The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4.
Signals released by the Spemann organizer of the amphibian gastrula can directly induce neural tissue from ectoderm and can dorsalize ventral mesoderm to form muscle. The secreted polypeptide noggin mimics these activities and is expressed at the appropriate time and place to participate in the organizer signal. Neural induction and mesoderm dorsalization are antagonized by bone morphogenetic proteins (BMPs), which induce epidermis and ventral mesoderm instead. Here we report that noggin protein binds BMP4 with high affinity and can abolish BMP4 activity by blocking binding to cognate cell-surface receptors. These data suggest that noggin secreted by the organizer patterns the embryo by interrupting BMP signaling.


A modified Phase I trial of radiation dose escalation in 3D conformal radiation therapy with concurrent vinorelbine and carboplatin chemotherapy for non-small-cell lung cancer.
The Radiation Therapy Oncology Group reported a maximum tolerated dose of 74 Gy for patients with non-small cell lung cancer (NSCLC); however, it was unclear whether this dose could be safely administered to Asian patients due to differences in their physique compared to Western patients. We therefore conducted a modified Phase I trial to determine whether 70 Gy could be safely delivered to Chinese patients with NSCLC undergoing 3D-conformal radiation therapy (3D-CRT) with concurrent chemotherapy. Previously untreated NSCLC patients received 3D-CRT (2 Gy/day, 5 fractions per week). Three dose levels were examined: 62, 66 and 70 Gy. Two cycles of concurrent chemotherapy (vinorelbine and carboplatin) were started on the first day of radiation therapy. Dose-limiting toxicity (DLT) was defined as severe or life-threatening side effects that altered the continued implementation of chemoradiotherapy. Among the 19 patients recruited in this study, most of the haematologic and non-haematologic toxicities were mild to moderate and clinically manageable. Only one patient, in the 70 Gy cohort, experienced a DLT of Grade 3 radiation-induced pneumonia. The overall response rate was 77.8% (14/18). The median progression-free survival (PFS) was 12 months, and the 1-year PFS was 37.6%. Our results support both the feasibility of incorporating 3D-CRT with concurrent vinorelbine and carboplatin and a dose escalation to 70 Gy for Chinese patients with NSCLC, based on the acceptable toxicity and encouraging overall response and survival rates. A further evaluation of this regimen in a prospective Phase II trial is ongoing.


Can Intralesional Epidermal Growth Factor Reduce Skin Graft Applications in Patients with Diabetic Foot Ulcer?
Diabetic foot ulcer (DFU) is a serious health problem. Major amputation increases the risk of mortality in patients with DFU; therefore, treatment methods other than major amputation come to the fore for these patients. Graft applications create an appropriate environment for the reproduction of epithelial cells. Similarly, epidermal growth factor (EGF) also stimulates epithelization and increases epidermis formation. In this study, we aimed to compare patients with DFU treated with EGF and those treated with a split-thickness skin graft. Patients who were treated for DFU in the general surgery clinic were included in the study. The patients were evaluated retrospectively according to their demographic characteristics, wound characteristics, duration of treatment, and treatment modalities. There were 26 patients in the EGF group and 21 patients in the graft group. The mean duration of treatment was 7 weeks (4-8 weeks) in the EGF group and 5.3 weeks (4-8 weeks) in the graft group (P < .05). In the EGF group, wound healing could not be achieved in one patient during the study period. In the graft group, no recovery was achieved in three patients (14.2%) in the donor site. Graft loss was detected in four patients (19%), and partial graft loss was observed in three patients (14.2%). The DFU of these patients were on the soles (85.7%). These patients have multiple comorbidities. EGF application may be preferred to avoid graft complications in the graft area and the donor site, especially in elderly patients with multiple comorbidities and wounds on the soles.


Visual tracking using neuromorphic asynchronous event-based cameras.
This letter presents a novel computationally efficient and robust pattern tracking method based on a time-encoded, frame-free visual data. Recent interdisciplinary developments, combining inputs from engineering and biology, have yielded a novel type of camera that encodes visual information into a continuous stream of asynchronous, temporal events. These events encode temporal contrast and intensity locally in space and time. We show that the sparse yet accurately timed information is well suited as a computational input for object tracking. In this letter, visual data processing is performed for each incoming event at the time it arrives. The method provides a continuous and iterative estimation of the geometric transformation between the model and the events representing the tracked object. It can handle isometry, similarities, and affine distortions and allows for unprecedented real-time performance at equivalent frame rates in the kilohertz range on a standard PC. Furthermore, by using the dimension of time that is currently underexploited by most artificial vision systems, the method we present is able to solve ambiguous cases of object occlusions that classical frame-based techniques handle poorly.


Evaluation of a UMLS Auditing Process of Semantic Type Assignments.
The UMLS is a terminological system that integrates many source terminologies. Each concept in the UMLS is assigned one or more semantic types from the Semantic Network, an upper level ontology for biomedicine. Due to the complexity of the UMLS, errors exist in the semantic type assignments. Finding assignment errors may unearth modeling errors. Even with sophisticated tools, discovering assignment errors requires manual review. In this paper we describe the evaluation of an auditing project of UMLS semantic type assignments. We studied the performance of the auditors who reviewed potential errors. We found that four auditors, interacting according to a multi-step protocol, identified a high rate of errors (one or more errors in 81% of concepts studied) and that results were sufficiently reliable (0.67 to 0.70) for the two most common types of errors. However, reliability was low for each individual auditor, suggesting that review of potential errors is resource-intensive.


[Studies on keratocystic odontogenic tumors].
Keratocystic odontogenic tumors (KCOTs, previously known as odontogenic keratocysts) are aggressive, noninflammatory jaw lesions with a putative high growth potential and a propensity for recurrence. This article puts together a summary of the serial studies related to KCOTs undertaken by the author's research group in recent years. Intraosseous jaw cysts with a solely orthokeratinized lining epithelium have been suggested to differ from the typical KCOTs. We report 20 cases of such cyst type under the term of 'orthokeratinized odontogenic cyst (OOC)'. Apart from the presence of a keratinizing epithelial lining, the OOC lacks the other histological features of KCOT, exhibits little if any tendency to recur, has no apparent association with NBCCS, may be cured by simple enucleation, and may thus constitute its own clinical entity. Mutations in PTCH1 gene are responsible for NBCCS and are related in tumors associated with this syndrome. We have so far detected 26 PTCH1 mutations (2 mutations occurred twice) in 10 out of 34 (29.4%) sporadic and 14 out of 16 (87.5%) NBCCS-associated KCOTs. The 26 mutations consisted of 10 frameshift, 2 nonsense, 3 aberrant splicing, 4 in-frame insertion/deletion/ duplication and 7 missense mutations. Two missense mutations in PTCH2 were also detected in 2 out of 15 NBCCS related KCOT patients. By contrast, no pathogenic mutation was detected in SMO. Thus, our data, together with reports from other groups, indicate that defects of PTCH1 are involved in the pathogenesis of syndromic as well as sporadic KCOTs. The pathogenic role of PTCH2 requires further investigation. A series of in vitro studies on bone resorption of KCOTs and ameloblastomas were undertaken by this group. The results indicate that odontogenic lesions could promote bone resorption in vitro and it is likely to be related to some of the cytokines secreted by the lesions.


Incidence of and risk indicators for vasa praevia: a systematic review.
Vasa praevia (VP) is a rare phenomenon that is assumed to increase the risk of severe complications, including fetal death. Critical data on its incidence are lacking, so there is no rational basis for prenatal screening. To review the literature on the incidence and risk indicators for VP. We searched OVID MEDLINE, OVID EMBASE, the Cochrane Library and PubMed for case-control and cohort studies on incidence and risk indicators for VP. Two reviewers selected studies and scored their methodological quality. We calculated the mean incidence of VP. We constructed 2 × 2 tables cross-classifying potential risk indicators against the incidence of VP to calculate common odds ratios and 95% confidence intervals, using the Mantel-Haenszel method. We included 13 studies (two prospective cohort studies, ten retrospective cohort studies and one case-control study) reporting on 569 410 patients with 325 cases of VP. Based on ten included cohort studies providing information on the incidence, the mean incidence of VP was 0.60 per 1000 pregnancies. We identified five different risk indicators and markers for VP: second-trimester placenta praevia, conception by assisted reproductive technologies, a bilobed or succenturiate placenta, umbilical cord insertion in the lower third part of the uterus at first-trimester ultrasound and velamentous cord insertion. Almost 83% of the cases of VP had one or more risk indicators. In view of the low incidence, screening for VP in an unselected population is not advised. Targeted screening of women with one or more risk indicators as a part of routine mid-gestation scanning should be considered. Vasa praevia is more common in placenta praevia, conception by ART, velamentous cord insertion and bilobed placenta.


IL-6 rescues resting mouse T cells from apoptosis.
It has previously been demonstrated that mature mouse T cells live for many weeks in vivo. In contrast, explanted lymph node or splenic T cells undergo spontaneous death within days, suggesting that survival factors supplied in vivo are not present in normal tissue culture medium. We discovered that IL-6 can rescue resting T cells from apoptosis in vitro. We show that recombinant mouse IL-6 as well as IL-6 in endothelial cell supernatants are sufficient to rescue T cells from death in the absence of additional cytokines. We show that CD4+ T cells express Bcl-2 immediately following isolation from the mouse, but after 24 h in culture Bcl-2 is undetectable. If during this time period the T cells are incubated with rIL-6, Bcl-2 expression is not down-regulated. It is, therefore, possible that IL-6 rescue from death is mediated by maintenance or induction of Bcl-2 expression. Addition of rIL-6 does not by itself induce blastogenesis or proliferation, and therefore, this cytokine appears to be a true survival factor rather than a mitogenic factor for resting T cells. Together, these results support a potential role for IL-6 as one of the factors important for prolonging resting T cell survival in vivo.


How well does the theory of planned behaviour predict alcohol consumption? A systematic review and meta-analysis.
This study aimed to quantify correlations between theory of planned behaviour (TPB) variables and (i) intentions to consume alcohol and (ii) alcohol consumption. Systematic literature searches identified 40 eligible studies that were meta-analysed. Three moderator analyses were conducted: pattern of consumption, gender of participants and age of participants. Across studies, intentions had the strongest relationship with attitudes (r+ = .62), followed by subjective norms (r+ = .47) and perceived behavioural control (PBC; r+ = .31). Self-efficacy (SE) had a stronger relationship with intentions (r+ = .48) compared with perceived control (PC; r+ = -.10). Intention had the strongest relationship with alcohol consumption (r+ = .54), followed by SE (r+ = .41). In contrast, PBC and PC had negative relationships with alcohol consumption (r+ = -.05 and -.13, respectively). All moderators affected TPB relationships. Patterns of consumption with clear definitions had stronger TPB relations, females reported stronger attitude-intention relations than males, and adults reported stronger attitude-intention and SE-intention relations than adolescents. Recommendations for future research include targeting attitudes and intentions in interventions to reduce alcohol consumption, using clear definitions of alcohol consumption in TPB items to improve prediction and assessing SE when investigating risk behaviours.


Stationary phase-induction of G-->T mutations in Escherichia coli.
A series of Escherichia coli mutants, constructed originally by Cupples and Miller [C.G. Cupples, J.H. Miller, A set of lacZ mutations in Escherichia coli that allow rapid detection of each of the six base substitutions, Proc. Natl. Acad. Sci. U.S.A. 86 (1989) 5345-5349], provides a unique system for quantifying base-change mutations, and the repair processes that limit their establishment, in bacteria under selective and non-selective conditions. We focussed on one strain in which a T-->G replacement inactivates the lacZ gene. Reversions of this strain can occur through oxidation of G, leading to G-->T transversions. We show that spontaneous reversions occurred both in lactose (selective) and glucose (non-selective) medium. The number of revertants per viable cell was much greater in medium containing lactose or both sugars than glucose alone. In glucose medium, the rate of reversion was highest below 0.6% glucose and strongly inhibited at and above that level. Evidence that reversions occurred through G-->T transversions in both lactose and glucose media came from two observations: by sequence analysis of a series of revertants and by comparing the reversion rates in strains possessing and lacking the mutM gene (encoding formamidopyrimidine DNA glycosylase, FPG). However, the rate of reversion was stimulated by reducing O2 to 1% and inhibited or delayed by increasing O2 to 90%. In mutM- cells grown on glucose medium, the proportion of revertants increased over a 5-day period. In contrast, in mutM+ cells, revertants appeared primarily during the first 2-3 days after plating; few new revertants appeared in the following days. These data imply that base excision repair initiated by FPG was less effective in the first 2 days and more effective later in stationary phase.


Sexual transmission of Zika virus and other flaviviruses: A living systematic review.
Health authorities in the United States and Europe reported an increasing number of travel-associated episodes of sexual transmission of Zika virus (ZIKV) following the 2015-2017 ZIKV outbreak. This, and other scientific evidence, suggests that ZIKV is sexually transmissible in addition to having its primary mosquito-borne route. The objective of this systematic review and evidence synthesis was to clarify the epidemiology of sexually transmitted ZIKV. We performed a living (i.e., continually updated) systematic review of evidence published up to 15 April 2018 about sexual transmission of ZIKV and other arthropod-borne flaviviruses in humans and other animals. We defined 7 key elements of ZIKV sexual transmission for which we extracted data: (1) rectal and vaginal susceptibility to infection, (2) incubation period following sexual transmission, (3) serial interval between the onset of symptoms in a primary and secondary infected individuals, (4) duration of infectiousness, (5) reproduction number, (6) probability of transmission per sex act, and (7) transmission rate. We identified 1,227 unique publications and included 128, of which 77 presented data on humans and 51 presented data on animals. Laboratory experiments confirm that rectal and vaginal mucosae are susceptible to infection with ZIKV and that the testis serves as a reservoir for the virus in animal models. Sexual transmission was reported in 36 human couples: 34/36 of these involved male-to-female sexual transmission. The median serial symptom onset interval in 15 couples was 12 days (interquartile range: 10-14.5); the maximum was 44 days. We found evidence from 2 prospective cohorts that ZIKV RNA is present in human semen with a median duration of 34 days (95% CI: 28-41 days) and 35 days (no CI given) (low certainty of evidence, according to GRADE). Aggregated data about detection of ZIKV RNA from 37 case reports and case series indicate a median duration of detection of ZIKV of 40 days (95% CI: 30-49 days) and maximum duration of 370 days in semen. In human vaginal fluid, median duration was 14 days (95% CI: 7-20 days) and maximum duration was 37 days (very low certainty). Infectious virus in human semen was detected for a median duration of 12 days (95% CI: 1-21 days) and maximum of 69 days. Modelling studies indicate that the reproduction number is below 1 (very low certainty). Evidence was lacking to estimate the incubation period or the transmission rate. Evidence on sexual transmission of other flaviviruses was scarce. The certainty of the evidence is limited because of uncontrolled residual bias. The living systematic review and sexual transmission framework allowed us to assess evidence about the risk of sexual transmission of ZIKV. ZIKV is more likely transmitted from men to women than from women to men. For other flaviviruses, evidence of sexual transmissibility is still absent. Taking into account all available data about the duration of detection of ZIKV in culture and from the serial interval, our findings suggest that the infectious period for sexual transmission of ZIKV is shorter than estimates from the earliest post-outbreak studies, which were based on reverse transcription PCR alone.


Mobile Technology-Based (mLearning) Intervention to Enhance Breast Cancer Clinicians' Communication About Sexual Health: A Pilot Trial.
Most breast cancer clinicians lack training to counsel patients about sexual concerns. The purpose of this study was to assess the feasibility, acceptability, and preliminary effects of a mobile learning (mLearning) intervention (improving Sexual Health and Augmenting Relationships through Education [iSHARE]) aimed at enhancing breast cancer clinicians' knowledge of, beliefs about, and comfort with discussing patients' sexual health concerns. Clinicians listened to a 2-part educational podcast series offering information on breast cancer-related sexual health concerns and effective communication on the topic, which consisted of interviews with expert guests. Intervention feasibility was assessed through rates of enrollment, retention, and intervention completion, with benchmarks of 40%, 70%, and 60%, respectively. Acceptability was assessed through program evaluations, with 75% of clinicians rating the intervention favorably (eg, relevance, satisfaction) signifying acceptability. Clinicians self-reported their knowledge about breast cancer-related sexual health concerns, beliefs (ie, self-efficacy for discussing sexual health concerns), and comfort with discussing sexual concerns measured at preintervention and postintervention. Qualitative analysis examined clinicians' perceptions of lessons learned from the intervention. A total of 32 breast cancer clinicians enrolled (46% of those invited; 97% of those who responded and screened eligible), 30 (94%) completed both the intervention and study surveys, and 80% rated the intervention favorably, demonstrating feasibility and acceptability. Results showed positive trends for improvement in clinician knowledge, beliefs, and comfort with discussing sexual health concerns. Clinicians reported key lessons learned, including taking a proactive approach to discussing sexual health concerns, normalizing the topic, addressing vaginal health, sending the message that help is available, and assessing sexual health concerns with patients from different backgrounds. Breast cancer clinicians were amenable to participating in the iSHARE intervention and found it useful. iSHARE showed promise for improving clinician's knowledge and comfort discussing patients' sexual health concerns. A larger trial is required to demonstrate efficacy. Future studies should also examine whether iSHARE can improve patient-clinician communication and address patients' sexual concerns.


Presence and Quality of Kindergarten Children's Friendships: Concurrent and Longitudinal Associations with Child Adjustment in the Early School Years.
The presence and quality of friendships are posited to have developmental significance, yet little is known about the extent to which children without friends versus low-quality friendships compare on socioemotional adjustment. The current study utilized data from a subsample of 567 children (289 boys) participating in the NICHD Study of Early Child Care and Youth Development. Based on maternal reports at kindergarten, four friendship groups were formed: no friends, low quality, average quality, and high quality, and these groups were used to predict teacher-reported behavior problems and social skills concurrently (in kindergarten) and longitudinally (in first and third grade). Concurrently, low-quality friendships were associated with greater externalizing behavior, whereas high-quality friendships were associated with greater social skills. Longitudinally, having no friends in kindergarten was associated with higher levels of externalizing behavior for boys, but lower levels for girls. Children without friends also showed more internalizing problems at first grade. Lastly, having a high-quality friendship in kindergarten was associated with greater social skills in first and third grades, but only for boys. Results underscore high-quality friendship as a context for the development of social skills and indicate different trajectories of problem behavior for kindergarten children with no friends versus low-quality friendships.


The 'LipoYeasts' project: using the oleaginous yeast Yarrowia lipolytica in combination with specific bacterial genes for the bioconversion of lipids, fats and oils into high-value products.
The oleochemical industry is currently still dominated by conventional chemistry, with biotechnology only starting to play a more prominent role, primarily with respect to the biosurfactants or lipases, e.g. as detergents, or for biofuel production. A major bottleneck for all further biotechnological applications is the problem of the initial mobilization of cheap and vastly available lipid and oil substrates, which are then to be transformed into high-value biotechnological, nutritional or pharmacological products. Under the EU-sponsored LipoYeasts project we are developing the oleaginous yeast Yarrowia lipolytica into a versatile and high-throughput microbial factory that, by use of specific enzymatic pathways from hydrocarbonoclastic bacteria, efficiently mobilizes lipids by directing its versatile lipid metabolism towards the production of industrially valuable lipid-derived compounds like wax esters (WE), isoprenoid-derived compounds (carotenoids, polyenic carotenoid ester), polyhydroxyalkanoates (PHAs) and free hydroxylated fatty acids (HFAs). Different lipid stocks (petroleum, alkane, vegetable oil, fatty acid) and combinations thereof are being assessed as substrates in combination with different mutant and recombinant strains of Y. lipolytica, in order to modulate the composition and yields of the produced added-value products.


Predicting independent survival after stroke: a European study for the development and validation of standardised stroke scales and prediction models of outcome.
Accurate prediction of stroke outcome is desirable for clinical management and provision of appropriate care, and potentially for stratification of patients into studies. To investigate the predictive properties of validated scales and severity measures, and their constituent variables, and to compare their prediction in six European populations. We studied 2033 first-ever stroke patients in population-based stroke registers in France, Italy, Lithuania, the UK, Spain and Poland. Logistic models were used to predict independent survival at 3 and 12 months after stroke using a range of measures including the Six Simple Variable (SSV), Barthel index (BI) and the National Institute of Heath Stroke Scale (NIHSS). Predictions were compared within and between populations using receiver operating characteristic curves. A five-variable scale was developed and validated. Comparisons of BI with BI+age, and NIHSS with NIHSS+age, across populations showed that inclusion of age significantly improved prediction. Fairly equal predictions were obtained by three models: five variables, BI+age, and NIHSS+age. Better agreement between predicted and actual outcomes, and more precise estimates were obtained by the five variables model (age, verbal component of the Glasgow Coma Scale, arm power, ability to walk, and pre-stroke dependency). Living alone before the stroke was not significantly associated with independent survival after the stroke. Five variables (excluding living alone, from the SSV) provided good prediction for all populations and subgroups. Further external validation for our estimates is recommended before utilisation of the model in practice and research.


Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety.
Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by γ-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 μL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.


Wide-field, high-resolution lensless on-chip microscopy via near-field blind ptychographic modulation.
We report a novel lensless on-chip microscopy platform based on near-field blind ptychographic modulation. In this platform, we place a thin diffuser in between the object and the image sensor for light wave modulation. By blindly scanning the unknown diffuser to different x-y positions, we acquire a sequence of modulated intensity images for quantitative object recovery. Different from previous ptychographic implementations, we employ a unit magnification configuration with a Fresnel number of ∼50 000, which is orders of magnitude higher than those of previous ptychographic setups. The unit magnification configuration allows us to have the entire sensor area, 6.4 mm by 4.6 mm, as the imaging field of view. The ultra-high Fresnel number enables us to directly recover the positional shift of the diffuser in the phase retrieval process, addressing the positioning accuracy issue plaguing regular ptychographic experiments. In our implementation, we use a low-cost, DIY scanning stage to perform blind diffuser modulation. Precise mechanical scanning that is critical in conventional ptychography experiments is no longer needed in our setup. We further employ an up-sampling phase retrieval scheme to bypass the resolution limit set by the imager pixel size and demonstrate a half-pitch resolution of 0.78 μm. We validate the imaging performance via in vitro cell cultures, transparent and stained tissue sections, and a thick biological sample. We show that the recovered quantitative phase map can be used to perform effective cell segmentation of a dense yeast culture. We also demonstrate 3D digital refocusing of the thick biological sample based on the recovered wavefront. The reported platform provides a cost-effective and turnkey solution for large field-of-view, high-resolution, and quantitative on-chip microscopy. It is adaptable for a wide range of point-of-care-, global-health-, and telemedicine-related applications.


Genomic analysis reveals the biotechnological and industrial potential of levan producing halophilic extremophile, Halomonas smyrnensis AAD6T.
Halomonas smyrnensis AAD6T is a gram negative, aerobic, and moderately halophilic bacterium, and is known to produce high levels of levan with many potential uses in foods, feeds, cosmetics, pharmaceutical and chemical industries due to its outstanding properties. Here, the whole-genome analysis was performed to gain more insight about the biological mechanisms, and the whole-genome organization of the bacterium. Industrially crucial genes, including the levansucrase, were detected and the genome-scale metabolic model of H. smyrnensis AAD6T was reconstructed. The bacterium was found to have many potential applications in biotechnology not only being a levan producer, but also because of its capacity to produce Pel exopolysaccharide, polyhydroxyalkanoates, and osmoprotectants. The genomic information presented here will not only provide additional information to enhance our understanding of the genetic and metabolic network of halophilic bacteria, but also accelerate the research on systematical design of engineering strategies for biotechnology applications.


Metabolism of tripelennamine in man.
Four polar metabolites were isolated from the urine of human subjects orally treated with tripelennamine, and their structures elucidated by various chemical and physical methods. One of the metabolites, which is a minor one, was identified as an N-oxide of tripelennamine, and the other three as glucuronide conjugates. One of the conjugates, which is a major metabolite, has been assigned a unique quaternary ammonium N-glucuronide structure, since it gave tripelennamine and D-glucuronic acid on incubation with beta-glucuronidase. The N-oxide, which has also been prepared synthetically, remained unchanged on similar treatment. The other two conjugates were O-glucuronides of hydroxylated derivatives, the glucuronide of hydroxytripelennamine being the principal metabolite. No desmethyltripelennamine was found in the urine, however. Hydroxylation in both cases had occurred in the pyridine ring.


Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes.
At 4 degrees C transferrin bound to receptors on the reticulocyte plasma membrane, and at 37 degrees C receptor-mediated endocytosis of transferrin occurred. Uptake at 37 degrees C exceeded binding at 4 degrees C by 2.5-fold and saturated after 20-30 min. During uptake at 37 degrees C, bound transferrin was internalized into a trypsin-resistant space. Trypsinization at 4 degrees C destroyed surface receptors, but with subsequent incubation at 37 degrees C, surface receptors rapidly appeared (albeit in reduced numbers), and uptake occurred at a decreased level. After endocytosis, transferrin was released, apparently intact, into the extracellular space. At 37 degrees C colloidal gold-transferrin (AuTf) clustered in coated pits and then appeared inside various intracellular membrane-bounded compartments. Small vesicles and tubules were labeled after short (5-10 min) incubations at 37 degrees C. Larger multivesicular endosomes became heavily labeled after longer (20-35 min) incubations. Multivesicular endosomes apparently fused with the plasma membrane and released their contents by exocytosis. None of these organelles appeared to be lysosomal in nature, and 98% of intracellular AuTf was localized in acid phosphatase-negative compartments. AuTf, like transferrin, was released with subsequent incubation at 37 degrees C. Freeze-dried and freeze-fractured reticulocytes confirmed the distribution of AuTf in reticulocytes and revealed the presence of clathrin-coated patches amidst the spectrin coating the inner surface of the plasma membrane. These data suggest that transferrin is internalized via coated pits and vesicles and demonstrate that transferrin and its receptor are recycled back to the plasma membrane after endocytosis.


Reconciling extreme branch length differences: decoupling time and rate through the evolutionary history of filmy ferns.
The rate of molecular evolution is not constant across the Tree of Life. Characterizing rate discrepancies and evaluating the relative roles of time and rate along branches through the past are both critical to a full understanding of evolutionary history. In this study, we explore the interactions of time and rate in filmy ferns (Hymenophyllaceae), a lineage with extreme branch length differences between the two major clades. We test for the presence of significant rate discrepancies within and between these clades, and we separate time and rate across the filmy fern phylogeny to simultaneously yield an evolutionary time scale of filmy fern diversification and reconstructions of ancestral rates of molecular evolution. Our results indicate that the branch length disparity observed between the major lineages of filmy ferns is indeed due to a significant difference in molecular evolutionary rate. The estimation of divergence times reveals that the timing of crown group diversification was not concurrent for the two lineages, and the reconstruction of ancestral rates of molecular evolution points to a substantial rate deceleration in one of the clades. Further analysis suggests that this may be due to a genome-wide deceleration in the rate of nucleotide substitution.


Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain.
Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection - without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.


Overfishing of small pelagic fishes increases trophic overlap between immature and mature striped dolphins in the Mediterranean Sea.
The interactions among diet, ecology, physiology, and biochemistry affect N and C stable isotope signatures in animal tissues. Here, we examined if ecological segregation among animals in relation to sex and age existed by analyzing the signatures of δ(15)N and δ(13)C in the muscle of Western Mediterranean striped dolphins. Moreover, we used a Bayesian mixing model to study diet composition and investigated potential dietary changes over the last two decades in this population. For this, we compared isotope signatures in samples of stranded dolphins obtained during two epizootic events occurring in 1990 and 2007-2008. Mean δ(13)C values for females and males were not significantly different, but age-related variation indicated δ(13)C enrichment in both sexes, suggesting that females and males most likely fed in the same general areas, increasing their consumption of benthic prey with age. Enrichment of δ(15)N was only observed in females, suggesting a preference for larger or higher trophic level prey than males, which could reflect different nutritional requirements. δ(13)C values showed no temporal variation, although the mean δ(15)N signature decreased from 1990 to 2007-2008, which could indicate a dietary shift in the striped dolphin over the last two decades. The results of SIAR indicated that in 1990, hake and sardine together contributed to 60% on the diet of immature striped dolphins, and close to 90% for mature striped dolphins. Conversely, the diet of both groups in 2007-2008 was more diverse, as hake and sardine contributed to less than 40% of the entire diet. These results suggest a dietary change that was possibly related to changes in food availability, which is consistent with the depletion of sardine stocks by fishing.


Finger Imprint of Poncirus trifoliata: A Specific Interaction of a Viroid, a Host, and Irrigation.
The unusual symptom, "finger imprint", described exclusively on Poncirus trifoliata, has been reported in only a single field trial investigating the effects of citrus viroids on crop performance. With this, the question has persisted whether the observed growth abnormality was a disease symptom induced by Citrus viroid IIIb (CVd-IIIb) or a consequence of mechanical damage caused by the handling of young trees during propagation or cultural practices in the field. The recurrence of finger imprint symptoms on trees after 5 years in the field in which no abnormal growth features were previously noted now supports the proposition of a viroid-induced disease. The symptom expression results from an unusual etiology of a complex relationship of the specific viroid CVd-IIIb on the specific rootstock P. trifoliata only when supplemental water is applied by sprinkler irrigation.


Engineering Cell Fate for Tissue Regeneration by In Vivo Transdifferentiation.
Changes in cell identity occur in adult mammalian organisms but are rare and often linked to disease. Research in the last few decades has thrown light on how to manipulate cell fate, but the conversion of a particular cell type into another within a living organism (also termed in vivo transdifferentiation) has only been recently achieved in a limited number of tissues. Although the therapeutic promise of this strategy for tissue regeneration and repair is exciting, important efficacy and safety concerns will need to be addressed before it becomes a reality in the clinical practice. Here, we review the most relevant in vivo transdifferentiation studies in adult mammalian animal models, offering a critical assessment of this potentially powerful strategy for regenerative medicine.


Stepwise synthesis of the heterotrimetallic chains [MRu2(dpa)4X2]0/1+ using group 7 to group 12 transition metal ions and [Ru2(dpa)4Cl].
The CoRu2(dpa)4Cl2 (1) (dpa: 2,2'-dipyridylamide) is synthesized by the reaction of Ru2(OAc)4Cl and Co3(dpa)4Cl2. By mixing 1 with NH3, Co2+ can be removed and result in the formation of unique binuclear complex 4,0-Ru2(dpa)4Cl (2) featuring one coordination pocket supported by free pyridine groups. Hence, this complex can act as an outstanding precursor for the formation of heterotrimetallic chains with MRu2 cores. A series of M-Ru25+ complexes (M = Co2+ (3), Ag+ (4), Mn2+ (5), Fe2+ (6), Zn2+ (7), Cd2+ (8), Pd2+ (9), Rh2+ (10), and Ir2+ (11)) were prepared and isolated, representing the most complete series of heterotrimetallic chains to date. All these metal string complexes are in a linear trimetallic framework helically wrapped by four dpa- ligands, characterized by X-ray diffraction measurements. The bending of the trinuclear metal cores in RhRu2 (10) and IrRu2 (11) (∠Ru-Ru-Rh: 167.58° and ∠Ru-Ru-Ir: 167.61°) indicates that a heterometallic metal-metal bonds (Ru-Rh; Ru-Ir) are generated. The studies from DFT calculation of 10 and 11 coincide with the experimental results. Furthermore, the MRu25+ distances are regulated by the factors including the bonding force of M-pyridyl and the static repulsion between M and Ru25+ unit. Interestingly, the trend for these distances is in line with that observed in trans-M(py)4Cl2 complexes.


Probabilistic alignment leads to improved accuracy and read coverage for bisulfite sequencing data.
DNA methylation has been linked to many important biological phenomena. Researchers have recently begun to sequence bisulfite treated DNA to determine its pattern of methylation. However, sequencing reads from bisulfite-converted DNA can vary significantly from the reference genome because of incomplete bisulfite conversion, genome variation, sequencing errors, and poor quality bases. Therefore, it is often difficult to align reads to the correct locations in the reference genome. Furthermore, bisulfite sequencing experiments have the additional complexity of having to estimate the DNA methylation levels within the sample. Here, we present a highly accurate probabilistic algorithm, which is an extension of the Genomic Next-generation Universal MAPper to accommodate bisulfite sequencing data (GNUMAP-bs), that addresses the computational problems associated with aligning bisulfite sequencing data to a reference genome. GNUMAP-bs integrates uncertainty from read and mapping qualities to help resolve the difference between poor quality bases and the ambiguity inherent in bisulfite conversion. We tested GNUMAP-bs and other commonly-used bisulfite alignment methods using both simulated and real bisulfite reads and found that GNUMAP-bs and other dynamic programming methods were more accurate than the more heuristic methods. The GNUMAP-bs aligner is a highly accurate alignment approach for processing the data from bisulfite sequencing experiments. The GNUMAP-bs algorithm is freely available for download at: http://dna.cs.byu.edu/gnumap. The software runs on multiple threads and multiple processors to increase the alignment speed.


Predictive perception of self-generated movements: Commonalities and differences in the neural processing of tool and hand actions.
Tool use is one of the most remarkable skills of the human species, enabling complex interactions with the environment. To establish such interactions, we predict the sensory consequences of our actions based on a copy of the motor command (efference copy), leading to an attenuated perception and neural suppression of the sensory input. Here, we investigated whether and how tools can be incorporated into these predictions. We hypothesized that similar predictive mechanisms are used for both hand and tool use actions, but that additional resources are needed to integrate the tool. During fMRI data acquisition, 19 healthy participants used either their right hand or a tool to hold the handle of a movement device. To manipulate the effect of the efference copy, the handle was moved either actively by participants or passively by the movement device. The sensory outcome, consisting of a real-time video of the hand or tool movement shown on a screen, was presented with varying delays (0-417 ms). Participants reported their perception of such delays. The processing of hand and tool movements yielded largely similar results when comparing active against passive conditions: Active movements were in both cases associated with worse delay detection performances. Moreover, during both hand and tool use actions, active movements led to a downregulation of sensory (somatosensory, visual) areas as well as the right cerebellum and right posterior parietal cortex, as assessed by a conjunction analysis. By contrast, an interaction analysis indicated differential processing of active vs. passive movements in hand vs. tool conditions in the left postcentral gyrus, right middle temporal gyrus (MTG), and bilateral caudate nuclei. Our findings provide behavioral and neural support that hand and tool actions share similar mechanisms for sensory predictions. We propose that the MTG and (sensori)motor areas (postcentral gyrus, caudate nuclei) contribute to these predictions by optimizing them to the physics of the end effector (hand or tool). Collectively, these results suggest that the brain dynamically adjusts sensorimotor predictive models to anticipate the dynamics of the end effector, be it a hand or a tool.


Neural gliding techniques for the treatment of carpal tunnel syndrome: a systematic review.
There are discrepancies regarding the efficacy of neural gliding exercises for the management of carpal tunnel syndrome (CTS). To conduct a systematic review assessing the efficacy of neural gliding in comparison to alternative nonsurgical treatment for the management of CTS. A computerized search was performed in April 2008. Criteria for inclusion required that studies (1) were written in English, (2) examined the efficacy of neural gliding techniques for treatment of CTS, and (3) included at least one of the selected patient-oriented outcomes. Effect sizes, relative risk, and 95% confidence intervals were calculated to compare neural gliding to alternative treatment. Six studies met inclusion criteria. For all variables, none were consistently favorable toward neural gliding over alternative treatment. However, comparisons across studies revealed a possible trend toward improved outcomes with the use neural gliding. The efficacy of neural gliding is not clear. More research is necessary to determine the population that may respond optimally to this treatment.


Skeletal muscle fiber cross-sectional area: effects of freezing procedures.
The cross-sectional area (CSA) of individual fibers is an important measure of skeletal muscle plasticity. To investigate the effects of different freezing procedures on CSA measurements, the CSA of type-identified fibers in the cat tibialis anterior were determined following quick-freezing the muscle at a fixed physiological length (ipsilateral, frozen at length) and compared to the fiber CSA following quick-freezing a mid-portion of the muscle where the fibers were allowed to freely shorten during tissue preparation (contralateral, frozen as a block). The mean CSA of each fiber type was significantly smaller in the muscles frozen at length vs. frozen as a block in both a deep (close to the bone) and a superficial (away from the bone) region of the muscle, except for the slow oxidative (SO) fibers in the superficial region. The percent difference in mean fiber CSA was smaller for the SO compared to the fast oxidative glycolytic and fast glycolytic fibers in both the deep (41, 47 and 56%, respectively) and superficial (20, 36 and 48%, respectively) regions. In addition, the differences in the mean CSAs of the fast fibers between the two freezing procedures were approximately 10% larger in the deep compared to the superficial region. The fiber-type differential responses may be related, at least in part, to the architectural features of the fibers. These data indicate that the freezing procedures used to prepare the muscle tissue are an important consideration when determining the CSA of individual skeletal muscle fibers and consequently the specific tension, tension per unit CSA, of the muscle units.


Automated whole-genome multiple alignment of rat, mouse, and human.
We have built a whole-genome multiple alignment of the three currently available mammalian genomes using a fully automated pipeline that combines the local/global approach of the Berkeley Genome Pipeline and the LAGAN program. The strategy is based on progressive alignment and consists of two main steps: (1) alignment of the mouse and rat genomes, and (2) alignment of human to either the mouse-rat alignments from step 1, or the remaining unaligned mouse and rat sequences. The resulting alignments demonstrate high sensitivity, with 87% of all human gene-coding areas aligned in both mouse and rat. The specificity is also high: <7% of the rat contigs are aligned to multiple places in human, and 97% of all alignments with human sequence >100 kb agree with a three-way synteny map built independently, using predicted exons in the three genomes. At the nucleotide level <1% of the rat nucleotides are mapped to multiple places in the human sequence in the alignment, and 96.5% of human nucleotides within all alignments agree with the synteny map. The alignments are publicly available online, with visualization through the novel Multi-VISTA browser that we also present.


Trends in bone graft use in the United States.
Bone graft and bone graft substitutes are used to provide structural support and enhance bone healing. Autogenous, allogeneic, and artificial bone grafts each have advantages and drawbacks. The development of allografts, synthetic bone grafts, and new operative techniques may have influenced the use of bone grafts in recent years. The goal of this study was to analyze the use of bone grafts and bone graft substitutes in the United States during a 16-year period. Using data from the National Hospital Discharge Survey, the authors analyzed the use of autogenous and artificial bone grafts in almost 2 million patients in the United States between 1992 and 2007 using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes in 4 periods (1992-1995, 1996-1999, 2000-2003, and 2004-2007). Among an estimated almost 2 million bone graft procedures (83% autogenous, 17% artificial), the use of both types of grafts decreased. The main diagnoses for which bone grafts were used did not change; however, cervical spine diseases and lower-limb fractures decreased more remarkably. Although sex (52% male in the early 1990s to 47% in 2000-2003) and discharge status (more discharges to a short-term or long-term-care facility) significantly changed, age increased from 47 to 53 years and inpatient days decreased significantly from 6 to 5 days during the study period. The use of bone grafts and bone graft substitutes is decreasing in the United States, with a slight shift from autogenous to substitute grafts.


Italian consensus conference on epilepsy and pregnancy, labor and puerperium.
To facilitate an integrated and rational approach to the care of women with epilepsy of childbearing potential, a group of experts appointed by Italian scientific societies in the fields of epileptology, neonatology, pediatrics, neuropediatrics, child neuropsychiatry, obstetrics, and gynecology held a joint meeting in Santa Trada di Cannitello, Reggio Calabria, Italy, on October 15-16, 2004, with the aim of reaching consensus on the optimal management of these women. An ad hoc system for the classification of available published evidence and the opinions of experts was developed and used to grade recommendations on different aspects related to counseling, diagnostic, and treatment issues. The present document summarizes available evidence on the reciprocal interactions between epilepsy, antiepileptic drugs, fertility, contraception, pregnancy, delivery, breastfeeding, and the offspring. Recommendations are made concerning the information and counseling that should be provided to women with epilepsy with respect to issues related to contraception, conception, pregnancy, labour, and puerperium. More detailed recommendations on the same issues are provided to physicians and other healthcare professionals involved in the care of these women, with special reference to choice of effective contraception, optimization of antiepileptic drug therapy, use of prenatal diagnostic tests and other monitoring procedures, and appropriate management practices in relation to childbirth, puerperium, and the care of the child.


Studying host cell protein interactions with monoclonal antibodies using high throughput protein A chromatography.
Protein A chromatography is typically used as the initial capture step in the purification of monoclonal antibodies produced in Chinese hamster ovary (CHO) cells. Although exploiting an affinity interaction for purification, the level of host cell proteins in the protein A eluent varies significantly with different feedstocks. Using a batch binding chromatography method, we performed a controlled study to assess host cell protein clearance across both MabSelect Sure and Prosep vA resins. We individually spiked 21 purified antibodies into null cell culture fluid generated with a non-producing cell line, creating mock cell culture fluids for each antibody with an identical composition of host cell proteins and antibody concentration. We demonstrated that antibody-host cell protein interactions are primarily responsible for the variable levels of host cell proteins in the protein A eluent for both resins when antibody is present. Using the additives guanidine HCl and sodium chloride, we demonstrated that antibody-host cell protein interactions may be disrupted, reducing the level of host cell proteins present after purification on both resins. The reduction in the level of host cell proteins differed between antibodies suggesting that the interaction likely varies between individual antibodies but encompasses both an electrostatic and hydrophobic component.


Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy.
The identification of somatic activating mutations in JAK2 (refs 1–4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK–STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors.


Frequency of congenital dyserythropoietic anemias in Europe.
Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders characterized by ineffective erythropoiesis and striking abnormalities of erythroblast morphology. The mutated genes are known for the most frequent types, CDA I and II, but data about their frequency do not exist. The objective of this retrospective study was to estimate the frequency of CDA I and II, based on all cases reported in the last 42 yr in publications and identified registries or surveys. Reports were collected of 124 and 377 confirmed cases of CDA I and CDA II cases, respectively. The cumulated incidence of both types combined varied widely between European regions, with minimal values of 0.08 cases/million in Scandinavia and 2.60 cases/million in Italy. CDA II is more frequent than CDA I, with an overall ratio of approximately 3.2, but the ratio also varied between different regions. The most likely explanations for the differences are both differences in the availability of advanced diagnostic procedures and different levels of the awareness for the diagnosis of the CDAs. The estimations reported here are most probably below the true incidence rates, because of failure to make the correct diagnosis and to underreporting. Limited data do not suggest differing levels of risk in identified ethnic groups.


IL-21 contributes to fatal inflammatory disease in the absence of Foxp3+ T regulatory cells.
The cytokine IL-21 has been shown to influence immune responses through both costimulatory effects on effector T cells and opposing inhibitory effects on T regulatory cells (Tregs). To distinguish the effect of IL-21 on the immune system from that of its effect on Tregs, we analyzed the role of IL-21/IL-21R signaling in mice made genetically deficient in IL-2, which exhibit a deficit in IL-2-dependent Foxp3 regulatory T cells and suffer from a fatal multiorgan inflammatory disease. Our findings demonstrate that in the absence of IL-21/IL-21R signaling, Il2(-/-) mice retained a deficiency in Tregs yet exhibited a reduced and delayed inflammatory disease. The improved health of Il2(-/-)Il21r(-/-) mice was reflected in reduced pancreatitis and hemolytic anemia and this was associated with distinct changes in lymphocyte effector populations, including the reduced expansion of both T follicular helper cells and Th17 cells and a compensatory increase in IL-22 in the absence of IL-21R. IL-21/IL-21R interactions were also important for the expansion of effector and memory CD8(+) T cells, which were critical for the development of pancreatitis in Il2(-/-) mice. These findings demonstrate that IL-21 is a major target of immune system regulation.


Criterion-based (proficiency) training to improve surgical performance.
OBJECTIVE To investigate whether training otorhinolaryngology residents to criterion performance levels (proficiency) on the Endoscopic Sinus Surgery Simulator produces individuals whose performance in the operating room is at least equal to those who are trained by performing a fixed number of surgical procedures. DESIGN Prospective cohort. SETTING Two academic medical centers in New York City. PARTICIPANTS Otorhinolaryngology junior residents composed of 8 experimental subjects and 6 control subjects and 6 attending surgeons. INTERVENTION Experimental subjects achieved benchmark proficiency criteria on the Endoscopic Sinus Surgery Simulator; control subjects repeated the surgical procedure twice. MAIN OUTCOME MEASURES Residents completed validated objective tests to assess baseline abilities. All subjects were videotaped performing an initial standardized surgical procedure. Residents were videotaped performing a final surgery. Videotapes were assessed for metrics by an expert panel. RESULTS Attendings outperformed the residents in most parameters on the initial procedure. Experimental and attending groups outperformed controls in some parameters on the final procedure. There was no difference between resident groups in initial performance, but the experimental subjects outperformed the control subjects in navigation in the final procedure. Most important, there was no difference in final performance between subgroups of the experimental group on the basis of the number of trials needed to attain proficiency. CONCLUSIONS Simulator training can improve resident technical skills so that each individual attains a proficiency level, despite the existence of an intrinsic range of abilities. This proficiency level translates to at least equal, if not superior, operative performance compared with that of current conventional training with finite repetition of live surgical procedures.


Increased exhaled nitric oxide in chronic bronchitis: comparison with asthma and COPD.
To test the hypothesis that exhaled nitric oxide (NO) is increased in patients with chronic bronchitis, and to compare the results with exhaled NO in patients with asthma and COPD. Cross-sectional survey. Veterans Administration pulmonary function laboratory. Patients (n = 179) were recruited from 234 consecutive patients. Two nonsmoking control groups of similar age, with normal spirometry measurements and no lung disease, were used (18 patient control subjects and 20 volunteers). Participants completed questionnaires and spirometry testing. Exhaled NO was measured by chemiluminescence using a single-breath exhalation technique. Current smoking status was associated with reduced levels of exhaled NO (smokers, 9. 2 +/- 0.9 parts per billion [ppb]; never and ex-smokers, 14.3 +/- 0. 6 ppb; p < 0.0001). Current smokers (n = 57) were excluded from further analysis. Among nonsmokers, the levels of exhaled NO were significantly higher in patients with chronic bronchitis (17.0 +/- 1. 1 ppb; p = 0.035) and asthma (16.4 +/- 1.3 ppb; p = 0.05) but not in those with COPD (14.7 +/- 1.0 ppb; p = 0.17) when compared with either control group (patient control subjects, 11.1 +/- 1.6 ppb; outside control subjects, 11.5 +/- 1.5 ppb). The highest mean exhaled NO concentration occurred in patients with both chronic bronchitis and asthma (20.2 +/- 1.6 ppb; p = 0.005 vs control subjects). Exhaled NO is increased in patients with chronic bronchitis. The increase of exhaled NO in patients with chronic bronchitis was similar to that seen in patients with asthma. The highest mean exhaled NO occurred in patients with both chronic bronchitis and asthma. Exhaled NO was not increased in patients with COPD. Although chronic bronchitis and asthma have distinct histopathologic features, increased exhaled NO in patients with both diseases suggests common features of inflammation.


A Prediction Rule for Risk Stratification of Incidentally Discovered Gallstones: Results From a Large Cohort Study.
No one knows exactly what proportion of gallstones cause clinical events among subjects unaware of their gallstone status. We investigated the long-term occurrence of clinical events of gallstones and associations between ultrasound observations and clinical events. We analyzed data from 3 randomly selected groups in the general population of urban Copenhagen (age, 30-70 y) participating in an international study of cardiovascular risk factors (the Multinational mONItoring of trends and determinants in CArdiovascular disease study). In this study, participants (n = 6037) were examined from 1982 through 1994, and underwent abdominal ultrasound examinations to detect gallstones. Our study population comprised 664 subjects with gallstones; subjects were not informed of their gallstone status. Participants were followed up for clinical events through central registers until December 31, 2011. Independent variables included ultrasound characteristics, age, sex, comorbidity, and female-associated factors, which were analyzed using Cox regression. Study participants were followed up for a median of 17.4 years (range, 0.1-29.1 y); 99.7% of participants completed the study. A total of 19.6% participants developed events (8.0% complicated and 11.6% uncomplicated). Ten percent had awareness of their gallstones; awareness was associated with uncomplicated and complicated events. Stones larger than 10 mm were associated with all events (hazard ratio [HR], 2.31; 95% confidence interval [CI], 1.45-3.69), acute cholecystitis (HR, 9.49; 95% CI, 2.05-43.92), and uncomplicated events (HR, 2.55; 95% CI, 1.38-4.71), including cholecystectomy (HR, 2.69; 95% CI, 1.29-5.60). Multiple stones were associated with all events (HR, 1.68; 95% CI, 1.00-2.81), complicated events (HR, 2.52; 95% CI, 1.05-6.04), and common bile duct stones (HR, 11.83; 95% CI, 1.54-91). There was an association between gallstones more than 5 years old and acute cholecystitis. Female sex was associated with all and uncomplicated events. We found a negative association between participant age and all events, uncomplicated events, and acute cholecystitis. Comorbidities and female-associated factors (intake of birth control pills or estrogens and number of births) were not associated with events. Compared with men with a single stone of 10 mm or smaller (reference), women with multiple stones greater than 10 mm had the highest risk for events (HR, 11.05; 95% CI, 3.76-32.44; unadjusted absolute risk, 0.0235 events/person-years). Fewer than 20% of subjects with gallstones develop clinical events. Larger, multiple, and older gallstones are associated with events. Further studies are needed to confirm the prediction rules.


Identification of Itk/Tsk Src homology 3 domain ligands.
The tyrosine kinase Itk/Tsk is a T cell specific analog of Btk, the tyrosine kinase defective in the human immunodeficiency X-linked agammaglobulinemia and in xid mice. T lymphocytes from Itk-deficient mice are refractory to mitogenic stimuli delivered through the T cell receptor (TCR). To gain insights into the biochemical role of Itk, the binding properties of the Itk SH3 domain were examined. An optimal Itk SH3 binding motif was derived by screening biased phage display libraries; peptides based on this motif bound with high affinity and selectivity to the Itk SH3 domain. Initial studies with T cell lysates indicated that the Itk SH3 domain bound Cbl, Fyn, and other tyrosine phosphoproteins from TCR-stimulated Jurkat cells. Under conditions of increased detergent stringency Sam 68, Wiskott-Aldrich Syndrome protein, and hnRNP-K, but not Cbl and Fyn, were bound to the Itk SH3 domain. By examining the ability of different SH3 domains to interact with deletion variants of Sam 68 and WASP, we demonstrated that the Itk-SH3 domain and the SH3 domains of Src family kinases bind to overlapping but distinct sets of proline-rich regions in Sam 68 and WASP.


What Is a Dingo? The Phenotypic Classification of Dingoes by Aboriginal and Torres Strait Islander Residents in Northern Australia.
Dingo classification and management is complicated by hybridisation with domestic dogs. Northern Australia is a relatively high-risk zone for a rabies incursion, and in the event of an incursion, Aboriginal and Torres Strait Islander peoples who reside in this region would prioritise the protection of dingoes. Therefore, the classification of dingoes in this context is important. Twelve pictures of canids with features associated with both dingoes and domestic dogs from camera traps in the Northern Peninsula Area (NPA), northern Queensland, were shown to Aboriginal and Torres Strait Islander rangers (n = 3), biosecurity officers (n = 2), environmental health workers (n = 2), and residents (n = 39) in the NPA. Nearly all pictures (10/12) were classified as dingo or domestic dog (none as hybrid) and two were inconclusive (no overall agreement). Dingoes were consistently identified as medium to large-framed dogs, with a long nose, pointed ears, narrow abdomen, a bushy or feathered tail, and smooth coats of a single base colour. Some hybrid features were acceptable, including sable coats, lack of white tail tip or feet, and curled tail. These findings are a preliminary guide for identifying canids in the NPA region for whom management might be controversial. Building on this approach via further consultation with residents is needed to inform rabies response policy. Our approach using locally acquired camera trap pictures could also be extended to other regions in which dingoes have value but their management is controversial.


The influence of the intrauterine environment on human placental development.
Development of the human placenta is modulated heavily by the intrauterine environment. During the first trimester, development takes place in a low oxygen environment supported by histiotrophic nutrition from the endometrial glands. Consequently, the rate of growth of the chorionic sac is almost invariable across this period, and is remarkably uniform between individuals. Towards the end of the first trimester the intrauterine environment undergoes radical transformation in association with onset of the maternal arterial circulation and the switch to haemotrophic nutrition. The accompanying rise in intraplacental oxygen concentration poses a major challenge to placental tissues, and extensive villous remodelling takes place at this time. Later in pregnancy a wide variety of stressors are capable of affecting placental growth, but in the human, the most common are nutrient deprivation and vascular compromise. The latter is usually secondary to deficient trophoblast invasion and can induce placental oxidative stress. Closely linked to oxidative stress is endoplasmic reticulum stress, and we recently provided the first evidence that the latter plays a major role in the pathophysiology of intrauterine growth restriction. The endoplasmic reticulum is a key regulator of protein synthesis, exerting its effects through the unfolded protein response. Consequently, we observed multiple blocks to translation initiation and elongation in growth restricted placentas. Nutrient deprivation also modulates protein synthesis through the mTOR pathway, and we demonstrated interactions between this pathway and endoplasmic reticulum stress. Protein synthesis inhibition therefore appears to be a common mechanism for regulating placental development under different adverse conditions.


Is there impact of mortality prior hemodialysis therapy in peritoneal dialysis patients?
The aim of this study is to investigate the mortality and the factors which may affect it in patients who were transferred to peritoneal dialysis (PD) from hemodialysis (HD), compared to patients assigned to PD as first-line therapy. A total of 322 patients treated with PD between 2001 and 2010 were evaluated retrospectively. Twenty three patients were excluded and the data of remaining 299 patients (167F, mean follow up time 38.5±26.8 months, mean age 44.7±15.9 years) were evaluated. Patients were separated into two groups according to their HD history. Group 1 and group 2 consisted of patients with (n=48) and without (n=251) a history of prior HD, respectively. Socio-demographic characteristics such as who helped administer the PD and the preference of patients (compulsory vs their preference) were obtained from the patient records. The clinical data obtained during the last clinical evaluation before the initiation of PD (blood pressure, daily urine volumes, daily ultrafiltration amounts and laboratory parameters) were recorded. Additional systemic diseases and information about the etiologies of the end stage renal disease (ESRD) of all patients were recorded. Frequencies of the infectious complications were recorded. Patient and technique survival were investigated and compared between groups. In group 1, the patients were older and had less urine amounts (p=0.028 and 0.041 respectively). Thirty five patients (70%) and 25 patients (9.3%) have been transferred to PD due to vascular problems in group 1 and 2, respectively (p<0.001). In group 1, 37 (74%) patients were carrying out PD treatment by themselves, compared to 222 (88.4%) patients in group 2 (p=0.016). Incidences of peritonitis and catheter exit site/tunnel infection attacks were found 24.9±26.8 and 27.2±26.5 patient-months in group 1, and 27.4±22.4 and 33.4±24.5 patient-months in group 2, respectively (p=0.50 and 0.12). In group 1, twenty three patients have death and 2 patients have discontinued the treatment due to transplantation. In group 2, 174 patients have discontinued the treatment (55 patients have died, 80 patients have been switched to hemodialysis and 39 patients have received renal transplantation). There were significant differences between groups according to the last condition (p<0.001). Mean patient survival were found 22.9±4.2 and 55.5±2.8 patient-months in group 1 and group 2, respectively. The patient survival rates by Kaplan-Meier analysis were 50%, 40.9%, 27.3% and 9.1% at 1, 2, 3, and 4 years in group 1 and 90.9%, 81.6%, 73.9%, 64.9% and 53.1% at 1, 2, 3, 4 and 5 years in group 2, respectively. The mortality rate is higher in patients who have undergone HD before PD compared without HD history (log rank:<0.001). In the Cox proportional hazards model analysis, preference of PD (RR: 7.72, p<0.001), presence of diabetes (RR: 2.26, p=0.01), pretreatment serum albumin level (RR: 0.37, p<0.001) and catheter exit size infection attacks (RR:0.34, p=0.01) were identified as predictors of mortality. Our data show that mortality in patients transferred to PD from HD was higher than in patients undergoing PD as first-line therapy. Compulsory choice such as vascular access problems and social factors were the most important causes of increasing mortality in patients transferred to PD from HD.


Adverse childhood experiences are associated with the risk of lung cancer: a prospective cohort study.
Strong relationships between exposure to childhood traumatic stressors and smoking behaviours inspire the question whether these adverse childhood experiences (ACEs) are associated with an increased risk of lung cancer during adulthood. Baseline survey data on health behaviours, health status and exposure to adverse childhood experiences (ACEs) were collected from 17,337 adults during 1995-1997. ACEs included abuse (emotional, physical, sexual), witnessing domestic violence, parental separation or divorce, or growing up in a household where members with mentally ill, substance abusers, or sent to prison. We used the ACE score (an integer count of the 8 categories of ACEs) as a measure of cumulative exposure to traumatic stress during childhood. Two methods of case ascertainment were used to identify incident lung cancer through 2005 follow-up: 1) hospital discharge records and 2) mortality records obtained from the National Death Index. The ACE score showed a graded relationship to smoking behaviors. We identified 64 cases of lung cancer through hospital discharge records (age-standardized risk = 201 x 100,000(-1) population) and 111 cases of lung cancer through mortality records (age-standardized mortality rate = 31.1 x 100,000(-1) person-years). The ACE score also showed a graded relationship to the incidence of lung cancer for cases identified through hospital discharge (P = 0.0004), mortality (P = 0.025), and both methods combined (P = 0.001). Compared to persons without ACEs, the risk of lung cancer for those with >or= 6 ACEs was increased approximately 3-fold (hospital records: RR = 3.18, 95%CI = 0.71-14.15; mortality records: RR = 3.55, 95%CI = 1.25-10.09; hospital or mortality records: RR = 2.70, 95%CI = 0.94-7.72). After a priori consideration of a causal pathway (i.e., ACEs --> smoking --> lung cancer), risk ratios were attenuated toward the null, although not completely. For lung cancer identified through hospital or mortality records, persons with >or= 6 ACEs were roughly 13 years younger on average at presentation than those without ACEs. Adverse childhood experiences may be associated with an increased risk of lung cancer, particularly premature death from lung cancer. The increase in risk may only be partly explained by smoking suggesting other possible mechanisms by which ACEs may contribute to the occurrence of lung cancer.


Teaching of evidence-based medicine to medical students in Mexico: a randomized controlled trial.
Evidence-Based Medicine (EBM) is an important competency for the healthcare professional. Experimental evidence of EBM educational interventions from rigorous research studies is limited. The main objective of this study was to assess EBM learning (knowledge, attitudes and self-reported skills) in undergraduate medical students with a randomized controlled trial. The educational intervention was a one-semester EBM course in the 5th year of a public medical school in Mexico. The study design was an experimental parallel group randomized controlled trial for the main outcome measures in the 5th year class (M5 EBM vs. M5 non-EBM groups), and quasi-experimental with static-groups comparisons for the 4th year (M4, not yet exposed) and 6th year (M6, exposed 6 months to a year earlier) groups. EBM attitudes, knowledge and self-reported skills were measured using Taylor's questionnaire and a summative exam which comprised of a 100-item multiple-choice question (MCQ) test. 289 Medical students were assessed: M5 EBM=48, M5 non-EBM=47, M4=87, and M6=107. There was a higher reported use of the Cochrane Library and secondary journals in the intervention group (M5 vs. M5 non-EBM). Critical appraisal skills and attitude scores were higher in the intervention group (M5) and in the group of students exposed to EBM instruction during the previous year (M6). The knowledge level was higher after the intervention in the M5 EBM group compared to the M5 non-EBM group (p<0.001, Cohen's d=0.88 with Taylor's instrument and 3.54 with the 100-item MCQ test). M6 Students that received the intervention in the previous year had a knowledge score higher than the M4 and M5 non-EBM groups, but lower than the M5 EBM group. Formal medical student training in EBM produced higher scores in attitudes, knowledge and self-reported critical appraisal skills compared with a randomized control group. Data from the concurrent groups add validity evidence to the study, but rigorous follow-up needs to be done to document retention of EBM abilities.


[Association between fruit consumption and stroke in adults in Qingdao: a prospective study].
Objective: To understand the fruit consumption of adults of Qingdao and examine the association between fruit consumption and stroke. Methods: We analyzed baseline data and stroke incidence of the participants who were aged 30-79 years and had been enrolled into the China Kadoorie Biobank (CKB) study from Qingdao city. Cox proportional hazards regression model was conducted to estimate the association of fruit consumption with risk of stroke. Results: A total of 35 509 participants were investgated in the baseline survey. Ratio of male to female was 1∶1.27, and the average age was (50.3±10.2) years. Respondents with higher frequency of fruit consumption were younger, more women, with higher education level and higher income (P<0.05). A total of 1 011 new cases of stroke were observed, with a stroke incidence of 387.63/100 000 person-years. Multivariate Cox regression analysis showed that fruit consumption had a protective effect on stroke incidence. Compared to the respondents who never consumed fruit, respondents who consumed fruit more than 4 days per week had a 44% lower risk of stroke incidence (HR=0.56, 95%CI: 0.50-0.62, P<0.05), and the risk reduced by 46% (HR=0.54, 95%CI: 0.46-0.64, P<0.05) and 42% (HR=0.58, 95%CI: 0.52-0.69, P<0.05) in male and female, respectively. Further adjustment for WC, BMI, SBP and random blood glucose did not change the association. Conclusion: Increasing fruit consumption can effectively decrease the risk of stroke. People should increase fruit consumption advisably to set up reasonable and healthy dietary habits.


Available Tools to Facilitate Early Patient Access to Medicines in the EU and the USA: Analysis of Conditional Approvals and the Implications for Personalized Medicine.
Scientific knowledge and our understanding of the human body and diseases have limited any possible treatment tailoring to each patient. The technological advances enabling the integration of various data sets (e.g. '-omics', microbiome, epigenetics and environmental exposure) have facilitated a greater understanding of the human body, the molecular basis of disease and all the factors influencing disease onset, progression and response to treatment, thereby ushering in the era of personalized medicine. We evaluate the regulatory approaches available to facilitate early patient access to efficacious and safe compounds in the EU and the USA in order to make more informed recommendations in the future as to the gaps in regulations for early patient access. An in-depth analysis of conditional approvals (EU) and accelerated approvals (USA) is performed based on the publicly available information (European public assessment reports and a summary review of products approved under both programmes). The types of product, indications, time to approval and type of evidence submitted were analysed. Between 2007 and early 2015, 17 products were conditionally approved in the EU and 25 in the USA, most of them in the area of oncology and based on evidence from phase II clinical trial data. Early approval of promising products based on data from early phases of development is already possible in the EU and the USA. Some of the improvements could entail implementing a rolling assessment of evidence in Europe and extending the scope of early dialogues.


Continued uncertainty regarding treatment of patent ductus arteriosus in premature infants and the role of clinical trials.
Despite several decades of research into treatments for patent ductus arteriosus (PDA), there is continued uncertainty regarding whether, when, and how best to treat PDA and the long-term consequences. There are almost 5000 babies enrolled into clinical trials, but the questions remain largely unanswered. Many of the trials performed over the period were well designed and addressed important clinical questions, but the results are not necessarily directly applicable to the clinical management dilemmas of today since perinatal care has improved over time per se, the patient population is typically more premature, and there have been technological advances in diagnosis. This article examines some of the approaches taken, how trial designs evolved over time, especially in terms of the patient population and outcomes evaluated, and it offers points to consider when planning future research.


WE-G-217A-05: Automatic Method for RF Coil Assessment in Clinical MRI: A Three-Dimensional Approach.
MRI RF coil assessment is usually evaluated with region-of-interest (ROI) analysis from a single 2D phantom image. This simple approach has worked well for large volume coils or phased-array coil with large receivers, but not the high density phased-array coils characterized by 3D array arrangement of their multiple receivers. This abstract proposes a novel approach for quantitative coil assessment based on 3D imaging and 3D ROI analysis. To characterize all receivers of the coil of interest, a large uniform phantom (preferably a corresponding anthropometric phantom) and a large 3D geometric coverage fully includes the coil sensitivity volume was applied during MR imaging. After imaging, data from all receivers were used to reconstruct a composite 3D image, and to reconstruct 3D images from each individual receiver, leading to a total of N+1 3D image datasets (where N is the number of coil channels). IDL programs were developed to automatically perform ROI analysis on the composite image and on the individual receiver images. Instead of choosing one single 2D slice out of each 3D dataset, the whole 3D dataset was treated as a 3D image, and 3D ROIs were automatically generated for coil assessment. This 3D coil evaluation approach could be applied to all clinical coils including quadrature body/head coils, and phased-array coils with 2 to 32 channels. 3D sensitivity map could be generated to check receiver function visually. 3D mean SNR, max SNR, and uniformity could be obtained from composite and individual channel 3D images fully automatically. Coil/receiver performance assessment was very fast and straightforward, regardless of the number of receivers of the coil. 3D imaging in combination with 3D automatic ROI analysis is a fast, convenient, and less subjective approach for quantitative coil assessment, particularly for high density phased-array coils.


Electrooxidation and Determination of Dopamine Using a Nafion®-Cobalt Hexacyanoferrate Film Modified Electrode.
The electrocatalysis of dopamine has been studied using a cobalt hexacyanoferrate film (CoHCFe)-modified glassy carbon electrode. Using a rotating disk CoHCFe-modified electrode, the reaction rate constant for dopamine was found to be 3.5 × 105 cm³ mol-1 s-1 at a concentration of 5.0 × 10-5 mol L-1. When a Nafion® film is applied to the CoHCFe-modified electrode surface a high selectivity for the determination of dopamine over ascorbic acid was obtained. The analytical curve for dopamine presented linear dependence over the concentration range from 1.2 × 10-5 to 5.0 × 10-4 mol L-1 with a slope of 23.5 mA mol-1 L and a linear correlation coefficient of 0.999. The detection limit of this method was 8.9 × 10-6 mol L-1 and the relative standard deviation for five measurements of 2.5 × 10-4 mol L-1 dopamine was 0.58%.


Relationship between environmental exposure to pesticides and anthropometric outcomes of boys in the rural Western Cape, South Africa.
Rural residents in the Western Cape (WC), South Africa (SA) are highly exposed to agricultural pesticides that could impact their reproductive development. However, epidemiological evidence of the effect of pesticides on pubertal growth is contradictory. To investigate the effect of pesticide exposure measured using indices of environmental exposure to pesticides on the pubertal growth of boys in rural WC, SA. A cross-sectional study of 269 boys (177 of whom gave a history of residing on farms) was conducted. A questionnaire was administered, height and weight were measured and body mass index was calculated. A proximity index (PI) and spraying index (SI) was developed, measuring the lifetime average home distance from pesticide spraying and average frequency of spraying pesticides on a farm, respectively. Median age of boys was 12.4 years (interquartile range 9.5 - 13.3). More than 60% boys had height and weight <50th percentile for age. After adjusting for confounders, PI was significantly associated with shorter stature and lower weight (-1.7 cm/10-fold decrease, p=0.02 and -1.24 kg/10-fold decrease, p=0.04; respectively) and SI was non-significantly associated (-1.4 cm/10-fold increase, p=0.05 and -1.1 cm/10-fold increase, p=0.06; respectively). Associations were stronger for boys aged <11 years and were weaker when excluding non- farm boys. There were no other associations between outcome and exposure. The use of quantitative exposure indices showed that lower heights and weights might be associated with pesticide exposure in farm boys v. non-farm boys, but not among farm boys. Lower anthropometric measurements among farm boys v. non-farm boys appear stronger at a younger age. The indices of environmental exposure to pesticides require further development.


Big Data Sensors of Organic Advocacy: The Case of Leonardo DiCaprio and Climate Change.
The strategies that experts have used to share information about social causes have historically been top-down, meaning the most influential messages are believed to come from planned events and campaigns. However, more people are independently engaging with social causes today than ever before, in part because online platforms allow them to instantaneously seek, create, and share information. In some cases this "organic advocacy" may rival or even eclipse top-down strategies. Big data analytics make it possible to rapidly detect public engagement with social causes by analyzing the same platforms from which organic advocacy spreads. To demonstrate this claim we evaluated how Leonardo DiCaprio's 2016 Oscar acceptance speech citing climate change motivated global English language news (Bloomberg Terminal news archives), social media (Twitter postings) and information seeking (Google searches) about climate change. Despite an insignificant increase in traditional news coverage (54%; 95%CI: -144 to 247), tweets including the terms "climate change" or "global warming" reached record highs, increasing 636% (95%CI: 573-699) with more than 250,000 tweets the day DiCaprio spoke. In practical terms the "DiCaprio effect" surpassed the daily average effect of the 2015 Conference of the Parties (COP) and the Earth Day effect by a factor of 3.2 and 5.3, respectively. At the same time, Google searches for "climate change" or "global warming" increased 261% (95%CI, 186-335) and 210% (95%CI 149-272) the day DiCaprio spoke and remained higher for 4 more days, representing 104,190 and 216,490 searches. This increase was 3.8 and 4.3 times larger than the increases observed during COP's daily average or on Earth Day. Searches were closely linked to content from Dicaprio's speech (e.g., "hottest year"), as unmentioned content did not have search increases (e.g., "electric car"). Because these data are freely available in real time our analytical strategy provides substantial lead time for experts to detect and participate in organic advocacy while an issue is salient. Our study demonstrates new opportunities to detect and aid agents of change and advances our understanding of communication in the 21st century media landscape.


Surgery for weight loss in adults.
Bariatric (weight loss) surgery for obesity is considered when other treatments have failed. The effects of the available bariatric procedures compared with medical management and with each other are uncertain. This is an update of a Cochrane review first published in 2003 and most recently updated in 2009. To assess the effects of bariatric surgery for overweight and obesity, including the control of comorbidities. Studies were obtained from searches of numerous databases, supplemented with searches of reference lists and consultation with experts in obesity research. Date of last search was November 2013. Randomised controlled trials (RCTs) comparing surgical interventions with non-surgical management of obesity or overweight or comparing different surgical procedures. Data were extracted by one review author and checked by a second review author. Two review authors independently assessed risk of bias and evaluated overall study quality utilising the GRADE instrument. Twenty-two trials with 1798 participants were included; sample sizes ranged from 15 to 250. Most studies followed participants for 12, 24 or 36 months; the longest follow-up was 10 years. The risk of bias across all domains of most trials was uncertain; just one was judged to have adequate allocation concealment.All seven RCTs comparing surgery with non-surgical interventions found benefits of surgery on measures of weight change at one to two years follow-up. Improvements for some aspects of health-related quality of life (QoL) (two RCTs) and diabetes (five RCTs) were also found. The overall quality of the evidence was moderate. Five studies reported data on mortality, no deaths occurred. Serious adverse events (SAEs) were reported in four studies and ranged from 0% to 37% in the surgery groups and 0% to 25% in the no surgery groups. Between 2% and 13% of participants required reoperations in the five studies that reported these data.Three RCTs found that laparoscopic Roux-en-Y gastric bypass (L)(RYGB) achieved significantly greater weight loss and body mass index (BMI) reduction up to five years after surgery compared with laparoscopic adjustable gastric banding (LAGB). Mean end-of-study BMI was lower following LRYGB compared with LAGB: mean difference (MD) -5.2 kg/m² (95% confidence interval (CI) -6.4 to -4.0; P < 0.00001; 265 participants; 3 trials; moderate quality evidence). Evidence for QoL and comorbidities was very low quality. The LRGYB procedure resulted in greater duration of hospitalisation in two RCTs (4/3.1 versus 2/1.5 days) and a greater number of late major complications (26.1% versus 11.6%) in one RCT. In one RCT the LAGB required high rates of reoperation for band removal (9 patients, 40.9%).Open RYGB, LRYGB and laparoscopic sleeve gastrectomy (LSG) led to losses of weight and/or BMI but there was no consistent picture as to which procedure was better or worse in the seven included trials. MD was -0.2 kg/m² (95% CI -1.8 to 1.3); 353 participants; 6 trials; low quality evidence) in favour of LRYGB. No statistically significant differences in QoL were found (one RCT). Six RCTs reported mortality; one death occurred following LRYGB. SAEs were reported by one RCT and were higher in the LRYGB group (4.5%) than the LSG group (0.9%). Reoperations ranged from 6.7% to 24% in the LRYGB group and 3.3% to 34% in the LSG group. Effects on comorbidities, complications and additional surgical procedures were neutral, except gastro-oesophageal reflux disease improved following LRYGB (one RCT). One RCT of people with a BMI 25 to 35 and type 2 diabetes found laparoscopic mini-gastric bypass resulted in greater weight loss and improvement of diabetes compared with LSG, and had similar levels of complications.Two RCTs found that biliopancreatic diversion with duodenal switch (BDDS) resulted in greater weight loss than RYGB in morbidly obese patients. End-of-study mean BMI loss was greater following BDDS: MD -7.3 kg/m² (95% CI -9.3 to -5.4); P < 0.00001; 107 participants; 2 trials; moderate quality evidence). QoL was similar on most domains. In one study between 82% to 100% of participants with diabetes had a HbA1c of less than 5% three years after surgery. Reoperations were higher in the BDDS group (16.1% to 27.6%) than the LRYGB group (4.3% to 8.3%). One death occurred in the BDDS group.One RCT comparing laparoscopic duodenojejunal bypass with sleeve gastrectomy versus LRYGB found BMI, excess weight loss, and rates of remission of diabetes and hypertension were similar at 12 months follow-up (very low quality evidence). QoL, SAEs and reoperation rates were not reported. No deaths occurred in either group.One RCT comparing laparoscopic isolated sleeve gastrectomy (LISG) versus LAGB found greater improvement in weight-loss outcomes following LISG at three years follow-up (very low quality evidence). QoL, mortality and SAEs were not reported. Reoperations occurred in 20% of the LAGB group and in 10% of the LISG group.One RCT (unpublished) comparing laparoscopic gastric imbrication with LSG found no statistically significant difference in weight loss between groups (very low quality evidence). QoL and comorbidities were not reported. No deaths occurred. Two participants in the gastric imbrication group required reoperation. Surgery results in greater improvement in weight loss outcomes and weight associated comorbidities compared with non-surgical interventions, regardless of the type of procedures used. When compared with each other, certain procedures resulted in greater weight loss and improvements in comorbidities than others. Outcomes were similar between RYGB and sleeve gastrectomy, and both of these procedures had better outcomes than adjustable gastric banding. For people with very high BMI, biliopancreatic diversion with duodenal switch resulted in greater weight loss than RYGB. Duodenojejunal bypass with sleeve gastrectomy and laparoscopic RYGB had similar outcomes, however this is based on one small trial. Isolated sleeve gastrectomy led to better weight-loss outcomes than adjustable gastric banding after three years follow-up. This was based on one trial only. Weight-related outcomes were similar between laparoscopic gastric imbrication and laparoscopic sleeve gastrectomy in one trial. Across all studies adverse event rates and reoperation rates were generally poorly reported. Most trials followed participants for only one or two years, therefore the long-term effects of surgery remain unclear.


Unrelated Future Costs and Unrelated Future Benefits: Reflections on NICE Guide to the Methods of Technology Appraisal.
In this editorial, we consider the vexing issue of 'unrelated future costs' (for example, the costs of caring for people with dementia or kidney failure after preventing their deaths from a heart attack). The National Institute of Health and Care Excellence (NICE) guidance is not to take such costs into account in technology appraisals. However, standard appraisal practice involves modelling the benefits of those unrelated technologies. We argue that there is a sound principled reason for including both the costs and benefits of unrelated care. Changing this practice would have material consequences for decisions about reimbursing particular technologies, and we urge future research to understand this better. Copyright © 2016 John Wiley & Sons, Ltd.