Morphometric analyses of petioles of seedlings grown in a spaceflight experiment.
Gravity is a constant unidirectional stimulus on Earth, and gravitropism in plants involves three phases: perception, transduction, and response. In shoots, perception takes place within the endodermis. To investigate the cellular machinery of perception in microgravity, we conducted a spaceflight study with Arabidopsis thaliana seedlings, which were grown in microgravity in darkness using the Biological Research in Canisters (BRIC) hardware during space shuttle mission STS-131. In the 14-day-old etiolated plants, we studied seedling development and the morphological parameters of the endodermal cells in the petiole. Seedlings from the spaceflight experiment (FL) were compared to a ground control (GC), which both were in the BRIC flight hardware. In addition, to assay any potential effects from growth in spaceflight hardware, we performed another control by growing seedlings in Petri dishes in standard laboratory conditions (termed the hardware control, HC). Seed germination was significantly lower in samples grown in flight hardware (FL, GC) compared to the HC. In terms of cellular parameters of endodermal cells, the greatest differences also were between seedlings grown in spaceflight hardware (FL, GC) compared to those grown outside of this hardware (HC). Specifically, the endodermal cells were significantly smaller in seedlings grown in the BRIC system compared to those in the HC. However, a change in the shape of the cell, suggesting alterations in the cell wall, was one parameter that appears to be a true microgravity effect. Taken together, our results suggest that caution must be taken when interpreting results from the increasingly utilized BRIC spaceflight hardware system and that it is important to perform additional ground controls to aid in the analysis of spaceflight experiments.


Publisher Correction: Whole genome sequencing in psychiatric disorders: the WGSPD consortium.
In the version of this article initially published, the consortium authorship and corresponding authors were not presented correctly. In the PDF and print versions, the Whole Genome Sequencing for Psychiatric Disorders (WGSPD) consortium was missing from the author list at the beginning of the paper, where it should have appeared as the seventh author; it was present in the author list at the end of the paper, but the footnote directing readers to the Supplementary Note for a list of members was missing. In the HTML version, the consortium was listed as the last author instead of as the seventh, and the line directing readers to the Supplementary Note for a list of members appeared at the end of the paper under Author Information but not in association with the consortium name itself. Also, this line stated that both member names and affiliations could be found in the Supplementary Note; in fact, only names are given. In all versions of the paper, the corresponding author symbols were attached to A. Jeremy Willsey, Steven E. Hyman, Anjene M. Addington and Thomas Lehner; they should have been attached, respectively, to Steven E. Hyman, Anjene M. Addington, Thomas Lehner and Nelson B. Freimer. As a result of this shift, the respective contact links in the HTML version did not lead to the indicated individuals. The errors have been corrected in the HTML and PDF versions of the article.


Radiometric model for propagation of coherence.
A radiometric model for the propagation of coherence is formulated, which greatly simplifies the determination of the cross-spectral density and of the spectral degree of coherence of the field at an arbitrary distance from any planar, secondary, quasi-homogeneous source. The radiance function, which plays a central role in this model, satisfies all the postulates of traditional radiometry.


Prevention of contrast-induced nephropathy in STEMI patients undergoing primary percutaneous coronary intervention: a systematic review.
To evaluate the current prophylactic strategies against CIN in patients with STEMI treated by primary percutaneous coronary intervention. Contrast-induced nephropathy (CIN) is the third leading course of acute renal failure and a recognized complication to cardiac catheterization. CIN is associated with increased risk of cardiac adverse events and mortality, and recent studies point at the risk of developing a transient or persistent renal dysfunction. Patients with ST-elevation myocardial infarction treated by primary percutaneous coronary intervention have a markedly increased risk of developing CIN. At present no strategy is universally accepted in the prevention of CIN in the acute setting of primary percutaneous coronary intervention. We performed a systematic search in Pubmed and EMBASE and ended up including nine randomised clinical trials; six studies of N-acetylcysteine, one study of early and late hydration regimens, one study of recombinant human brain natriuretic peptide and one study comparing a low-osmolar contrast agent with an iso-osmolar contrast agent. Recombinant human brain natriuretic peptide and the regimens of hydration significantly reduced the incidence of CIN and administration of N-acetylcysteine in one of the six studies significantly reduced the occurrence of CIN. The iso-osmolar contrast agent was not proven to be superior to the low-osmolar contrast agent in terms of preventing CIN. Preliminary studies are promising but further studies are needed before any prevention strategy against CIN can be recommended in routine care of patients undergoing primary percutaneous coronary intervention for STEMI.


Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure.
Catechol-O-methyltransferase (COMT) is a key regulator of pain perception, cognitive function, and affective mood. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous position, code for differences in COMT enzymatic activity and are associated with pain sensitivity. Haplotypes divergent in synonymous changes exhibited the largest difference in COMT enzymatic activity, due to a reduced amount of translated protein. The major COMT haplotypes varied with respect to messenger RNA local stem-loop structures, such that the most stable structure was associated with the lowest protein levels and enzymatic activity. Site-directed mutagenesis that eliminated the stable structure restored the amount of translated protein. These data highlight the functional significance of synonymous variations and suggest the importance of haplotypes over single-nucleotide polymorphisms for analysis of genetic variations.


Fatty-acid amide hydrolase polymorphisms and post-traumatic stress disorder after penetrating brain injury.
The past few years have seen an increase in the clinical awareness of post-traumatic stress disorder (PTSD), one of the most disabling and least understood behavioral disorders. Although the biological bases of PTSD are poorly understood, fatty-acid amide hydrolase (FAAH) activity has been linked with arousability and aversive-memories extinction, that is, two key features of PTSD. In this study, we investigated the association between the FAAH genetic polymorphisms and PTSD development and maintenance. We assessed PTSD frequency in a group of male Vietnam war veterans who suffered combat-related penetrating traumatic brain injury, that is, a relatively homogeneous population regarding the nature of the events that led to PTSD. We showed that rs2295633, a single-nucleotide polymorphism of FAAH, was significantly associated with PTSD diagnosis in subjects without lesions in the ventromedial prefrontal cortex. Moreover, the presence of the C allele was associated with more severe re-experiencing of trauma and more negative reported childhood experiences. In conclusion, our data suggest that FAAH has an important role in PTSD through modulation of aversive memories and point to both a novel therapeutic target and a possible risk marker for this condition.


IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid.
Maternal hyperhomocysteinemia is detrimental for reproduction, but the effects on embryo quality are unknown. The aim of this study was to investigate whether biomarkers of the homocysteine pathway are associated with in vitro fertilization (IVF) outcome. In a prospective study, we investigated biomarkers of the homocysteine pathway for associations with embryo quality and biochemical pregnancy in women undergoing IVF or intracytoplasmic sperm injection treatment (n = 181). In the treatment cycle, blood and monofollicular fluid samples were collected for determination of folate, cobalamin and total homocysteine (tHcy) concentrations. Of all the women in the study, 67% used folic acid supplements. In blood, a significant correlation was established between high cobalamin and better embryo quality [standardized adjusted regression coefficient: -0.17, 95% confidence interval (CI): -0.30, -0.01]. In monofollicular fluid of non-supplemented women, high cobalamin correlated with better embryo quality (estimate: -0.87; 95% CI: -1.68, -0.06), whereas high tHcy resulted in poor embryo quality (estimate: 1.01; 95% CI: 0.08, 1.95). However, in monofollicular fluid of supplemented women, high tHcy correlated with better embryo quality (estimate: -0.58; 95% CI: -1.12, -0.04). In the total group, a 2-fold increase of monofollicular fluid folate corresponded with a 3.3 times higher chance (95% CI: 1.09, 9.71) of achieving pregnancy. An optimal homocysteine pathway in follicular fluid is associated with a better embryo quality and chance of pregnancy.


Cytoadherence characteristics of Plasmodium falciparum isolates from Thailand: evidence for chondroitin sulfate a as a cytoadherence receptor.
The association between cytoadherence of Plasmodium falciparum-infected erythrocytes and the severity of malaria has been evaluated. In this study, we investigate adherence to C32 melanoma cells, CD36, intracellular adhesion molecule-1 (ICAM-1), thrombospondin (TSP), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and chondroitin sulfate A (CSA) of 36 P. falciparum isolates from patients suffering from acute falciparum malaria. Adherence to purified adhesion molecules varied greatly among different parasite isolates. All isolates but one adhered to CD36, but none bound to E-selectin and VCAM-1 beyond control levels. Some P. falciparum isolates adhered to ICAM-1 and to CSA, a newly identified receptor for adherence. There was no correlation between in vitro binding to any one receptor and the patients' conditions. In addition, we investigated the characteristics of adherence to CSA and to C32 melanoma cells. Infected erythrocytes continued to adhere after trypsin digestion and soluble CSA inhibited adherence to C32 melanoma cells in a dose-dependent manner. The results imply a role for CSA in the natural infection of P. falciparum.


Skin exposure to isocyanates: reasons for concern.
Isocyanates (di- and poly-), important chemicals used worldwide to produce polyurethane products, are a leading cause of occupational asthma. Respiratory exposures have been reduced through improved hygiene controls and the use of less-volatile isocyanates. Yet isocyanate asthma continues to occur, not uncommonly in settings with minimal inhalation exposure but opportunity for skin exposure. In this review we evaluate the potential role of skin exposure in the development of isocyanate asthma. We reviewed the published animal and human literature on isocyanate skin-exposure methods, workplace skin exposure, skin absorption, and the role of skin exposure in isocyanate sensitization and asthma. We selected relevant articles from computerized searches on Medline, U.S. Environmental Protection Agency, Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, and Google databases using the keywords "isocyanate," "asthma," "skin," "sensitization," and other synonymous terms, and our own extensive collection of isocyanate publications. Isocyanate production and use continues to increase as the polyurethane industry expands. There is substantial opportunity for isocyanate skin exposure in many work settings, but such exposure is challenging to quantify and continues to be underappreciated. Isocyanate skin exposure can occur at work, even with the use of personal protective equipment, and may also occur with consumer use of certain isocyanate products. In animals, isocyanate skin exposure is an efficient route to induce sensitization, with subsequent inhalation challenge resulting in asthma-like responses. Several lines of evidence support a similar role for human isocyanate skin exposure, namely, that such exposure occurs and can contribute to the development of isocyanate asthma in certain settings, presumably by inducing systemic sensitization. Integrated animal and human research is needed to better understand the role of skin exposure in human isocyanate asthma and to improve diagnosis and prevention. In spite of substantial research needs, sufficient evidence already exists to justify greater emphasis on the potential risks of isocyanate skin exposure and the importance of preventing such exposures at work and during consumer use of certain isocyanate products.


Growth-inhibitory effects of the astaxanthin-rich alga Haematococcus pluvialis in human colon cancer cells.
The growth-inhibitory effects of the astaxanthin-rich Haematococcus pluvialis were studied in HCT-116 colon cancer cells. H. pluvialis extract (5-25 microg/ml) inhibited cell growth in a dose- and time-dependent manner, by arresting cell cycle progression and by promoting apoptosis. At 25 microg/ml of H. pluvialis extract, an increase of p53, p21(WAF-1/CIP-1) and p27 expression (220%, 160%, 250%, respectively) was observed, concomitantly with a decrease of cyclin D1 expression (58%) and AKT phosphorylation (21%). Moreover, the extract, at the same concentration, strongly up-regulated apoptosis by modifying the ratio of Bax/Bcl-2 and Bcl-XL, and increased the phosphorylation of p38, JNK, and ERK1/2 by 160%, 242%, 280%, respectively. Growth-inhibitory effects by H. pluvialis were also observed in HT-29, LS-174, WiDr, SW-480 cells. This study suggests that H. pluvialis may protect from colon cancer.


A small domain in the N terminus of the regulatory alpha-subunit Kv2. 3 modulates Kv2.1 potassium channel gating.
Recent work has demonstrated the existence of regulatory K(+) channel alpha-subunits that are electrically silent but capable of forming heterotetramers with other pore-forming subunits to modify their function. We have investigated the molecular determinant of the modulatory effects of Kv2.3, a silent K(+) channel alpha-subunit specific of brain. This subunit induces on Kv2.1 channels a marked deceleration of activation, inactivation, and closing kinetics. We constructed chimeras of the Kv2.1 and Kv2.3 proteins and analyzed the K(+) currents resulting from the coexpression of the chimeras with Kv2.1. The data indicate that a region of 59 amino acids in the N terminus, adjacent to the first transmembrane segment, is the major structural element responsible for the regulatory function of Kv2.3. The sequence of this domain of Kv2.3 is highly divergent compared with the same region in the other channels of the Kv2 family. Replacement of the regulatory fragment of Kv2.3 by the equivalent of Kv2.1 leads to loss of modulatory function, whereas gain of modulatory function is observed when the Kv2.3 fragment is transferred to Kv2.1. Thus, this study identifies a N-terminus domain involved in Kv2.1 channel gating and in the modulation of this channel by a regulatory alpha-subunit.


Public attitudes towards community pharmacy attributes and preferences for methods for promotion of public health services.
To identify attitudes towards pharmacy characteristics and promotional methods for selected pharmacy public health services (lifestyle advice and screening for cardiovascular risk factors) among different sectors of the general public. Cross-sectional survey, using a previously validated questionnaire. Three survey methods were used, across 15 areas of England, to maximize diversity: face-to-face; telephone; and self-completion of paper questionnaires. Responses to closed questions regarding characteristics and promotion were quantified and differences among sub-groups explored by univariate and multivariate analysis. In total, 2661 responses were available for analysis: 2047 face-to-face; 301 telephone; and 313 paper. There were strong preferences for a pharmacy near to home or doctor's surgery and for long opening hours, particularly among employed people and non-whites. Fifty percent preferred not to use a pharmacy in a supermarket, particularly older people, the retired, those of lower education and frequent pharmacy users. Personal recommendation by health professionals or family/friends was reported as most likely to encourage uptake of pharmacy public health services, with older people and males being less likely and frequent pharmacy users more likely to perceive any promotional method as influential. Posters/leaflets were preferred over mass-media methods, with fewer than 30% perceiving the latter as potentially influential. Pharmacists, pharmacy companies and service commissioners should use promotional methods favoured by potential users of pharmacy public health services and be aware of differences in attitudes when trying to reach specific population sub-groups. For personal recommendation to be successful, good inter-professional working and a pro-active approach to existing customers are needed.


A National Assessment on Patient Safety Curricula in Undergraduate Medical Education: Results From the 2012 Clerkship Directors in Internal Medicine Survey.
Patient safety is a cornerstone of quality patient care, and educating medical students about patient safety is of growing importance. This investigation was a follow-up to a 2006 study to assess the current status of patient safety curricula within undergraduate medical education in North America with the additional goals of identifying areas for improvement and barriers to implementation. Thirteen items regarding patient safety were part of the 2012 Clerkship Directors in Internal Medicine annual survey. Questions addressed curriculum content, delivery, and barriers to implementation. Ninety-nine clerkship directors (82%) responded. Forty-one (45.6%) reported that their medical school had a patient safety curriculum taught during medical school as compared with 25% in a 2006 survey. Fifteen (20%) reported satisfaction with students' level of safety competency at the end of the clerkship. Barriers to implementation included lack of faculty time (n = 57, 78.1%), lack of trained faculty (n = 47, 65.3%), and lack of a mandate from school's dean's office (n = 27, 38.0%). Our study found that less than half of North American medical schools have a formal patient safety curriculum; although this is higher than in 2006, it still exemplifies a major gap in undergraduate medical education.


SHINE: protein language model-based pathogenicity prediction for short inframe insertion and deletion variants.
Accurate variant pathogenicity predictions are important in genetic studies of human diseases. Inframe insertion and deletion variants (indels) alter protein sequence and length, but not as deleterious as frameshift indels. Inframe indel Interpretation is challenging due to limitations in the available number of known pathogenic variants for training. Existing prediction methods largely use manually encoded features including conservation, protein structure and function, and allele frequency to infer variant pathogenicity. Recent advances in deep learning modeling of protein sequences and structures provide an opportunity to improve the representation of salient features based on large numbers of protein sequences. We developed a new pathogenicity predictor for SHort Inframe iNsertion and dEletion (SHINE). SHINE uses pretrained protein language models to construct a latent representation of an indel and its protein context from protein sequences and multiple protein sequence alignments, and feeds the latent representation into supervised machine learning models for pathogenicity prediction. We curated training data from ClinVar and gnomAD, and created two test datasets from different sources. SHINE achieved better prediction performance than existing methods for both deletion and insertion variants in these two test datasets. Our work suggests that unsupervised protein language models can provide valuable information about proteins, and new methods based on these models can improve variant interpretation in genetic analyses.


The age-related decline in Olympic distance triathlon performance differs between males and females.
The aim of this cross-sectional study was to compare the age-related declines in swimming, cycling, and running and overall race times between males and females in an Olympic distance triathlon, the 'Zürich Triathlon' in Switzerland. Swimming (1.5 km), cycling (40 km), running (10 km) and overall race times of 7939 total finishers (1666 females and 6273 males) from 2000 to 2010 in the "Zürich Triathlon" were analysed. There was a significant (P<0.001) age effect on performance for both males and females independently of the discipline. No significant difference in the overall race time was observed between 18 and 34 years for both genders. There was an interaction (P<0.001) of age and gender for swimming, cycling and overall race times, but not for running times. The age-related declines in performance were significantly less pronounced for males compared with females for swimming (>50 years), for cycling (>40 years) and for overall race time (>40 years). These data suggest that the age and gender interactions in an Olympic distance triathlon performance differ between the three locomotion modes. Further studies investigating training regimes, competition experience or socio-demographic factors are needed to get a better insight in the phenomenon of the gender specific age-related declines in endurance performance.


An improved genome assembly uncovers prolific tandem repeats in Atlantic cod.
The first Atlantic cod (Gadus morhua) genome assembly published in 2011 was one of the early genome assemblies exclusively based on high-throughput 454 pyrosequencing. Since then, rapid advances in sequencing technologies have led to a multitude of assemblies generated for complex genomes, although many of these are of a fragmented nature with a significant fraction of bases in gaps. The development of long-read sequencing and improved software now enable the generation of more contiguous genome assemblies. By combining data from Illumina, 454 and the longer PacBio sequencing technologies, as well as integrating the results of multiple assembly programs, we have created a substantially improved version of the Atlantic cod genome assembly. The sequence contiguity of this assembly is increased fifty-fold and the proportion of gap-bases has been reduced fifteen-fold. Compared to other vertebrates, the assembly contains an unusual high density of tandem repeats (TRs). Indeed, retrospective analyses reveal that gaps in the first genome assembly were largely associated with these TRs. We show that 21% of the TRs across the assembly, 19% in the promoter regions and 12% in the coding sequences are heterozygous in the sequenced individual. The inclusion of PacBio reads combined with the use of multiple assembly programs drastically improved the Atlantic cod genome assembly by successfully resolving long TRs. The high frequency of heterozygous TRs within or in the vicinity of genes in the genome indicate a considerable standing genomic variation in Atlantic cod populations, which is likely of evolutionary importance.


Long-term survivors of childhood, adolescent and young adult non-Hodgkin lymphoma.
Progress in overall survival rates for childhood non-Hodgkin lymphoma (NHL) can be largely attributed to effective development and conduct of a number of international treatment studies. Knowledge gained from these studies has shifted the treatment paradigm from a "one-size fits all" strategy to a histologically dependent approach. More specifically, many now adhere to a risk-stratified approach, prescribing cumulative doses and intensities of chemotherapeutic exposures based upon the aggressiveness of disease. Moreover, recognition that high cure rates could be achieved without the use of radiation has eliminated the use of this modality in frontline settings for the majority of newly diagnosed children. These changes have contributed to the emergence of a heterogeneous group of NHL survivors. As the number of NHL survivors continues to increase, providers will encounter a wide spectrum of individuals whose risk for long-term complications are accordingly diverse. The following review summarizes the existing literature surrounding late effects, such as chronic health conditions, functional and neurocognitive performance outcomes, and health-related quality of life, that are unique to NHL survivors, as well as those extrapolated from the broader childhood cancer survivor population.


Computed Tomographic Evaluation of Joint Geometry in Patients With End-Stage Ankle Osteoarthritis.
Deformation of the talus and the distal tibia can be frequently observed during ankle joint osteoarthritis (OA). The aim of this study was to objectify these morphologic changes. We hypothesized that a flattening of the talus and a broadening of the distal tibia surface occurs in end-stage OA of the ankle joint. Twenty-seven computed tomography (CT) ankle joint examinations of unilateral ankle OA were matched by sex and age with 27 CT examinations of healthy ankle joints. Three-dimensional reformatting and measurements were performed with geometry analysis software. The following parameters were assessed: sagittal radius of the talus, talus height, and mediolateral and anteroposterior width of the distal tibial joint surface. Medial, midsagittal, and lateral sagittal arc radii of osteoarthritic tali were significantly larger compared to tali of controls. There was a statistically significant difference in the height of the osteoarthritic talar dome in the medial and in the lateral frontal segment and in the medial central segment compared to tali of controls. The anteroposterior width and the sagittal curvature of the distal tibia was significantly larger in OA ankles than in the control group. The mediolateral measurements were comparable across both groups. Flattening of the talus appears to be more pronounced in the frontal aspect of the talus. The distal tibia broadens anteroposteriorly. These findings may contribute to better understanding of ankle OA development. Level III, retrospective comparative cohort study.


Adverse perinatal outcomes associated with protease inhibitor-based antiretroviral therapy in pregnant women living with HIV: A systematic review and meta-analysis.
The World Health Organization recommends protease inhibitor (PI)-based antiretroviral therapy (ART) as second-line and third-line regimens in pregnant women living with HIV (WLHIV). US, European, and UK guidelines include PI-based ART as first-line regimens, but advise against the use of lopinavir/ritonavir (LPV/r)-based ART, citing an increased risk of preterm birth (PTB). We aimed to assess the risk of adverse perinatal outcomes in WLHIV receiving PI-ART and the comparative risks associated with different PI-ART regimens. We conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between Jan 1, 1980, and April 20, 2020. Two investigators independently selected studies and extracted data from studies reporting on the association of pregnant WLHIV receiving PI-ART with 11 perinatal outcomes: PTB, very PTB (VPTB), spontaneous PTB (sPTB), low birth weight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Pairwise random-effects meta-analyses examined the risk of each adverse perinatal outcome in WLHIV receiving PI-ART compared to non-PI-based ART (non-PI-ART), and comparisons of different PI-ART regimens. Quality assessments of studies were performed, subgroup and sensitivity analyses were conducted based on country income status and study quality, heterogeneity assessed, and the effect of adjustment for confounding factors assessed. The protocol is registered with PROSPERO, CRD42021248987. Of 94,594 studies identified, 34 cohort studies including 57,546 women met the inclusion criteria. Random-effects meta-analyses showed that PI-ART was associated with a significantly increased risk of SGA (Relative Risk [RR] 1.24, 95% CI 1.08-1.43; I2 =66.7%) and VSGA (RR 1.40, 1.09-1.81; I2 =0.0%), but not PTB (RR 1.09, 0.95-1.24; I2 =68.3%), VPTB (RR 1.30, 0.78-2.18; I2 =43.0%), sPTB (RR 1.91, 0.61-5.99; I2 =95.7%), LBW (RR 1.04, 0.85-1.27; I2 =63.9%), VLBW (RR 0.72, 0.37-1.43; I2 =37.9%), term LBW (RR 0.94, 0.30-3.02; I2 =0.0%), stillbirth (RR 1.04, 0.60-1.79; I2 =0.0%), and neonatal death (RR 1.82, 0.97-3.40; I2 =0.0%), compared to non-PI-ART. We found no significant differences in perinatal outcomes between ART regimens containing LPV/r, atazanavir/ritonavir (ATV/r), and darunavir/ritonavir (DRV/r), which are the most commonly used PIs. PI-ART is associated with an increased risk of SGA and VSGA, but not PTB or other perinatal outcomes. No significant differences in perinatal outcomes were found between LPV/r, ATV/r, and DRV/r. These findings should inform clinical guidelines, and further efforts should be made to improve perinatal outcomes among pregnant WLHIV. None.


Damming the rivers of the Amazon basin.
More than a hundred hydropower dams have already been built in the Amazon basin and numerous proposals for further dam constructions are under consideration. The accumulated negative environmental effects of existing dams and proposed dams, if constructed, will trigger massive hydrophysical and biotic disturbances that will affect the Amazon basin's floodplains, estuary and sediment plume. We introduce a Dam Environmental Vulnerability Index to quantify the current and potential impacts of dams in the basin. The scale of foreseeable environmental degradation indicates the need for collective action among nations and states to avoid cumulative, far-reaching impacts. We suggest institutional innovations to assess and avoid the likely impoverishment of Amazon rivers.


Direct and continuous dosing of propofol can saturate Ex vivo ECMO circuit to improve propofol recovery.
Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device that provides life-saving complete respiratory and cardiac support in patients with cardiorespiratory failure. The majority of drugs prescribed to patients on ECMO lack a dosing strategy optimized for ECMO patients. Several studies demonstrated that dosing is different in this population because the ECMO circuit components can adsorb drugs and affect drug exposure substantially. Saturation of ECMO circuit components by drug disposition has been posited but has not been proven. In this study, we have attempted to determine if propofol adsorption is saturable in ex vivo ECMO circuits. We injected ex vivo ECMO circuits with propofol, a drug that is highly adsorbed to the ECMO circuit components. Propofol was injected as a bolus dose (50 μg/mL) and a continuous infusion dose (6 mg/h) to investigate the saturation of the ECMO circuit. After the bolus dose, only 27% of propofol was recovered after 30 minutes which is as expected. However, >80% propofol was recovered after the infusion dose which persisted even when the infusion dose was discontinued. Our results suggest that if ECMO circuits are dosed directly with propofol, drug adsorption can be eliminated as a cause for altered drug exposure. Field of Research: Artificial Lung/ECMO.


Hyperbaric oxygen as a radiotherapeutic adjuvant in advanced cancer of the uterine cervix: preliminary results of a randomized trial.
From September 1968 to March 1974, a randomized clinical trial was carried out, using conventional fractionation, i.e., five treatments per week, in 233 patients with advanced cancers of the uterine cervix--Stages IIB, IIA, IIIB and IVA. The age limit was 70 years and all patients had medical clearance. Lymphangiography and, in some patients, an exploratory laparotomy with selective lymphadenectomy, were done prior to treatment to determine the extent of nodal disease. The staging has not been changed either by lymphangiogram or lymphadenectomy findings. A few patients with bulky Stage I and IIA lesions were entered into the trial because of extensive nodal disease demonstrated either by lymphangiogram and/or lymphadenectomy. First, the patients were grouped according to the clinical stage. The secondary stratification was according to the lymphangiogram and/or selective lymphadenectomy findings. The patients were then randomized to air or hyperbaric oxygen within each group. The patients were pressurized in a Vickers chamber at 3 atmosphere absolute, using a 20-minute soak time prior to the irradition. The size of the external beam portal was determined by the status of the nodes. The difference in absolute NED (no evidence of disease) survival rates for both groups as a whole and by stages is not statistically significant. There is no difference in the incidence of failures in the irradiated area between the HPO and air patients. There is no increase in distant metastases in the HP group. It does not seem that the HPO has had an effect on the major complications. However, there was an increase in the incidence of complications with extended fields. The addition of lymphadenectomy had increased the incidence of fatal complications, even with routine pelvic portals. The negative results of this trial with conventional fractioantion should not lead to the conclusion that HPO could not be useful with schemes using a few high dose fractions.


Computer simulation of metabolism in pyruvate-perfused rat heart. III. Pyruvate dehydrogenase.
A physiologically and biochemically realistic model of the regulation of pyruvate dehydrogenase complex (PDH) was constructed for the perfused rat heart. It includes conversion between inactive (phospho) and active (dephospho) forms by a specific protein kinase (PDHK) and phosphoprotein phosphatase (PDHP). The activity of the tightly bound PDHK is influenced by synergistic activation/inhibition by acetyl CoA/CoASH and NADH/NAD. PDHK in this simulation was more sensitive to the fraction of ADP that was Mg2+-chelated than to the ATP-to-ADP ratio. Ca2+ stimulates binding of Mg2+-dependent PDHP to the complex; the bound enzyme was considered to be the active species. The fraction of PDH in the active form, rather than substrate and inhibitor levels, determines PDH activity under these conditions. This fraction depends on the present value and recent history of the difference between PDHK and PDHP activities. Both of these are active continuously and continuously control PDH.


Factors associated with awareness of vocational rehabilitation services after traumatic brain injury.
To determine the characteristics of persons with traumatic brain injury (TBI) who were aware of vocational rehabilitation (VR) services 1 year after hospital discharge. Medical record and longitudinal survey data on persons with TBI were analyzed using logistic regression and bivariate analyses. The study sample was drawn from a population-based sample of persons hospitalized in 1 of 8 hospitals in north-central Alabama. Criteria for inclusion were: (1) being at least 18 years of age or older when injured; (2) having sustained a TBI; (3) being discharged alive after a hospital stay of at least 3 days; (4) residing and having been injured in the state of Alabama; (5) participation in a 12-month follow-up interview. Patients' awareness of VR service programs and benefits. Awareness of VR service programs was associated with: (1) being Caucasian; (2) being more often employed at the time of injury; (3) being more often severely injured; and (4) more frequently receiving outpatient rehabilitation. Interventions should target non-Caucasians, those who were unemployed when injured, those less severely injured, and those not receiving outpatient rehabilitation services after hospital discharge. Periodic review of VR benefits with patients and their families should be undertaken by health care and VR professionals.


Intrauterine insemination in The Netherlands.
The aim of this retrospective study was to assess the results of intrauterine insemination (IUI) in The Netherlands, using data from 2003 taken from hospital annual reports and reports from individual gynaecologists. By extrapolation, the total number of IUI cycles performed that year nationwide, and the related outcomes, was estimated. IUI was performed in 91 of the country's 101 hospitals. Of these, 58 (64%) registered their IUI results and performed 19,846 IUI cycles. The mean pregnancy rate per cycle was 9.0% and the ongoing pregnancy rate per cycle was 7.3%. Multiple pregnancies occurred in 9.5% of the ongoing pregnancies. Extrapolation of the data suggested that approximately 28,500 IUI cycles were performed, of which approximately 2000 resulted in an ongoing pregnancy. The number of multiple pregnancies following IUI was estimated to be 180 (9.0%). According to the national IVF registry, 9761 IVF cycles were started in 2003, resulting in 2,028 ongoing pregnancies (20.8% per cycle) and 439 twin pregnancies (21.6% per ongoing pregnancy). In conclusion, the pregnancy rate per IUI cycle in The Netherlands (9.0%) was comparable with that reported in the international literature (8.7%). The contribution made by IUI to the number of multiple pregnancies in The Netherlands was much smaller than the contribution made by IVF.


Cumulative doses analysis in young trauma patients: a single-centre experience.
Multidetector computed tomography (MDCT) represents the main source of radiation exposure in trauma patients. The radiation exposure of young patients is a matter of considerable medical concern due to possible long-term effects. Multiple MDCT studies have been observed in the young trauma population with an increase in radiation exposure. We have identified 249 young adult patients (178 men and 71 women; age range 14-40 years) who had received more than one MDCT study between June 2010 and June 2014. According to the International Commission on Radiological Protection publication, we have calculated the cumulative organ dose tissue-weighting factors by using CT-EXPO software(®). We have observed a mean cumulative dose of about 27 mSv (range from 3 to 297 mSv). The distribution analysis is characterised by low effective dose, below 20 mSv, in the majority of the patients. However, in 29 patients, the effective dose was found to be higher than 20 mSv. Dose distribution for the various organs analysed (breasts, ovaries, testicles, heart and eye lenses) shows an intense peak for lower doses, but in some cases high doses were recorded. Even though cumulative doses may have long-term effects, which are still under debate, high doses are observed in this specific group of young patients.


Predicting gene function using hierarchical multi-label decision tree ensembles.
S. cerevisiae, A. thaliana and M. musculus are well-studied organisms in biology and the sequencing of their genomes was completed many years ago. It is still a challenge, however, to develop methods that assign biological functions to the ORFs in these genomes automatically. Different machine learning methods have been proposed to this end, but it remains unclear which method is to be preferred in terms of predictive performance, efficiency and usability. We study the use of decision tree based models for predicting the multiple functions of ORFs. First, we describe an algorithm for learning hierarchical multi-label decision trees. These can simultaneously predict all the functions of an ORF, while respecting a given hierarchy of gene functions (such as FunCat or GO). We present new results obtained with this algorithm, showing that the trees found by it exhibit clearly better predictive performance than the trees found by previously described methods. Nevertheless, the predictive performance of individual trees is lower than that of some recently proposed statistical learning methods. We show that ensembles of such trees are more accurate than single trees and are competitive with state-of-the-art statistical learning and functional linkage methods. Moreover, the ensemble method is computationally efficient and easy to use. Our results suggest that decision tree based methods are a state-of-the-art, efficient and easy-to-use approach to ORF function prediction.


Surgical intervention for paediatric infusion-related extravasation injury: a systematic review.
This systematic review aims to assess the quality of literature supporting surgical interventions for paediatric extravasation injury and to determine whether there is sufficient evidence to support invasive techniques in children. We performed a systematic review by searching Ovid MEDLINE and EMBASE as well as AMED, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and clinicaltrials.gov from inception to February 2019. Studies other than case reports were eligible for inclusion if the population was younger than 18 years old, if there was a surgical intervention aimed at treating extravasation injury and if they reported on outcomes. Study quality was graded according to the National Institutes of Health study quality assessment tools. 26 studies involving 728 children were included-one before-and-after study and 25 case series. Extravasation injuries were mainly confined to skin and subcutaneous tissues but severe complications were also encountered, including amputation (one toe and one below elbow). Of the surgical treatments described, the technique of multiple puncture wounds and instillation of saline and/or hyaluronidase was the most commonly used. However, there were no studies in which its effectiveness was tested against another treatment or a control and details of functional and aesthetic outcomes were generally lacking. Surgical management is commonly reported in the literature in cases where there is significant soft tissue injury but as there are no comparative studies, it is unclear whether this is optimal. Further observational and experimental research evaluating extravasation injuries, including a centralised extravasation register using a universal grading scheme and core outcome set with adequate follow-up, are required to provide evidence to guide clinician decision-making.


Magnetic Functionalized Nanoparticles for Biomedical, Drug Delivery and Imaging Applications.
Medicine is constantly looking for new and improved treatments for diseases, which need to have a high efficacy and be cost-effective, creating a large demand on scientific research to discover such new treatments. One important aspect of any treatment is the ability to be able to target only the illness and not cause harm to another healthy part of the body. For this reason, metallic nanoparticles have been and are currently being extensively researched for their possible medical uses, including medical imaging, antibacterial and antiviral applications. Superparamagnetic metal nanoparticles possess properties that allow them to be directed around the body with a magnetic field or directed to a magnetic implant, which opens up the potential to conjugate various bio-cargos to the nanoparticles that could then be directed for treatment in the body. Here we report on some of the current bio-medical applications of various metal nanoparticles, including single metal nanoparticles, functionalized metal nanoparticles, and core-shell metal nanoparticles using a core of Fe3O4 as well as synthesis methods of these core-shell nanoparticles.


Discordance between mycobacterial interspersed repetitive-unit-variable-number tandem-repeat typing and IS6110 restriction fragment length polymorphism genotyping for analysis of Mycobacterium tuberculosis Beijing strains in a setting of high incidence of tuberculosis.
IS6110 restriction fragment length polymorphism (RFLP) genotyping is the most widely used genotyping method to study the epidemiology of Mycobacterium tuberculosis. However, due to the complexity of the IS6110 RFLP genotyping technique, and the interpretation of RFLP data, mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) genotyping has been proposed as the new genotyping standard. This study aimed to determine the discriminatory power of different MIRU-VNTR locus combinations relative to IS6110 RFLP genotyping, using a collection of Beijing genotype M. tuberculosis strains with a well-established phylogenetic history. Clustering, diversity index, clustering concordance, concordance among unique genotypes, and divergent and convergent evolution were calculated for seven combinations of 27 different MIRU-VNTR loci and compared to IS6110 RFLP results. Our results confirmed previous findings that MIRU-VNTR genotyping can be used to estimate the extent of recent or ongoing transmission. However, molecular epidemiological linking of cases varied significantly depending on the genotyping method used. We conclude that IS6110 RFLP and MIRU-VNTR loci evolve independently and at different rates, which leads to discordance between transmission chains predicted by the respective genotyping methods. Concordance between the two genotyping methods could be improved by the inclusion of genetic distance (GD) into the clustering formulae for some of the MIRU-VNTR loci combinations. In summary, our findings differ from previous reports, which may be explained by the fact that in settings of low tuberculosis incidence, the genetic distance between epidemiologically unrelated isolates was sufficient to define a strain using either marker, whereas in settings of high incidence, continuous evolution and persistence of strains revealed the weaknesses inherent to these markers.


Distribution of corticosteroid receptors in mature oligodendrocytes and oligodendrocyte progenitors of the adult mouse brain.
The expression of glucocorticoid receptors (GRs) was investigated immunohistochemically in two different lineages of oligodendrocytes, using carbonic anhydrase (CA) II and neuron glial antigen (NG) 2 as markers of mature oligodendrocytes and oligodendrocyte progenitors, respectively. We focused on the gray matter regions, including CA1, CA3 and the dentate gyrus of the hippocampus, the primary somatosensory cortex barrel field and the basolateral amygdala, and the white matter regions, including the corpus callosum, external capsule and fimbria of the hippocampus. More than 80% of CAII-immunoreactive (IR) cells and more than 95% of NG2-IR cells expressed GRs in various regions of the brain. In contrast, neither CAII-IR cells nor NG2-IR cells expressed mineralocorticoid receptors (MRs) in the same regions. The intensity of GR expression was drastically reduced in CA II-IR cells and NG2-IR cells in the same regions in adrenalectomized mice. Finally, steroid receptor co-activator (SRC)-1 and p300, both of which are cofactors for GR, were expressed in the gray and white matter regions in NG2-IR cells, but not in CAII-IR cells. These results suggest that the expression of GRs in oligodendrocytes and their progenitor cells mediates several functions in vivo, including differentiation and myelination, as a major target of glucocorticoids and their cofactors.


A pilot study of a mindfulness based stress reduction program in adolescents with implantable cardioverter defibrillators or pacemakers.
Adolescents with implantable cardioverter defibrillators (ICDs) or pacemakers (PMs) face unique challenges that can cause psychosocial distress. Psychosocial interventions are effective for adults with cardiac devices and could potentially impact adolescents' adjustment to these devices. Mindfulness Based Stress Reduction (MBSR) is a structured psycho-educational program that includes meditation, yoga, and group support and has been studied extensively among adults. This study examined the feasibility of the MBSR program for adolescents with ICDs/PMs, a population previously unexamined in the research literature. The participants completed measures of anxiety and depression (Hospital Anxiety and Depression Scale) and coping (Responses to Stress Questionnaire) at baseline and after the six-session MBSR intervention. Mean age of the cohort (n = 10) was 15 ± 3 years, 6 were male, 6 had a PM, and 4 had an ICD. Feasibility was demonstrated by successful recruitment of 10 participants, 100 % participation and completion. Anxiety decreased significantly following the intervention, with a large effect size, t[9] = 3.67, p < .01, ŋ (2) = .59. Anxiety frequency decreased from baseline to post-intervention (Fisher's exact test p = .024), and 90 % of participants reported decreased anxiety scores post-intervention. Coping skills related negatively to anxiety (r = -.65, p = .04) and depression (r = -.88, p = .001). Post-intervention, the group independently formed their own Facebook group and requested to continue meeting monthly. Although generalizability is limited due to the small sample size, this successful pilot study paves the way for larger studies to examine the efficacy of MBSR interventions in adolescents with high-risk cardiac diagnoses.


Thalidomide for the treatment of esophageal aphthous ulcers in patients with human immunodeficiency virus infection. National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group.
A multicenter, double-blind, randomized, placebo-controlled clinical trial was conducted to determine the safety and efficacy of thalidomide for treating esophageal aphthous ulceration in persons infected with human immunodeficiency virus (HIV). Twenty-four HIV-infected patients with biopsy-confirmed aphthous ulceration of the esophagus were randomly assigned to receive either oral thalidomide, 200 mg/day, or oral placebo daily for 4 weeks. Eight (73%) of 11 patients randomized to receive thalidomide had complete healing of aphthous ulcers at the 4-week endoscopic evaluation, compared with 3 (23%) of 13 placebo-randomized patients (odds ratio, 13.82; 95% confidence interval, 1.16-823.75; P=.033). Odynophagia and impaired eating ability caused by esophageal aphthae were improved markedly by thalidomide treatment. Adverse events among patients receiving thalidomide included somnolence (4 patients), rash (2 patients), and peripheral sensory neuropathy (3 patients). Thalidomide is effective in healing aphthous ulceration of the esophagus in patients infected with HIV.


Acceptability of Health Care-Related Risks: A Literature Review.
Risk management aims at reducing risks associated with hospital care to an acceptable level, both in their frequency and their impact on health. The social acceptability of risk on the part of the general population and of the health-care professionals, faced with regular information about adverse events, is undoubtedly evolving rapidly.In contrast to risk acceptability, the concept of risk perception is of limited interest to risk managers because it does not inform on the behaviors and actions resulting from these perceptions. The aim of this work was to define the concept of social acceptability of risk through an in-depth examination of a wide-ranging and multidisciplinary literature. A 1990-2010 English and French literature review was carried out in medical, epidemiological, and human and social sciences online databases, gray literature, and books. Of the 5931 references retrieved, 203 met the inclusion criteria. We identified contributions from 5 major research fields: economic, sociocognitive, psychometric, sociological/anthropological, and interactionist. When assessing risks, individuals use a variety of psychological and social processes that include their perception not only of a given risk but also of their own personal and social resources. This global perception has a direct impact on the responses and actual behavior of individuals and groups, enabling them to cope with the risk and/or manage it. Social acceptability includes perceptions related to risks and the stated intentions of individual behavior. This concept may therefore be relevant for defining local and national patient safety priorities.


Experiences of Mothers Who Are Child Sexual Abuse Survivors: A Qualitative Exploration.
Child sexual abuse has been associated with a number of problems affecting women over their lifespan, including difficulties with parenting. However, there is a modest number of qualitative studies examining the impact of child sexual abuse on survivors who are mothers. There is a particular need for qualitative investigations that ask survivors who are mothers general questions about the impact of child sexual abuse on their lives rather than those that specifically ask about the impact of child sexual abuse on parenting. The former approach would allow survivors to describe effects that may impact parenting but that survivors do not consciously link to affecting their parenting. Such information may inform interventions to assist this population of survivors. This secondary data analysis examined themes revealed in interviews with 44 survivors of child sexual abuse who were mothers. Participants were seeking treatment for their child sexual abuse and completed an in-person interview in which they were asked open-ended questions about the sexual abuse they experienced as a child and how their abuse affects them now as adults. The interviews were recorded, transcribed, and coded using thematic analysis. The following six themes emerged from the narratives: (a) being a parent, (b) family of origin dysfunction, (c) the impact of abuse, (d) the abuse history and response to abuse, (e) coping, and (f) hopes and desires for the future. This study highlights several ways in which child sexual abuse impacts survivors who are mothers, areas for further study, and the need for interventions to assist this population in meeting the challenges they face as mothers.


Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease.
In this study, we describe the generation and partial characterization of Krüppel-like zinc finger protein Glis3 mutant (Glis3(zf/zf)) mice. These mice display abnormalities very similar to those of patients with neonatal diabetes and hypothyroidism syndrome, including the development of diabetes and polycystic kidney disease. We demonstrate that Glis3 localizes to the primary cilium, suggesting that Glis3 is part of a cilium-associated signaling pathway. Although Glis3(zf/zf) mice form normal primary cilia, renal cysts contain relatively fewer cells with a primary cilium. We further show that Glis3 interacts with the transcriptional modulator Wwtr1/TAZ, which itself has been implicated in glomerulocystic kidney disease. Wwtr1 recognizes a P/LPXY motif in the C terminus of Glis3 and enhances Glis3-mediated transcriptional activation, indicating that Wwtr1 functions as a coactivator of Glis3. Mutations in the P/LPXY motif abrogate the interaction with Wwtr1 and the transcriptional activity of Glis3, indicating that this motif is part of the transcription activation domain of Glis3. Our study demonstrates that dysfunction of Glis3 leads to the development of cystic renal disease, suggesting that Glis3 plays a critical role in maintaining normal renal functions. We propose that localization to the primary cilium and interaction with Wwtr1 are key elements of the Glis3 signaling pathway.


Electrocardiographic and cardiovascular effects of subconvulsive stimulation during titrated right unilateral ECT.
The American Psychiatric Association Task Force on ECT has recommended that electroconvulsive therapy (ECT) stimuli be dosed at "moderately suprathreshold" intensities. Empiric estimation of the convulsive threshold by stimulus dose titration may expose the patient to subconvulsive stimuli, and subconvulsive stimuli have been reported by some to carry serious cardiovascular risk. This study examines the electrocardiographic (ECG) and cardiovascular effects of subconvulsive stimuli. Forty consecutive inpatients (29 women, 11 men; mean age 68 years) with major depression received subconvulsive stimuli during titrated, right unilateral (RUL) ECT. Successively larger stimuli were administered until a convulsion began. The effects of subconvulsive stimuli on the ECG, heart rate (HR), and blood pressure (BP) were assessed with multivariate repeated measures analysis. Subconvulsive stimuli prolonged the R-R interval and decreased HR compared with baseline values immediately before the subconvulsive stimulus, but the changes were of questionable clinical significance. BP was not changed. In conclusion, subconvulsive stimuli are well tolerated in the context of titrated RUL ECT. If stimulus dose titration proves to be useful in optimizing efficacy with fewer cognitive side effects, then cardiovascular considerations should not be an obstacle in the application of stimulus dose titration in most patients.


Out of balance--systemic iron homeostasis in iron-related disorders.
Iron is an essential element in our daily diet. Most iron is required for the de novo synthesis of red blood cells, where it plays a critical role in oxygen binding to hemoglobin. Thus, iron deficiency causes anemia, a major public health burden worldwide. On the other extreme, iron accumulation in critical organs such as liver, heart, and pancreas causes organ dysfunction due to the generation of oxidative stress. Therefore, systemic iron levels must be tightly balanced. Here we focus on the regulatory role of the hepcidin/ferroportin circuitry as the major regulator of systemic iron homeostasis. We discuss how regulatory cues (e.g., iron, inflammation, or hypoxia) affect the hepcidin response and how impairment of the hepcidin/ferroportin regulatory system causes disorders of iron metabolism.


Psychogenic amnesia--a malady of the constricted self.
Autobiographical-episodic memory is the conjunction of subjective time, autonoetic consciousness and the experiencing self. Understanding the neural correlates of autobiographical-episodic memory might therefore be essential for shedding light on the neurobiology underlying the experience of being an autonoetic self. In this contribution we illustrate the intimate relationship between autobiographical-episodic memory and self by reviewing the clinical and neuropsychological features and brain functional imaging correlates of psychogenic amnesia - a condition that is usually characterized by severely impaired retrograde memory functioning, in absence of structural brain damage as detected by standard imaging. We demonstrate that in this disorder the autobiographical-episodic memory deficits do not exist in isolation, but occur with impairments of the autonoetic self-consciousness, emotional processing, and theory of mind or executive functions. Furthermore functional and metabolic brain alterations involving regions that are agreed upon to exert crucial roles in memory processes were frequently found to accompany the psychogenic memory "loss".


SOX11 augments BCR signaling to drive MCL-like tumor development.
Mantle cell lymphoma (MCL) is characterized by increased B-cell receptor (BCR) signaling, and BTK inhibition is an effective therapeutic intervention in MCL patients. The mechanisms leading to increased BCR signaling in MCL are poorly understood, as mutations in upstream regulators of BCR signaling such as CD79A, commonly observed in other lymphomas, are rare in MCL. The transcription factor SOX11 is overexpressed in the majority (78% to 93%) of MCL patients and is considered an MCL-specific oncogene. So far, attempts to understand SOX11 function in vivo have been hampered by the lack of appropriate animal models, because germline deletion of SOX11 is embryonically lethal. We have developed a transgenic mouse model (Eμ-SOX11-EGFP) in the C57BL/6 background expressing murine SOX11 and EGFP under the control of a B-cell-specific IgH-Eμ enhancer. The overexpression of SOX11 exclusively in B cells exhibits oligoclonal B-cell hyperplasia in the spleen, bone marrow, and peripheral blood, with an immunophenotype (CD5+CD19+CD23-) identical to human MCL. Furthermore, phosphocytometric time-of-flight analysis of the splenocytes from these mice shows hyperactivation of pBTK and other molecules in the BCR signaling pathway, and serial bone marrow transplant from transgenic donors produces lethality with decreasing latency. We report here that overexpression of SOX11 in B cells promotes BCR signaling and a disease phenotype that mimics human MCL.


The M-channel blocker linopirdine is an agonist of the capsaicin receptor TRPV1.
Linopirdine is a well known blocker of voltage-gated potassium channels from the Kv7 (or KCNQ) family that generate the so called M current in mammalian neurons. Kv7 subunits are also expressed in pain-sensing neurons in dorsal root ganglia, in which they modulate neuronal excitability. In this study we demonstrate that linopirdine acts as an agonist of TRPV1 (transient receptor potential vanilloid type 1), another ion channel expressed in nociceptors and involved in pain signaling. Linopirdine induces increases in intracellular calcium concentration in human embryonic kidney 293 (HEK293) cells expressing TRPV1, but not TRPA1 and TRPM8 or in wild-type HEK293 cells. Linopirdine also activates an inward current in TRPV1-expressing HEK293 cells that is almost completely blocked by the selective TRPV1 antagonist capsazepine. At low concentrations linopirdine sensitizes both recombinant and native TRPV1 channels to heat, in a manner that is not prevented by the Kv7-channel opener flupirtine. Taken together, these results indicate that linopirdine exerts an excitatory action on mammalian nociceptors not only through inhibition of the M current but also through activation of the capsaicin receptor TRPV1.


Induced cell proliferation in putative haematopoietic tissues of the sea star, Asterias rubens (L.).
The coelomic fluid of the echinoderm Asterias rubens possesses large populations of circulating coelomocytes. This study aimed to expand the knowledge about the haematopoietic sources of these cells. Injection of the immune-stimulating molecules lipopolysaccharide (LPS) and concanavalin A (ConA) resulted in an increase in coelomocytes. To investigate if these molecules induce cell proliferation in putative haematopoietic tissues (HPTs), short-term exposure of the substitute nucleotide 5-bromo-2'-deoxyuridine (BrdU) was conducted. Immunohistochemical analysis, using fluorescein-labelled antibodies to trace BrdU, showed pronounced cell division in the coelomic epithelium and axial organ. In the pyloric caeca, not considered as an HPT, proliferation was not detected. BrdU labelling of monolayers of cells obtained by collagenase treatment of coelomic epithelium, axial organ and Tiedemann body revealed induced cell proliferation in response to both LPS and ConA while proliferation of pyloric caeca and circulating coelomocytes remained sparse. By using confocal microscopy it was observed that both the morphology and functional behaviour of cells released from explants of coelomic epithelium showed high similarity to those of circulating phagocytes. It was concluded that the increased coelomocyte numbers observed in response to LPS and ConA were reflected in an induced cell proliferation in coelomic epithelium, axial organ and Tiedemann body, which reinforces the idea that these organs are HPTs and the sources of coelomocyte renewal.


Experimental observations of mode-converted ion cyclotron waves in a tokamak plasma by phase contrast imaging.
The process of mode conversion, whereby an externally launched electromagnetic wave converts into a shorter wavelength mode(s) in a thermal plasma near a resonance in the index of refraction, is particularly important in a multi-ion species plasma near the ion cyclotron frequency. Using phase contrast imaging techniques (PCI), mode-converted electromagnetic ion cyclotron waves have been detected for the first time in the Alcator C-Mod tokamak near the H-3He ion-ion hybrid resonance region during high power rf heating experiments. The results agree with theoretical predictions.


Individual white matter bundle trajectories are associated with deep brain stimulation response in obsessive-compulsive disorder.
The ventral anterior limb of the internal capsule (vALIC) is a target for deep brain stimulation (DBS) in obsessive-compulsive disorder (OCD). Conventional surgical planning is based on anatomical landmarks. We hypothesized that treatment response depends on the location of the active DBS contacts with respect to individual white matter bundle trajectories. This study thus aimed to elucidate whether vALIC DBS can benefit from bundle-specific targeting. We performed tractography analysis of two fiber bundles, the anterior thalamic radiation (ATR) and the supero-lateral branch of the medial forebrain bundle (MFB), using diffusion-weighted magnetic resonance imaging (DWI) data. Twelve patients (10 females) who had received bilateral vALIC DBS for at least 12 months were included. We related the change in OCD symptom severity on the Yale-Brown obsessive-compulsive scale (Y-BOCS) between baseline and one-year follow-up with the distances from the active contacts to the ATR and MFB. We further analyzed the relation between treatment response and stimulation sites in standard anatomical space. We found that active stimulation of the vALIC closer to the MFB than the ATR was associated with better treatment outcome (p = 0.04; r2 = 0.34). In standard space, stimulation sites were largely overlapping between treatment (non)responders, suggesting response is independent of the anatomically defined electrode position. These findings suggest that vALIC DBS for OCD may benefit from MFB-specific implantation and highlight the importance of corticolimbic connections in OCD response to DBS. Prospective investigation is necessary to validate the clinical use of MFB targeting.


Extension of displacement limits in multiple-exposure sequences of apparent motion.
In order to examine the processes by which motion signals are combined over time, we presented subjects with random dot kinematograms which could vary in terms of the number of frames in the sequence and the duration between the onset of each stationary frame. Performance (as measured by the greatest displacement at which subjects could discriminate opposite directions of movement) improved with increasing number of displacements up to around 5 displacements, whilst manipulations of the frame duration had no affect upon this figure. Thus the results cannot be described in terms of a limited integration time. By creating sequences in which no dots underwent more than a single displacement we show that the improvement is not specific to individual dot paths. We suggest that these results could be accounted for in terms of a co-operative network in which mutual facilitation can propagate between detectors tuned to a common direction of motion.


Meta-analysis of erythrocyte polyunsaturated fatty acid biostatus in bipolar disorder.
Dietary deficiency in polyunsaturated fatty acids (PUFAs), including the omega-3 fatty acids eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), and excesses in omega-6 fatty acids, including linoleic acid (LA; 18:2n-6) and arachidonic acid (AA; 20:4n-6), may be associated with the pathophysiology of bipolar disorder. In an effort to provide clarification regarding the relationship between PUFA biostatus and bipolar disorder, this meta-analysis investigated studies comparing erythrocyte (red blood cell) membrane PUFA composition in patients with bipolar disorder and healthy controls. A meta-analysis was performed on case-control studies comparing erythrocyte PUFA (EPA, DHA, LA and AA) levels in patients with bipolar I disorder and healthy controls. Standardized effect sizes were calculated and combined using a random effects model. Six eligible case-control studies comprising n = 118 bipolar I patients and n = 147 healthy controls were included in the analysis. Compared with healthy controls, patients with bipolar I disorder exhibited robust erythrocyte DHA deficits (p = 0.0008) and there was a trend for lower EPA (p = 0.086). There were no significant differences in LA (p = 0.42) or AA (p = 0.64). Bipolar I disorder is associated with robust erythrocyte DHA deficits. These findings add to a growing body of evidence implicating omega-3 PUFA deficiency in the pathophysiology of bipolar disorder.


Medium-scale carbon nanotube thin-film integrated circuits on flexible plastic substrates.
The ability to form integrated circuits on flexible sheets of plastic enables attributes (for example conformal and flexible formats and lightweight and shock resistant construction) in electronic devices that are difficult or impossible to achieve with technologies that use semiconductor wafers or glass plates as substrates. Organic small-molecule and polymer-based materials represent the most widely explored types of semiconductors for such flexible circuitry. Although these materials and those that use films or nanostructures of inorganics have promise for certain applications, existing demonstrations of them in circuits on plastic indicate modest performance characteristics that might restrict the application possibilities. Here we report implementations of a comparatively high-performance carbon-based semiconductor consisting of sub-monolayer, random networks of single-walled carbon nanotubes to yield small- to medium-scale integrated digital circuits, composed of up to nearly 100 transistors on plastic substrates. Transistors in these integrated circuits have excellent properties: mobilities as high as 80 cm(2) V(-1) s(-1), subthreshold slopes as low as 140 m V dec(-1), operating voltages less than 5 V together with deterministic control over the threshold voltages, on/off ratios as high as 10(5), switching speeds in the kilohertz range even for coarse (approximately 100-microm) device geometries, and good mechanical flexibility-all with levels of uniformity and reproducibility that enable high-yield fabrication of integrated circuits. Theoretical calculations, in contexts ranging from heterogeneous percolative transport through the networks to compact models for the transistors to circuit level simulations, provide quantitative and predictive understanding of these systems. Taken together, these results suggest that sub-monolayer films of single-walled carbon nanotubes are attractive materials for flexible integrated circuits, with many potential areas of application in consumer and other areas of electronics.


Population structure of colonizing and invasive Staphylococcus aureus strains in northern Vietnam.
Staphylococcus aureus is an important global health problem worldwide. There is still scarce information on the population structure of S. aureus strains in Asia, where the majority of the world population lives. This study characterized the diversity of S. aureus strains in northern Vietnam through multilocus sequence typing (MLST). Eighty-five carriage isolates from the community and 77 invasive isolates from the clinical setting were selected and tested for meticillin resistance and the presence of Panton-Valentine leukocidin (PVL). MLST was performed on these isolates, of which CC59 (25.4 %), CC188 (17.3 %) and CC45 (16.7 %) were the predominant clonal complexes (CCs). CC59 carriage isolates had significantly lower rates of meticillin-resistant S. aureus (MRSA) than their corresponding clinical group isolates (32 vs 83 %). There were no significant differences in rates of MRSA between carriage isolates and clinical isolates of CC45 and CC188. CC59 carriage isolates were significantly lower in rates of PVL+ than CC59 clinical isolates (32 vs 83 %), but the converse was shown in CC45 isolates (14 vs 0 %, respectively). This study revealed vast differences in the molecular epidemiology and population structure of S. aureus in community and clinical settings in Vietnam. Nevertheless, the data underline the spread of virulent and/or resistant strains (MRSA and/or PVL+) in the community, suggesting the necessity for further surveillance to determine the mechanism of transmission of these strains (i.e. MRSA/PVL+) outside clinical settings.


The distraction effects of phone use during a crucial driving maneuver.
Forty-two licensed drivers were tested in an experiment that required them to respond to an in-vehicle phone at the same time that they were faced with making a crucial stopping decision. Using test track facilities, we also examined the influence of driver gender and driver age on these dual-task response capacities. Each driver was given task practice and then performed a first block of 24 trials, where one trial represented one circuit of the test track. Half of the trials were control conditions in which neither the stop-light was activated nor was the in-vehicle phone triggered. Four trials required only stop-light response and a further four, phone response only. The remaining four trials required the driver to complete each task simultaneously. The order of presentation of specific trials was randomized and the whole sequence was repeated in a second block giving 48 trials per driver. In-vehicle phone response also contained an embedded memory task that was evaluated at the end of each trial circuit. Results confirmed our previous observation that in the dual-task condition there was a slower response to the light change. To compensate for this slowed response, drivers subsequently brake more intensely. Most importantly, we recorded a critical 15% increase in non-response to the stop-light in the presence of the phone distraction task which equates with increased stop-light violations on the open road. These response patterns varied by driver age and driver gender. In particular, age had a large effect on task components that required speed of response to multiple, simultaneous demands. Since driving represents a highly complex and interactive environment, it is not possible to specify a simplistic relationship between these distraction effects and outcome crash patterns. However, we can conclude that such in-vehicle technologies erode performance safety margin and distract drivers from their critical primary task of vehicle control. As such it can be anticipated that a causal relation exists to collision events. This is a crucial concern for all in-vehicle device designers and for the many safety researchers and professionals seeking to reduce the adverse impacts of vehicle collisions.


Investigation of suspected nosocomial clusters of Staphylococcus haemolyticus infections.
To determine whether typing methods can discriminate among Staphylococcus haemolyticus isolates. Molecular epidemiological evaluation of S. haemolyticus isolates obtained from patients hospitalized on a hematology service and in a surgical intensive-care unit (SICU). A large Midwestern teaching hospital. None. Over 22 days, S. haemolyticus was isolated from five patients on the hematology service. Isolates from four patients had the same unusual antibiogram and biotype. Ribotyping, restriction endonuclease digestion of plasmid DNA (REAP), and whole chromosomal DNA analysis by pulsed-field gel electrophoresis (PFGE) confirmed that these isolates were identical and different from the fifth patient's isolate and from 6 control isolates. In a second cluster, 11 S. haemolyticus isolates obtained from eight patients in the SICU had similar antibiograms and biotypes. By REAP and ribotype analysis, isolates from four patients were identical. However, PFGE indicated that only two of these patients shared a common strain. Antibiograms or biotyping may discriminate among isolates of S. haemolyticus if the results of these tests are unusual. Many clinical isolates can be differentiated by REAP analysis, ribotyping, or PFGE. However, some isolates are identical by all of these methods, suggesting that they may have been transmitted nosocomially.


A Steiner tree-based method for biomarker discovery and classification in breast cancer metastasis.
Metastatic breast cancer is a leading cause of cancer-related deaths in women worldwide. DNA microarray has become an important tool to help identify biomarker genes for improving the prognosis of breast cancer. Recently, it was shown that pathway-level relationships between genes can be incorporated to build more robust classification models and to obtain more useful biological insight from such models. Due to the unavailability of complete pathways, protein-protein interaction (PPI) network is becoming more popular to researcher and opens a new way to investigate the developmental process of breast cancer. In this study, a network-based method is proposed to combine microarray gene expression profiles and PPI network for biomarker discovery for breast cancer metastasis. The key idea in our approach is to identify a small number of genes to connect differentially expressed genes into a single component in a PPI network; these intermediate genes contain important information about the pathways involved in metastasis and have a high probability of being biomarkers. We applied this approach on two breast cancer microarray datasets, and for both cases we identified significant numbers of well-known biomarker genes for breast cancer metastasis. Those selected genes are significantly enriched with biological processes and pathways related to cancer carcinogenic process, and, importantly, have much higher stability across different datasets than in previous studies. Furthermore, our selected genes significantly increased cross-data classification accuracy of breast cancer metastasis. The randomized Steiner tree based approach described in this study is a new way to discover biomarker genes for breast cancer, and improves the prediction accuracy of metastasis. Though the analysis is limited here only to breast cancer, it can be easily applied to other diseases.


Supervisor continuity or co-location: which matters in residency education? Findings from a qualitative study of remote supervisor family physicians in Australia and Canada.
Changes to health care systems and working hours have fragmented residents' clinical experiences with potentially negative effects on their development as professionals. Investigation of off-site supervision, which has been implemented in isolated rural practice, could reveal important but less overt components of residency education. Insights from sociocultural learning theory and work-based learning provided a theoretical framework. In 2011-2012, 16 family physicians in Australia and Canada were asked in-depth how they remotely supervised residents' work and learning, and for their reflections on this experience. The verbatim interview transcripts and researchers' memos formed the data set. Template analysis produced a description and interpretation of remote supervision. Thirteen Australian family physicians from five states and one territory, and three Canadians from one province, participated. The main themes were how remoteness changed the dynamics of care and supervision; the importance of ongoing, holistic, nonhierarchical, supportive supervisory relationships; and that residents learned "clinical courage" through responsibility for patients' care over time. Distance required supervisors to articulate and pass on their expertise to residents but made monitoring difficult. Supervisory continuity encouraged residents to build on past experiences and confront deficiencies. Remote supervision enabled residents to develop as clinicians and professionals. This questions the supremacy of co-location as an organizing principle for residency education. Future specialists may benefit from programs that give them ongoing and increasing responsibility for a group of patients and supportive continuity of supervision as residents.


Preexposure Prophylaxis for the Prevention of HIV Infection: US Preventive Services Task Force Recommendation Statement.
An estimated 1.1 million individuals in the United States are currently living with HIV, and more than 700 000 persons have died of AIDS since the first cases were reported in 1981. In 2017, there were 38 281 new diagnoses of HIV infection reported in the United States; 81% of these new diagnoses were among males and 19% were among females. Although treatable, HIV infection has no cure and has significant health consequences. To issue a new US Preventive Services Task Force (USPSTF) recommendation on preexposure prophylaxis (PrEP) for the prevention of HIV infection. The USPSTF reviewed the evidence on the benefits of PrEP for the prevention of HIV infection with oral tenofovir disoproxil fumarate monotherapy or combined tenofovir disoproxil fumarate and emtricitabine and whether the benefits vary by risk group, population subgroup, or regimen or dosing strategy; the diagnostic accuracy of risk assessment tools to identify persons at high risk of HIV acquisition; the rates of adherence to PrEP in primary care settings; the association between adherence and effectiveness of PrEP; and the harms of PrEP when used for HIV prevention. The USPSTF found convincing evidence that PrEP is of substantial benefit in decreasing the risk of HIV infection in persons at high risk of HIV acquisition. The USPSTF also found convincing evidence that adherence to PrEP is highly associated with its efficacy in preventing the acquisition of HIV infection; thus, adherence to PrEP is central to realizing its benefit. The USPSTF found adequate evidence that PrEP is associated with small harms, including kidney and gastrointestinal adverse effects. The USPSTF concludes with high certainty that the magnitude of benefit of PrEP with oral tenofovir disoproxil fumarate-based therapy to reduce the risk of acquisition of HIV infection in persons at high risk is substantial. The USPSTF recommends offering PrEP with effective antiretroviral therapy to persons at high risk of HIV acquisition. (A recommendation).


Smartphones in ecology and evolution: a guide for the app-rehensive.
Smartphones and their apps (application software) are now used by millions of people worldwide and represent a powerful combination of sensors, information transfer, and computing power that deserves better exploitation by ecological and evolutionary researchers. We outline the development process for research apps, provide contrasting case studies for two new research apps, and scan the research horizon to suggest how apps can contribute to the rapid collection, interpretation, and dissemination of data in ecology and evolutionary biology. We emphasize that the usefulness of an app relies heavily on the development process, recommend that app developers are engaged with the process at the earliest possible stage, and commend efforts to create open-source software scaffolds on which customized apps can be built by nonexperts. We conclude that smartphones and their apps could replace many traditional handheld sensors, calculators, and data storage devices in ecological and evolutionary research. We identify their potential use in the high-throughput collection, analysis, and storage of complex ecological information.


Development and validation of a new measure of student attitudes and knowledge of international health and medicine.
There is increasing awareness of the importance of international health and medicine (IHM) but there is a paucity of data regarding medical students' attitudes towards and knowledge of the subject. To the best of our knowledge there is currently no validated measure to assess this. The aim of the present study was to develop a validated measure of medical students' attitudes and knowledge of IHM and examine its correlates. A panel experienced in IHM formulated attitude and general knowledge items and clinical cases based on personal experience, literature review and texts. The survey was piloted and then administered to 82 students of the Ben Gurion University-Columbia University MD program in IHM, and 59 students from programs without specific IHM focus. Cronbach's a was 0.87. Test-retest reliability of attitudes was r=0.87. Correlation of openness to experience with attitudes was r=0.376, showing construct validity. Third-year IHM students scored higher than incoming students on IHM knowledge and clinical cases, demonstrating sensitivity. General IHM knowledge was positively correlated to clinical IHM knowledge r=0.36, but not attitude or openness to experience. Those with previous IHM work experience showed greater openness and positive attitude. Women showed more positive attitudes towards IHM than men. Attitude was negatively correlated with number of languages spoken r=-0.198. The survey may be a reliable and valid tool to assess and compare medical students' knowledge and attitude toward international health. This survey can be used to evaluate curricular innovations in the field.


Nucleotide sequence analysis of a gene from Burkholderia (Pseudomonas) cepacia encoding an outer membrane lipoprotein involved in multiple antibiotic resistance.
Antibiotic-resistant Burkholderia (Pseudomonas) cepacia is an important etiologic agent of nosocomial and cystic fibrosis infections. The primary resistance mechanism which has been reported is decreased outer membrane permeability. We previously reported the cloning and characterization of a chloramphenicol resistance determinant from an isolate of B. cepacia from a patient with cystic fibrosis that resulted in decreased drug accumulation. In the present studies we subcloned and sequenced the resistance determinant and identified gene products related to decreased drug accumulation. Additional drug resistances encoded by the determinant include resistances to trimethoprim and ciprofloxacin. Sequence analysis of a 3.4-kb subcloned fragment identified one complete and one partial open reading frame which are homologous with two of three components of a potential antibiotic efflux operon from Pseudomonas aeruginosa (mexA-mexB-oprM). On the basis of sequence data, outer membrane protein analysis, protein expression systems, and a lipoprotein labelling assay, the complete open reading frame encodes an outer membrane lipoprotein which is homologous with OprM. The partial open reading frame shows homology at the protein level with the C terminus of the protein product of mexB. DNA hybridization studies demonstrated homology of an internal mexA probe with a larger subcloned fragment from B. cepacia. The finding of multiple antibiotic resistance in B. cepacia as a result of an antibiotic efflux pump is surprising because it has long been believed that resistance in this organism is caused by impermeability to antibiotics.


Clinical Efficacy of Self-applied Blue Light Therapy for Mild-to-Moderate Facial Acne.
This study was an evaluation of the performance of self-applied, blue light, light-emitting diode therapy in the treatment of mild-to-moderate inflammatory acne on the face, concerning: 1) time to improvement and/or resolution of the number of blemishes and lesions on the face; 2) quality of skin condition; 3) occurrence and count of the number of new blemishes and lesions; and 4) ease of product use; patient comfort, wellbeing, and satisfaction during the treatment period; and safety of treatment. Subjects (N=21) were included according to the inclusion/exclusion criteria and after they had given informed consent. The blue light treatment was conducted over an eight-week period. For study data management and analysis, SPSS 16.0 statistical software was used. Data management and analysis was performed independently using, where appropriate, ANOVA, student t-test, and Mann-Whitney test for N=20. Tests were carried out at the five-percent significance level. The confidence interval was 95 percent. Twenty-one subjects concluded the study (18/21 were female and 3/21 were male). Upon the first outbreak of acne, subjects had a mean age of 15 years (range 8-28 years), and 19 subjects had mild-to-moderate acne for a mean duration of 13.1 years. During the study period with self-applied blue light treatment, the total number of comedones on the face had significantly reduced for the assessment at Day 7 (p<0.019) and at Day 28 (p<0.001). The total number of open comedones (blackheads) on the face during the treatment period was reduced significantly (p<0.02) for assessment at treatment Day 7 (p<0.005) and for the assessment at Day 28. The total number of closed comedones (whiteheads) on the face during the treatment period, was reduced significantly (p<0.007) for the assessment at Day 28. The total number of papules during treatment had reduced significantly for assessment at Day 7 (p<0.048) and Day 28 (p<0.005). The total number of pustules during treatment had reduced, but this difference was not statistically significant. This was similar for nodules present. Subjects expressed confidence in using the self-applied blue light without the supervision of a doctor. Regarding previous treatments, subjects expressed dissatisfaction and considered self-applied blue light treatment to be better for their condition. Self-applied blue light treatment was reported to be easy and safe to use.


Trigeminal neuralgia treatment dosimetry of the Cyberknife.
There are 2 Cyberknife units at Stanford University. The robot of 1 Cyberknife is positioned on the patient's right, whereas the second is on the patient's left. The present study examines whether there is any difference in dosimetry when we are treating patients with trigeminal neuralgia when the target is on the right side or the left side of the patient. In addition, we also study whether Monte Carlo dose calculation has any effect on the dosimetry. We concluded that the clinical and dosimetric outcomes of CyberKnife treatment for trigeminal neuralgia are independent of the robot position. Monte Carlo calculation algorithm may be useful in deriving the dose necessary for trigeminal neuralgia treatments.


Looking Back on Self-Poisoning: The Relationship between Depressed Mood and Reporting of Suicidal Intent in People Who Deliberately Self-Poison.
Lifetime worst-point suicidality is associated with risk of subsequent death by suicide. Yet little is known about how people who deliberately self-poison (DSP) change their appraisal of suicidal intent of a single DSP episode over time. We assessed whether suicidal intent for a single index episode of DSP changed over time and factors associated with such change. We studied 202 patients admitted for DSP (66.3% female, all Caucasian), 18-85 years old (M = 37.8, SD = 14.8), using a longitudinal design (0, 3, and 12 months). The primary outcome measure was change in suicidal intent for a single index DSP episode, analyzed using multilevel modeling. Wish to die and whether the episode was considered a suicide attempt increased significantly with depressed mood. Wish to die associated with the index episode also increased over time independently of depressed mood. No association with time or depressed mood was found for perceived likelihood of dying. Depressed mood was strongly associated with appraisal of suicidal intent associated with a DSP episode. In suicide risk assessment, reports of the nature and severity of past DSP should be interpreted in light of current mood.


Population genetic analyses of Helicobacter pylori isolates from Gambian adults and children.
The gastric pathogen Helicobacter pylori is one of the most genetically diverse of bacterial species. Much of its diversity stems from frequent mutation and recombination, preferential transmission within families and local communities, and selection during persistent gastric mucosal infection. MLST of seven housekeeping genes had identified multiple distinct H. pylori populations, including three from Africa: hpNEAfrica, hpAfrica1 and hpAfrica2, which consists of three subpopulations (hspWAfrica, hspCAfrica and hspSAfrica). Most detailed H. pylori population analyses have used strains from non-African countries, despite Africa's high importance in the emergence and evolution of humans and their pathogens. Our concatenated sequences from seven H. pylori housekeeping genes from 44 Gambian patients (MLST) identified 42 distinct sequence types (or haplotypes), and no clustering with age or disease. STRUCTURE analysis of the sequence data indicated that Gambian H. pylori strains belong to the hspWAfrica subpopulation of hpAfrica1, in accord with Gambia's West African location. Despite Gambia's history of invasion and colonisation by Europeans and North Africans during the last millennium, no traces of Ancestral Europe1 (AE1) population carried by those people were found. Instead, admixture of 17% from Ancestral Europe2 (AE2) was detected in Gambian strains; this population predominates in Nilo-Saharan speakers of North-East Africa, and might have been derived from admixture of hpNEAfrica strains these people carried when they migrated across the Sahara during the Holocene humid period 6,000-9,000 years ago. Alternatively, shared AE2 ancestry might have resulted from shared ancestral polymorphisms already present in the common ancestor of sister populations hpAfrica1 and hpNEAfrica.


A programming language for composable DNA circuits.
Recently, a range of information-processing circuits have been implemented in DNA by using strand displacement as their main computational mechanism. Examples include digital logic circuits and catalytic signal amplification circuits that function as efficient molecular detectors. As new paradigms for DNA computation emerge, the development of corresponding languages and tools for these paradigms will help to facilitate the design of DNA circuits and their automatic compilation to nucleotide sequences. We present a programming language for designing and simulating DNA circuits in which strand displacement is the main computational mechanism. The language includes basic elements of sequence domains, toeholds and branch migration, and assumes that strands do not possess any secondary structure. The language is used to model and simulate a variety of circuits, including an entropy-driven catalytic gate, a simple gate motif for synthesizing large-scale circuits and a scheme for implementing an arbitrary system of chemical reactions. The language is a first step towards the design of modelling and simulation tools for DNA strand displacement, which complements the emergence of novel implementation strategies for DNA computing.


Risk factors and direct medical cost of early versus late unplanned readmissions among diabetes patients at a tertiary hospital in Singapore.
To examine the risk factors and direct medical costs associated with early (≤30 days) versus late (31-180 days) unplanned readmissions among patients with type 2 diabetes in Singapore. Risk factors and associated costs among diabetes patients were investigated using electronic medical records from a local tertiary care hospital from 2010 to 2012. Multivariable logistic regression was used to identify risk factors associated with early and late unplanned readmissions while a generalized linear model was used to estimate the direct medical cost. Sensitivity analysis was also performed. A total of 1729 diabetes patients had unplanned readmissions within 180 days of an index discharge. Length of index stay (a marker of acute illness burden) was one of the risk factors associated with early unplanned readmission while patient behavior-related factors, like diabetes-related medication adherence, were associated with late unplanned readmission. Adjusted mean cost of index admission was higher among patients with unplanned readmission. Sensitivity analysis yielded similar results. Existing routinely captured data can be used to develop prediction models that flag high risk patients during their index admission, potentially helping to support clinical decisions and prevent such readmissions.


Ultrafast dynamics of polarons in conductive polyaniline: comparison of primary and secondary doped forms.
Time- and wavelength-resolved pump-probe measurements are performed on the conductive, primary and secondary doped, forms of polyaniline in solution to investigate the relaxation dynamics of photoexcited polarons. Contrasting dynamics observed in the two forms allow investigation of electronic (and structural) relaxation of this material. Pump pulse at 800 nm photoexcites an electron from the valence to polaron band, and subsequent relaxation dynamics are probed by a white light continuum pulse. Three distinct features are observed in the primary doped sample: (1) absorption near time zero in the 900-1025 nm probe wavelength region; (2) delayed absorption from 850 to 1025 nm; (3) pronounced oscillations with frequencies of 165 and 210 cm(-1). The first two features are associated with intraband absorptions to higher-lying states in the polaron band from the initial excited and conformationally changed intermediate states. The oscillations reflect torsional motions associated with photoexcitation and relaxation. In the secondary doped material, only bleaching and stimulated emission are observed throughout the whole spectral region; neither transient absorption signals nor oscillatory dynamics are observed. Kinetic modeling is performed to establish the mechanism of relaxation. We propose that the excited polaron relaxes nonradiatively to the ground state through an intermediate state(s) with a twisted geometry. Our measurements and analysis allow us to describe the structure of the polaron bands for primary and secondary doped polyaniline; they are in the small and large polaron limits, respectively, and are consistent with a bandgap for the primary doped form and without a bandgap (i.e., metallic) for the secondary doped material.