Feasibility and impact study of a reward-based mobile application to improve adolescents' snacking habits.
Adolescents' snacking habits are driven by both explicit reflective and implicit hedonic processes. Hedonic pathways and differences in sensitivity to food rewards in addition to reflective determinants should be considered. The present study evaluated the feasibility and impact of a mobile phone-delivered intervention, incorporating explicit reflective and implicit rewarding strategies, on adolescents' snack intake. Adolescents (n 988; mean age 14·9 (sd 0·70) years, 59·4 % boys) completed a non-randomized clustered controlled trial. Adolescents (n 416) in the intervention schools (n 3) were provided with the intervention application for four weeks, while adolescents (n 572) in the control schools (n 3) followed the regular curriculum. Outcomes were differences in healthy snacking ratio and key determinants (awareness, intention, attitude, self-efficacy, habits and knowledge). Process evaluation data were collected via questionnaires and through log data of the app. No significant positive intervention effects on the healthy snack ratio (b=-3·52 (se 1·82), P>0·05) or targeted determinants were observed. Only 268 adolescents started using the app, of whom only fifty-five (20·5 %) still logged in after four weeks. Within the group of users, higher exposure to the app was not significantly associated with positive intervention effects. App satisfaction ratings were low in both high and low user groups. Moderation analyses revealed small positive intervention effects on the healthy snack ratio in high compared with low reward-sensitive boys (b=1·38 (se 0·59), P<0·05). The intervention was not able to improve adolescents' snack choices, due to low reach and exposure. Future interventions should consider multicomponent interventions, teacher engagement, exhaustive participatory app content development and tailoring.


The influence of controlled surface nanotopography on the early biological events of osseointegration.
The early cell and tissue interactions with nanopatterned titanium implants are insufficiently described in vivo. A limitation has been to transfer a pre-determined, well-controlled nanotopography to 3D titanium implants, without affecting other surface parameters, including surface microtopography and chemistry. This in vivo study aimed to investigate the early cellular and molecular events at the bone interface with screw-shaped titanium implants superimposed with controlled nanotopography. Polished and machined titanium implants were firstly patterned with 75-nm semispherical protrusions. Polished and machined implants without nano-patterns were designated as controls. Thereafter, all nanopatterned and control implants were sputter-coated with a 30nm titanium layer to unify the surface chemistry. The implants were inserted in rat tibiae and samples were harvested after 12h, 1d and 3d. In one group, the implants were unscrewed and the implant-adherent cells were analyzed using quantitative polymerase chain reaction. In another group, implants with surrounding bone were harvested en bloc for histology and immunohistochemistry. The results showed that nanotopography downregulated the expression of monocyte chemoattractant protein-1 (MCP-1), at 1d, and triggered the expression of osteocalcin (OC) at 3d. This was in parallel with a relatively lower number of recruited CD68-positive macrophages in the tissue surrounding the nanopatterned implants. Moreover, a higher proportion of newly formed osteoid and woven bone was found at the nanopatterned implants at 3d. It is concluded that nanotopography, per se, attenuates the inflammatory process and enhances the osteogenic response during the early phase of osseointegration. This nanotopography-induced effect appeared to be independent of the underlying microscale topography. This study provides a first line of evidence that pre-determined nanopatterns on clinically relevant, screw-shaped, titanium implants can be recognized by cells in the complex in vivo environment. Until now, most of the knowledge relating to cell interactions with nanopatterned surfaces has been acquired from in vitro studies involving mostly two-dimensional nanopatterned surfaces of varying chemical composition. We have managed to superimpose pre-determined nanoscale topography on polished and micro-rough, screw-shaped, implants, without changes in the microscale topography or chemistry. This was achieved by colloidal lithography in combination with a thin titanium film coating on top of both nanopatterned and control implants. The early events of osseointegration were evaluated at the bone interface to these implants. The results revealed that nanotopography, as such, elicits downregulatory effects on the early recruitment and activity of inflammatory cells while enhancing osteogenic activity and woven bone formation.


Evidence for ectopic neurotransmission at a neuronal synapse.
Neurotransmitter release is well known to occur at specialized synaptic regions that include presynaptic active zones and postsynaptic densities. At cholinergic synapses in the chick ciliary ganglion, however, membrane formations and physiological measurements suggest that release distant from postsynaptic densities can activate the predominantly extrasynaptic alpha7 nicotinic receptor subtype. We explored such ectopic neurotransmission with a novel model synapse that combines Monte Carlo simulations with high-resolution serial electron microscopic tomography. Simulated synaptic activity is consistent with experimental recordings of miniature excitatory postsynaptic currents only when ectopic transmission is included in the model, broadening the possibilities for mechanisms of neuronal communication.


Ergodic theorems along sequences and Hardy fields.
Let a(x) be a real function with a regular growth as x --> infinity. [The precise technical assumption is that a(x) belongs to a Hardy field.] We establish sufficient growth conditions on a(x) so that the sequence ([a(n)])(infinity)(n=1) is a good averaging sequence in L2 for the pointwise ergodic theorem. A sequence (an) of positive integers is a good averaging sequence in L2 for the pointwise ergodic theorem if in any dynamical system (Omega, Sigma, m, T) for f [symbol, see text] in L2(Omega) the averages [equation, see text] converge for almost every omicron in. Our result implies that sequences like ([ndelta]), where delta > 1 and not an integer, ([n log n]), and ([n2/log n]) are good averaging sequences for L2. In fact, all the sequences we examine will turn out to be good averaging for Lp, p > 1; and even for L log L. We will also establish necessary and sufficient growth conditions on a(x) so that the sequence ([a(n)]) is good averaging for mean convergence. Note that for some a(x) (e.g., a(x) = log2 x), ([a(n)]) may be good for mean convergence without being good for pointwise convergence.


Nurses' perceptions of end-of-life care after multiple interventions for improvement.
Nurses working in intensive care units may lack knowledge and skills in end-of-life care, find caring for dying patients and the patients' families stressful, and lack support to provide this care. To describe nurses' perceptions of (1) knowledge and ability, (2) work environment, (3) support for staff, (4) support for patients and patients' families, and (5) stress related to specific work situations in the context of end-of-life care before (phase 1) and after (phase 2) implementation of approaches to improve end-of-life care. The approaches were a nurse-developed bereavement program for patients' families, use of a palliative medicine and comfort care team, preprinted orders for the withdrawal of life-sustaining treatment, hiring of a mental health clinical nurse specialist, and staff education in end-of-life care. Nurses in 4 intensive care units at a university medical center reported their perceptions of end-of-life care by using a 5-subscale tool consisting of 30 items scored on a 4-point Likert scale. The tool was completed by 91 nurses in phase 1 and 127 in phase 2. Improvements in overall mean scores on the 5 sub-scales indicated that the approaches succeeded in improving nurses' perceptions. In phase 2, most of the subscale overall mean scores were higher than a desired criterion (<2.0, good). Analysis of variance indicated that some improvements occurred over time differently in the units; other improvements occurred uniformly. Continued practice development is needed in end-of-life care issues.


Water Pipe Smoking Reduction in the Male Adolescent Students: An Educational Intervention Using Multi-Theory Model.
Water pipe smoking (WPS) has increased and is becoming a major leisure pastime among young people in Iran. The aim of this study was to determine of efficacy of an educational intervention based on Multi-Theory Model (MTM) to reduce WPS in the male adolescent students in Iran. A randomized controlled trial. Overall, 94 male adolescent students (grades 10, 11) smoked water pipe (WP) in the past month (current WP smokers) were selected, allocated randomly in two groups (47 students in intervention group and 47 students in control group), in two different schools in 2018 in Hamadan City, western Iran. Data were collected utilizing a valid and reliable questionnaire based on MTM constructs and demographic variables. Educational intervention was designed in five 45-min sessions. Two groups were followed-up three-months after completion of intervention. The collected data were analyzed using SPSS 22 software through Chi-square test, independent-sample t-test, paired-samples t-test, and Friedman test. There were significant differences between the mean score of participatory dialogue, behavioral confidence, emotional transformation and practice for change in the intervention group compared with the control group after the intervention (P<0.001). In addition, significant reductions in the frequency of WPS (from 14.9% to 4.3%) were observed in the intervention group compared to the control group (P<0.001). The developed educational intervention based on MTM constructs was efficacious and can be replicated for effectiveness studies to reduce WPS in the male adolescent students in Iran.


Spatial and temporal analysis of black carbon aerosols in Istanbul megacity.
Black carbon (BC) is an important component of particulate matter due to its effects on human health and climate. In this study, we present the first BC concentrations measured in the Istanbul megacity (~15 million inhabitants). Two measurement campaigns have been conducted to measure BC and fine particulate matter (PM2.5) concentrations at four locations, characterized by different traffic densities. In the first campaign, BC daily mean concentrations have been found to be between 4 μg/m(3) and 10 μg/m(3). In the second campaign, BC and PM2.5 have been measured at the site with the highest traffic density for an entire year. Annually averaged BC contributes by 38 ± 14% to the PM2.5 levels (annual average BC: 13 μg/m(3) and PM2.5: 36 μg/m(3)). Diurnal variations of BC concentrations followed those of traffic density (correlation coefficient of 0.87). These measurements are essential to identify the sources of BC and PM2.5 concentrations in Istanbul and develop mitigation measures.


Role of PDGF receptor-α during human cytomegalovirus entry into fibroblasts.
Human CMV (HCMV) exhibits a broad cell tropism that depends on two virion glycoprotein complexes: a trimeric complex (gH/gL/gO) that facilitates viral infection primarily in fibroblasts and a pentameric complex (gH/gL/pUL128-pUL130-pUL131A) that mediates infection in epithelial and endothelial cells. We performed genome-wide CRISPR screens in which the PDGF receptor-α (PDGFRα) was identified as the most significant cellular gene product essential for infection by HCMV virions containing only trimeric complex (trimer-only virus). Trimer-only virus did not enter PDGFRα knockout fibroblasts. By using knockout fibroblasts, the extracellular domain of PDGFRα required for virus entry was mapped, and the intracellular tyrosine kinase domain was shown to be nonessential. In addition, direct cell-to-cell spread of virus from knockout cells transfected with trimer-only viral DNA was blocked, despite the production of infectious virus in the transfected cells. In contrast to trimer-only virus, wild-type HCMV virions containing both trimeric and pentameric complexes entered PDGFRα knockout cells, reinforcing the view that fibroblasts contain a second, independent receptor for the pentameric complex. Importantly, however, wild-type virus entered the knockout fibroblasts at reduced efficiency compared with parental fibroblasts, arguing that the cellular receptor for the virion pentameric complex is limiting or that virions are produced containing different relative amounts of the two glycoprotein complexes. Finally, ectopic expression of PDGFRα in ARPE-19 epithelial cells and THP-1 monocytic cells, which have little to no endogenous PDGFRα expression, markedly enhanced their susceptibility to trimer-only virions. In sum, our data clarify several key determinants of HCMV tropism.


Wound contraction effects and antibacterial properties of Tualang honey on full-thickness burn wounds in rats in comparison to hydrofibre.
Full-thickness burn wounds require excision and skin grafting. Multiple surgical procedures are inevitable in managing moderate to severe full-thickness burns. Wound bed preparations prior to surgery are necessary in order to prevent wound infection and promote wound healing. Honey can be used to treat burn wounds. However, not all the honey is the same. This study aims to evaluate the wound contraction and antibacterial properties of locally-produced Tualang honey on managing full-thickness burn wounds in vivo. Thirty-six female Sprague Dawley rats were randomly divided into three groups. Under anaesthesia, three full-thickness burn wounds were created on the dorsum of the rats. The full-thickness burn wounds were inoculated with a specific organism (10(4)), namely Pseudomonas aeruginosa (n = 12), Klebsiella pneumoniae (n = 12), or Acinetobacter baumannii (n = 12). The three burn wounds were dressed with Tualang honey, hydrofibre and hydrofibre silver respectively. Swab samples were obtained every 3 days (day 3, 6, 9, 12, 15, 18 and 21) for quantitative and semi-quantitative microbiological analyses. Clinical assessments, including observations concerning the appearance and wound size, were measured at the same time. There was a rapid 32.26% reduction in wound size by day 6 (p = 0.008) in the Tualang honey-treated wounds, and 49.27% by day 15 (p = 0.005). The wounds remained smaller by day 18 (p < 0.032). Tualang honey-treated rats demonstrated a reduction in bacterial growth in Pseudomonas aeruginosa inoculated wounds (p = 0.005). However, hydrofibre silver and hydrofibre-treated wounds are superior to honey-treated wounds with Acinetobacter baumannii (p = 0.035). There was no statistical significant of antibacterial property in Klebsiella pneumonia inoculated wounds. Tualang honey has better results with regards to its control of Pseudomonas aeruginosa and its wound contraction effects on full-thickness burn wound in vivo.


Statistical analysis of life history calendar data.
The life history calendar is a data-collection tool for obtaining reliable retrospective data about life events. To illustrate the analysis of such data, we compare the model-based probabilistic event history analysis and the model-free data mining method, sequence analysis. In event history analysis, we estimate instead of transition hazards the cumulative prediction probabilities of life events in the entire trajectory. In sequence analysis, we compare several dissimilarity metrics and contrast data-driven and user-defined substitution costs. As an example, we study young adults' transition to adulthood as a sequence of events in three life domains. The events define the multistate event history model and the parallel life domains in multidimensional sequence analysis. The relationship between life trajectories and excess depressive symptoms in middle age is further studied by their joint prediction in the multistate model and by regressing the symptom scores on individual-specific cluster indices. The two approaches complement each other in life course analysis; sequence analysis can effectively find typical and atypical life patterns while event history analysis is needed for causal inquiries.


Intramodal perceptual grouping modulates multisensory integration: evidence from the crossmodal dynamic capture task.
We investigated the extent to which intramodal visual perceptual grouping influences the multisensory integration (or grouping) of auditory and visual motion information. Participants discriminated the direction of motion of two sequentially presented sounds (moving leftward or rightward), while simultaneously trying to ignore a task-irrelevant visual apparent motion stream. The principles of perceptual grouping were used to vary the direction and extent of apparent motion within the irrelevant modality (vision). The results demonstrate that the multisensory integration of motion information can be modulated by the perceptual grouping taking place unimodally within vision, suggesting that unimodal perceptual grouping processes precede multisensory integration. The present study therefore illustrates how intramodal and crossmodal perceptual grouping processes interact to determine how the information in complex multisensory environments is parsed.


Truth and investment: lies are told to those who care.
Participants discussed paintings they liked and disliked with artists who were or were not personally invested in them. Participants were urged to be honest or polite or were given no special instructions. There were no conditions under which the artists received totally honest feedback about the paintings they cared about. As predicted by the defensibility postulate, participants stonewalled, amassed misleading evidence, and conveyed positive evaluations by implications. They also told some outright lies. But the participants also communicated clearly their relative degrees of liking for the different special paintings. The results provide new answers to the question of why beliefs about other people's appraisals do not always correspond well with their actual appraisals.


A comparison of case-only designs for detecting gene x gene interaction in rheumatoid arthritis using genome-wide case-control data in Genetic Analysis Workshop 16.
We compare and contrast case-only designs for detecting gene x gene (G x G) interaction in rheumatoid arthritis (RA) using the genome-wide data provided by Genetic Analysis Workshop 16 Problem 1. Logistic as well as novel multinomial and proportional odds models that do not depend on the specification of additive or dominant models for susceptibility loci were applied to the case-only sample. We identified 519 significant interactions (p < 1 x 10-4 in at least one test). All methods detected unique significant interactions; 169 were common to more than one model and only 21 were common to all models. Results emphasize that categorization of the genetic variables and choice of regression model are critical and hugely influential in the identification of G x G. Porportional odds and multinomial methods provide new tools for identification of G x G interactions.


Clinical relevance of serum antibodies to GD1b in immune-mediated neuropathies.
Antibodies to the ganglioside GD1b have been reported in various forms of immune-mediated neuropathy, but their clinical relevance for diagnosis and prognosis is unknown. We investigated the prevalence of anti-GD1b antibodies in acute and chronic immune-mediated neuropathies, and the clinical presentation and outcome in Guillain-Barré syndrome (GBS) and Miller Fisher-GBS overlap syndrome (MF-GBS). Anti-GD1b, anti-GM1 and anti-GQ1b antibodies were tested in serum of patients with GBS (N = 165), Miller Fisher syndrome (N = 10), MF-GBS (N = 28), monoclonal gammopathy of unknown significance neuropathy (MGUS; N = 101), chronic inflammatory demyelinating polyneuropathy (N = 29), paraneoplastic syndrome with anti-Hu-associated neuropathy (PNS; N = 11), other auto-immune diseases (AID; N = 60), and healthy controls (HC; N = 60). All samples were tested by enzyme-linked immunosorbent assay according to the Inflammatory Neuropathy Cause and Treatment protocol. IgM anti-GD1b antibodies were found in GBS (N = 4; 2.4%), MGUS (N = 3; 3.0%), and PNS patients (N = 1; 9.1%). IgG anti-GD1b antibodies were found in GBS (N = 20; 12.1%) and MF-GBS (N = 4; 14.3%) patients, but not in the AID and HC group. In the combined group of MF-GBS and GBS patients ((MF-)GBS), 14/36 (38.9%) patients with IgG anti-GD1b antibodies also had IgG anti-GM1 antibodies, and IgG anti-GD1b and IgG anti-GQ1b antibodies were found in 3/29 (10.3%) patients. Patients with (MF-)GBS and anti-GD1b without anti-GM1 antibodies did not differ regarding sensory disturbances or disease severity but recovered faster regarding the ability to walk independently compared with patients without anti-GD1b antibodies (P = 0.031) and with patients with both anti-GD1b and anti-GM1 antibodies (P = 0.034). In conclusion, testing for anti-GD1b antibodies may identify a specific group of immune-mediated neuropathies and (MF-)GBS patients with only anti-GD1b antibodies tend to recover faster.


Rapid genetic divergence in response to 15 years of simulated climate change.
Genetic diversity may play an important role in allowing individual species to resist climate change, by permitting evolutionary responses. Our understanding of the potential for such responses to climate change remains limited, and very few experimental tests have been carried out within intact ecosystems. Here, we use amplified fragment length polymorphism (AFLP) data to assess genetic divergence and test for signatures of evolutionary change driven by long-term simulated climate change applied to natural grassland at Buxton Climate Change Impacts Laboratory (BCCIL). Experimental climate treatments were applied to grassland plots for 15 years using a replicated and spatially blocked design and included warming, drought and precipitation treatments. We detected significant genetic differentiation between climate change treatments and control plots in two coexisting perennial plant study species (Festuca ovina and Plantago lanceolata). Outlier analyses revealed a consistent signature of selection associated with experimental climate treatments at individual AFLP loci in P. lanceolata, but not in F. ovina. Average background differentiation at putatively neutral AFLP loci was close to zero, and genomewide genetic structure was associated neither with species abundance changes (demography) nor with plant community-level responses to long-term climate treatments. Our results demonstrate genetic divergence in response to a suite of climatic environments in reproductively mature populations of two perennial plant species and are consistent with an evolutionary response to climatic selection in P. lanceolata. These genetic changes have occurred in parallel with impacts on plant community structure and may have contributed to the persistence of individual species through 15 years of simulated climate change at BCCIL.


MR imaging findings in hepatic encephalopathy.
The term hepatic encephalopathy (HE) includes a spectrum of neuropsychiatric abnormalities occurring in patients with liver dysfunction. Most cases are associated with cirrhosis and portal hypertension or portal-systemic shunts, but the condition can also be seen in patients with acute liver failure and, rarely, with portal-systemic bypass and no associated intrinsic hepatocellular disease. Although HE is a clinical condition, several neuroimaging techniques, particularly MR imaging, may eventually be useful for the diagnosis because they can identify and measure the consequences of central nervous system (CNS) increase in substances that under normal circumstances, are efficiently metabolized by the liver. Classic MR imaging abnormalities include high signal intensity in the globus pallidum on T1-weighted images, likely a reflection of increased tissue concentrations of manganese, and an elevated glutamine/glutamate peak coupled with decreased myo-inositol and choline signals on proton MR spectroscopy, representing disturbances in cell-volume homeostasis secondary to brain hyperammonemia. Recent data have shown that white matter abnormalities, also related to increased CNS ammonia concentration, can also be detected with several MR imaging techniques such as magnetization transfer ratio measurements, fast fluid-attenuated inversion recovery sequences, and diffusion-weighted images. All these MR imaging abnormalities, which return to normal with restoration of liver function, probably reflect the presence of mild diffuse brain edema, which seems to play an essential role in the pathogenesis of HE. It is likely that MR imaging will be increasingly used to evaluate the mechanisms involved in the pathogenesis of HE and to assess the effects of therapeutic measures focused on correcting brain edema in these patients.


A new hepatoma cell line exhibiting high susceptibility to hepatitis B virus infection.
Hepatitis B virus (HBV) infection, which increases the risk of cirrhosis and hepatocellular carcinoma and requires lifelong treatment, has become a major global health problem. However, host factors essential to the HBV life cycle are still unclear, and the development of new drugs is needed. Cells derived from the human hepatoma cell line HepG2 and engineered to overexpress sodium taurocholate cotransporting polypeptide (NTCP: a receptor for HBV), termed HepG2/NTCP cells, are widely used as the cell-based HBV infection and replication systems for HBV research. We recently found that human hepatoma cell line Li23-derived cells overexpressing NTCP (A8 cells subcloned from Li23 cells), whose gene expression profile was distinct from that of HepG2/NTCP cells, were also sensitive to HBV infection. However, the HBV susceptibility of A8 cells was around 1/100 that of HepG2/NTCP cells. Since we considered that plural cell assay systems will be needed for the objective evaluation of anti-HBV reagents, as we previously demonstrated in hepatitis C virus research, we here attempted to develop a new Li23 cell-derived assay system equivalent to that using HepG2/NTCP cells. By repeated subcloning of A8 cells, we successfully established a new cell line (A184.108.40.206) exhibiting high HBV susceptibility equal to that of HepG2/NTCP cells. Characterization of A188.8.131.52 cells revealed that the increase of HBV susceptibility was correlated with increases in the protein and glycosylation levels of NTCP, and with decreased expression of STING, a factor contributing to innate immunity. Finally, we performed a comparative evaluation of HBV entry inhibitors (cyclosporin A and rosiglitazone) by an HBV/secNL reporter assay using A188.8.131.52 cells or HepG2/NTCP cells. The results confirmed that cyclosporin A exhibited anti-HBV activity in both cell lines, as previously reported. However, we found that rosiglitazone did not show the anti-HBV activity in A18.104.22.168 cells, although it worked in HepG2/NTCP cells as previously reported. This suggested that the difference in anti-HBV activity between cyclosporin A and rosiglitazone was due to the different types of cells used for the assay. In conclusion, plural assay systems using different types of cells are required for the objective and impartial evaluation of anti-HBV reagents.


Surgical complications requiring early relaparotomy after pancreas transplantation: a multivariate risk factor and economic impact analysis of the cyclosporine era.
To study significant surgical complications requiring early (< or = 3 months posttransplant) relaparotomy (relap) after pancreas transplants, and to develop clinically relevant surgical and peritransplant decision-making guidelines for preventing and managing such complications. Pancreas grafts are still associated with the highest surgical complication rate of all routinely transplanted solid organs. However, the impact of surgical complications on morbidity, hospital costs, and graft and patient survival rates has not been analyzed in detail to date. We retrospectively studied surgical complications requiring relap in 441 consecutive cadaver, bladder-drained pancreas transplants (54% simultaneous pancreas and kidney [SPK]; 22% pancreas after kidney [PAK]; 24% pancreas transplant alone [PTA]; 37% retransplant). Outcome and hospital charges were analyzed separately for recipients with versus without reoperation. The overall relap rate was 32% (SPK, 36%; PAK, 25%; PTA, 16%; p = 0.04). The most common causes were intraabdominal infection and graft pancreatitis (38%), pancreas graft thrombosis (27%), and anastomotic leak (15%). Perioperative relap mortality was 9%; transplant pancreatectomy was necessary in 57% of all recipients with one or more relaps. The pancreas graft was lost in 80% of recipients with versus 41% without relap (p < 0.0001). Patient survival rates were significantly lower (p < 0.05) for recipients with versus without relap. By multivariate analysis, significant risk factors for graft loss included older donor age (SPK, PAK), retransplant (PAK), relap for infection (SPK, PAK), and relap for leak or bleeding (PAK). For death, risk factors included older recipient age (SPK, PAK),retransplant (SPK, PAK), relap for thrombosis (PAK), relap for infection or leak (SPK), and relap for bleeding (PTA). Posttransplant surgical complications requiring relap were frequent, resulted in a high rate of pancreas (SPK, PAK, PTA) and kidney (SPK, PAK) graft loss, and had a major economic impact (p = 0.0001). Complications were associated with substantial perioperative mortality and decreased patient survival rates. The focus must therefore shift from graft salvage to preservation of the recipient's life once a pancreas graft-related complication requiring relap occurs. Thus, the threshold for pancreatectomy should be low. In this context, acceptance of older donors and recipients must be reconsidered.


Bimetallic Radical Redox-Relay Catalysis for the Isomerization of Epoxides to Allylic Alcohols.
Organic radicals are generally short-lived intermediates with exceptionally high reactivity. Strategically, achieving synthetically useful transformations mediated by organic radicals requires both efficient initiation and selective termination events. Here, we report a new catalytic strategy, namely, bimetallic radical redox-relay, in the regio- and stereoselective rearrangement of epoxides to allylic alcohols. This approach exploits the rich redox chemistry of Ti and Co complexes and merges reductive epoxide ring opening (initiation) with hydrogen atom transfer (termination). Critically, upon effecting key bond-forming and -breaking events, Ti and Co catalysts undergo proton transfer/electron transfer with one another to achieve turnover, thus constituting a truly synergistic dual catalytic system.


[Recommendations for the complementary feeding of the breastfed child].
To present a review on the evidence that support the current recommendations for breastfed children feeding. An extensive bibliographic review of the topic was carried out. Articles selected in the MEDLINE and Lilacs databases, publications from national and international organizations, theses and dissertations were reviewed. Some key articles were also selected from the citations referred in other papers. New knowledge acquired about child feeding over the last 20 years have led to a significant change in the current feeding recommendations for breastfed children in relation to the prior recommendations. The current recommended nutritional needs are lower than the old recommendations, complementary food is introduced in a more precise age, around 6 months, and new methods are recommended for promoting the child's healthy eating. The new recommendations emphasize the health feeding practices which comprise both the adequate food quantity and quality, including care with food handling and preparation, feeding and storage practices, and the respect and adequacy to the cultural characteristics of each people. The adequate complementary feeding of the breastfed child is critical for the optimal child growth and development. Therefore, it is an essential factor for both the populations food security and the development of nations. The health professionals ought to effectively pass on to mothers/care takers the new recommendations for promoting the healthy complementary feeding of the breastfed child. It is up to the governments to provide the adequate conditions for supporting such a promotion.


ESCMID* guideline for the diagnosis and management of Candida diseases 2012: diagnostic procedures.
As the mortality associated with invasive Candida infections remains high, it is important to make optimal use of available diagnostic tools to initiate antifungal therapy as early as possible and to select the most appropriate antifungal drug. A panel of experts of the European Fungal Infection Study Group (EFISG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) undertook a data review and compiled guidelines for the clinical utility and accuracy of different diagnostic tests and procedures for detection of Candida infections. Recommendations about the microbiological investigation and detection of candidaemia, invasive candidiasis, chronic disseminated candidiasis, and oropharyngeal, oesophageal, and vaginal candidiasis were included. In addition, remarks about antifungal susceptibility testing and therapeutic drug monitoring were made.


Spatial organization of protein aggregates on red blood cells as physical biomarkers of Alzheimer's disease pathology.
Quantifying physical differences of protein aggregates implicated in Alzheimer's disease (AD), in blood, could provide crucial information on disease stages. Here, red blood cells (RBCs) from 50 patients with neurocognitive complaints and 16 healthy individuals were profiled using an atomic force microscope (AFM). AFM measurements revealed patient age– and stage of neurocognitive disorder–dependent differences in size, shape, morphology, assembly, and prevalence of protein aggregates on RBCs, referred to as physical biomarkers. Crystals composed of fibrils were exclusively detected on RBCs for AD patients aged above 80 years. Fibril prevalence was negatively correlated with the cerebrospinal fluid (CSF) β-amyloid (Aβ) 42/40 ratio and was observed to be higher in the Aβ-positive patient category. Using a cutoff of ≥40% fibril prevalence, the CSF Aβ status was classified with 88% accuracy (sensitivity 100%, specificity 73%). The merits and challenges in integrating physical biomarkers in AD diagnosis are discussed.


The social structure of Golfo Dulce bottlenose dolphins (Tursiops truncatus) and the influence of behavioural state.
Ecological factors such as habitat and food availability affect the social structure of bottlenose dolphins (Tursiops spp.). Here, we describe the social structure of bottlenose dolphins (T. truncatus) in Golfo Dulce, Costa Rica, a semi-enclosed, fjord-like tropical embayment resembling a pelagic system. We also examine behaviour-linked social strategies by comparing social structure relative to behavioural state: feeding versus non-feeding. We analysed 333 sightings over 210 days from boat-based surveys. Despite the uniqueness of the area, the 47 analysed adults had a social structure similar to other populations: a well-differentiated fission-fusion society with sex-specific patterns of associations and aggression. These results indicate that differences in social structure relative to other populations were a matter of degree. Association strength of dyads was highly correlated across behavioural states, indicating constraints on social fluidity. Males displayed a marked difference in lagged association rate and females displayed a small difference in association homogeneity between states. We suggest this difference in population-wide social connections between behavioural states, particularly for males, was due to mating strategies, a pressure which is strongest during non-feeding behaviour and relaxed during feeding. This finding highlights the importance of considering behavioural state when examining individual bonds and the behavioural plasticity for which the bottlenose dolphin is well known.


Couple-based expanded carrier screening provided by general practitioners to couples in the Dutch general population: psychological outcomes and reproductive intentions.
The aim of expanded preconception carrier screening (ECS) is to inform any couple wishing to conceive about their chances of having children with severe autosomal or X-linked recessive conditions. Responsible implementation of ECS as reproductive genetic screening in routine care requires assessment of benefits and harms. We examined the psychological outcomes of couple-based ECS for 50 autosomal recessive (AR) conditions provided by general practitioners (GPs) to couples from the Dutch general population. Dutch GPs invited 4,295 women aged 18-40. We examined anxiety (State-Trait Anxiety Inventory, STAI-6), worry, decisional conflict (DCS) over time in participants declining GP counseling or attending GP counseling with/without testing. One hundred ninety couples participated; 130 attended counseling, of whom 117 proceeded with testing. No carrier couples were identified. Before counseling, worry (median 6.0) and anxiety (mean 30-34) were low and lower than the population reference (36.4), although some individuals reported increased anxiety or worry. At follow-up, test acceptors reported less anxiety than test decliners (mean 29 vs. 35); differences in anxiety after testing compared to before counseling were not meaningful. Most participants (90%) were satisfied with their decision (not) to undergo testing. Some individuals reported temporarily clinically relevant distress. Overall, the psychological outcomes are acceptable and no barrier to population-wide implementation.


Severe tetanus in immunized patients with high anti-tetanus titers.
Severe (grade III) tetanus occurred in three immunized patients who had high serum levels of anti-tetanus antibody. The disease was fatal in one patient. One patient had been hyperimmunized to produce commercial tetanus immune globulin. Two patients had received immunizations 1 year before presentation. Anti-tetanus antibody titers on admission were 25 IU/ml to 0.15 IU/ml by hemagglutination and ELISA assays; greater than 0.01 IU/ml is considered protective. Even though one patient had seemingly adequate anti-tetanus titers by in vitro measurement (0.20 IU), in vivo mouse protection bioassays showed a titer less than 0.01 IU/ml, implying that there may have been a hole in her immune repertoire to tetanus neurotoxin but not to toxoid. This is the first report of grade III tetanus with protective levels of antibody in the United States. The diagnosis of tetanus, nevertheless, should not be discarded solely on the basis of seemingly protective anti-tetanus titers.


Estimation of multiple transmission rates for epidemics in heterogeneous populations.
One of the principal challenges in epidemiological modeling is to parameterize models with realistic estimates for transmission rates in order to analyze strategies for control and to predict disease outcomes. Using a combination of replicated experiments, Bayesian statistical inference, and stochastic modeling, we introduce and illustrate a strategy to estimate transmission parameters for the spread of infection through a two-phase mosaic, comprising favorable and unfavorable hosts. We focus on epidemics with local dispersal and formulate a spatially explicit, stochastic set of transition probabilities using a percolation paradigm for a susceptible-infected (S-I) epidemiological model. The S-I percolation model is further generalized to allow for multiple sources of infection including external inoculum and host-to-host infection. We fit the model using Bayesian inference and Markov chain Monte Carlo simulation to successive snapshots of damping-off disease spreading through replicated plant populations that differ in relative proportions of favorable and unfavorable hosts and with time-varying rates of transmission. Epidemiologically plausible parametric forms for these transmission rates are compared by using the deviance information criterion. Our results show that there are four transmission rates for a two-phase system, corresponding to each combination of infected donor and susceptible recipient. Knowing the number and magnitudes of the transmission rates allows the dominant pathways for transmission in a heterogeneous population to be identified. Finally, we show how failure to allow for multiple transmission rates can overestimate or underestimate the rate of spread of epidemics in heterogeneous environments, which could lead to marked failure or inefficiency of control strategies.


Ultrasonography of the Mediastinum: Techniques, Current Practice, and Future Directions.
In the everyday practice of respiratory physicians, ultrasound techniques play a key role by enabling several diagnostic and interventional procedures. The application of ultrasound to endoscopic procedures allows both a visualization and a guided sampling of mediastinal and hilar lymph nodes. Endobronchial ultrasound can be combined with transbronchial needle aspiration, and, similarly, endoscopic ultrasound can be combined with fine-needle aspiration to sample virtually all mediastinal nodal stations from the airways and the esophagus. Endobronchial ultrasound-transbronchial needle aspiration and endoscopic ultrasound-fine needle aspiration showed a complementary diagnostic yield, and, recently, endoscopic ultrasound with bronchoscope was introduced in clinical practice to perform a transesophageal needle aspiration by using an ultrasound bronchoscope. This technique allows a single operator to perform both transbronchial and transesophageal needle sampling with the same instrument during a single bronchoscopic procedure. Mediastinal staging impacts the management of patients affected by lung cancer, and the most recent guidelines clearly state that endobronchial ultrasound and endoscopic ultrasound should be the initial tissue sampling procedure over surgical staging. In addition, endoscopic ultrasound techniques demonstrated an excellent yield in diagnosing lymphoma and benign diseases, for example, sarcoidosis. The aim of this review was to discuss the current role and future perspectives of endosonography techniques available for the evaluation of the mediastinum. Special emphasis was placed on equipment and technical aspects, the diagnostic role, and future directions of development.


Demographics and clinical patterns of burns requiring emergency hospitalization at a regional north-eastern us burn center.
There are known demographic and clinical patterns related to burn injuries and care associated with national and global geography. Still, limited data sources exist to facilitate the study of trends in the regionalization of burn care. The current study aims to investigate the demographics and clinical characteristics of patients that presented to the Emergency Department (ED) and were subsequently admitted for treatment to the inpatient unit of a regional burn center. This retrospective, single-center study was conducted between 1 February 2018 and 31 July 2019, of ED patients who presented with a burn injury and were subsequently admitted to the hospital. We identified 329 patients with burn injuries requiring hospitalization. The median age was 22 years [IQR 2-53], and 195 (59%) subjects were males. Monthly and seasonal variations in admissions were identified. The majority of burns occurred at home (84%) and secondary to a scalding injury (59%). The lower extremity was the most common site of injury (29%). Most subjects received antibiotics (59%) and narcotic analgesia (56%) in the ED. The median hospital length of stay was four days [IQR 2-11]. Many subjects did not require surgical intervention (64%) and did not experience complications (79%). In this study, we describe the demographics and clinical characteristics of patients that presented to the ED and were subsequently admitted to a regional burn center. Analyzing the epidemiological information and clinical management of burns may better prepare healthcare providers to offer care to patients with burn injuries.


A ligand binding domain mutation in the mouse glucocorticoid receptor functionally links chromatin remodeling and transcription initiation.
We utilized the mouse mammary tumor virus (MMTV) long terminal repeat (LTR) in vivo to understand how the interaction of the glucocorticoid receptor (GR) with a nucleosome-assembled promoter allows access of factors required for the transition from a repressed promoter to a derepressed, transcriptionally competent promoter. A mutation (C644G) in the ligand binding domain (LBD) of the mouse GR has provided information regarding the steps required in the derepression/activation process and in the functional significance of the two major transcriptional activation domains, AF1 and AF2. The mutant GR activates transcription from a transiently transfected promoter that has a disordered nucleosomal structure, though significantly less well than the wild-type GR. With an integrated, replicated promoter, which is assembled in an ordered nucleosomal array, the mutant GR does not activate transcription, and it fails to induce chromatin remodeling of the MMTV LTR promoter, as indicated by nuclease accessibility assays. Together, these findings support a two-step model for the transition of a nucleosome-assembled, repressed promoter to its transcriptionally active, derepressed form. In addition, we find that the C-terminal GR mutation is dominant over the transcription activation function of the N-terminal GR activation domain. These findings suggest that the primary activation function of the C-terminal activation domain is different from the function of the N-terminal activation domain and that it is required for derepression of the chromatin-repressed MMTV promoter.


The Influence of an Enriched Environment in Enhancing Recognition Memory in Zebrafish (Danio rerio).
Environmental enrichment is used to increase social and physical stimulation for animals in captivity which can lead to enhanced cognition. Fundamental to the positive effect enrichment has on the brain is that it provides opportunities for captive animals to recognize and discriminate between different stimuli in the environment. In the wild, being able to discriminate between novel or familiar stimuli has implications for survival, for example finding food, hiding from predators, or even choosing a mate. The novel object recognition (NOR) test is a cognitive task that is used extensively in the rodent literature to assess object recognition and memory, where the amount of time an animal spends exploring a novel vs. familiar object is quantified. Enrichment has been shown to enhance object recognition in rodents. More recently, the use of the NOR test has been applied to another animal model, zebrafish (Danio rerio), however, the effects of enrichment have not yet been explored. In the current study we looked at the effects of enrichment on object recognition in zebrafish using the NOR test. Adult zebrafish were housed in either enriched conditions (gravel substrate, plastic plants, shelter, heater and a filter) or plain conditions (heater and filter only) for 6 months before behavioral NOR tests were conducted. Enriched fish showed a preference for a novel object over a familiar one at a distance but did not show a preference during close inspection. Control fish did not show a preference at either distance. Our results suggest that enrichment can enhance zebrafish ability to discriminate between novel and familiar objects, but distance from the object may be an important factor. Future research is needed to determine whether any enhancements in object recognition are a result of an increase in sensory stimulation from being reared with enrichment, or whether it is due to a reduction in stress reactivity.


Sensitivity to communicative and non-communicative gestures in adolescents and adults with autism spectrum disorder: saccadic and pupillary responses.
Nonverbal communication using social cues, like gestures, governs a great part of our daily interactions. It has been proposed that people with autism spectrum disorder (ASD) show a deviant processing of social cues throughout their social cognitive development. However, social cues do not always convey an intention to communicate. Hence, the aim of this study was to test the sensitivity of adolescents and adults with ASD and neurotypical controls to social cues of high communicative (pointing) and low communicative values (grasping). For this purpose, we employed a spatial cueing paradigm with both Cue Types and compared saccadic reaction times (SRTs) between conditions in which the target appeared at a location which was congruent versus incongruent with the direction of the cue. Results showed that both adolescents and adults with ASD had slower SRTs for the incongruent relative to the congruent condition for both Cue Types, reflecting sensitivity to these cues. Additionally, mental effort during the processing of these social cues was assessed by means of pupil dilation. This analysis revealed that, while individuals with and without ASD required more mental effort to process incongruent compared to the congruent cues, cues with higher communicative value posed more processing load for the ASD group. These findings suggest that the perception of social gestures is intact in ASD but requires additional mental effort for gestures with higher communicative value.


EEG effects of ECT: implications for rTMS.
Electroconvulsive therapy (ECT) involves the use of electrical stimulation to elicit a series of generalized tonic-clonic seizures for therapeutic purposes and is the most effective treatment known for major depression. These treatments have significant neurophysiologic effects, many of which are manifest in the electroencephalogram (EEG). The relationship between EEG data and the response to ECT has been studied since the 1940s, but for many years no consistent correlates were found. Recent studies indicate that a number of specific EEG features recorded during the induced seizures (ictal EEG) as well as before and after a course of treatment (interictal EEG) are related to both the therapeutic efficacy and cognitive side effects. Similar to ECT, repetitive transcranial magnetic stimulation (rTMS), which involves focal electromagnetic stimulation of cortical neurons, has also been studied as an antidepressant therapy and also appears to have neurophysiologic effects, although these have not been as fully investigated as is the case with ECT. Given the similarity of these treatments, it is natural to consider whether advances in understanding the electrophysiologic correlates of the ECT response might have implications for rTMS. The present article reviews the literature on the EEG effects of ECT and discusses the implications in terms of the likely efficacy and side effects associated with rTMS in specific anatomic locations, the potential for producing an antidepressant response with rTMS without eliciting seizure activity, eliciting focal seizures with rTMS, and the possibility of using rTMS to focally modulate seizure induction and spread with ECT to optimize treatment.


State-of-the-art human gene therapy: part I. Gene delivery technologies.
Safe and effective gene delivery is a prerequisite for successful gene therapy. In the early age of human gene therapy, setbacks due to problematic gene delivery vehicles plagued the exciting therapeutic outcome. However, gene delivery technologies rapidly evolved ever since. With the advancement of gene delivery techniques, gene therapy clinical trials surged during the past decade. As the first gene therapy product (Glybera) has obtained regulatory approval and reached clinic, human gene therapy finally realized the promise that genes can be medicines. The diverse gene delivery techniques available today have laid the foundation for gene therapy applications in treating a wide range of human diseases. Some of the most urgent unmet medical needs, such as cancer and pandemic infectious diseases, have been tackled by gene therapy strategies with promising results. Furthermore, combining gene transfer with other breakthroughs in biomedical research and novel biotechnologies opened new avenues for gene therapy. Such innovative therapeutic strategies are unthinkable until now, and are expected to be revolutionary. In part I of this review, we introduced recent development of non-viral and viral gene delivery technology platforms. As cell-based gene therapy blossomed, we also summarized the diverse types of cells and vectors employed in ex vivo gene transfer. Finally, challenges in current gene delivery technologies for human use were discussed.


Entrapment of the long head of the biceps tendon: the hourglass biceps--a cause of pain and locking of the shoulder.
We describe an unrecognized mechanical condition affecting the long head of the biceps (LHB) tendon with entrapment of the tendon within the joint and subsequent pain and locking of the shoulder on elevation of the arm. We identified 21 patients with a hypertrophic intraarticular portion of the LHB tendon during open surgery (14 patients) or arthroscopic surgery (7 patients). All cases but one were associated with a rotator cuff rupture. Patients were treated by biceps tenotomy (2 patients) or tenodesis (19 patients) after removal of the hypertrophic intraarticular portion of the tendon and appropriate treatment of concomitant lesions. Minimum follow-up was 1 year. All patients presented with anterior shoulder pain and loss of active and passive elevation averaging 10 degrees to 20 degrees. A dynamic intraoperative test, involving forward elevation with the elbow extended, demonstrated entrapment of the tendon within the joint in each case. This test creates a characteristic buckling of the tendon and squeezing of it between the humeral head and the glenoid (hourglass test). The mean Constant score improved from 38 to 76 points at the final follow-up (P <.05). Complete and symmetric elevation was restored in all cases after resection of the intraarticular portion of the LHB tendon. The hourglass biceps is caused by a hypertrophic intraarticular portion of the tendon that is unable to slide into the bicipital groove during elevation of the arm; it can be compared with the condition of trigger finger in the hand. A loss of 10 degrees to 20 degrees of passive elevation, bicipital groove tenderness, and radiographic findings of a hypertrophied tendon can aid in the diagnosis. A definitive diagnosis is made at surgery with the hourglass test: incarceration and squeezing of the tendon within the joint during forward elevation of the arm with the elbow extended. The hourglass biceps is responsible for a mechanical block, which is similar to a locked knee with a bucket-handle meniscal tear. Simple tenotomy cannot resolve this mechanical block. Excision of the intraarticular portion of the LHB tendon, during bipolar biceps tenotomy or tenodesis, must be performed. The hourglass biceps is an addition to the familiar pathologies of the LHB (tenosynovitis, prerupture, rupture, and instability) and should be considered in cases of shoulder pain associated with a loss of elevation.


HIV/AIDS in women and children in India.
Management of HIV in India has significantly improved with many international and local programmes supporting prevention and treatment. However, there are areas in India where women and children living with HIV endure a myriad of medical, psychological and social challenges. Women in rural poor areas in India have little control over important aspects of their life. Often, they have little decision-making powers within their families on matters that affect them personally. They find themselves unable to negotiate to protect themselves from harm or risk of infection. Those who are known to have contracted HIV are reluctant to access health care for fear of discrimination and marginalization, leading to a disproportionate death rate in HIV women. India is arguably home to the largest number of orphans of the HIV epidemic. These children face an impenetrable barrier in many Indian societies and endure stigmatization. This situation encourages concealment of the disease and discourages children and their guardians from accessing available essential services. This article provides an overview of the relevant literature and presents an insight into a complex mix of issues that arise directly out of the HIV diagnosis, including the role of social attitudes in the spread of HIV, and in creating barriers to accessing care. The review identifies international programmes and local initiatives that have ensured better access to antiretroviral therapy and have led to prolonged survival and reduction in the vertical transmission of HIV in India.


Coffee consumption, health benefits and side effects: a narrative review and update for dietitians and nutritionists.
Coffee is one of the most popular beverages worldwide; however, its impact on health outcomes and adverse effects is not fully understood. The current review aims to establish an update about the benefits of coffee consumption on health outcomes highlighting its side effects, and finally coming up with an attempt to provide some recommendations on its doses. A literature review using the PubMed/Medline database was carried out and the data were summarized by applying a narrative approach using the available evidence based on the literature. The main findings were the following: first, coffee may contribute to the prevention of inflammatory and oxidative stress-related diseases, such as obesity, metabolic syndrome and type 2 diabetes; second, coffee consumption seems to be associated with a lower incidence of several types of cancer and with a reduction in the risk of all-cause mortality; finally, the consumption of up to 400 mg/day (1-4 cups per day) of caffeine is safe. However, the time gap between coffee consumption and some drugs should be taken into account in order to avoid interaction. However, most of the data were based on cross-sectional or/and observational studies highlighting an association of coffee intake and health outcomes; thus, randomized controlled studies are needed in order to identify a causality link.


Left ventricular non-compaction -challenges and controversies.
Cardiomyopathies classification is based on morphological and functional phenotypes and subcategories of familial/genetic and non-familial/non-genetic disease. The non-compaction cardiomyopathy is a rare disorder which is considered to be an unclassified cardiomyopathy according to the ESC Working Group on Myocardial and Pericardial Diseases and the World Health Organization or a primary genetically-determined cardiomyopathy according to the American Heart Association. The diagnosis of non-compaction is challenging and its nosology is debated since this morphological trait can be shared by different cardiomyopathies and non-cardiomyopathy conditions. Myocardial structure has a spectrum from normal variants to the pathological phenotype of non-compaction cardiomyopathy, which reflects the embryonic structure of the human heart due to an arrest in the compaction process during the first trimester. However, when a definite diagnosis of non-compaction is made, the diagnostic process should orient towards a genetic disease with a relatively high probability of sarcomere mutations. Non-compaction cardiomyopathy is a diagnostically challenging entity. Nowadays there are some controversies associated with this cardiomyopathy, that it worth to be discussed.


[Hemophilia and anesthesia.].
For more than 25 years, there has been no discussion in the Brazilian Journal of Anesthesiology about hemophiliac patients' perioperative management. Hemophilia has been described as a disease from the early 19th Century, but still today there are many hemophilia-related breakthroughs. This review aimed at pointing hemophilia patient-related perioperative care, focusing on hemophilia A management and the role of the anesthesiologist as part of the multidisciplinary team. Hemophilia features are described in terms of clinical and laboratory findings, current pharmacological therapy and intraoperative care of hemophilia patients. Hemophiliac patients management has improved. As a consequence of this advance, it is important that new knowledge, especially related to replacement therapy, be mastered not only by hematologists but also by the whole clinical-surgical team. A multidisciplinary team of which the anesthesiologist is part has to be involved when hemophilia patients are submitted to surgical procedures. The anesthesiologist should be in charge of adopting most adequate approaches for hemophilia patients, actively participating and communicating with the members of the multidisciplinary team.


The short musculoskeletal functional assessment (SMFA) score amongst surgical patients with reconstructive lower limb injuries in war wounded civilians.
The MSF programme in Jordan provides specialized reconstructive surgical care to war-wounded civilians in the region. The short musculoskeletal functional assessment score (SMFA) provides a method for quantitatively assessing functional status following orthopaedic trauma. In June 2010 the Amman team established SMFA as the standard for measuring patients' functional status. The objective of this retrospective study is to evaluate whether the SMFA scores can be useful for patients with chronic war injuries. All patients with lower limb injuries requiring reconstruction were enrolled in the study. Each patient's SMFA was assessed at admission, at discharge from Amman and during follow-up in home country. In the analysis we compared patients with infected versus non-infected injuries as well as with both high and low admissions dysfunctional index (ADI). Among infected patients, higher ADI correlated with more surgeries and longer hospital stay. Infected patients with ADI >50 required an average of 2.7 surgeries while those with ADI <50, averaged 1.7 operations (p = 0.0809). Non-infected patients with ADI >50 required an average of 1.6 operations compared to 1.5 for those with ADI <50 (p = 0.4168). The ADI score in our sample appeared to be useful in two areas: (1) hospital course in patients with infection, where a high ADI score correlated with longer hospital stays and more surgeries, and (2) prognosis, which was better for non-infected patients who had high ADI scores. A scoring system that predicts functional outcome following surgical reconstruction of lower limb injuries would be enormously useful.


Non-battle Emergency Department Utilization of the First Modular Army Field Hospital Prototype in Support of Operation INHERENT RESOLVE.
The 2010-2011 withdrawal from Iraq included the closure of all fixed-facility military medical resources. Operation INHERENT RESOLVE, the United States-led counter-terrorism mission in Iraq and Syria, subsequently commenced in 2014. With increasing combat operations, the 28th Combat Support Hospital deployed to Iraq to support that mission as a limited footprint unit prototyped after the new modular Army Field Hospital. We describe the non-battle utilization of the emergency medical treatment section. We prospectively collected data for this project as part of a performance improvement initiative to track healthcare utilization to guide emergency medical treatment section staffing. The project took place at a combat support hospital near Baghdad, Iraq from July 2016 through January 2017. During this time, the emergency department (ED) averaged 3.5 visits per day totaling 675 non-battle encounters. Most (84.6%) were U.S. military personnel with a median age of 32 (IQR 26-38). The most common procedure performed was point-of-care ultrasound (n = 33). Most patients (96.9%) underwent discharge from the ED. Of the 21 subjects admitted, 6 were for surgical intervention and the remaining for medical or observational indications. The most common chief complaints were musculoskeletal (31.1%, n = 210), respiratory (15.3%, n = 103), and dermatologic (12.0%, n = 81). Non-battle injuries and illnesses were the predominant reason for ED utilization. Most subjects were discharged back to duty with relatively low-resource utilization. Few visits required procedural interventions.


An integrated narrative nursing model: towards a new healthcare paradigm.
In the traditional biomedical model of clinical practice, which assumes a medicine focused on disease, diseases are considered as biological or psycho-physiological universal entities. This explanation, although necessary, is not enough. Several authors have recently become interested in the use of narrative practices in the medical care setting, underlining the increasing importance of "a patient-centered approach", a "relationship -centered care" and "narrative medicine". Even in Nursing, the challenge was to combine two models that seemed incompatible: the Evidence-Based Nursing Model and the Narrative-Based Nursing Model. The first one is based on the disease and is capable of reaching measurable objectives. It is marked by rationality, objectivity, determinism, unilateralism and linearity, and its methods emphasize logic, control, measurement and deduction. The second model is based on a global approach, resulting in a psycho-social perspective which stresses the importance of individuality, interpersonal relationship, and the illness and sickness as significant parts of healthcare. Through a short examination of different narrative models in medicine, we underlined some principles which can be used in nursing practice and we suggested a new healthcare paradigm based on integrated narrative nursing. It represents a groundbreaking new normative approach, deriving from different epistemological (positivist paradigm and interpretive paradigm) and methodological approaches that integrate quantitative data already normally detected on the patient, with subjective information obtained from the person and his family, and by the social impact that the disease causes. The integrated narrative nursing makes use of quantitative (e.g. scales and scientific evidence) and qualitative tools (e.g. narratives, autobiographies, therapeutic emplotment and patient's agenda). This approach, based on holistic comprehension, hermeneutic dialogue and a high degree of narrative skill, produces different ways of understanding and offering cure, care and assistance. This could allow a targeted assessment, a precise diagnosis and a personalized education. The benefits coming from the use of this paradigm are several, as for example, to disseminate a personal experience in a perspective of humanization, to improves quality of life and to create a positive effects on patient care outcomes.


Abnormal corticomuscular and intermuscular coupling in high-frequency rhythmic myoclonus.
Frequency analysis may have some advantages over back-averaging in the neurophysiological assessment of patients with suspected cortical myoclonus in whom myoclonic EMG bursts repeat rhythmically at high frequency. However, the clinical utility of EEG-EMG coherence and related EMG-EMG coherence is not established. Equally, there is an incomplete understanding of the physiology of the systems contributing to the coherence evident between signals in cortical myoclonus. Here we address these issues in an investigation of EEG-EMG and EMG-EMG coupling in proximal and distal muscles of the upper extremities in nine patients with multifocal high frequency rhythmic myoclonus due to non-progressive conditions. We found exaggerated coherence between EEG and contralateral EMG and between pairs of ipsilateral EMG signals. The results of frequency analysis of EMG-EMG mirrored those for EEG-EMG, but the former technique was superior in distinguishing a pathologically exaggerated common drive in distal upper limb muscles. Both techniques were more sensitive than back-averaging. Frequency analysis also revealed important disparities between proximal and distal upper limb muscles. In the latter case, the functional coupling between cortex and muscle was dominated by efferent processes. In contrast, there was considerable inter-individual variation in the extent to which EEG-EMG and EMG-EMG coupling in proximal muscles reflected afferent and efferent loops. Thus, the processes sustaining myoclonic discharges may differ for proximal and distal muscles and between patients.


Comparison of mortality prediction models after open abdominal aortic aneurysm repair.
Comparison of the accuracy of prediction of contemporary mortality prediction models after open Abdominal Aortic Aneurysm (AAA) surgery. Post-operative data were collected from AAA patients from 2 UK Intensive Care Units (ICU). POSSUM and VBHOM based models were compared to the APACHE-AAA model which was able to adjust for the hospital-related effect on outcome. Model performance was assessed using measures of calibration, discrimination and subgroup analysis. 541 patients were studied. The in-hospital mortality rate for elective AAA repair (325 patients) was: 6.2% (95% confidence interval (c.i.) 3.5 to 8.8) and for emergency repair (216 patients) was: 28.7% (95% c.i. 22.5-34.9). The APACHE-based model had the best overall fit to the whole population of AAA patients, and also separately in elective and emergency patients. The V-POSSUM physiology-only (p<0.001) and VBHOM (p=0.011) models had a poor fit in elective patients. The RAAA-POSSUM physiology-only (p<0.001) and VBHOM models (p=0.010) had a poor fit in emergency patients. The APACHE-AAA model with its ability to adjust for both the hospital-related "effect" as well as the patient case-mix, was a more accurate risk stratification model than other contemporary models, in the post-operative AAA patient managed in ICU.


Continuous quality improvement in ESRD: the role of networks, the United States Renal Data System, and facility-specific reports.
End-stage renal disease (ESRD) outcome improvement involves many different private and governmental entities. Networks have fulfilled a pivotal role in ESRD quality improvement by facilitating the change from quality assurance (QA) to continuous quality improvement (CQI) methodology, providing the collection and dissemination of outcome measures to facilities and developing quality improvement projects (QIPs) that interface directly with facilities. Improving outcomes in hemodialysis is generally limited to adequacy of hemodialysis and anemia management. Opportunities in peritoneal dialysis, nutrition, vascular access, and quality-of-life outcomes persist. Interaction between facilities and Medical Review Boards (MRBs) using workshops, site visits, and facility report cards can provide continuing ESRD outcome improvement. Every facility has unique people, procedures, and equipment producing their processes of care. Therefore, a certain amount of autonomy is required to encompass individual variation. Quality improvement methodology, although less rigorous than traditional outcome research, provides efficient and effective intervention when a rapid response is required to improve clinical outcomes. The two methods are not mutually exclusive but require distinct methodology to accomplish.


Ergonomics Climate Assessment: A measure of operational performance and employee well-being.
Ergonomics interventions have the potential to improve operational performance and employee well-being. We introduce a framework for ergonomics climate, the extent to which an organization emphasizes and supports the design and modification of work to maximize both performance and well-being outcomes. We assessed ergonomics climate at a large manufacturing facility twice during a two-year period. When the organization used ergonomics to promote performance and well-being equally, and at a high level, employees reported less work-related pain. A larger discrepancy between measures of operational performance and employee well-being was associated with increased reports of work-related pain. The direction of this discrepancy was not significantly related to work-related pain, such that it didn't matter which facet was valued more. The Ergonomics Climate Assessment can provide companies with a baseline assessment of the overall value placed on ergonomics and help prioritize areas for improving operational performance and employee well-being.


Clinical risk score correlates with yield of PET scan in patients with colorectal hepatic metastases.
Although positron emission tomography (PET) detects occult metastatic disease in approximately 20% of patients with isolated hepatic colorectal metastases, it is associated with false negative results in up to 16%. We hypothesized that patients with a poorer prognosis (as defined by clinical risk score [CRS]) would have a higher yield from PET. All patients with colorectal liver metastases who were imaged by means of PET between 1998 and 2002 were identified from a prospective PET database. All patients were assigned a CRS, with one point added for each of five preoperative factors (disease-free interval <1 year, tumor size >5 cm, tumor number >1, carcinoembryonic antigen >200, and node-positive primary lesion). A total of 85 PET scans were reviewed. In half the patients (53%), PET provided no additional information over conventional imaging. Occult extrahepatic disease was detected or questionable findings seen on conventional imaging were confirmed in 20% of PET scans, whereas PET readings were inaccurate in 27%. PET findings were correlated with CRS in a subset of 63 patients presenting with a first occurrence of hepatic colorectal metastases. Among patients with a CRS of 0, no patient had extrahepatic disease detected by PET and 57% had false positive readings, whereas among patients with a CRS of 1 or more, 14% were found to have additional disease that was detected only by PET, and there were no false positive readings (P<0.001, Fisher's exact test). Patients with isolated hepatic colorectal metastases and a CRS of 0 should undergo conventional imaging alone prior to surgical exploration.


Congenital Zika syndrome and neuroimaging findings: what do we know so far?
Although infection with the Zika virus was first recognized in 1942, it received little attention until 2007, when a true pandemic spread throughout Africa, Asia, and the Americas. Since then, numerous forms of central nervous system involvement have been described, mainly malformations related to congenital infection. Although the neuroimaging findings in congenital Zika syndrome are not pathognomonic, many are quite suggestive of the diagnosis, and radiologists should be prepared to interpret such findings accordingly. The objective of this article is to review the computed tomography and magnetic resonance imaging findings in congenital Zika syndrome.


Development and Implementation of a Novel HIV Primary Care Track for Internal Medicine Residents.
Declining mortality has led to a rising number of persons living with HIV (PLWH) and concerns about a future shortage of HIV practitioners. To develop an HIV Primary Care Track for internal medicine residents. Academic hospital and community health center with a history of caring for PLWH and lesbian, gay, bisexual, and transgender (LGBT) patients. Internal medicine residents. We enrolled four residents annually in a 3-year track with the goal of having each provide continuity care to at least 20 PLWH. The curriculum included small group learning sessions, outpatient electives, a global health opportunity, and the development of a scholarly project. All residents successfully accrued 20 or more PLWH as continuity patients. Senior residents passed the American Academy of HIV Medicine certification exam, and 75 % of graduates took positions in primary care involving PLWH. Clinical performance of residents in HIV care quality measures was comparable to those reported in published cohorts. We developed and implemented a novel track to train medical residents in the care of PLWH and LGBT patients. Our results suggest that a designated residency track can serve as a model for training the next generation of HIV practitioners.


Immune deviation of 2C transgenic intraepithelial lymphocytes in antigen-bearing hosts.
The present study examined self-tolerance for T cell receptor (TCR) alpha beta intestinal intraepithelial lymphocytes (iIELs) using the 2C transgenic (Tg) mouse model specific for a peptide antigen (Ag) presented by the class I major histocompatibility complex H-2Ld. Although Tg+ T cells were largely deleted from the periphery of Ag+ mice, equivalent numbers of Tg iIELs were present in Ag+ compared to Ag- mice. Tg iIELs in Ag- mice contained CD8 alpha beta, CD8 alpha alpha, and CD4-CD8- subsets, whereas only CD8 alpha alpha and CD4-CD8- Tg iIEL subsets were detected in Ag+ mice. Analysis of surface markers revealed that Tg iIELs in Ag+ mice expressed decreased levels of Thy-1 and increased CD45R/B220 as compared to Ag- Tg iIELs. In response to activation with exogenous peptide or immobilized anti-TCR mAB, iIELs from Ag- mice proliferated at high levels and produced interleukin (IL)-2 and interferon (IFN)-gamma, while Tg+ iIELs from Ag+ mice proliferated at low levels and failed to produce detectable IL-2 or IFN-gamma. Activation of sorted iIEL subsets from Ag- mice revealed that CD8 alpha alpha and CD4-CD8- subsets produced low levels of IL-2 and IFN-gamma in response to activation with antigen-presenting cells and added peptide or immobilized anti-TCR mAb, while CD8 alpha beta + iIELs responded to endogenous levels of peptide. In response to APC and exogenous peptide, sorted iIEL subsets from Ag+ mice produced IL-2 and IFN-gamma, and proliferated at greatly reduced levels compared to corresponding subsets from Ag- mice. Analysis of cytokine mRNA levels revealed that activation in vitro induced IL-2 mRNA only in Ag-, but not Ag+ iIELs, whereas a high level of IL-4 mRNA induction was detected in Tg+ iIELs from Ag+ mice, and to a lesser degree, from Ag- mice. These data suggest that tolerance for Tg+ iIELs resulted in the deletion of CD8 alpha beta + subsets and the persistence of Tg+ iIEL subsets with decreased sensitivity to endogenous levels of self-peptide. A comparison of the cytokine profiles expressed by Tg+ iIEL subsets in Ag- and Ag+ mice suggested that tolerance induction had involved the functional deviation of cells from TC1 (T helper-1-like) to a less inflammatory TC2 (T helper-2-like) phenotype capable of mediating humoral immune responses in the mucosa.


Managing thyrotoxicosis in the acute medical setting.
Thyrotoxicosis is common and can present in numerous ways with patients exhibiting a myriad of symptoms and signs. It affects around 1 in 2000 people annually in Europe1. The thyroid gland produces two thyroid hormones - thyroxine (T4) and triiodothyronine (T3). Thyroxine is inactive and is converted by the tissues and organs that need it into tri-iodothyronine. In health, the production of these thyroid hormones is tightly regulated by the secretion of thyroid stimulating hormone (TSH; thyrotropin) from the pituitary gland. The term 'thyrotoxicosis' refers to the clinical manifestations of hyperthyroidism.


Simplifying minimally invasive transhiatal esophagectomy with the inversion approach: Lessons learned from the first 20 cases.
The laparoscopic transhiatal esophagectomy can be simplified and performed safely and effectively by using a novel esophageal inversion technique. Case series describing technique, initial experience, and learning curve with laparoscopic inversion esophagectomy. Tertiary care university hospital and veteran's hospital. Twenty consecutive patients with high-grade dysplasia (n = 16) and esophageal adenocarcinoma (n = 4). Laparoscopic inversion esophagectomy, a totally laparoscopic approach to transhiatal esophagectomy that incorporates distal to proximal inversion to improve mediastinal exposure and ease of dissection. Perioperative end points and complications, compared between the first and second groups of 10 patients. There were 19 men and 1 woman. Median operative time was 448 minutes. Median blood loss was 175 cm3. Median intensive care unit stay was 4 days, and median total hospital stay was 9 days. Overall anastomotic leak rate was 20%. Five patients developed an anastomotic stricture, all successfully managed with endoscopic dilation. There were 2 recurrent laryngeal nerve injuries, which resolved. There was no intraoperative or 30-day mortality. Between the first 10 consecutive cases and last 10 procedures, the incidence of anastomotic leak and stricture formation decreased from 30% to 10% and 40% to 10%, respectively. During this period, the number of lymph nodes harvested increased 9-fold, and duration of intensive care unit stay decreased from 8.00 to 2.50 days. Laparoscopic inversion esophagectomy is a safe procedure. The learning curve for the inversion approach is approximately 10 operations in the hands of esophageal surgeons with advanced laparoscopic expertise.


Efficacy and tolerance of an injectable medical device containing stable hybrid cooperative complexes of high- and low-molecular-weight hyaluronic acid: a monocentric 16 weeks open-label evaluation.
An injectable medical device containing stable hybrid cooperative complexes of high- and low-molecular-weight hyaluronic acid (HA) has been developed with characteristics suited for a global improvement of facial esthetics. To evaluate the HA product performance in improving some key facial esthetic features. The study employed clinical scales, subjective evaluations, and facial skin objective measurements. A single Italian site treated 64 female subjects aged 38-60 years, with injections at five predetermined points, on each side of the face, with a 4-week time lapse between the first and the second product administration. Subjects were evaluated after 4, 8, 12, and 16 weeks, using validated clinical scales, subjective evaluation, and objective quantitative outcome measures. Assessment of esthetic results included photographic documentation. Both the clinical and subjective assessments, and the majority of objective instrumental parameters indicated an improvement throughout the study and were already significant at week 4 or 8 and were still significant at week 16 (3 months after the second treatment). Minor and temporary local skin reactions were observed in 23% of subjects at the site of the injections, and the global judgment on tolerability was good or excellent, both in the investigators' opinion and volunteers' self-evaluation. Both subjective and objective improvement of the facial parameters was consistent with the bio-remodeling purpose, and persistent and still statistically significant at the end of the study. The tolerability and safety profile of the product were judged good or excellent both by investigators and volunteers. This study supports the claim for bio-remodeling of these stable hybrid cooperative complexes of low- and high-molecular-weight HA.


Heart regeneration after myocardial infarction using synthetic biomaterials.
Myocardial infarction causes almost 7.3 million deaths each year worldwide. However, current treatments are more palliative than curative. Presently, cell and protein therapies are considered the most promising alternative treatments. Clinical trials performed until now have demonstrated that these therapies are limited by protein short half-life and by low transplanted cell survival rate, prompting the development of novel cell and protein delivery systems able to overcome such limitations. In this review we discuss the advances made in the last 10years in the emerging field of cardiac repair using biomaterial-based delivery systems with focus on the progress made on preclinical in vivo studies. Then, we focus in cardiac tissue engineering approaches, and how the incorporation of both cells and proteins together into biomaterials has opened new horizons in the myocardial infarction treatment. Finally, the ongoing challenges and the perspectives for future work in cardiac tissue engineering will also be discussed.


Inserting random and site-specific changes into the genome of chickens.
During the past decade, modifications to the chicken genome have evolved from random insertions of small transgenes using viral vectors to site-specific deletions using homologous recombination vectors and nontargeted insertions of large transgenes using phi-31 integrase. Primordial germ cells (PGC) and gonocytes are the germline-competent cell lines in which targeted modifications and large transgenes are inserted into the genome. After extended periods of in vitro culture, PGC retain their capacity to form functional gametes when reintroduced in vivo. Rates of stable germline modification vary from 1×10(-5) for nontargeted insertions to 1×10(-8) for targeted insertions. Following transfection, clonally derived cell lines are expanded, injected into Stage 13-15 Hamburger and Hamilton embryos, and putative chimeras are incubated to term in surrogate shells. Green fluorescent protein (GFP) is incorporated into transgenes to reveal the presence of genetically modified PGC in culture and the extent of colonization of the gonad during the first week posthatch. If the extent of colonization is adequate, cohorts of putative chimeras are reared to sexual maturity. Semen is collected and the contribution from donor PGC is estimated by evaluating GFP expression using flow cytometry and PCR. The most promising candidates are selected for breeding to obtain G1 heterozygote offspring. To date, this protocol has been used to (1) knockout the immunoglobulin heavy and light chain genes and produce chickens lacking humoral immunity, (2) insert human V genes and arrays of pseudo V genes into the heavy and light immunoglobulin loci to produce chickens making antibodies with human V regions, (3) insert GFP into nontargeted locations within the genome to produce chickens expressing GFP, and (4) insert Cre recombinase into the genome to produce chickens that excise sequences of DNA flanked by loxP sites.


Mimicry among Unequally Defended Prey Should Be Mutualistic When Predators Sample Optimally.
Understanding the conditions under which moderately defended prey evolve to resemble better-defended prey and whether this mimicry is parasitic (quasi-Batesian) or mutualistic (Müllerian) is central to our understanding of warning signals. Models of predator learning generally predict quasi-Batesian relationships. However, predators' attack decisions are based not only on learning alone but also on the potential future rewards. We identify the optimal sampling strategy of predators capable of classifying prey into different profitability categories and contrast the implications of these rules for mimicry evolution with a classical Pavlovian model based on conditioning. In both cases, the presence of moderately unprofitable mimics causes an increase in overall consumption. However, in the case of the optimal sampling strategy, this increase in consumption is typically outweighed by the increase in overall density of prey sharing the model appearance (a dilution effect), causing a decrease in mortality. It suggests that if predators forage efficiently to maximize their long-term payoff, genuine quasi-Batesian mimicry should be rare, which may explain the scarcity of evidence for it in nature. Nevertheless, we show that when moderately defended mimics are profitable to attack by hungry predators, then they can be parasitic on their models, just as classical Batesian mimics are.


Current state of prostate cancer treatment in Jamaica.
Prostate cancer is the commonest cancer in Jamaica as well as the leading cause of cancer-related deaths. One report suggested that Jamaica has the highest incidence rate of prostate cancer in the world, with an age-standardised rate of 304/100,000 per year. The Caribbean region is reported to have the highest mortality rate of prostate cancer worldwide. Prostate cancer accounts for a large portion of the clinical practice for health-care practitioners in Jamaica. The Jamaica Urological Society is a professional body comprising 19 urologists in Jamaica who provide most of the care for men with prostate cancer in collaboration with medical oncologists, radiation oncologists, and a palliative care physician. The health-care system is structured in two tiers in Jamaica: public and private. The urologist-to-patient ratio is high, and this limits adequate urological care. Screening for prostate cancer is not a national policy in Jamaica. However, the Jamaica Urological Society and the Jamaica Cancer Society work synergistically to promote screening as well as to provide patient education for prostate cancer. Adequate treatment for localised prostate cancer is available in Jamaica in the forms of active surveillance, nerve-sparing radical retropubic prostatectomy, external beam radiation, and brachytherapy. However, there is a geographic maldistribution of centres that provide prostate cancer treatment, which leads to treatment delays. Also, there is difficulty in affording some treatment options in the private health-care sectors. Androgen deprivation therapy is available for treatment of locally advanced and metastatic prostate cancer and is subsidised through a programme called the National Health Fund. Second-line hormonal agents and chemotherapeutic agents are available but are costly to most of the population. The infrastructure for treatment of prostate cancer in Jamaica is good, but it requires additional technological advances as well as additional specialist services.


Polyprotein strategy for stoichiometric assembly of nitrogen fixation components for synthetic biology.
Re-engineering of complex biological systems (CBS) is an important goal for applications in synthetic biology. Efforts have been made to simplify CBS by refactoring a large number of genes with rearranged polycistrons and synthetic regulatory circuits. Here, a posttranslational protein-splicing strategy derived from RNA viruses was exploited to minimize gene numbers of the classic nitrogenase system, where the expression stoichiometry is particularly important. Operon-based nif genes from Klebsiella oxytoca were regrouped into giant genes either by fusing genes together or by expressing polyproteins that are subsequently cleaved with Tobacco Etch Virus protease. After several rounds of selection based on protein expression levels and tolerance toward a remnant C-terminal ENLYFQ-tail, a system with only five giant genes showed optimal nitrogenase activity and supported diazotrophic growth of Escherichia coli This study provides an approach for efficient translation from an operon-based system into a polyprotein-based assembly that has the potential for portable and stoichiometric expression of the complex nitrogenase system in eukaryotic organisms.


[Oxidative stress in pathogenesis of COPD].
Cigarette smoke and aging are major risk factors of chronic obstructive pulmonary disease(COPD). It remains unsolved how long -term smoking with age affects the molecular responses in the lung. Respiratory tract is the major interface to the environment and is rich in glutathione, which protects lung from oxidative stress. We performed bronchoalveolar lavage for nonsmokers and smokers of various ages, who were further categorized according to the presence of emphysema on high-resolution computed tomography. We thus evaluated glutathione antioxidant system in BAL fluid. Characterization of older smokers with long-term smoking histories, contrasted with young recent smokers, may in part explain the predisposition of the lungs to destructive lung diseases. On the other hands, oxidative stress results from an imbalance in aerobic metabolism and poses a serious threat to cellular apoptosis, leading to emphysematous lung destruction. The therapeutic interference with targeted up-regulation of protective mechanisms might be critical for the success of future COPD therapies.


Assessment of transverse ultrasonographic parameters to optimize carpal tunnel syndrome diagnosis in a case-control study.
Transverse ultrasound measurements of the median nerve (MN) for diagnosis of carpal tunnel syndrome (CTS) suffer from inconsistent findings within and between patients and healthy subjects. The objective of this study was to improve ultrasound assessment of CTS. In a case-control study (51 patients, 25 controls) we evaluated the performance gained by: (1) correcting for ultrasound probe angulation; (2) including active parameters such as forceful gripping of the hand; and (3) including hand flexor tendon parameters. Correcting ultrasound probe angulation increased the correct classification rate by 4.5%; including forceful gripping resulted in increasing it by 2.8%; and including the hand flexor tendon resulted in an increase of 1.3%. The best predictive model combines correcting probe angulation with forceful gripping parameters and hand flexor tendon parameters. However, the clinically most practical model might use only probe angulation correction.


Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins.
Somatic mutations of mtDNA are implicated in the aging process, but there is no universally accepted method for their accurate quantification. We have used ultra-deep sequencing to study genome-wide mtDNA mutation load in the liver of normally- and prematurely-aging mice. Mice that are homozygous for an allele expressing a proof-reading-deficient mtDNA polymerase (mtDNA mutator mice) have 10-times-higher point mutation loads than their wildtype siblings. In addition, the mtDNA mutator mice have increased levels of a truncated linear mtDNA molecule, resulting in decreased sequence coverage in the deleted region. In contrast, circular mtDNA molecules with large deletions occur at extremely low frequencies in mtDNA mutator mice and can therefore not drive the premature aging phenotype. Sequence analysis shows that the main proportion of the mutation load in heterozygous mtDNA mutator mice and their wildtype siblings is inherited from their heterozygous mothers consistent with germline transmission. We found no increase in levels of point mutations or deletions in wildtype C57Bl/6N mice with increasing age, thus questioning the causative role of these changes in aging. In addition, there was no increased frequency of transversion mutations with time in any of the studied genotypes, arguing against oxidative damage as a major cause of mtDNA mutations. Our results from studies of mice thus indicate that most somatic mtDNA mutations occur as replication errors during development and do not result from damage accumulation in adult life.


The Sound of Silence: Activating Silent Biosynthetic Gene Clusters in Marine Microorganisms.
Unlocking the rich harvest of marine microbial ecosystems has the potential to both safeguard the existence of our species for the future, while also presenting significant lifestyle benefits for commercial gain. However, while significant advances have been made in the field of marine biodiscovery, leading to the introduction of new classes of therapeutics for clinical medicine, cosmetics and industrial products, much of what this natural ecosystem has to offer is locked in, and essentially hidden from our screening methods. Releasing this silent potential represents a significant technological challenge, the key to which is a comprehensive understanding of what controls these systems. Heterologous expression systems have been successful in awakening a number of these cryptic marine biosynthetic gene clusters (BGCs). However, this approach is limited by the typically large size of the encoding sequences. More recently, focus has shifted to the regulatory proteins associated with each BGC, many of which are signal responsive raising the possibility of exogenous activation. Abundant among these are the LysR-type family of transcriptional regulators, which are known to control production of microbial aromatic systems. Although the environmental signals that activate these regulatory systems remain unknown, it offers the exciting possibility of evoking mimic molecules and synthetic expression systems to drive production of potentially novel natural products in microorganisms. Success in this field has the potential to provide a quantum leap forward in medical and industrial bio-product development. To achieve these new endpoints, it is clear that the integrated efforts of bioinformaticians and natural product chemists will be required as we strive to uncover new and potentially unique structures from silent or cryptic marine gene clusters.


Maternal obesity drives functional alterations in uterine NK cells.
Over one-fifth of North American women of childbearing age are obese, putting these women at risk for a variety of detrimental chronic diseases. In addition, obesity increases the risk for developing major complications during pregnancy. The mechanisms by which obesity contributes to pregnancy complications and loss remain unknown. Increasing evidence indicates that obesity results in major changes to adipose tissue immune cell composition and function; whether or not obesity also affects immune function in the uterus has not been explored. Here we investigated the effect of obesity on uterine natural killer (uNK) cells, which are essential for uterine artery remodeling and placental development. Using a cohort of obese or lean women, we found that obesity led to a significant reduction in uNK cell numbers accompanied with impaired uterine artery remodeling. uNK cells isolated from obese women had altered expression of genes and pathways associated with extracellular matrix remodeling and growth factor signaling. Specifically, uNK cells were hyper-responsive to PDGF, resulting in overexpression of decorin. Functionally, decorin strongly inhibited placental development by limiting trophoblast survival. Together, these findings establish a potentially new link between obesity and poor pregnancy outcomes, and indicate that obesity-driven changes to uterine-resident immune cells critically impair placental development.