with acute ankle sprains. Then, we assessed the subjective pain experienced by ten subjects with acute ankle sprains while they jogged. During each part of the study, we tested the subjects while they were using a molded orthotic, an unmolded orthotic, and no orthotic in their shoes. We alternated the order of these treatments with each consecutive subject. The results indicate that subjects with a history of recent inversion ankle sprains had poorer balance than uninjured subjects. Molded orthotics had no effect on balance scores in the uninjured group, but their use improved balance scores in the ankle sprain group. Unmolded orthotics did not improve balance scores. Molded orthotics helped to decrease ankle pain during jogging for those with an ankle sprain, but unmolded orthotics did not. These findings suggest that molded orthotics may play a role in the treatment of inversion ankle sprains.


Prediction of the skeletal medio-lateral dimension using non-invasive anthropometric measurements for the provision of ischial containment sockets: a pilot study.
Great emphasis is placed on the skeletal medio-lateral to maintain the normal adduction of the remnant femur and to ensure coronal plane stability in an ischial containment socket. Given the invasiveness of the skeletal medio-lateral measurement, an alternative approach using prediction based on non-invasive measures would be welcomed. Determine the accuracy with which the skeletal medio-lateral dimension could be predicted using sex, stature, anterior-posterior dimension and iliofemoral angle. Cross-sectional. Anthropometric measurements on 77 persons were recorded and used as input data into a standard multiple regression. The regression model explained 59% of the variance in skeletal medio-lateral (r(2) = 0.59) that was statistically significant (F(4,72) = 25.37, p = 0.000). Only sex contributed significantly to the prediction of skeletal medio-lateral (β = 0.67, t = 6.15, p = 0.00). The degree of error associated with the regression model (sum of squared errors = 0.009) indicated that the actual skeletal medio-lateral could be predicted within ±18 mm in 95% of the cases. The regression model is not sufficiently accurate to predict skeletal medio-lateral for clinical purposes. Accuracy of the prediction could be improved with more accurate input data from computed tomography scans and use of other independent variables that explain the unique variance not already described by the participants' sex. Clinical relevance This pilot study demonstrates potential for the skeletal medio-lateral to be predicted using non-invasive anthropometric measurements. Given this proof of concept, future investigators should use more accurate input data from computed tomography scans and identify alternative independent variables that explain the variance in the skeletal medio-lateral not attributable to sex.


Spectrophotometric Study of Charge-Transfer Complexes of Ruxolitinib with Chloranilic Acid and 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone: An Application to the Development of a Green and High-Throughput Microwell Method for Quantification of Ruxolitinib in Its Pharmaceutical Formulations.
Ruxolitinib (RUX) is a potent drug that has been approved by the Food and Drug Administration for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. This study describes the formation of colored charge-transfer complexes (CTCs) of RUX, an electron donor, with chloranilic acid (CLA) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the π-electron acceptors. The CTCs were characterized using UV-visible spectrophotometry. The formation of CTCs in methanol was confirmed via formation of new absorption bands with maximum absorption at 530 and 470 nm for CTCs with CLA and DDQ, respectively. The molar absorptivity and other physicochemical and electronic properties of CTCs were determined. The molar ratio was found to be 1:1 for both CTCs with CLA and CTCs with DDQ. The site of interaction on RUX molecules was assigned and the mechanisms of the reactions were postulated. The reactions were employed as basis for the development of a novel green and one-step microwell spectrophotometric method (MW-SPM) for high-throughput quantitation of RUX. Reactions of RUX with CLA and DDQ were carried out in 96-well transparent plates, and the absorbances of the colored CTCs were measured by an absorbance microplate reader. The MW-SPM was validated according to the ICH guidelines. The limits of quantitation were 7.5 and 12.6 µg/mL for the methods involving reactions with CLA and DDQ, respectively. The method was applied with great reliability to the quantitation of RUX content in Jakavi® tablets and Opzelura® cream. The greenness of the MW-SPM was assessed by three different metric tools, and the results proved that the method fulfills the requirements of green analytical approaches. In addition, the one-step reactions and simultaneous handling of a large number of samples with micro-volumes using the proposed method enables the high-throughput analysis. In conclusion, this study describes the first MW-SPM, a valuable analytical tool for the quality control of pharmaceutical formulations of RUX.


Intelligence, income, and education as potential influences on a child's home environment: A (maternal) sibling-comparison design.
The quality of the home environment, as a predictor, is related to health, education, and emotion outcomes. However, factors influencing the quality of the home environment, as an outcome, have been understudied-particularly how children construct their own environments. Further, most previous research on family processes and outcomes has implemented between-family designs, which limit claims of causality. The present study uses kinship data from the National Longitudinal Survey of Youth to construct a maternal sibling-comparison design to investigate how maternal and child traits predict the quality of home environment. Using a standard between-family analysis, we first replicate previous research showing a relationship between maternal intelligence and the quality of the home environment. Then, we reevaluate the link between maternal intelligence and the home environment using differences between maternal sisters on several characteristics to explain differences between home environments for their children. Following, we evaluate whether child intelligence differences are related to home environment differences in the presence of maternal characteristics. Results are compared with those from the between-family analysis. Past causal interpretations are challenged by our findings, and the role of child intelligence in the construction of the home environment emerges as a critical contributor that increases in importance with development. (PsycINFO Database Record


A scale without anthropometric measurements can be used to identify low weight-for-age in children less than five years old.
Malnutrition and morbidity have a synergistic association that often leads to death. However, malnutrition in children who die is largely underreported, because anthropometry of the deceased child is rarely known. This study had two purposes: i) to develop a scale that would help determine if a child had low weight-for-age (w/a), in the absence of anthropometric measures; and ii) to select an appropriate cut-off that would give the best sensitivity (Se) and specificity (Sp) of the proposed scale when contrasted with actual w/a measurement. The study was designed as a diagnostic test, and carried out in a rural area in central Mexico. We included 132 children under 5 y old with w/a under -2 Z score and 284 children with marginal or no w/a deficit as a control group. The proposed scale included potential predictive variables from clinical, socioeconomic and family factors. The best logistic regression model to predict low w/a included: birth weight less than 2,800 g, introduction of weaning foods after the sixth month of life, introduction of animal protein after the sixth month of life, low socioeconomic status, low w/a in siblings and more than three morbidity episodes in the previous 6 mon. Selecting a cut-off of 4 for this model to identify children with low w/a showed a Se and Sp of 85 and 95%, respectively. We tested the external validity of the scale in a different locale, and included 877 children under 5 y old from 10 rural communities. In this population, the scale showed Se of 84% and Sp of 81% to identify low w/a. Based on these results, we propose that the scale be included as a means of identifying low w/a in children who have died. We believe that this should be done in verbal autopsies, which, based on our previous research, the Ministry of Health adopted as part of the regular activities to monitor problems in the disease to health-seeking to death process.


Effect of different fixative solutions on eyes with experimental proliferative vitreoretinopathy.
The aim of this study was to evaluate the use of different fixatives on the reliability of histopathological changes in a rabbit model of proliferative vitreoretinopathy (PVR). Twenty eyes from 10 rabbits were divided into four groups. The right eyes were used in two experimental groups (each n = 5), and the left, in two control groups (each n = 5). Using a newly developed scleral incision marker, an oblique scleral incision was standardized in the experimental groups, followed by intravitreal injection of 0.4 ml autologous blood and the left for wound repair for four weeks. Eyes were enucleated at four weeks. The groups differed in the type of used fixative solution (formaldehyde 4% vs. 1% buffered formaldehyde and 1.25% glutaraldehyde). The eyes were evaluated for the development of fibrosis, retinal detachment (RD), and processed for histopathology. Fibrous ingrowth of a variable degree was present in the experimental groups originating from the trauma site. Experimental eyes fixed with formaldehyde 4% had RD extension that was greater than that fixed in formaldehyde/glutaraldehyde mixture; however, the difference did not reach statistical significance (P = 0.15). This difference was not fully explained by the fibrosis which developed. In addition, in control groups, formaldehyde 4% induced a fixative-dependent retinal separation that was absent in eyes fixed with formaldehyde/glutaraldehyde mixture (P = 0.03). In conclusion, a mixture of buffered formaldehyde 1% and glutaraldehyde 1.25% combined with standardized scleral incision resulted in consistent pathological changes. A reliable PVR model is a condition sine qua non to evaluate antifibrotic treatment strategies.


Renal function status in patients with primary osteoporosis (type 2).
Several studies correlate renal function with lower bone mineral density (BMD); however, the relationship between early stages of renal dysfunction and BMD has not been clearly defined. Our objective was to determine renal function in patients with primary osteoporosis (type 2) and its relationship with BMD. Patients with primary osteoporosis diagnosed using DEXA were evaluated in this cross-sectional analysis. Renal function was estimated according to the modification of diet in renal disease (MDRD) equation and classified according to the National Kidney Foundation for chronic kidney disease (CKD). The relationship between renal function and BMD was analyzed. Included in the study were 120 women with a mean age 67.9 + or - 6.56 years. There was a positive relationship between spine BMD and moderate affection of renal function (F = 4.860, p = 0.009). No relationship was found between hip BMD or fracture with renal function (p = 0.223). Although women with poor renal function have significantly lower spine BMD, no relationship between early stages of CKD and low BMD has been demonstrated.


Left atrial anteroposterior diameter in dogs: reference interval, allometric scaling, and agreement with the left atrial-to-aortic root ratio.
Left atrial enlargement (LAE) is a well-known negative prognostic factor in dogs with myxomatous mitral valve disease (MMVD). Left atrial-to-aortic root ratio (LA/Ao) is the most commonly used method to evaluate left atrial (LA) size in dogs, while the left atrial anteroposterior diameter (LAD) has been proposed as an additional measurement of LA size in different species. The aim of this study was to establish a normal reference range of LAD normalized to body weight (LADn) in dogs using allometric scales, and to evaluate the agreement between LADn and LA/Ao in the detection of LAE in dogs with MMVD. This was a retrospective, multicenter, observational study. We included 330 healthy dogs, 30 dogs with MMVD in ACVIM stage B1, 30 dogs in ACVIM stage B2, and 30 dogs in ACVIM stage C. The reference range for the LAD, depending on body weight, was between 16.91 mm and 49.68 mm. The reference range for the LADn in healthy dogs was between 10.49 and 15.72. LADn was significantly greater in dogs with MMVD compared to healthy dogs, and a significant difference in LADn was noted between different ACVIM stages (P<0.001). The most accurate cut-off value of LADn to differentiate between dogs in groups B2 and C was 20.3 (sensitivity, 83.3%; specificity, 83.3%). There was a misclassification rate of 37% between LADn and LA/Ao in the detection of LAE in group B1. This study provides a normal reference range for LAD in dogs, which can be used as an additional tool to assess LAE in dogs with MMVD.


The unique characteristics and management of patients over 60 years of age with classic Hodgkin lymphoma.
In recent decades, the prognosis of Hodgkin lymphoma has been substantially improved, but these successes have been restricted to younger patients and could not be translated into a major benefit for older patients, especially those with advanced-stage disease. Major problems in treating older patients include a different biology, frailty, comorbidities, and poorer tolerance of therapy. Additionally, these patients are often excluded from randomized trials, so an evidence-based standard of care is lacking. Importantly, the proportion of older patients with HL will increase over the next 50 years. Currently, ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) is considered to be the gold standard, even though it has some toxicity in older patients and prospective data are not available. Thus, further studies are required, including the assessment of comorbidities and the incorporation of new drugs such as immunomodulatory agents, antibody-drug conjugates, mTOR inhibitors, or histone deacetylase (HDAC) inhibitors.


Reduction of heat loss during transurethral resection of the prostate.
A prospective trial was performed on 100 patients to determine whether using a reflective blanket (Space Blanket) and heated glycine 1.5% bladder irrigation solution would decrease the fall in body temperature associated with transurethral resection of the prostate under spinal anaesthesia. Patients who received a combination of reflective blanket and heated glycine 1.5% solution had their fall in body temperature significantly reduced when compared with those patients managed without a reflective blanket and/or heated 1.5% glycine. There was a marked decrease in the number of patients shivering and no increase in blood loss was seen when heated bladder irrigation solution was used.


Validation of the fetal alcohol spectrum disorder (FASD) 4-Digit Diagnostic Code.
The fetal alcohol spectrum disorder (FASD) 4-Digit Diagnostic Code has been used by interdisciplinary diagnostic teams worldwide for 17 years. It was created to improve the ease, accuracy, and reproducibility of diagnoses across the full spectrum of FASD. Over the years, a number of FAS/D diagnostic guidelines have been proposed. As the field of FASD moves forward, it will be important to adopt a single set of diagnostic guidelines worldwide. To achieve this, the performance (validity) of current diagnostic guidelines must be rigorously assessed and reported. To summarize the body of evidence that has amassed over 20 years that validates the performance of the FASD 4-Digit Diagnostic Code. The evidence validating the 4-Digit Code is documented across 35 studies published between 1992 and 2012, including new information presented in this report. These studies and data sources include the delineation of the FAS facial phenotype; creation of the 4-Digit Code (1997-2004); our 10-year, foster-care FAS screening program; our MRI/fMRI/MRS studies; analysis of 2,550 individuals evaluated for FASD over 20 years in the WA State FASDPN clinics, and analysis of 622 patient satisfaction/follow-up surveys; surveys of 10,000 professionals attending the University of Washington FASD diagnostic clinic trainings; and surveys of over 700 professionals worldwide who completed the 4-Digit Code Online Course. The 4-Digit Code is a simple, comprehensive, evidence-based, validated diagnostic system. It has served as the cornerstone of a fully integrated FASD screening, diagnostic, intervention, prevention, and surveillance program in Washington State for the past 20 years.


How valuable is word of mouth?
The customers who buy the most from you are probably not your best marketers. What's more, your best marketers may be worth far more to your company than your most enthusiastic consumers. Those are the conclusions of professors Kumar and Petersen at the University of Connecticut and professor Leone at Ohio State University, who analyzed thousands of customers in research focused on a telecommunications company and a financial services firm. In this article, the authors present a straightforward tool that can be used to calculate both customer lifetime value (CLV), the worth of your customers' purchases, and customer referral value (CRV), the value of their referrals. Knowing both enables you to segment your customers into four constituent parts: those that buy a lot but are poor marketers (which they term Affluents); those that don't buy much but are very strong salespeople for your firm (Advocates); those that do both well (Champions); and those that do neither well (Misers). In a series of one-year experiments, the authors demonstrated the effectiveness of this segmentation approach. Offering purchasing incentives to Advocates, referral incentives to Affluents, and both to Misers, they were able to move significant proportions of all three into the Champions category. Both companies reaped returns on their marketing investments greater than 12-fold--more than double the normal marketing ROI for their industries. The power of this tool is its ability to help marketers decide where to focus their efforts. Rather than waste funds encouraging big spenders to spend slightly more while overlooking the power of customer evangelists who don't buy enough to seem important, you can reap much higher rewards by nudging big spenders to make referrals and urging enthusiastic proponents of your wares to buy a bit more.


Quasi-planar aromatic B36 and B36(-) clusters: all-boron analogues of coronene.
Flat boron has recently emerged as a fascinating concept in cluster science. Here we present computational evidence for the quasi-planar all-boron aromatic B36 (C6v, (1)A1) and B36(-) (C2v, (2)A1) clusters, established as the global-minimum structures on the basis of Stochastic Surface Walking (SSW) searches. The energetics for low-lying isomeric structures are evaluated using the validated density-functional method at the PBE0/6-311+G* level. Our global-minimum structures are in line with a recent report (Z. A. Piazza et al., Nat. Commun., 2014, 5, 3113). These structures consist of two-dimensional close-packing boron with a perfect hexagonal hole at the center, which may serve as molecular models for the monolayer boron α sheet. Chemical bonding analysis indicates that B36 and B36(-) are all-boron analogues of coronene (C24H12), featuring concentric dual π aromaticity with an inner π sextet and an outer π sextet. The hydrogenated B36H6 (C6v, (1)A1) model cluster shows similar bonding properties, which possesses concentric triple aromaticity with inner π, outer π, and outer σ sextets.


Evidence for Exciton Crystals in a 2D Semiconductor Heterotrilayer.
Two-dimensional (2D) transition metal dichalcogenides (TMDC) and their moiré interfaces have been demonstrated for correlated electron states, including Mott insulators and electron/hole crystals commensurate with moiré superlattices. Here we present spectroscopic evidence for ordered bosons─interlayer exciton crystals in a WSe2/MoSe2/WSe2 trilayer, where the enhanced Coulomb interactions over those in heterobilayers have been predicted to result in exciton ordering. Ordered interlayer excitons in the trilayer are characterized by negligible mobility and by sharper PL peaks persisting to an exciton density of nex ∼ 1012 cm-2, which is an order of magnitude higher than the corresponding limit in the heterobilayer. We present evidence for the predicted quadrupolar exciton crystal and its transitions to dipolar excitons either with increasing nex or by an applied electric field. These ordered interlayer excitons may serve as models for the exploration of quantum phase transitions and quantum coherent phenomena.


Septic tank additive impacts on microbial populations.
Environmental health specialists, other onsite wastewater professionals, scientists, and homeowners have questioned the effectiveness of septic tank additives. This paper describes an independent, third-party, field scale, research study of the effects of three liquid bacterial septic tank additives and a control (no additive) on septic tank microbial populations. Microbial populations were measured quarterly in a field study for 12 months in 48 full-size, functioning septic tanks. Bacterial populations in the 48 septic tanks were statistically analyzed with a mixed linear model. Additive effects were assessed for three septic tank maintenance levels (low, intermediate, and high). Dunnett's t-test for tank bacteria (alpha = .05) indicated that none of the treatments were significantly different, overall, from the control at the statistical level tested. In addition, the additives had no significant effects on septic tank bacterial populations at any of the septic tank maintenance levels. Additional controlled, field-based research iswarranted, however, to address additional additives and experimental conditions.


Evolution of the structure of amorphous ice: from low-density amorphous through high-density amorphous to very high-density amorphous ice.
We report results of molecular dynamics simulations of amorphous ice for pressures up to 22.5 kbar. The high-density amorphous ice (HDA) as prepared by pressure-induced amorphization of I(h) ice at T=80 K is annealed to T=170 K at various pressures to allow for relaxation. Upon increase of pressure, relaxed amorphous ice undergoes a pronounced change of structure, ranging from the low-density amorphous ice at p=0, through a continuum of HDA states to the limiting very high-density amorphous ice (VHDA) regime above 10 kbar. The main part of the overall structural change takes place within the HDA megabasin, which includes a variety of structures with quite different local and medium-range order as well as network topology and spans a broad range of densities. The VHDA represents the limit to densification by adapting the hydrogen-bonded network topology, without creating interpenetrating networks. The connection between structure and metastability of various forms upon decompression and heating is studied and discussed. We also discuss the analogy with amorphous and crystalline silica. Finally, some conclusions concerning the relation between amorphous ice and supercooled water are drawn.


Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin.
Conformational changes are thought to underlie the activation of heterotrimeric GTP-binding protein (G protein)-coupled receptors. Such changes in rhodopsin were explored by construction of double cysteine mutants, each containing one cysteine at the cytoplasmic end of helix C and one cysteine at various positions in the cytoplasmic end of helix F. Magnetic dipolar interactions between spin labels attached to these residues revealed their proximity, and changes in their interaction upon rhodopsin light activation suggested a rigid body movement of helices relative to one another. Disulfide cross-linking of the helices prevented activation of transducin, which suggests the importance of this movement for activation of rhodopsin.


The self-trapping attractor neural network. I. Analysis of a simple 1-D model.
Attractor neural networks (ANNs) based on the Ising model are naturally fully connected and are homogeneous in structure. These features permit a deep understanding of the underlying mechanism, but limit the applicability of these models to the brain. A more biologically realistic model can be derived from an equally simple physical model by utilizing recurrent self-trapping inputs to supplement very sparse intranetwork interactions. This paper reports the analysis of a one-dimensional (1-D) ANN coupled to a second system that computes overlaps with a single stored memory. Results show that: 1) the 1-D self-trapping model is equivalent to an isolated ANN with both full connectivity of one strength and nearest neighbor synapses of an independent strength; 2) the dynamics of ANN and self-trapping updates are independent; 3) there is a critical synaptic noise level below which memory retrieval occurs; 4) the 1-D self-trapping model converges to a fully connected Hopfield model for zero strength nearest neighbor synapses, and has a greater magnitude memory overlap for nonzero strength nearest neighbor synapses; and (5) the mechanism of self-trapping is an iterative map on the mean overlap as a function of the reentrant input.


Detection of differences in oligonucleotide-influenced aggregation of colloidal gold nanoparticles using absorption spectroscopy.
A rapid, simple, and reproducible assay is described that can be used to detect differences in the ability of oligonucleotides to influence the aggregation of colloidal gold nanoparticles. The aggregation reaction of the gold colloid was monitored through UV-visible absorption spectroscopy. Single isolated colloidal gold particles have a surface plasmon resonance manifested as a single absorbance peak at approximately 520 nm, and aggregated gold complexes develop new red-shifted peaks/shoulders depending on the nature and extent of the aggregated complex. A simple ratiometric study of the area under the single and aggregated plasmon resonance peaks thus gives information about the extent of the aggregation. It is postulated that differences in dynamic flexibility of the oligonucleotides affect their influence on the aggregation state of the gold nanoparticles. The results of this study provide new clues toward unraveling the causes behind the preferential affinity of the Hermes transposable element for certain insertion sites compared to other sequences that also contain recognizable target sites. The technique is robust and thus can potentially be used to study similar questions for numerous transposable elements and target sequences.