Electroacoustic absorbers: bridging the gap between shunt loudspeakers and active sound absorption.
The acoustic impedance at the diaphragm of an electroacoustic transducer can be varied using a range of basic electrical control strategies, amongst which are electrical shunt circuits. These passive shunt techniques are compared to active acoustic feedback techniques for controlling the acoustic impedance of an electroacoustic transducer. The formulation of feedback-based acoustic impedance control reveals formal analogies with shunt strategies, and highlights an original method for synthesizing electric networks ("shunts") with positive or negative components, bridging the gap between passive and active acoustic impedance control. This paper describes the theory unifying all these passive and active acoustic impedance control strategies, introducing the concept of electroacoustic absorbers. The equivalence between shunts and active control is first formalized through the introduction of a one-degree-of-freedom acoustic resonator accounting for both electric shunts and acoustic feedbacks. Conversely, electric networks mimicking the performances of active feedback techniques are introduced, identifying shunts with active impedance control. Simulated acoustic performances are presented, with an emphasis on formal analogies between the different control techniques. Examples of electric shunts are proposed for active sound absorption. Experimental assessments are then presented, and the paper concludes with a general discussion on the concept and potential improvements.


Changes in the renin-angiotensin-aldosterone system and in sodium and potassium balance during development of renal hypertension in rats.
1. The relationships between the renin-angiotensin-aldosterone system, sodium and potassium balance and systolic blood pressure were studied during development of moderate (160-180 mmHg; clip i.d. 0.25 mm) and severe (200-230 mmHg; clip i.d. 0.20 mm) renal hypertension in rats with an undisturbed contralateral kidney. 2. In severely hypertensive rats renin activity in the peripheral plasma increased from day 9, by which time the systolic blood pressure was elevated to 160-180 mmHg. The rate of total corticosteroid and aldosterone production in vitro increased from day 14 and plasma renin substrate concentration increased from day 24. In moderately hypertensive rats, none of these changes occurred. 3. During the first 10 days after the application of 0.25 and 0.20 mm clips, sodium and potassium retention/g gain in body weight were higher than in sham-operated controls. During the next 10 days, the positive balance stabilized in animals with a 0.25 mm clip whereas, in animals with a 0.20 mm clip, sodium and potassium balance returned to the level of the sham-operated controls through increased renal losses. Despite these changes the systolic pressure rose further in animals with a 0.20 mm clip. 4. The initial sodium retention could be a factor in the early rise of blood pressure and could account for the delay in the rise of peripheral plasma renin activity. The subsequent loss of the retained sodium and potassium during the development of severe hypertension could have facilitated the rise in peripheral plasma renin activity, but did not initiate this rise.


Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: a randomized, double-blind, placebo-controlled trial.
Therapies for breast cancer may induce hot flashes that can affect quality of life. We undertook a double-blind, placebo-controlled trial with the primary objective of comparing the average daily hot flash scores in the twelfth week among patients treated with venlafaxine, clonidine, and placebo. Additional analyses of the hot flash score over the full 12 weeks of treatment were performed. In all, 102 patients with a history of breast cancer were randomly assigned (2:2:1) to venlafaxine 75 mg, clonidine 0.1 mg, or placebo daily for 12 weeks. Questionnaires at baseline and during treatment assessed daily hot flash scores, sexual function, sleep quality, anxiety, and depression. After 12 weeks, a total of 80 patients were evaluable for the primary end point. During week 12, hot flash scores were significantly lower in the clonidine group versus placebo (P = .03); for venlafaxine versus placebo, the difference was borderline not significant (P = .07). However, hot flash scores were equal in the clonidine and venlafaxine groups. Over the course of 12 weeks, the differences between both treatments and placebo were significant (P <.001 for venlafaxine v placebo; P = .045 for clonidine v placebo). Frequencies of treatment-related adverse effects of nausea (P = .02), constipation (P = .04), and severe appetite loss were higher in the venlafaxine group. Venlafaxine and clonidine are effective treatments in the management of hot flashes in patients with breast cancer. Venlafaxine resulted in a more immediate reduction of hot flash scores when compared with clonidine; however, hot flash scores at week 12 were lower in the clonidine group than in the venlafaxine group.


Complete genome sequence of the obligate piezophilic hyperthermophilic archaeon Pyrococcus yayanosii CH1.
Pyrococcus yayanosii CH1 is the first obligate piezophilic hyperthermophilic archaeon isolated from the deep-sea hydrothermal site Ashadze on the mid-Atlantic ridge at a depth of 4,100 m. This organism grows within a temperature range of 80 to 108°C and a hydrostatic pressure range of 20 to 120 MPa, with optima at 98°C and 52 MPa, respectively. Here, we report the complete genome sequence (1,716,817 bp, with a G+C content of 51.6%) of the type strain P. yayanosii CH1(T) (= JCM 16557). This genomic information reveals a systematic view of the piezoadaptation strategy and evolution scenario of metabolic pathways in Thermococcales.


Holding the baby: head downwards positioning for physiotherapy does not cause gastro-oesophageal reflux.
The head-downwards tipped position for physiotherapy has been claimed to exacerbate gastro-oesophageal reflux (GOR) in infants with cystic fibrosis (CF). This was investigated using lower oesophageal pH monitoring during physiotherapy. Twenty-one infants (age range 1-27 months) with respiratory disorders (CF=11), undergoing lower oesophageal pH monitoring were recruited. Subjects received two physiotherapy episodes in random order, A/B or B/A, 12 h apart. A began the gravity-assisted positioning head downward tip for: right lower lobe, middle lobe, left lower lobe and lingula; then supine with no tip for anterior segments of the upper lobes followed by apical segments of upper lobes in a sitting position. B was in the reverse order. Intermittent chest clapping was carried out for 4 min in each position by a physiotherapist blinded to the pH data. During episode A, the median change in pH from baseline was -0.32 (range -2.07 to +1.0) in non-CF subjects (NS) and -0.52 (range -2.7 to +0.52) in CF subjects (p<0.02). During episode B, the median change in non-CF subjects was -0.1 (NS; range - 1.7 to -0.15) and in CF subjects was -0.05 (NS; range -0.67 to +0.5). There was no order effect for positioning. In the CF subjects the sitting position was twice as likely to have the lowest pH measurement during physiotherapy than the other positions (p<0.04). In conclusion, the head-downward tipped positioning for physiotherapy treatment neither induces nor aggravates gastro-oesophageal reflux. There is no justification for routinely changing the way in which infant physiotherapy is carried out.


gamma/delta T lymphocytes express CD40 ligand and induce isotype switching in B lymphocytes.
T cells expressing gamma/delta T cell receptors home to epithelial tissue and may play a role in immunity to infectious agents and foreign antigens. In an effort to understand the role of gamma/delta T cells in directing B cell responses, we investigated the capacity of human gamma/delta T cells to express CD40 ligand (CD40L) and to drive immunoglobulin (Ig) isotype switching in B cells. A multiple step purification procedure resulted in the recovery of highly pure populations of peripheral blood CD4-CD8- gamma/delta T cells. Neither CD40L surface expression nor CD40L mRNA were detected in unstimulated gamma/delta T cells. Stimulation with phorbol ester and ionomycin induced CD40L mRNA and surface CD40L expression by gamma/delta T cells. Both the percentage of CD40L+ cells and the cell surface density of CD40L were significantly lower in gamma/delta T cells compared to unselected T cells. We further demonstrated that in the presence of neutralizing monoclonal antibody to interferon gamma (IFN-gamma), gamma/delta T cells could induce IgE synthesis in B cells, albeit to a lesser extent than unselected T cells. Furthermore, IgE synthesis driven by gamma/delta T cells was inhibited by monoclonal antibody to CD40L. These observations demonstrate that activated gamma/delta T cells express CD40L and can induce isotype switching in B cells.


Effects of spaceflight on rat peripheral blood leukocytes and bone marrow progenitor cells.
The white blood cell (WBC) elements and the bone marrow myeloid progenitor cell populations were analyzed to ascertain adaptation to micro-gravity and subsequent readaptation to 1 G in rats flown on the 14-day Spacelab Life Sciences-2 (SLS-2) mission. Bone marrow cells were harvested from one group of rats killed inflight (FD13) and blood was drawn from three other groups at various times. The WBC level was normal on FD14 with the exception of neutrophilia. On FD13, numbers of colony-forming units-granulocyte (CFU-G), CFU-GM, and CFU-M from flight animals were decreased compared with ground controls when incubated with recombinant rat interleukin-3 (rrIL-3) alone or in combination with recombinant human erythropoietin (rhEpo). On recovery (R + 0), flight rats had decreased numbers of total leukocytes and absolute numbers of lymphocytes and monocytes with elevated neutrophils compared with control rats. They had lower numbers of CD4, CD8, CD2, CD3, and B cells in the peripheral blood but no differences in spleen lymphocytes.


Rapid Onset of the Effects of Combined Selective Serotonin Reuptake Inhibitors and Electroacupuncture on Primary Depression: A Meta-Analysis.
To evaluate the efficacy and safety of combined selective serotonin reuptake inhibitors (SSRIs) and electroacupuncture therapies for the early treatment of primary depression. Randomized controlled trials (RCTs) were analyzed to compare therapy combining SSRIs and electroacupuncture to SSRI therapy alone. The RCTs were identified by searching, among others, PubMed, the Cochrane Library, the Chinese National Knowledge Infrastructure, the Chongqing VIP database for Chinese Technical Periodicals, WANFANG DATA, and the Chinese Biological Medical Literature Database. Scores from Self-Rated Depression Scale (SDS), the Hamilton Depression Scale (HAMD), the Side Effect Rating Scale (SERS), and the Treatment Emergent Symptom Scale (TESS) were analyzed and coded by two independent investigators and used to evaluate the safety and efficacy of treatment. Statistical analyses were performed using RevMan 5.2 software. Six RCTs were analyzed. The meta-analysis revealed that the combined therapy of SSRIs and electroacupuncture were associated with superior scores on the HAMD, SDS, and SERS measures compared with SSRIs alone after 1-4 weeks of treatment: HAMD scores, mean difference (MD)(1 week), 2.32 (95% confidence interval [CI](1 week), 1.47-3.16, p(1 week)<0.00001); MD(2 weeks), 2.65 (95% CI(2 weeks), 1.81- 3.50, p(2 weeks)<0.00001); MD(4 weeks), 2.70 (95% CI(4 weeks), 1.90-3.51, p(4 weeks)<0.00001); SDS scores: MD(1 week), 3.13 (95% CI(1 week), 1.22-5.03, p(1 week) = 0.001); MD(2 weeks), 4.05 (95% CI(2 weeks), 0.22-7.87, p(2 weeks) = 0.04); MD(4 weeks), 5.02 (95% CI(4 weeks), 1.61-8.43, p(4 weeks) = 0.004); SERS scores: MD(2 weeks), 2.20 (95% CI(2 weeks), 1.43-2.96, p(2 weeks)<0.00001); MD(4 weeks), 2.12 (95% CI(4 weeks), 1.42-2.83, p(4 weeks)<0.00001). However, two of the aforementioned outcomes were rated as medium quality because of heterogeneity, as assessed using the Grading of Recommendations Assessment, Development and Evaluation system. The available evidence suggests that the early treatment of primary depression using both SSRI and electroacupuncture therapies is more efficient than treatments with SSRIs alone and leads to a better and earlier control of depressive symptoms.


A light-up fluorescence assay for tumor cell detection based on bifunctional split aptamers.
Light-up aptamers have attracted growing attention due to their advantages of being label-free and having low fluorescence background. In this work, we developed a light-up fluorescence assay for label-free detection of tumor cells based on a bifunctional split aptamer (BFSA) that contained two DNA strands (BFSA-a and BFSA-b). BFSA-a and BFSA-b were constructed by combining aptamers ZY11 and ThT.2-2, which could specifically bind to the tumor cell SMMC-7721 and activate the fluorescence of thioflavin T (ThT). A Helper strand was introduced to hybridize with BFSA-b, and then BFSA-a and BFSA-b were separated if the target cell was absent. Only when the target cell is present can BFSA-a approach and hybridize with BFSA-b due to the 'induced-fit effect', which made the Helper strand dissociate. Then ThT bound to BFSA and the fluorescence of ThT was activated. The results indicated that this fluorescence assay had a good linear response to the target cells in the range of 250-20 000 cells in 100 μL binding buffer; the lowest cell number actually detected was 125 cells in 100 μL buffer. This assay also displayed excellent selectivity and was successfully applied to detect target cells in 20% human serum samples. The design of bifunctional split aptamers realized no-washing, label-free, low-cost, one-step detection of tumor cells, which could generate detectable fluorescence signals just by mixing nucleic acid aptamers and fluorescent reporter molecules with target cells. Such a design of aptamer probes also has the potential to construct stimuli-responsive controlled drug delivery systems.


Early-life gut microbiome composition and milk allergy resolution.
Gut microbiota may play a role in the natural history of cow's milk allergy. We sought to examine the association between early-life gut microbiota and the resolution of cow's milk allergy. We studied 226 children with milk allergy who were enrolled at infancy in the Consortium of Food Allergy observational study of food allergy. Fecal samples were collected at age 3 to 16 months, and the children were followed longitudinally with clinical evaluation, milk-specific IgE levels, and milk skin prick test performed at enrollment, 6 months, 12 months, and yearly thereafter up until age 8 years. Gut microbiome was profiled by 16s rRNA sequencing and microbiome analyses performed using Quantitative Insights into Microbial Ecology (QIIME), Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), and Statistical Analysis of Metagenomic Profiles (STAMP). Milk allergy resolved by age 8 years in 128 (56.6%) of the 226 children. Gut microbiome composition at age 3 to 6 months was associated with milk allergy resolution by age 8 years (PERMANOVA P = .047), with enrichment of Clostridia and Firmicutes in the infant gut microbiome of subjects whose milk allergy resolved. Metagenome functional prediction supported decreased fatty acid metabolism in the gut microbiome of subjects whose milk allergy resolved (η2 = 0.43; ANOVA P = .034). Early infancy is a window during which gut microbiota may shape food allergy outcomes in childhood. Bacterial taxa within Clostridia and Firmicutes could be studied as probiotic candidates for milk allergy therapy.


Antibodies against the envelope glycoprotein promote infectivity of immature dengue virus serotype 2.
Cross-reactive dengue virus (DENV) antibodies directed against the envelope (E) and precursor membrane (prM) proteins are believed to contribute to the development of severe dengue disease by facilitating antibody-dependent enhancement of infection. We and others recently demonstrated that anti-prM antibodies render essentially non-infectious immature DENV infectious in Fcγ-receptor-expressing cells. Immature DENV particles are abundantly present in standard (st) virus preparations due to inefficient processing of prM to M during virus maturation. Structural analysis has revealed that the E protein is exposed in immature particles and this prompted us to investigate whether antibodies to E render immature particles infectious. To this end, we analyzed the enhancing properties of 27 anti-E antibodies directed against distinct structural domains. Of these, 23 bound to immature particles, and 15 enhanced infectivity of immature DENV in a furin-dependent manner. The significance of these findings was subsequently tested in vivo using the well-established West Nile virus (WNV) mouse model. Remarkably, mice injected with immature WNV opsonized with anti-E mAbs or immune serum produced a lethal infection in a dose-dependent manner, whereas in the absence of antibody immature WNV virions caused no morbidity or mortality. Furthermore, enhancement infection studies with standard (st) DENV preparations opsonized with anti-E mAbs in the presence or absence of furin inhibitor revealed that prM-containing particles present within st virus preparations contribute to antibody-dependent enhancement of infection. Taken together, our results support the notion that antibodies against the structural proteins prM and E both can promote pathogenesis by enhancing infectivity of prM-containing immature and partially mature flavivirus particles.


Identification of novel pathogenic copy number aberrations in multiple myeloma: the Malaysian context.
Multiple myeloma is an incurable disease. Little is known about the genetic and molecular mechanisms governing the pathogenesis of multiple myeloma. The risk of multiple myeloma predispositions varies among different ethnicities. More than 50% of myeloma cases showed normal karyotypes with conventional cytogenetic analysis due to the low mitotic activity and content of plasma cells in the bone marrow. In the present study, high resolution array comparative genomic hybridization technique was used to identify copy number aberrations in 63 multiple myeloma patients of Malaysia. Copy number aberrations were identified in 100% of patients analyzed (n = 63). Common chromosomal gains were detected at regions 1q, 2q, 3p, 3q, 4q, 5q, 6q, 8q, 9q, 10q, 11q, 13q, 14q, 15q, 21q and Xq while common chromosomal losses were identified at regions 3q and 14q. There were a total of 25 and 5 genes localized within the regions of copy number gains and losses, respectively (>30% penetrance). The LYST, CLK1, ACSL1 and NFKBIA are genes localized within the copy number aberration regions and they represent novel information that has never been previously described in multiple myeloma patients. In general, due to the differences in genetic background, dietary and lifestyle practices of Malaysian compared to the Caucasian population, these chromosomal alterations might be unique for Asian MM patients. Genes identified in this study could be potential molecular therapeutic targets for the treatment and management of patients with multiple myeloma.


Lengthening of the G1 phase is not strictly correlated with differentiation in Friend erythroleukemia cells.
Friend murine erythroleukemia cells (Friend cells) undergo erythroid differentiation in vitro with an increased probability when cells are cultured in the presence of dimethyl sulfoxide (Me2SO) or other agents. Exponentially growing Friend cells, after dilution into medium containing Me2SO, underwent a transient lengthening of the G1 phase of the cell cycle before they became committed to erythroid differentiation. For nine inducing agents, a positive correlation was found between the percentage of cells that had differentiated and synthesized heme, and the percentage of progenitor cells in which a lengthened G1 phase had previously been observed. This correlation was not found, however, with two other potent inducing agents, hypoxanthine and actinomycin D. Moreover, cells that underwent a lengthened G1 phase did not always terminally differentiate. One such example was a Me2SO-resistant, variant Friend cell line (520a) grown in the presence of Me2SO. These results imply that the prolonged G1 phase, although observed with many inducers, is not a prerequisite for erythroid differentiation with all inducers.


Post-Movement Beta Activity in Sensorimotor Cortex Indexes Confidence in the Estimations from Internal Models.
Beta oscillations are a dominant feature of the sensorimotor system. A transient and prominent increase in beta oscillations is consistently observed across the sensorimotor cortical-basal ganglia network after cessation of voluntary movement: the post-movement beta synchronization (PMBS). Current theories about the function of the PMBS have been focused on either the closure of motor response or the processing of sensory afferance. Computational models of sensorimotor control have emphasized the importance of the integration between feedforward estimation and sensory feedback, and therefore the putative motor and sensory functions of beta oscillations may reciprocally interact with each other and in fact be indissociable. Here we show that the amplitude of sensorimotor PMBS is modulated by the history of visual feedback of task-relevant errors, and negatively correlated with the trial-to-trial exploratory adjustment in a sensorimotor adaptation task in young healthy human subjects. The PMBS also negatively correlated with the uncertainty associated with the feedforward estimation, which was recursively updated in light of new sensory feedback, as identified by a Bayesian learning model. These results reconcile the two opposing motor and sensory views of the function of PMBS, and suggest a unifying theory in which PMBS indexes the confidence in internal feedforward estimation in Bayesian sensorimotor integration. Its amplitude simultaneously reflects cortical sensory processing and signals the need for maintenance or adaptation of the motor output, and if necessary, exploration to identify an altered sensorimotor transformation. For optimal sensorimotor control, sensory feedback and feedforward estimation of a movement's sensory consequences should be weighted by the inverse of their corresponding uncertainties, which require recursive updating in a dynamic environment. We show that post-movement beta activity (13-30 Hz) over sensorimotor cortex in young healthy subjects indexes the evaluation of uncertainty in feedforward estimation. Our work contributes to the understanding of the function of beta oscillations in sensorimotor control, and provides further insight into how aberrant beta activity can contribute to the pathophysiology of movement disorders.


Metastasis of malignant peritoneal epithelioid mesothelioma in endoscopic gastric biopsy: a diagnostic pitfall.
To describe a case of metastasis of malignant peritoneal epithelioid mesothelioma in gastric antral mucosa in a patient with a cryptogenic liver cirrhosis associated with esophageal varices, abdominal pain and distension, ascites, and weight loss. The patient underwent esophageal gastric endoscopy for varices, and a biopsy of a polypoid antral lesion was performed. The latter revealed a proliferation of polygonal cells with moderately atypical nuclei and pale eosinophilic, peripherally condensed cytoplasm infiltrating into the lamina propria between the normal mucosal glands of the antrum. The tumor cells were diffusely positive to anticalretinin antibody, whereas anti-claudin 4 and anti-CEA antisera were negative. Metastases of malignant peritoneal mesotheliomas are unusual, and a predominantly gastrointestinal localization is rare. Pathologists should be aware of this possibility to avoid misdiagnosis, particularly in small biopsy specimens.


Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome.
The benefits of early continuous neuromuscular blockade in patients with acute respiratory distress syndrome (ARDS) who are receiving mechanical ventilation remain unclear. We randomly assigned patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg with a positive end-expiratory pressure [PEEP] of ≥8 cm of water) to a 48-hour continuous infusion of cisatracurium with concomitant deep sedation (intervention group) or to a usual-care approach without routine neuromuscular blockade and with lighter sedation targets (control group). The same mechanical-ventilation strategies were used in both groups, including a strategy involving a high PEEP. The primary end point was in-hospital death from any cause at 90 days. The trial was stopped at the second interim analysis for futility. We enrolled 1006 patients early after the onset of moderate-to-severe ARDS (median, 7.6 hours after onset). During the first 48 hours after randomization, 488 of the 501 patients (97.4%) in the intervention group started a continuous infusion of cisatracurium (median duration of infusion, 47.8 hours; median dose, 1807 mg), and 86 of the 505 patients (17.0%) in the control group received a neuromuscular blocking agent (median dose, 38 mg). At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between-group difference, -0.3 percentage points; 95% confidence interval, -6.4 to 5.9; P = 0.93). While in the hospital, patients in the intervention group were less physically active and had more adverse cardiovascular events than patients in the control group. There were no consistent between-group differences in end points assessed at 3, 6, and 12 months. Among patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets. (Funded by the National Heart, Lung, and Blood Institute; ROSE ClinicalTrials.gov number, NCT02509078.).


[GRADE: Evidence to Decision (EtD) framework for coverage decisions].
Coverage decisions are decisions by third party payers about whether and how much to pay for technologies or services, and under what conditions. Given their complexity, a systematic and transparent approach is needed. The DECIDE project, a GRADE working group initiative funded by the European Union, has developed GRADE Evidence to Decision (EtD) frameworks for different types of decisions, including coverage ones. We used an iterative approach, including brainstorming to generate ideas, consultation with stakeholders, user testing, and pilot testing of the framework. The general structure of the EtD includes formulation of the question, an assessment using 12 criteria, and conclusions. Criteria that are relevant for coverage decisions are similar to those for clinical recommendations from a population perspective. Important differences between the two include the decision-making processes, accountability, and the nature of the judgments that need to be made for some criteria. Although cost-effectiveness is a key consideration when making coverage decisions, it may not be the determining factor. Strength of recommendation is not directly linked to the type of coverage decisions, but when there are important uncertainties, it may be possible to cover an intervention for a subgroup, in the context of research, with price negotiation, or with restrictions. The EtD provides a systematic and transparent approach for making coverage decisions. It helps ensure consideration of key criteria that determine whether a technology or service should be covered and that judgments are informed by the best available evidence.


Signaling effects of sodium hydrosulfide in healthy donor peripheral blood mononuclear cells.
Hydrogen sulfide (H2S) is an endogenous gasotransmitter in human physiology and inflammatory disease, however, with limited knowledge of how signal transduction pathways are involved in immune cells. To examine the effects of sulfide on relevant intracellular signaling in human peripheral blood mononuclear cells (PBMCs), we stimulated healthy donor PBMCs with sodium hydrosulfide (NaHS, 1-1000μM) to mimic H2S stimulation, and analyzed phosphorylation of p38 mitogen activated protein kinase (MAPK) (pT180/pY182), NF-κB p65 (pS529), Akt (pS473) and CREB/ATF1 (pS133/pS63) with flow and mass cytometry. In contrast to transient effects in subsets of lymphocytes, classical monocytes demonstrated sustained phosphorylation of p38, Akt and CREB/ATF1. NaHS induced calcium dependent phosphorylation of p38, Akt and CREB, but not NF-κB, and the phosphorylation of Akt was partly dependent on p38, indicative of p38-Akt crosstalk. Attenuation of these effects by molecules targeting p38 and Hsp90 indicated Hsp90 as a possible target for H2S-induced activation of p38. These results provide a description of a NaHS-induced signal transduction pathway in human primary immune cells that may have relevance for the role of sulfides in inflammation.


Leprosy perceptions and knowledge in endemic districts in India and Indonesia: Differences and commonalities.
Understanding how knowledge, attitudes and practices regarding leprosy differ in endemic countries can help us develop targeted educational and behavioural change interventions. This study aimed to examine the differences and commonalities in and determinants of knowledge, attitudes, practices and fears regarding leprosy in endemic districts in India and Indonesia. A cross-sectional mixed-methods design was used. Persons affected by leprosy, their close contacts, community members and health workers were included. Through interview-administered questionnaires we assessed knowledge, attitudes, practices and fears with the KAP measure, EMIC-CSS and SDS. In addition, semi-structured interviews and focus group discussions were conducted. The quantitative data were analysed using stepwise multivariate regression. Determinants of knowledge and stigma that were examined included age, gender, participant type, education, occupation, knowing someone affected by leprosy and district. The qualitative data were analysed using open, inductive coding and content analysis. We administered questionnaires to 2344 participants (46% from India, 54% from Indonesia) as an interview. In addition, 110 participants were interviewed in-depth and 60 participants were included in focus group discussions. Knowledge levels were low in both countries: 88% of the participants in India and 90% of the participants in Indonesia had inadequate knowledge of leprosy. In both countries, cause, mode of transmission, early symptoms and contagiousness of leprosy was least known, and treatment and treatability of leprosy was best known. In both countries, health workers had the highest leprosy knowledge levels and community members the highest stigma levels (a mean score of up to 17.4 on the EMIC-CSS and 9.1 on the SDS). Data from the interviews indicated that people were afraid of being infected by leprosy. Local beliefs and misconceptions differed, for instance that leprosy is in the family for seven generations (Indonesia) or that leprosy is a result of karma (India). The determinants of leprosy knowledge and stigma explained 10-29% of the variability in level of knowledge and 3-10% of the variability in level of stigma. Our findings show the importance of investigating the perceptions regarding leprosy prior to educational interventions in communities: even though knowledge levels were similar, local beliefs and misconceptions differed per setting. The potential determinants we included in our study explained very little of the variability in level of knowledge and stigma and should be explored further. Detailed knowledge of local knowledge gaps, beliefs and fears can help tailor health education to local circumstances.


Ensuring clinical utility and function in a large scale national project in Australia by embedding clinical informatics into design.
Across the globe, healthcare delivery is being transformed by electronic sharing of health information. Such large scale health projects with a national focus are a challenge to design and implement. Delivering clinical outcomes in the context of policy, technical, and design environments represents a particular challenge. On July 1, 2012, Australia delivered the first stage of a personally controlled electronic health record - a national program for sharing a variety of health information between health professionals and between health professionals and consumers. As build of the system commenced, deficiencies of the traditional stakeholder consultation model were identified and replaced by a more structured approach, called clinical functional assurance. Utilising clinical scenarios linked to detailed design requirements, a team of clinicians certified clinical utility at implementation and release points.


Spatial patterns of close relationships across the lifespan.
The dynamics of close relationships is important for understanding the migration patterns of individual life-courses. The bottom-up approach to this subject by social scientists has been limited by sample size, while the more recent top-down approach using large-scale datasets suffers from a lack of detail about the human individuals. We incorporate the geographic and demographic information of millions of mobile phone users with their communication patterns to study the dynamics of close relationships and its effect in their life-course migration. We demonstrate how the close age- and sex-biased dyadic relationships are correlated with the geographic proximity of the pair of individuals, e.g., young couples tend to live further from each other than old couples. In addition, we find that emotionally closer pairs are living geographically closer to each other. These findings imply that the life-course framework is crucial for understanding the complex dynamics of close relationships and their effect on the migration patterns of human individuals.


Ginsenoside Rg3 enhances radiosensitization of hypoxic oesophageal cancer cell lines through vascular endothelial growth factor and hypoxia inducible factor 1α.
To determine if the pretreatment of hypoxic human oesophageal carcinoma cell lines (EC109, TE1 and KYSE170) with ginsenoside Rg3 (Rg3) increases their radiosensitivity to X-rays. The growth inhibitory effect of different Rg3 concentrations was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. Radiation sensitivity was measured using a clone formation assay and flow cytometry was used to measure the effects of Rg3 on radiation-induced apoptosis. Western blot analysis was used to measure the effects of Rg3 on the levels of hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). Rg3 inhibited EC109, TE1 and KYSE170 cell growth in a dose- and time-dependent manner. Pretreatment with 10 µmol/ml Rg3 increased EC109, TE1 and KYSE170 radiosensitivity. Rg3 plus radiation significantly increased the apoptosis rate compared with radiation alone. Rg3 also decreased VEGF and HIF-1α protein levels in EC109 cells in a dose-dependent manner. The combination of Rg3 and radiation increased the fragmentation of double-stranded DNA. Rg3 enhanced the radiosensitivity of human oesophageal carcinoma cell lines cultured under hypoxic conditions possibly by downregulating VEGF and HIF-1α protein levels.


Did the strategy of skilled attendance at birth reach the poor in Indonesia?
To assess whether the strategy of "a midwife in every village" in Indonesia achieved its aim of increasing professional delivery care for the poorest women. Using pooled Demographic and Health Surveys (DHS) data from 1986-2002, we examined trends in the percentage of births attended by a health professional and deliveries via caesarean section. We tested for effects of the economic crisis of 1997, which had a negative impact on Indonesias health system. We used logistic regression, allowing for time-trend interactions with wealth quintile and urban/rural residence. There was no change in rates of professional attendance or caesarean section before the programmes full implementation (1986-1991). After 1991, the greatest increases in professional attendance occurred among the poorest two quintiles -- 11% per year compared with 6% per year for women in the middle quintile (P = 0.02). These patterns persisted after the economic crisis had ended. In contrast, most of the increase in rates of caesarean section occurred among women in the wealthiest quintile. Rates of caesarean deliveries remained at less than 1% for the poorest two-fifths of the population, but rose to 10% for the wealthiest fifth. The Indonesian village midwife programme dramatically reduced socioeconomic inequalities in professional attendance at birth, but the gap in access to potentially life-saving emergency obstetric care widened. This underscores the importance of understanding the barriers to accessing emergency obstetric care and of the ways to overcome them, especially among the poor.


A genome-wide association study of production traits in a commercial population of Large White pigs: evidence of haplotypes affecting meat quality.
Numerous quantitative trait loci (QTL) have been detected in pigs over the past 20 years using microsatellite markers. However, due to the low density of these markers, the accuracy of QTL location has generally been poor. Since 2009, the dense genome coverage provided by the Illumina PorcineSNP60 BeadChip has made it possible to more accurately map QTL using genome-wide association studies (GWAS). Our objective was to perform high-density GWAS in order to identify genomic regions and corresponding haplotypes associated with production traits in a French Large White population of pigs. Animals (385 Large White pigs from 106 sires) were genotyped using the PorcineSNP60 BeadChip and evaluated for 19 traits related to feed intake, growth, carcass composition and meat quality. Of the 64,432 SNPs on the chip, 44,412 were used for GWAS with an animal mixed model that included a regression coefficient for the tested SNPs and a genomic kinship matrix. SNP haplotype effects in QTL regions were then tested for association with phenotypes following phase reconstruction based on the Sscrofa10.2 pig genome assembly. Twenty-three QTL regions were identified on autosomes and their effects ranged from 0.25 to 0.75 phenotypic standard deviation units for feed intake and feed efficiency (four QTL), carcass (12 QTL) and meat quality traits (seven QTL). The 10 most significant QTL regions had effects on carcass (chromosomes 7, 10, 16, 17 and 18) and meat quality traits (two regions on chromosome 1 and one region on chromosomes 8, 9 and 13). Thirteen of the 23 QTL regions had not been previously described. A haplotype block of 183 kb on chromosome 1 (six SNPs) was identified and displayed three distinct haplotypes with significant (0.0001 < P < 0.03) associations with all evaluated meat quality traits. GWAS analyses with the PorcineSNP60 BeadChip enabled the detection of 23 QTL regions that affect feed consumption, carcass and meat quality traits in a LW population, of which 13 were novel QTL. The proportionally larger number of QTL found for meat quality traits suggests a specific opportunity for improving these traits in the pig by genomic selection.


Conformational ensembles, signal transduction and residue hot spots: application to drug discovery.
A key step in drug development is the identification of both a protein target and its topological cellular network location and interactions, with regard to information flow in disease-causing events and to medication effects. Information flow involves a cascade of binding or covalent modification processes, with each step being affected by those that occur previously. Proteins are flexible, and information flows via dynamic changes in the distribution of conformational protein ensembles; molecular recognition is mainly determined by these changes. Drug discovery often focuses on signaling proteins situated at the crossroads of cellular networks; such signaling proteins have multiple partners that bind through shared binding sites. This review highlights these shared binding sites, and describes research to suggest that partners binding at these sites could at least partly interact via different energetically dominant 'hot-spot' residues. The data also indicate that, despite dynamic changes in the distribution of the conformational ensembles, the hot-spot conformations are retained in their pre-organized states.


Internet filters and entry pages do not protect children from online alcohol marketing.
We review programs and policies to prevent children from accessing alcohol marketing online. To update the literature, we present our recent studies that assess (i) in-built barriers to underage access to alcohol brand websites and (ii) commercial internet filters. Alcohol websites typically had poor filter systems for preventing entry of underage persons; only half of the sites required the user to provide a date of birth, and none had any means of preventing users from trying again. Even the most effective commercial internet filters allowed access to one-third of the sites we examined.


Enhanced in vitro hair growth at the air-liquid interface: minoxidil preserves the root sheath in cultured whisker follicles.
Inasmuch as hair follicles are difficult to maintain in culture, the study of hair biology using cultured hair follicles has met with only limited success. In our attempts to solve the problem of follicle degeneration, we cultured follicles at the air-surface interface on a modified collagen matrix (Gelfoam). In follicles cultured at the air-surface or submerged, we examined follicular morphology, hair shaft growth, sulfotransferase levels, cysteine incorporation, an expression of a tissue inhibitor of metalloproteinase (TIMP), and ultra-high sulfur keratin (UHSK). Follicles cultured at the air-liquid interface produced a 2.7-fold increase in hair growth and maintained an anagen-like morphology. Substrates such as nylon mesh seeded with fibroblasts, Full Thickness Skin, or 5-microns polycarbonate filter also supported hair growth, whereas Gelfilm, GF-A glass filter, filter paper, or 1-micron polycarbonate filter did not. The UHSK expression was significantly higher in the air-liquid interface cultures compared to the submerged culture. Several potassium channel openers, including minoxidil, a minoxidil analog, and the pinacidil analog (P-1075), all stimulated significant cysteine incorporation in follicles. Minoxidil and its analog specifically preserved the follicular root sheath, in contrast to P-1075 which did not, indicating a difference in the two drug types. The preservation of the root sheath was measured by increased TIMP expression and sulfotransferase activity and indicates that the root sheath is a target tissue for minoxidil. Our results show that follicles cultured at the air-liquid interface maintain a better morphology and produced greater hair growth than follicles cultured on tissue culture plastic.


Health policy basics: health insurance marketplaces.
Starting on 1 October 2013, most individuals and small businesses will be able to shop for and enroll in health insurance coverage through their state's health insurance marketplace, also known as an exchange. The health insurance marketplaces will serve as a one-stop resource to help the uninsured and the underinsured find comprehensive health coverage that fits their needs and budget and determine whether they qualify for health insurance tax credits provided by the Patient Protection and Affordable Care Act. Physicians may benefit because insured patients are more likely to have a regular source of care, adhere to medical regimens, and access preventive care. However, implementation of the marketplaces may prove challenging if enrollment numbers are insufficient, technical problems arise, and patients are unable to access providers. Despite these potential issues, physicians are encouraged to educate themselves about how the marketplaces work so they can direct their patients to find the coverage that best meets their medical needs.


Open Notes in Swedish Psychiatric Care (Part 2): Survey Among Psychiatric Care Professionals.
This is the second of two papers presenting the results from a study of the implementation of patient online access to their electronic health records (here referred to as Open Notes) in adult psychiatric care in Sweden. The study contributes an important understanding of both the expectations and concerns that existed among health care professionals before the introduction of the Open Notes Service in psychiatry and the perceived impact of the technology on their own work and patient behavior after the implementation. The results from the previously published baseline survey showed that psychiatric health care professionals generally thought that Open Notes would influence both the patients and their own practice negatively. The objective of this study was to describe and discuss how health care professionals in adult psychiatric care in Region Skåne in southern Sweden experienced the influence of Open Notes on their patients and their own practice, and to compare the results with those of the baseline study. We distributed a full population Web-based questionnaire to psychiatric care professionals in Region Skåne in the spring of 2017, which was one and a half years after the implementation of the service. The response rate was 27.73% (699/2521). Analyses showed that the respondents were representative of the staff as a whole. A statistical analysis examined the relationships between health professional groups and attitudes to the Open Notes Service. A total of 41.5% (285/687) of the health care professionals reported that none of their patients stated that they had read their Open Notes. Few health care professionals agreed with the statements about the potential benefits for patients from Open Notes. Slightly more of the health care professionals agreed with the statements about the potential risks. In addition, the results indicate that there was little impact on practice in terms of longer appointments or health care professionals having to address patients' questions outside of appointments. However, the results also indicate that changes had taken place in clinical documentation. Psychologists (39/63, 62%) and doctors (36/94, 38%) in particular stated that they were less candid in their documentation after the implementation of Open Notes. Nearly 40% of the health care professionals (239/650, 36.8%) reported that the Open Notes Service in psychiatry was a good idea. Most health care professionals who responded to the postimplementation survey did not experience that patients in adult psychiatric care had become more involved in their care after the implementation of Open Notes. The results also indicate that the clinical documentation had changed after the implementation of Open Notes. Finally, the results indicate that it is important to prepare health care professionals before an implementation of Open Notes, especially in medical areas where the service is considered sensitive.


MRI for Detecting Root Avulsions in Traumatic Adult Brachial Plexus Injuries: A Systematic Review and Meta-Analysis of Diagnostic Accuracy.
Background Traumatic brachial plexus injuries affect 1% of patients involved in major trauma. MRI is the best test for traumatic brachial plexus injuries, although its ability to differentiate root avulsions (which require urgent reconstructive surgery) from other types of nerve injury remains unknown. Purpose To evaluate the accuracy of MRI for diagnosing root avulsions in adults with traumatic brachial plexus injuries. Materials and Methods For this systematic review, MEDLINE and Embase were searched from inception to August 20, 2018. Studies of adults with traumatic nonpenetrating unilateral brachial plexus injuries were included. The target condition was root avulsion. The index test was preoperative MRI, and the reference standard was surgical exploration. A bivariate meta-analysis was used to estimate summary sensitivities and specificities of MRI for avulsion. Results Eleven studies of 275 adults (mean age, 27 years; 229 men) performed between 1992 and 2016 were included. Most participants had been injured in motorcycle collisions (84%). All studies were at risk of bias, and there were high applicability concerns for the index test (ie, MRI) in four studies given the lack of diagnostic criteria, inadequate descriptions of pulse sequences, and multiplicity of reporting radiologists. Overall, 72% of patients with brachial plexus injuries had at least one root avulsion (interquartile range [IQR]: 53%-86%); meta-analysis of patient-level data was not performed because of sparse and heterogeneous data. With the nerve root as the unit of analysis, 583 of 918 roots were avulsed (median, 55%; IQR: 38%-71%); the mean sensitivity of MRI for root avulsion was 93% (95% confidence interval [CI]: 77%, 98%) with a mean specificity of 72% (95% CI: 42%, 90%). Conclusion On the basis of limited data, MRI offers modest diagnostic accuracy for traumatic brachial plexus root avulsion(s), and early surgical exploration should remain as the preferred method of diagnosis. Published under a CC BY 4.0 license. Online supplemental material is available for this article.


In-vitro experimental analysis and numerical study of temperature in bone drilling.
Bone drilling is a common practice of surgical treatments in orthopaedics and traumatology. Penetration of a high-speed drill into bone tissue is accompanied by generation of a significant amount of heat. Cooling of the drilling region is necessary to avoid potential risk of thermal damage to bone. The purpose of this study was to measure and predict bone temperature by conducting experiments and numerical simulations using cooling by means of irrigation at two different temperatures. A series of experiments and numerical studies were performed to investigate the effect of cooling conditions on the rise in bone temperature in drilling. The temperature increase in bone was assessed for different drilling speeds and feed rates in the presence irrigation at 5 °C and 25 °C. Bone temperature was found to be strongly affected by the drilling parameters and cooling conditions. Irrigation with water at 5 °C kept bone temperature well below the thermal threshold level. This study strongly recommends the use of irrigation at lower temperature for safe surgical incision.


Population-Based Active Surveillance for Culture-Confirmed Candidemia - Four Sites, United States, 2012-2016.
Candidemia is a bloodstream infection (BSI) caused by yeasts in the genus Candida. Candidemia is one of the most common health care-associated BSIs in the United States, with all-cause in-hospital mortality of up to 30%. 2012-2016. CDC's Emerging Infections Program (EIP), a collaboration among CDC, state health departments, and academic partners that was established in 1995, was used to conduct active, population-based laboratory surveillance for candidemia in 22 counties in four states (Georgia, Maryland, Oregon, and Tennessee) with a combined population of approximately 8 million persons. Laboratories serving the catchment areas were recruited to report candidemia cases to the local EIP program staff. A case was defined as a blood culture that was positive for a Candida species collected from a surveillance area resident during 2012-2016. Isolates were sent to CDC for species confirmation and antifungal susceptibility testing. Any subsequent blood cultures with Candida within 30 days of the initial positive culture in the same patient were considered part of the same case. Trained surveillance officers collected clinical information from the medical chart for all cases, and isolates were sent to CDC for species confirmation and antifungal susceptibility testing. Across all sites and surveillance years (2012-2016), 3,492 cases of candidemia were identified. The crude candidemia incidence averaged across sites and years during 2012-2016 was 8.7 per 100,000 population; important differences in incidence were found by site, age group, sex, and race. The crude annual incidence was the highest in Maryland (14.1 per 100,000 population) and lowest in Oregon (4.0 per 100,000 population). The crude annual incidence of candidemia was highest among adults aged ≥65 years (25.5 per 100,000 population) followed by infants aged <1 year (15.8). The crude annual incidence was higher among males (9.4) than among females (8.0) and was approximately 2 times greater among blacks than among nonblacks (13.7 versus 5.8). Ninety-six percent of cases occurred in patients who were hospitalized at the time of or during the week after having a positive culture. One third of cases occurred in patients who had undergone a surgical procedure in the 90 days before the candidemia diagnosis, 77% occurred in patients who had received systemic antibiotics in the 14 days before the diagnosis, and 73% occurred in patients who had had a central venous catheter (CVC) in place within 2 days before the diagnosis. Ten percent were in patients who had used injection drugs in the past 12 months. The median time from admission to candidemia diagnosis was 5 days (interquartile range [IQR]: 0-16 days). Among 2,662 cases that were treated in adults aged >18 years, 34% were treated with fluconazole alone, 30% with echinocandins alone, and 34% with both. The all-cause, in-hospital case-fatality ratio was 25% for any time after admission; the all-cause in-hospital case-fatality ratio was 8% for <48 hours after a positive culture for Candida species. Candida albicans accounted for 39% of cases, followed by Candida glabrata (28%) and Candida parapsilosis (15%). Overall, 7% of isolates were resistant to fluconazole and 1.6% were resistant to echinocandins, with no clear trends in resistance over the 5-year surveillance period. Approximately nine out of 100,000 persons developed culture-positive candidemia annually in four U.S. sites. The youngest and oldest persons, men, and blacks had the highest incidences of candidemia. Patients with candidemia identified in the surveillance program had many of the typical risk factors for candidemia, including recent surgery, exposure to broad-spectrum antibiotics, and presence of a CVC. However, an unexpectedly high proportion of candidemia cases (10%) occurred in patients with a history of injection drug use (IDU), suggesting that IDU has become a common risk factor for candidemia. Deaths associated with candidemia remain high, with one in four cases resulting in death during hospitalization. Active surveillance for candidemia yielded important information about the disease incidence and death rate and persons at greatest risk. The surveillance was expanded to nine sites in 2017, which will improve understanding of the geographic variability in candidemia incidence and associated clinical and demographic features. This surveillance will help monitor incidence trends, track emergence of resistance and species distribution, monitor changes in underlying conditions and predisposing factors, assess trends in antifungal treatment and outcomes, and be helpful for those developing prevention efforts. IDU has emerged as an important risk factor for candidemia, and interventions to prevent invasive fungal infections in this population are needed. Surveillance data documenting that approximately two thirds of candidemia cases were caused by species other than C. albicans, which are generally associated with greater antifungal resistance than C. albicans, and the presence of substantial fluconazole resistance supports 2016 clinical guidelines recommending a switch from fluconazole to echinocandins as the initial treatment for candidemia in most patients.


Optimization of CO₂fixation in photosynthetic cells via thermodynamic buffering.
Stable operation of photosynthesis is based on the establishment of local equilibria of metabolites in the Calvin cycle. This concerns especially equilibration of stromal contents of adenylates and pyridine nucleotides and buffering of CO₂ concentration to prevent its depletion at the sites of Rubisco. Thermodynamic buffering that controls the homeostatic flux in the Calvin cycle is achieved by equilibrium enzymes such as glyceraldehyde phosphate dehydrogenase, transaldolase and transketolase. Their role is to prevent depletion of ribulose-1,5-bisphosphate, even at high [CO₂], and to maintain conditions where the only control is exerted by the CO₂ supply. Buffering of adenylates is achieved mainly by chloroplastic adenylate kinase, whereas NADPH level is maintained by mechanisms involving alternative sinks for electrons both within the chloroplast (cyclic phosphorylation, chlororespiration, etc.) and shuttling of reductants outside chloroplast (malate valve). This results in optimization of carbon fixation in chloroplasts, illustrating the principle that the energy of light is used to support stable non-equilibrium which drives all living processes in plants.


A qualitative study exploring factors that influence enrollment in outpatient cardiac rehabilitation.
This study explored patients' decision-making about whether or not to enroll in cardiac rehabilitation (CR), an underutilized program that is associated with significantly improved health outcomes. Face-to-face interviews were conducted with acute coronary syndrome patients (n = 14) after referral to a local CR center, but prior to program enrollment. Thematic analysis was used to derive themes from interview transcripts. Three themes emerged including anticipated benefit, perceived ability, and contextual influences. Participants believed key benefits of CR would be access to specialist health care providers, improved longevity, reduced cardiovascular risk, as well as improved motivation, accountability, learning opportunities, and general fitness. Participants were concerned about their ability to engage in and travel to exercise sessions, pay the program fee, and manage scheduling conflicts. Contextual influences on decision-making included health care provider recommendation, first impressions of the CR center, knowledge gaps about what CR entails, input from family and peers, and psychological distress. The period following CR referral but prior to enrollment represents an optimal opportunity to promote in-the-moment decisions in favor of CR. Patients report both positive and negative aspects of CR, suggesting individualized efforts to resolve ambivalence may increase program participation. Implications for Rehabilitation Cardiovascular disease is a leading cause of mortality worldwide. Cardiac rehabilitation (CR) is an effective secondary prevention strategy to improve cardiovascular morbidity and mortality, but only a subset of eligible patients enroll. After referral but prior to enrollment, patients anticipate both positive and negative aspects of CR participation. Individualized efforts to resolve ambivalence, address knowledge gaps, and problem-solve barriers may increase uptake into CR programs.


Trapped by a first hypothesis: How rudeness leads to anchoring.
In this article we explore the effect of encounters with rudeness on the tendency to engage in anchoring, one of the most robust and widespread cognitive biases. Integrating the self-immersion framework with the selective accessibility model (SAM), we propose that rudeness-induced negative arousal will narrow individuals' perspectives in a way that will make anchoring more likely. Additionally, we posit that perspective taking and information elaboration will attenuate the effect of rudeness on both negative arousal and subsequent anchoring. Across four experimental studies, we test the impact of exposure to rudeness on anchoring as manifested in a variety of tasks (medical diagnosis, judgment tasks, and negotiation). In a pilot study, we find that rudeness is associated with anchoring among a group of medical students making a medical diagnosis. In Study 1, we show that negative arousal mediates the effect of rudeness on anchoring among medical residents treating a patient, and that perspective taking moderates these effects. Study 2 replicates the results of Study 1 using a common anchoring task, and Study 3 builds on these results by replicating them in a negotiation setting and testing information elaboration as a boundary condition. Across the four studies, we find consistent evidence that rudeness-induced negative arousal leads to anchoring, and that these effects can be mitigated by perspective taking and information elaboration. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Multicolor wavefront reconstruction.
Two and three primary colors derived from an He-Ne gas laser and an argon gas laser were employed in recording and reconstructing holograms. For the tricolor case it is possible to reconstruct a three-dimensional multicolor image which possesses almost all the natural hues of the original object. Each wavelength generates an independent fringe system that is recorded on a photographic plate with a thick emulsion that constitutes a three-dimensional recording medium. In reconstruction, each fringe system diffracts light in a manner satisfying the Bragg relation for a particular reconstructing wavelength. If the reconstruction wavelengths are the same as the original wavelengths used to record the fringe systems, the result is a multicolor reconstruction possessing few or no ghost images. In our experiments, the angle between the object beam and the reference beam was greater than 100 degrees , and the photographic plates were oriented so that the fringe surfaces were approximately perpendicular to the emulsion surfac This minimized the deleterious effects of single-color, ghost image formation and shrinkage during development. Finally, a method of synthesizing multicolor scenes using a multiple-exposure recording with one wavelength and reconstructing with several wavelengths is described.


Tumor receptor imaging: proceedings of the National Cancer Institute workshop, review of current work, and prospective for further investigations.
In February 1994, the National Cancer Institute held a workshop to evaluate the current and future role of emission tomographic imaging methods, positron emission tomography and single-photon emission computed tomography, in improving the accuracy of cancer diagnosis and the effectiveness of treatment and in elucidating basic aspects of human cancer biology. Reviews covered many of the receptor and transport systems for hormones and growth factors, as well as metabolic changes important in human cancer, and topical presentations reviewed the current status of receptor-based imaging in the most well-characterized systems: somatostatin receptor imaging of neuroendocrine tumors, estrogen receptor imaging of breast cancer, and epidermal growth factor receptor and tumor metabolic imaging. A critical analysis was made of the current research and of new directions for the future development and use of receptor-imaging methods in oncology. In each area, recommendations were made for further investigation, where emerging understanding of tumor cell biology and defined molecular targets might be combined with the methods of radiopharmaceutical design and evaluation, to develop new approaches to critical issues in the diagnosis, staging, and treatment of cancer through tumor receptor imaging.


Survival and activity of Pseudomonas sp. strain B13(FR1) in a marine microcosm determined by quantitative PCR and an rRNA-targeting probe and its effect on the indigenous bacterioplankton.
Genetically engineered Pseudomonas sp. strain B13(FR1) was released into laboratory-scale marine ecosystem models (microcosms). Survival of the introduced population in the water column and the sediment was determined by plating on a selective medium and by quantitative competitive PCR. The activity of the released bacteria was determined by in situ hybridization of single cells with a specific rRNA-targeting oligonucleotide probe. Two microcosms were inoculated with 10(6) cells ml-1, while an uninoculated microcosm served as a control. The number of Pseudomonas sp. strain B13(FR1) cells decreased rapidly to ca. 10(2) cells ml-1 within 2 days after the release, which is indicative of grazing by protozoa. Three days after the introduction into seawater, cells were unculturable, but PCR continued to detect cells in low numbers. Immediately after the release, the ribosomal content of Pseudomonas sp. strain B13(FR1) corresponded to a generation time of 2 h. The growth rate decreased to less than 0.04 h-1 in 5 days and remained low, probably because of carbon limitation of the cells. Specific amendment of the microcosms with 10 mM 4-chlorobenzoate resulted in a rapid increase of the growth rate and an exponentially increasing number of cells detected by PCR, but not in resuscitation of the cells to a culturable state. The release of Pseudomonas sp. strain B13(FR1) into the microcosms seemed to affect only the indigenous bacterioplankton community transiently. Effects on the community were also apparent from the handling of water during filling of the microcosms and the amendment with 4-chlorobenzoate.


FeCl3/ZnI2-Catalyzed regioselective synthesis of angularly fused furans.
The FeCl3/ZnI2-catalyzed synthesis of angularly fused furans by intermolecular coupling between enols and alkynes has been developed in ambient air. The methodology is successfully applicable to 4-hydroxycoumarin, 4-hydroxyquinolinone and α-tetralone affording regioselective 2-aryl furans in good yields. The control experiments suggest the possibility of a radical reaction mechanism.


Health care providers and human trafficking: what do they know, what do they need to know? Findings from the middle East, the Caribbean, and central america.
Human trafficking is a crime that commonly results in acute and chronic physical and psychological harm. To foster more informed health sector responses to human trafficking, training sessions for health care providers were developed and pilot-tested in the Middle East, Central America, and the Caribbean. This study presents the results of an investigation into what health care providers knew and needed to know about human trafficking as part of that training program. Participants attended one of seven two-day training courses in Antigua and Barbuda, Belize, Costa Rica, Egypt, El Salvador, Guyana, and Jordan. We assessed participants' knowledge about human trafficking and opinions about appropriate responses in trafficking cases via questionnaires pre-training, and considered participant feedback about the training post-training. 178 participants attended the trainings. Pre-training questionnaires were completed by 165 participants (93%) and post-training questionnaires by 156 participants (88%). Pre-training knowledge about health and human trafficking appeared generally high for topics such as the international nature of trafficking and the likelihood of poor mental health outcomes among survivors. However, many participants had misconceptions about the characteristics of trafficked persons and a provider's role in responding to cases of trafficking. The most valued training components included the "Role of the Health Provider," "Basic Definitions and Concepts," and "Health Consequences of Trafficking." Training health care providers on caring for trafficked persons has the potential to improve practitioners' knowledge about human trafficking and its health consequences, and to increase safe practices when responding in cases of trafficking. This study provides lessons for the design of training programs on human trafficking that aim to help health care providers identify and refer victims, and provide care for survivors.


Life table evaluation of survival and reproduction of the aphid, Sitobion avenae, exposed to cadmium.
The effects of cadmium (Cd) on the development, fecundity, and reproduction of the grain aphid, Sitobion avenae Fabricius (Hemiptera: Aphididae) were estimated by constructing a life table of S. avenae exposed to Cd. The concentrations of Cd in the soil were as follows: 0, 10, 20, 40, 80, and 160 mg/kg. The correlation analysis of the Cd concentration in soil and wheat revealed that the amount in the wheat increased with the increase of Cd concentrations in soil. The results indicated that, the latter part of the reproduction period was significantly affected by Cd, according to the curve of the total survival rate (l(x)). The net reproductive rate (R(0)), innate capacity of increase (r), and finite rate of increase (λ) of S. avenae all decreased under the stress of Cd, and were lowest at a Cd concentration of 20 mg/kg. Cd also negatively affected fecundity and m(x) (the number of offspring produced by an individual female). At 20 mg/kg, the decline of them was most obvious. In conclusion, survival and reproduction of S. avenae were inhibited under the treatment of the heavy metal Cd. Sitobion avenae was more sensitive to Cd at concentration of 20 mg/kg compared to the other concentrations. This concentration can be used to examine the mechanisms behind population genetics and biological mutation of S. avenae when exposed to heavy metal.


Lactate metabolism in inactive skeletal muscle during lactacidosis.
Contributions of carbohydrate and fat metabolism to the removal of a lactate (Lac-) load were quantified in inactive soleus (SL), plantaris (PL), and white gastrocnemius (WG) rat hindlimb muscle. Male Sprague-Dawley rats were perfused for 60 min with normal perfusate (NP, n = 8) or a high-lactate perfusate (LP, n = 8), simulating ionic conditions found in arterial blood and plasma after intense exercise: Lac- = 11.0 mM, K+ = 7.88 mM, and pH = 7.15. Metabolite fluxes across the hindlimb were calculated from blood flow and arteriovenous differences. In NP, Lac- was continuously released (2.9 +/- 0.2 mumol.min-1 x 100 g-1). However, in LP, a rapid and significant uptake of Lac- increased muscle Lac- fivefold to 39.6 +/- 1.1, 33.1 +/- 2.2, and 28.8 +/- 1.7 mumol/g dry wt in SL, PL, and WG, respectively. Glucose and O2 uptakes were similar during LP and NP perfusion. Glycerol release increased eightfold to 3.3 +/- 0.7 mumol.min-1 x 100 g-1 in response to LP. Muscle ATP, creatine phosphate, glycogen, glycolytic intermediate, and triacylglycerol concentrations did not change. However, muscle lactate-to-pyruvate ratios were elevated in all muscles of the LP group postperfusion, indicating changes in the mass action ratio at the pyruvate dehydrogenase reaction. In LP, of 80 mumol of Lac- taken up, 11% was accounted for by increased muscle Lac-, 12-24% was oxidized, and 5% may have been involved in glycerol release. The remaining Lac- may have been involved in metabolic cycling along the glyconeogenic-glycolytic pathway and/or in triacylglycerol-free fatty acid substrate cycling.


Intensive individualized induction therapy with behenoyl cytarabine, daunorubicin and 6-mercaptopurine followed by intensive consolidation including intermediate-dose continuous cytarabine, mitoxantron, etoposide and vinca alkaloids in acute myeloid leukemia in adults.
Forty-one consecutive adult patients with acute myeloid leukemia (AML) were treated with an intensive individualized induction therapy of behenoyl cytarabine, daunorubicin, and 6-mercaptopurine, 29 patients (71%) achieved complete remission (CR). Patients then received three courses of intensive consolidation therapy, including intermediate-dose continuous cytarabine (400 mg/m2, for 5 days) and non-cross resistant drugs such as mitoxantron, etoposide and vincristine. During the course of the consolidation therapy, three patients died of infections and one died of myocardial infarction. Four patients underwent allogeneic bone marrow transplantation. The patients then received six courses of moderately intensive maintenance therapy for 1 year. The predicted 5-year continuing CR and disease-free survival rates of the CR patients were 62% (95% confidence limit, 41% to 83%) and 53% (33% to 73%), respectively. Although the number of patients in this study is small, the present study indicated that it may be possible to cure a fairly large proportion of AML patients by chemotherapy alone, if intensive induction therapy is followed by intensive consolidation therapy.


Characterisation of the Immunophenotype of Dogs with Primary Immune-Mediated Haemolytic Anaemia.
Immune-mediated haemolytic anaemia (IMHA) is reported to be the most common autoimmune disease of dogs, resulting in significant morbidity and mortality in affected animals. Haemolysis is caused by the action of autoantibodies, but the immunological changes that result in their production have not been elucidated. To investigate the frequency of regulatory T cells (Tregs) and other lymphocyte subsets and to measure serum concentrations of cytokines and peripheral blood mononuclear cell expression of cytokine genes in dogs with IMHA, healthy dogs and dogs with inflammatory diseases. 19 dogs with primary IMHA, 22 dogs with inflammatory diseases and 32 healthy control dogs. Residual EDTA-anti-coagulated blood samples were stained with fluorophore-conjugated monoclonal antibodies and analysed by flow cytometry to identify Tregs and other lymphocyte subsets. Total RNA was also extracted from peripheral blood mononuclear cells to investigate cytokine gene expression, and concentrations of serum cytokines (interleukins 2, 6 10, CXCL-8 and tumour necrosis factor α) were measured using enhanced chemiluminescent assays. Principal component analysis was used to investigate latent variables that might explain variability in the entire dataset. There was no difference in the frequency or absolute numbers of Tregs among groups, nor in the proportions of other lymphocyte subsets. The concentrations of pro-inflammatory cytokines were greater in dogs with IMHA compared to healthy controls, but the concentration of IL-10 and the expression of cytokine genes did not differ between groups. Principal component analysis identified four components that explained the majority of the variability in the dataset, which seemed to correspond to different aspects of the immune response. The immunophenotype of dogs with IMHA differed from that of dogs with inflammatory diseases and from healthy control dogs; some of these changes could suggest abnormalities in peripheral tolerance that permit development of autoimmune disease. The frequency of Tregs did not differ between groups, suggesting that deficiency in the number of these cells is not responsible for development of IMHA.


Predictors of success for combined endoscopic third ventriculostomy and choroid plexus cauterization in a North American setting: a Hydrocephalus Clinical Research Network study.
Endoscopic third ventriculostomy combined with choroid plexus cauterization (ETV+CPC) has been adopted by many pediatric neurosurgeons as an alternative to placing shunts in infants with hydrocephalus. However, reported success rates have been highly variable, which may be secondary to patient selection, operative technique, and/or surgeon training. The objective of this prospective multicenter cohort study was to identify independent patient selection, operative technique, or surgical training predictors of ETV+CPC success in infants. This was a prospective cohort study nested within the Hydrocephalus Clinical Research Network's (HCRN) Core Data Project (registry). All infants under the age of 2 years who underwent a first ETV+CPC between June 2006 and March 2015 from 8 HCRN centers were included. Each patient had a minimum of 6 months of follow-up unless censored by an ETV+CPC failure. Patient and operative risk factors of failure were examined, as well as formal ETV+CPC training, which was defined as traveling to and working with the experienced surgeons at CURE Children's Hospital of Uganda. ETV+CPC failure was defined as the need for repeat ETV, shunting, or death. The study contained 191 patients with a primary ETV+CPC conducted by 17 pediatric neurosurgeons within the HCRN. Infants under 6 months corrected age at the time of ETV+CPC represented 79% of the cohort. Myelomeningocele (26%), intraventricular hemorrhage associated with prematurity (24%), and aqueductal stenosis (17%) were the most common etiologies. A total of 115 (60%) of the ETV+CPCs were conducted by surgeons after formal training. Overall, ETV+CPC was successful in 48%, 46%, and 45% of infants at 6 months, 1 year, and 18 months, respectively. Young age (< 1 month) (adjusted hazard ratio [aHR] 1.9, 95% CI 1.0-3.6) and an etiology of post-intraventricular hemorrhage secondary to prematurity (aHR 2.0, 95% CI 1.1-3.6) were the only two independent predictors of ETV+CPC failure. Specific subgroups of ages within etiology categories were identified as having higher ETV+CPC success rates. Although training led to more frequent use of the flexible scope (p < 0.001) and higher rates of complete (> 90%) CPC (p < 0.001), training itself was not independently associated (aHR 1.1, 95% CI 0.7-1.8; p = 0.63) with ETV+CPC success. This is the largest prospective multicenter North American study to date examining ETV+CPC. Formal ETV+CPC training was not found to be associated with improved procedure outcomes. Specific subgroups of ages within specific hydrocephalus etiologies were identified that may preferentially benefit from ETV+CPC.


Miniaturized high-throughput synthesis and screening of responsive hydrogels using nanoliter compartments.
The traditional pipeline of hydrogel development includes individual one-by-one synthesis and characterization of hydrogels. This approach is associated with the disadvantages of low-throughput and high cost. As an alternative approach to classical one-by-one synthesis, high-throughput development of hydrogels is still tremendously under-represented in the field of responsive material development, despite the urgent requirement for such techniques. Here, we report a platform that combines highly miniaturized hydrogel synthesis with screening for responsive properties in a high-throughput manner. The platform comprises a standard glass slide patterned with 1 × 1 mm hydrophilic regions separated by superhydrophobic liquid-impermeable barriers, thus allowing deposition of various precursor solutions onto the hydrophilic spots without cross-contamination. The confinement of these solutions provided by the hydrophilic/superhydrophobic pattern allows encapsulation of cells within the hydrogel, and enables variation in hydrogel height and width. We have also proved the proper mixing of chemicals within the nanoliter-sized droplets. We have successfully implemented this platform for the synthesis of hydrogels, constructing 53 unique hydrogels, to demonstrate the versatility and utility of the platform. Photodegradation studies were performed on 20 hydrogels, revealing structure/function relationships between the hydrogel composition and photodegradability, and covering the range of degradability from non-degradable to rapidly degradable materials.


How are we evaluating the cost-effectiveness of companion biomarkers for targeted cancer therapies? A systematic review.
Despite the increasing economic assessment of biomarker-guided therapies, no clear agreement exists whether existing methods are sufficient or whether different methods might produce different cost-effectiveness results. This study aims to examine current practices of modeling companion biomarkers when assessing the cost-effectiveness of targeted cancer therapies. It investigates the current methods in modeling the characteristics of companion diagnostics based on existing economic evaluations of biomarker-guided therapies in cancer. A literature search was performed using Medline, Embase, EconLit, Cochrane library for economic evaluations of biomarker-guided therapies with companion diagnostics in cancer. Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Studies were selected using pre-specified eligibility criteria based on the PICO framework. To make the included studies more comparable, we qualitatively synthesized the data under nine domains of methods where consensus was deemed lacking. Only four of the twenty-two studies included in this review were found to be of good quality with respect to incorporating the characteristics of companion biomarkers in economic evaluations. However, many evaluations focused on a pre-selected patient group rather than including all patients regardless of their biomarker status. Companion biomarker characteristics captured in evaluations were often limited to the cost or the accuracy of the test. Often, only the costs of biomarker testing were modelled. Clinical outcomes and health state utilities were often not included due to the limited data generated by clinical trials. Methods of economic evaluation were not applied consistently in assessments of companion cancer biomarkers for targeted therapies. It was also shown that conflicting cost-effectiveness results were likely depending on what comparator arm was chosen and what comparison structure was designed in the model. We found no consistent approach applied in assessing the value of companion biomarker tests and including the characteristics of biomarkers in an economic evaluation of targeted oncology therapies. Currently, many economic evaluations fail to capture the full value of companion biomarkers beyond sensitivity/specificity and cost related to biomarker testing.


More doctors or better care?
The Canadian Medical Association's More Doctors, More Care campaign seeks to align physician supply targets with policy decisions elsewhere in the Organisation for Economic Co-operation and Development (OECD). Using OECD data for 19 countries to assess the relationship between physician supply and healthcare outcomes, we have determined that there is no association between avoidable mortality and overall physician supply. Similarly, there is no relationship between avoidable mortality and general practitioners and family physicians per capita, specialists per capita, nurses per capita, doctors and nurses per capita or health expenditures per capita. These findings should move us to recognize that (a) more doctors will not necessarily translate into better healthcare outcomes for Canadians and (b) it is in Canadians' better interests that we instead focus on realizing opportunities to improve access to high-quality care and to ensure that changes in physician turnover do not threaten the current generalist-to-specialist mix.


Serum anti-Helicobacter pylori antibody titer and its association with gastric nodularity, atrophy, and age: A cross-sectional study.
To clarify the role of serum anti-Helicobacter pylori (H. pylori) antibody titers in gastric cancer. In this cross-sectional study, the effect of patients' baseline characteristics and endoscopic findings on their serum antibody titers were assessed. We evaluated consecutive patients who underwent esophagogastroduodenoscopy and their first evaluation for H. pylori infection using a serum antibody test. We excluded patients with a history of eradication therapy. The participants were divided into four groups according to their E-plate serum antibody titer. Patients with serum antibody titers < 3, 3-9.9, 10-49.9, and ≥ 50 U/mL were classified into groups A, B, C, and D, respectively. In total, 874 participants were analyzed with 70%, 16%, 8.7%, and 5.1% of them in the groups A, B, C, and D, respectively. Patients in group C were older than patients in groups A and B. Gastric open-type atrophy, intestinal metaplasia, enlarged folds, diffuse redness, and duodenal ulcers were associated with a high titer. Regular arrangements of collecting venules, fundic gland polyps, superficial gastritis, and gastroesophageal reflux disease were related to a low titer. Multivariate analysis revealed that nodularity (P = 0.0094), atrophy (P = 0.0076), and age 40-59 years (vs age ≥ 60 years, P = 0.0090) were correlated with a high serum antibody titer in H. pylori-infected patients. Intestinal metaplasia and atrophy were related to age ≥ 60 years in group C and D. Serum antibody titer changes with age, reflects gastric mucosal inflammation, and is useful in predicting the risk of gastric cancer.


Nlgn4 knockout induces network hypo-excitability in juvenile mouse somatosensory cortex in vitro.
Neuroligins (Nlgns) are postsynaptic cell adhesion molecules that form transynaptic complexes with presynaptic neurexins and regulate synapse maturation and plasticity. We studied the impact of the loss of Nlgn4 on the excitatory and inhibitory circuits in somatosensory cortical slices of juvenile mice by electrically stimulating these circuits using a multi-electrode array and recording the synaptic input to single neurons using the patch-clamp technique. We detected a decreased network response to stimulation in both excitatory and inhibitory circuits of Nlgn4 knock-out animals as compared to wild-type controls, and a decreased excitation-inhibition ratio. These data indicate that Nlgn4 is involved in the regulation of excitatory and inhibitory circuits and contributes to a balanced circuit response to stimulation.


Scintillations of optical plane and spherical waves in underwater turbulence.
The scintillation indices of optical plane and spherical waves propagating in underwater turbulent media are evaluated by using the Rytov method, and the variations in the scintillation indices are investigated when the rate of dissipation of mean squared temperature, the temperature and salinity fluctuations, the propagation distance, the wavelength, the Kolmogorov microscale length, and the rate of dissipation of the turbulent kinetic energy are varied. Results show that as in the atmosphere, also in underwater media the plane wave is more affected by turbulence as compared to the spherical wave. The underwater turbulence effect becomes significant at 5-10 m for a plane wave and at 20-25 m for a spherical wave. The turbulence effect is relatively small in deep water and is large at the surface of the water. Salinity-induced turbulence strongly dominates the scintillations compared to temperature-induced turbulence.


Secure polarization-independent subcarrier quantum key distribution in optical fiber channel using BB84 protocol with a strong reference.
A quantum key distribution system based on the subcarrier wave modulation method has been demonstrated which employs the BB84 protocol with a strong reference to generate secure bits at a rate of 16.5 kbit/s with an error of 0.5% over an optical channel of 10 dB loss, and 18 bits/s with an error of 0.75% over 25 dB of channel loss. To the best of our knowledge, these results represent the highest channel loss reported for secure quantum key distribution using the subcarrier wave approach. A passive unidirectional scheme has been used to compensate for the polarization dependence of the phase modulators in the receiver module, which resulted in a high visibility of 98.8%. The system is thus fully insensitive to polarization fluctuations and robust to environmental changes, making the approach promising for use in optical telecommunication networks. Further improvements in secure key rate and transmission distance can be achieved by implementing the decoy states protocol or by optimizing the mean photon number used in line with experimental parameters.


PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.
Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.


Connectivity of the Cingulate Sulcus Visual Area (CSv) in the Human Cerebral Cortex.
The human cingulate sulcus visual area (CSv) responds selectively to visual and vestibular cues to self-motion. Although it is more selective for visual self-motion cues than any other brain region studied, it is not known whether CSv mediates perception of self-motion. An alternative hypothesis, based on its location, is that it provides sensory information to the motor system for use in guiding locomotion. To evaluate this hypothesis we studied the connectivity pattern of CSv, which is completely unknown, with a combination of diffusion MRI and resting-state functional MRI. Converging results from the 2 approaches suggest that visual drive is provided primarily by areas hV6, pVIP (putative intraparietal cortex) and PIC (posterior insular cortex). A strong connection with the medial portion of the somatosensory cortex, which represents the legs and feet, suggests that CSv may receive locomotion-relevant proprioceptive information as well as visual and vestibular signals. However, the dominant connections of CSv are with specific components of the motor system, in particular the cingulate motor areas and the supplementary motor area. We propose that CSv may provide a previously unknown link between perception and action that serves the online control of locomotion.


Coordination chemistry in the design of heterogeneous photocatalysts.
Heterogeneous catalysts have been widely used for photocatalysis, which is a highly important process for energy conversion, owing to their merits such as easy separation of catalysts from the reaction products and applicability to continuous chemical industry and recyclability. Yet, homogenous photocatalysis receives tremendous attention as it can offer a higher activity and selectivity with atomically dispersed catalytic sites and tunable light absorption. For this reason, there is a major trend to combine the advantages of both homogeneous and heterogeneous photocatalysts, in which coordination chemistry plays a role as the bridge. In this article, we aim to provide the first systematic review to give a clear picture of the recent progress from taking advantage of coordination chemistry. We specifically summarize the role of coordination chemistry as a versatile tool to engineer catalytically active sites, tune light harvesting and maneuver charge kinetics in heterogeneous photocatalysis. We then elaborate on the common fundamentals behind various materials systems, together with key spectroscopic characterization techniques and remaining challenges in this field. The typical applications of coordination chemistry in heterogeneous photocatalysis, including proton reduction, water oxidation, carbon dioxide reduction and organic reactions, are highlighted.


Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score.
To develop and validate a pragmatic risk score to predict mortality in patients admitted to hospital with coronavirus disease 2019 (covid-19). Prospective observational cohort study. International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study (performed by the ISARIC Coronavirus Clinical Characterisation Consortium-ISARIC-4C) in 260 hospitals across England, Scotland, and Wales. Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited after model development between 21 May and 29 June 2020. PARTICIPANTS: Adults (age ≥18 years) admitted to hospital with covid-19 at least four weeks before final data extraction. In-hospital mortality. 35 463 patients were included in the derivation dataset (mortality rate 32.2%) and 22 361 in the validation dataset (mortality rate 30.1%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein (score range 0-21 points). The 4C Score showed high discrimination for mortality (derivation cohort: area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.78 to 0.79; validation cohort: 0.77, 0.76 to 0.77) with excellent calibration (validation: calibration-in-the-large=0, slope=1.0). Patients with a score of at least 15 (n=4158, 19%) had a 62% mortality (positive predictive value 62%) compared with 1% mortality for those with a score of 3 or less (n=1650, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (area under the receiver operating characteristic curve range 0.61-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73). An easy-to-use risk stratification score has been developed and validated based on commonly available parameters at hospital presentation. The 4C Mortality Score outperformed existing scores, showed utility to directly inform clinical decision making, and can be used to stratify patients admitted to hospital with covid-19 into different management groups. The score should be further validated to determine its applicability in other populations. ISRCTN66726260.


Clinically Positive Axillary Lymphadenopathy May Lead to False Diagnosis of Overstaged Breast Cancer in Patients with Sjögren's Syndrome: A Case Report.
Sjögren's syndrome (SS) is an autoimmune disease that chronic inflammation and lymph node proliferation. Patients with SS carry a greater risk of developing lymphoproliferative malignancy. In addition to other organ cancers, breast cancer may also occur in these patients. Considering these, breast cancer in patients with SS can be misdiagnosed as being in an advanced stage particularly in the presence of axillary lymphadenopathy. Here, we report a rare case of a 45-year-old woman with SS who presented with a breast mass. Radiology showed a 4 cm solid lesion and conglomerates of axillary lymphadonepathy. A breast biopsy revealed ductal carcinoma in situ. A modified radical mastectomy was performed; however, no axillary metastases were detected. Clinicians should remain vigilant to the possibility that a false clinical impression of axillary metastasis may occur in such patients with breast cancer. Therefore, axillary node status should be verified first.


Transitions between bursting modes in the integrated oscillator model for pancreatic β-cells.
Insulin-secreting β-cells of pancreatic islets of Langerhans produce bursts of electrical impulses, resulting in intracellular Ca2+ oscillations and pulsatile insulin secretion. The mechanism for this bursting activity has been the focus of mathematical modeling for more than three decades, and as new data are acquired old models are modified and new models are developed. Comprehensive models must now account for the various modes of bursting observed in islet β-cells, which include fast bursting, slow bursting, and compound bursting. One such model is the Integrated Oscillator Model (IOM), in which β-cell electrical activity, intracellular Ca2+, and glucose metabolism interact via numerous feedforward and feedback pathways. These interactions can produce metabolic oscillations with a sawtooth time course or a pulsatile time course, reflecting very different oscillation mechanisms. In this report, we determine conditions favorable to one form of oscillations or the other, and examine the transitions between modes of bursting and the relationship of the transitions to the patterns of metabolic oscillations. Importantly, this work clarifies what can be expected in experimental measurements of β-cell oscillatory activity, and suggests pathways through which oscillations of one type can be converted to oscillations of another type.


Pathogenic orphan transduction created by a nonreference LINE-1 retrotransposon.
Long INterspersed Element-1 (LINE-1) retrotransposons comprise 17% of the human genome, and move by a potentially mutagenic "copy and paste" mechanism via an RNA intermediate. Recently, the retrotransposition-mediated insertion of a new transcript was described as a novel cause of genetic disease, Duchenne muscular dystrophy, in a Japanese male. The inserted sequence was presumed to derive from a single-copy, noncoding RNA transcribed from chromosome 11q22.3 that retrotransposed into the dystrophin gene. Here, we demonstrate that a nonreference full-length LINE-1 is situated in the proband and maternal genome at chromosome 11q22.3, directly upstream of the sequence, whose copy was inserted into the dystrophin gene. This LINE-1 is highly active in a cell culture assay. LINE-1 insertions are often associated with 3' transduction of adjacent genomic sequences. Thus, the likely explanation for the mutagenic insertion is a LINE-1-mediated 3' transduction with severe 5' truncation. This is the first example of LINE-1-induced human disease caused by an "orphan" 3' transduction.