The effect of air pollution on pneumonia-related emergency department visits in a region of extensive sugar cane plantations: a 30-month time-series study.
In Brazil, many cities are surrounded by sugar cane plantations, and when these plantations are burnt prior to harvesting, millions of people are exposed to the smoke from these fires from May to November every year. A daily time-series regression analysis was conducted in a city located in the sugar cane plantation region of São Paulo State, Brazil, between 1 February 2005 and 31 July 2007. The percentage increase in the number of pneumonia-related emergency department visits (PEDV) associated with a 10 µg/m(3) increase in the total suspended particles (TSP) concentration was measured, including any effects that were delayed for up to 6 days. A total of 1505 PEDV (a median of two events per day) were analysed. During the burning period, there was an acute effect that began on the day of exposure and remained for 2 days. An increase of 6% (95% CI 2.4 to 9.9) in PEDV was observed for the 2 days following the TSP increase. This pattern and the size of the effect were similar to those observed for the whole period and also during the non-burning period. Increases in TSP concentrations were found to be associated with increased PEDV in a region affected by air pollution from sugar cane burning. This finding reinforces the need for polices and efforts to ban sugar cane burning prior to harvesting.


Antimicrobial overuse and misuse in the community in Greece and link to antimicrobial resistance using methicillin-resistant S. aureus as an example.
Both antimicrobial consumption and antimicrobial resistance are very high in Greece, ranking among the highest of Europe. The link between antimicrobial consumption and resistance is well-known. Here, we discuss the reasons of antimicrobial overuse in Greece in the community (such as self-medication, dispersion of antibiotics by pharmacies without prescription, over-prescription by physicians, patient expectations and liability pressure) and we explore the misuse of antibiotics for common community infections. Furthermore, we discuss how such overuse/misuse can drive antimicrobial resistance, using methicillin-resistance in Staphylococcus aureus as an example. S. aureus is one of the pathogens with high rates of resistance in Greece. Comparing the rate of antimicrobial susceptibility to non-beta lactams between methicillin-resistant and methicillin-sensitive S. aureus we highlight the antibiotics that have the potential to drive methicillin-resistance through co-selection. Based on the above we identify targets for intervention in order to reduce antimicrobial overuse/misuse in the community in Greece.


Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles.
Alpha satellite is a tandemly organized type of repetitive DNA that comprises 5% of the genome and is found at all human centromeres. A defined number of 171-bp monomers are organized into chromosome-specific higher-order repeats (HORs) that are reiterated thousands of times. At least half of all human chromosomes have two or more distinct HOR alpha satellite arrays within their centromere regions. We previously showed that the two alpha satellite arrays of Homo sapiens Chromosome 17 (HSA17), D17Z1 and D17Z1-B, behave as centromeric epialleles, that is, the centromere, defined by chromatin containing the centromeric histone variant CENPA and recruitment of other centromere proteins, can form at either D17Z1 or D17Z1-B. Some individuals in the human population are functional heterozygotes in that D17Z1 is the active centromere on one homolog and D17Z1-B is active on the other. In this study, we aimed to understand the molecular basis for how centromere location is determined on HSA17. Specifically, we focused on D17Z1 genomic variation as a driver of epiallele formation. We found that D17Z1 arrays that are predominantly composed of HOR size and sequence variants were functionally less competent. They either recruited decreased amounts of the centromere-specific histone variant CENPA and the HSA17 was mitotically unstable, or alternatively, the centromere was assembled at D17Z1-B and the HSA17 was stable. Our study demonstrates that genomic variation within highly repetitive, noncoding DNA of human centromere regions has a pronounced impact on genome stability and basic chromosomal function.


SMART Arm Training With Outcome-Triggered Electrical Stimulation in Subacute Stroke Survivors With Severe Arm Disability: A Randomized Controlled Trial.
Stroke survivors with severe upper limb disability need opportunities to engage in task-oriented practice to achieve meaningful recovery. To compare the effect of SMART Arm training, with or without outcome-triggered electrical stimulation to usual therapy, on arm function for stroke survivors with severe upper limb disability undergoing inpatient rehabilitation. A prospective, multicenter, randomized controlled trial was conducted with 3 parallel groups, concealed allocation, assessor blinding and intention-to-treat analysis. Fifty inpatients within 4 months of stroke with severe upper limb disability were randomly allocated to 60 min/d, 5 days a week for 4 weeks of (1) SMART Arm with outcome-triggered electrical stimulation and usual therapy, (2) SMART Arm alone and usual therapy, or (3) usual therapy. Assessment occurred at baseline (0 weeks), posttraining (4 weeks), and follow-up (26 and 52 weeks). The primary outcome measure was Motor Assessment Scale item 6 (MAS6) at posttraining. All groups demonstrated a statistically ( P < .001) and clinically significant improvement in arm function at posttraining (MAS6 change ≥1 point) and at 52 weeks (MAS6 change ≥2 points). There were no differences in improvement in arm function between groups (P = .367). There were greater odds of a higher MAS6 score in SMART Arm groups as compared with usual therapy alone posttraining (SMART Arm stimulation generalized odds ratio [GenOR] = 1.47, 95%CI = 1.23-1.71) and at 26 weeks (SMART Arm alone GenOR = 1.31, 95% CI = 1.05-1.57). SMART Arm training supported a clinically significant improvement in arm function, which was similar to usual therapy. All groups maintained gains at 12 months.


Percutaneous coronary interventions and cardiovascular outcomes for patients with chronic total occlusions.
This study sought to assess the benefits of a coronary chronic total occlusion CTO recanalization after adjusting for the case-mix and the propensity to undergo the CTO intervention in a population of patients with stable coronary artery disease. The benefits of percutaneous recanalization of CTO are disputed. In 1,602 patients with a least one CTO and treated by percutaneous coronary intervention (PCI), we derived a propensity score to undergo a CTO recanalization by comparing the characteristics of patients who did (n = 346) and did not (n = 1,256) undergo a CTO PCI attempt. Among the patients who underwent a CTO PCI attempt, we identified the angiographic predictors of failure. The primary analysis was ultimately performed by looking at the association between the outcome of the CTO recanalization and the survival free of death and cardiovascular rehospitalizations. Sensitivity analyses were performed by adjusting for the propensity to undergo a CTO recanalization, for the anatomical predictors of failure, and for the extent of coronary artery revascularization achieved. A successful CTO recanalization was not significantly associated with survival free of death and cardiovascular rehospitalization (HR = 0.90, 95% CI 0.64-1.25). Even more conservative hazards ratio point estimates were obtained with the sensitivity analyses. Successful percutaneous CTO recanalization is not associated with survival free of death and cardiovascular hospitalizations in a contemporary population of patients with symptomatic coronary artery disease.


Predictors for neoplastic progression in patients with Barrett's Esophagus: a prospective cohort study.
Patients with Barrett's esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors. We included 713 patients with BE (≥ 2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance. After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥ 10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3-7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01-1.2), esophagitis (RR 3.5; 95% CI 1.3-9.5), and LGD (RR 9.7; 95% CI 4.4-21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18-40%). In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.


Patient evaluation of end-of-life care.
The Dutch health care system is characterized by a strong emphasis on primary care. To get insight into the strengths and gaps in end-of-life care in the Netherlands, data are needed about use and patient evaluation of end-of-life care. We assessed the experiences of patients with end-of-life care during the last months of life. We followed 128 patients with incurable lung, breast, ovarian, colorectal or prostate cancer. At inclusion they were interviewed personally at home. During follow-up, every 6 months, we asked them to fill out a questionnaire on the end-of-life care they had received. One-hundred of them died during the research period. Eighty-seven of the deceased patients were able to fill out a questionnaire in the last 6 months of their lives. They reported that, on average, 4.2 disciplines were involved in their care. Most patients indicated to be satisfied with the care offered by their caregivers. Problems in end-of-life care concerned communication, difficulties in coordination, accessibility of end-of-life care and responding quickly to acute problems. We conclude that comprehensive and interdisciplinary end-of-life care may address patients' needs, but that it simultaneously is a challenge to optimal communication among disciplines and between caregivers and the patient.


Flow-dependent myosin recruitment during Drosophila cellularization requires zygotic dunk activity.
Actomyosin contractility underlies force generation in morphogenesis ranging from cytokinesis to epithelial extension or invagination. In Drosophila, the cleavage of the syncytial blastoderm is initiated by an actomyosin network at the base of membrane furrows that invaginate from the surface of the embryo. It remains unclear how this network forms and how it affects tissue mechanics. Here, we show that during Drosophila cleavage, myosin recruitment to the cleavage furrows proceeds in temporally distinct phases of tension-driven cortical flow and direct recruitment, regulated by different zygotic genes. We identify the gene dunk, which we show is transiently transcribed when cellularization starts and functions to maintain cortical myosin during the flow phase. The subsequent direct myosin recruitment, however, is Dunk-independent but requires Slam. The Slam-dependent direct recruitment of myosin is sufficient to drive cleavage in the dunk mutant, and the subsequent development of the mutant is normal. In the dunk mutant, cortical myosin loss triggers misdirected flow and disrupts the hexagonal packing of the ingressing furrows. Computer simulation coupled with laser ablation suggests that Dunk-dependent maintenance of cortical myosin enables mechanical tension build-up, thereby providing a mechanism to guide myosin flow and define the hexagonal symmetry of the furrows.


Emerging therapies and challenges in spinal muscular atrophy.
Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease-modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease-modifying therapies will necessitate monitoring programs to determine the long-term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355-368.


Treatment for severe and enduring anorexia nervosa: a review.
Many patients with anorexia nervosa develop an intractable and debilitating illness course. Our aims were to (i) conduct a systematic review of randomised controlled trials (RCTs) of treatment for chronic anorexia nervosa participants, and (ii) identify research informing novel therapeutic approaches for this group. Systematic search (SCOPUS plus previous reviews date 2011) of literature for (i) RCTs of treatment that included anorexia nervosa participants with a mean duration of illness of at least 3 years, (ii) studies reporting new treatments addressing factors associated with chronicity. Evidence of efficacy for treatment approaches in severe and enduring anorexia nervosa is limited. Only one unpublished RCT designed to test a specific psychological approach for these patients was identified. There is a probable advantage for specialist psychotherapy over treatment as usual, and a promising study of relapse prevention with cognitive behaviour therapy (CBT) for anorexia nervosa (CBT-AN). Open trials have, however, reported developments in psychological therapies that warrant further specific evaluation. These include forms of CBT modified for anorexia nervosa, cognitive remediation therapy with emotion skills training, the Maudsley Model for Treatment of Adults with Anorexia Nervosa, the Community Outreach Partnership Program, Specialist Supportive Clinical Management and the approach of Strober with its emphasis on therapeutic alliance and flexible goals. Treatment trials need to move beyond targeting core eating disorder pathology (primarily weight restoration) and examine efficacy and effectiveness in minimising harm and reducing personal and social costs of chronic illness. There is also a need to develop better definitions of chronicity, with or without treatment 'resistance' specifiers.


Epidemiology of echinococcosis/hydatidosis in Anambra State, Nigeria.
The prevalence of hydatidosis in cattle, goats and pigs slaughtered in Anambra State, eastern Nigeria during 1973 to 1979, as determined from official meat inspection records, was 7/373,242 (0.002%), 249/476,249 (0.05%) and 1/31,005 (0.003%), respectively. Special point surveys conducted from September 1979 to February 1980 and from March 1985 to September 1987 in two of the slaughterhouses that officially recorded zero infection rates also found no infection in the 551 cattle, 3830 goats and 2126 pigs examined. Similarly, none of the 80 dogs obtained from some of the rural communities in the localities served by these slaughterhouses harboured tapeworms (Echinococcus) at necropsy. Information obtained from rural health centres and some rural and urban-located hospitals, including records of hospital admissions, revealed insufficient awareness of the nature and importance of the disease in man and no evidence even of suspected cases. The apparent absence of infection in humans was confirmed by records at the main specialist hospital in the area, which showed that only one case of human hydatid disease had ever been diagnosed by that hospital. The most important factors that might have been responsible for the virtual absence of canine and human infections include the extremely low infection rates in food animals, limited access by dogs to offal, limited contact between dogs and potential domestic intermediate hosts of hydatid, and absence of a wild-life cycle.


Factors affecting feasibility and acceptability of a practice-based educational intervention to support evidence-based prescribing: a qualitative study.
Inappropriate and costly GP prescribing is a major problem facing Primary Care Trusts. Educational outreach into practices, alongside other measures, such as audit and feedback, have the potential to enable GP prescribing to become more evidence based. High GP prescribing costs are associated with GPs who see drug company representatives; tend to end consultations with prescriptions; and 'try out' new drugs on an 'ad hoc basis' and use this as evidence of the drug's effect. An educational intervention called 'reflective practice' was developed to meet these and other educational needs. The design of the intervention was informed by studies that have identified the pre-requisites of successful behaviour change in general practice. The study investigated the following: (i) Is it feasible for GPs to attend the sessions included in the educational intervention? (ii) Is the intervention acceptable to the participants and the session facilitators? (iii) What are the barriers to the group educational processes, and how can these be overcome? Four practices were recruited in South West England, all of them experiencing problems with prescribing appropriateness and cost. Reflective practice sessions (including a video-taped scenario) were run in each of these practices and qualitative methods were used to explore the complex attitudes and behaviour of the participants. A researcher observed and audio-taped sessions in each practice. At the end of the programme, a sample of doctors and all the facilitators were interviewed about their experiences. The recorded data were transcribed and analysed using standard qualitative methods. The doctors in the largest partnerships were those who had the greatest difficulty in attending the sessions. Elsewhere, doctors were also reluctant to become involved because of previous experience of top-down managerial initiatives about prescribing quality. Facilitators came from a broad range of professional backgrounds. While knowledge of prescribed drug management issues was important, the professional background of the facilitator was less important than group facilitation skills in creating a group process which participating GPs found satisfactory. The video-taped scenario was found to be useful to set the scene for the discussion. Preserving the anonymity of responses of the GPs in the initial stages of the sessions was important in ensuring honesty in the discussion. Reaching a consensus on management of common conditions was sometimes difficult, partly because the use of the term 'best buy' implies economic pressures, rather than benefits to patients, and partly because of the value with which GPs regard the concept of clinical autonomy. 'Reflective Practice' appeared to have the potential to make GPs aware of the link to be made between their clinical management decisions and the evidence provided by the British National Formulary and Clinical Evidence. The study indicates the importance of preparing the practice adequately, including providing protected time for all GPs to attend the educational intervention. Scenarios and the structure of the sessions need to make more explicit the links between everyday practice and published evidence of effectiveness. Emphasis on cost-effectiveness may be counterproductive and wider benefits need to be emphasized. We have also identified the skill profile of the facilitator role. Our study indicates a need for a clearer understanding of GPs' perception of clinical autonomy and how this conflicts with the goal of agreement on practice guidelines for treatment. The intervention is now ripe for further development, perhaps by integrating it with other interventions to change professional behaviour. The improved intervention should then be evaluated in a randomized controlled trial.


Suspect filler similarity in eyewitness lineups: a literature review and a novel methodology.
Eyewitness lineups typically contain a suspect (guilty or innocent) and fillers (known innocents). The degree to which fillers should resemble the suspect is a complex issue that has yet to be resolved. Previously, researchers have voiced concern that eyewitnesses would be unable to identify their target from a lineup containing highly similar fillers; however, our literature review suggests highly similar fillers have only rarely been shown to have this effect. To further examine the effect of highly similar fillers on lineup responses, we used morphing software to create fillers of moderately high and very high similarity to the suspect. When the culprit was in the lineup, a higher correct identification rate was observed in moderately high similarity lineups than in very high similarity lineups. When the culprit was absent, similarity did not yield a significant effect on innocent suspect misidentification rates. However, the correct rejection rate in the moderately high similarity lineup was 20% higher than in the very high similarity lineup. When choosing rates were controlled by calculating identification probabilities for only those who made a selection from the lineup, culprit identification rates as well as innocent suspect misidentification rates were significantly higher in the moderately high similarity lineup than in the very high similarity lineup. Thus, very high similarity fillers yielded costs and benefits. Although our research suggests that selecting the most similar fillers available may adversely affect correct identification rates, we recommend additional research using fillers obtained from police databases to corroborate our findings.


Mitral annular growth in children following early mechanical mitral valve replacement.
Irreparable mitral pathology may lead to early mitral valve replacement (MVR) in children. Often, a small mechanical prosthesis (<23 mm) is required, raising concerns about annular growth in patients who may eventually require subsequent mitral valve re-replacement (MVRR). The aim of this study was to evaluate interval mitral annular growth in this cohort. Between January 1972 and December 2006, 164 children underwent MVR with a mechanical prosthesis; 110 of these children (median age, 4 years; range, 7 days to 14 years) received a small mechanical prosthesis (<23 mm). The most common diagnoses were congenital mitral stenosis (10%), regurgitation (46%), and left atrioventricular valve dysfunction after previous atrioventricular septal defect repair (44%). The cohort was analyzed for age, body surface area (BSA), prosthesis size, and Z score at the time of MVR and MVRR. At the time of MVR, 78 patients had a BSA of 0.77 ± 0.06 m(2), had an annular size of 24 ± 0.62 mm (Z score, 2.91 ± 0.23), and ultimately did not require MVRR. Another cohort, who eventually did require MVRR (n = 24), had an initial BSA at the time of MVR of 0.62 ± 0.05 m(2) (P = NS vs MVR only) and an annular size of 20 ± 0.49 mm (Z score, 1.85 ± 0.22) (P = .008 vs MVR only). In the interval between MVR and MVRR (7.8 ± 1.1 years), BSA increased to 1.12 ± 0.07 m(2), and annulus size increased to 24 ± 0.47 mm (Z score, 1.80 ± 0.28). These data suggest growth of the mitral annulus following MVR with a small mechanical prosthesis, as evidenced by an unchanged Z score in the setting of normal interval increase in BSA. Additionally, there was a statistically significant difference in initial Z scores between the cohorts requiring MVRR and those who have not needed re-replacement, suggesting that the feasibility of placement of a slightly larger prosthesis may be associated with a decreased need for MVRR.


Prolactin concentrations in serum and milk of mothers with and without insulin-dependent diabetes mellitus.
Diabetes may affect the secretion of prolactin, the principal lactogenic hormone. Because adequate amounts are critical to the establishment of lactation, we assessed the prolactin status of 33 women with insulin-dependent diabetes mellitus (IDDM), 33 women without diabetes, and 11 reference women participating in a study of lactation from 2 to 84 d postpartum. Circulating concentrations of serum prolactin declined temporally for all women and did not differ significantly among any of the groups. During the first postnatal week, milk immunoreactive prolactin concentrations were lower for women with IDDM than for control and reference women and the inverse relationship between lactose and milk prolactin, which was significant at day 2 postpartum for reference women, was delayed until day 14 postpartum for women with IDDM. Early breast-feeding activity, increased breast-feeding frequency, and good glycemic control enhance prolactin secretion and should be promoted during lactation in women with IDDM.


Private sector role, readiness and performance for malaria case management in Uganda, 2015.
Several interventions have been put in place to promote access to quality malaria case management services in Uganda's private sector, where most people seek treatment. This paper describes evidence using a mixed-method approach to examine the role, readiness and performance of private providers at a national level in Uganda. These data will be useful to inform strategies and policies for improving malaria case management in the private sector. The ACTwatch national anti-malarial outlet survey was conducted concurrently with a fever case management study. The ACTwatch nationally representative anti-malarial outlet survey was conducted in Uganda between May 18th 2015 and July 2nd 2015. A representative sample of sub-counties was selected in 14 urban and 13 rural clusters with probability proportional to size and a census approach was used to identify outlets. Outlets eligible for the survey met at least one of three criteria: (1) one or more anti-malarials were in stock on the day of the survey; (2) one or more anti-malarials were in stock in the 3 months preceding the survey; and/or (3) malaria blood testing (microscopy or RDT) was available. The fever case management study included observations of provider-patient interactions and patient exit interviews. Data were collected between May 20th and August 3rd, 2015. The fever case management study was implemented in the private sector. Potential outlets were identified during the main outlet survey and included in this sub-sample if they had both artemisinin-based combination therapy (ACT) [artemether-lumefantrine (AL)], in stock on the day of survey as well as diagnostic testing available. A total of 9438 outlets were screened for eligibility in the ACTwatch outlet survey and 4328 outlets were found to be stocking anti-malarials and were interviewed. A total of 9330 patients were screened for the fever case management study and 1273 had a complete patient observation and exit interview. Results from the outlet survey illustrate that the majority of anti-malarials were distributed through the private sector (54.3%), with 31.4% of all anti-malarials distributed through drug stores and 14.4% through private for-profit health facilities. Availability of different anti-malarials and diagnostic testing in the private sector was: ACT (80.7%), quality-assured (QA) ACT (72.0%), sulfadoxine-pyrimethamine (SP) (47.1%), quinine (73.2%) and any malaria blood testing (32.9%). Adult QAACT ($1.62) was three times more expensive than SP ($0.48). The results from the fever case management study found 44.4% of respondents received a malaria test, and among those who tested positive for malaria, 60.0% received an ACT, 48.5% received QAACT; 14.4% a non-artemisinin therapy; 14.9% artemether injection, and 42.5% received an antibiotic. The private sector plays an important role in malaria case management in Uganda. While several private sector initiatives have improved availability of QAACT, there are gaps in malaria diagnosis and distribution of non-artemisinin monotherapies persists. Further private sector strategies, including those focusing on drug stores, are needed to increase coverage of parasitological testing and removal of non-artemisinin therapies from the marketplace.


Identification of protein motifs using conserved amino acid properties and partitioning techniques.
Analyzing a set of protein sequences involves a fundamental relationship between the coherency of the set and the specificity of the motif that describes it. Motifs may be obscured by training sets that contain incoherent sequences, in part due to protein subclasses, contamination, or errors. We develop an algorithm for motif identification that systematically explores possible patterns of coherency within a set of protein sequences. Our algorithm constructs alternative partitions of the training set data, where one subset of each partition is presumed to contain coherent data and is used for forming a motif. The motif is represented by multiple overlapping amino acid groups based on evolutionary, biochemical, or physical properties. We demonstrate our method on a training set of reverse transcriptases that contains subclasses, sequence errors, misalignments, and contaminating sequences. Despite these complications, our program identifies a novel motif for the subclass of retroviral and retrovirus-related reverse transcriptases. This motif has a much higher specificity than previously reported motifs and suggests the importance of conserved hydrophilic and hydrophobic residues in the structure of reverse transcriptases.


A novel member of the transmembrane serine/threonine kinase receptor family is specifically expressed in the gonads and in mesenchymal cells adjacent to the müllerian duct.
The activin and TGF-beta type II receptors are members of a separate subfamily of transmembrane receptors with intrinsic protein kinase activity, which also includes the recently cloned TGF-beta type I receptor. We have isolated and characterized a cDNA clone (C14) encoding a new member of this subfamily. The domain structure of the C14-encoded protein corresponds with the structure of the other known transmembrane serine/threonine kinase receptors. It also contains the two inserts in the kinase domain that are characteristic for this subfamily. Using in situ hybridization, C14 mRNA was detected in the mesenchymal cells located adjacent to the müllerian ducts of males and females at day 15 (E15) of embryonic development. Marked C14 mRNA expression was also detected in the female gonads. In female E16 embryos, the C14 mRNA expression pattern remained similar to that in E15 embryos. However, in male E16 embryos C14 mRNA was detected in a circular area that includes the degenerating müllerian duct. The expression of C14 mRNA was also studied using RNase protection assays. At E15 and E16, C14 mRNA is expressed in the female as well as in the male urogenital ridge. However, at E19, a high C14 mRNA level in the female urogenital ridge contrasts with a lack of C14 mRNA in the male urogenital ridge. This correlates with the almost complete degeneration of the müllerian ducts in male embryos at E19. C14 mRNA expression was also detected in embryonic testes at E15, E16 and E19 using RNase protection assays, but at much lower levels than those found in the developing ovaries.(ABSTRACT TRUNCATED AT 250 WORDS)


Impact of HIV knowledge and stigma on the uptake of HIV testing - Results from a community-based participatory research survey among migrants from sub-Saharan Africa in Germany.
In 2015, 3,674 new HIV diagnoses were notified in Germany; 16% of those newly diagnosed cases originated from sub-Saharan Africa (sSA). One quarter of the newly diagnosed cases among migrants from sSA (MisSA) are notified as having acquired the HIV infection in Germany. In order to reach MisSA with HIV testing opportunities, we aimed to identify which determinants influence the uptake of HIV testing among MisSA in Germany. To identify those determinants, we conducted a quantitative cross-sectional survey among MisSA in Germany. The survey was designed in a participatory process that included MisSA and other stakeholders in HIV-prevention. Peer researchers recruited participants to complete standardized questionnaires on HIV knowledge and testing. We conducted multivariable analyses (MVA) to identify determinants associated with ever having attended voluntary HIV testing; and another MVA to identify determinant associated with having had the last voluntary HIV test in Germany. Peer researchers recruited 2,782 participants eligible for inclusion in the MVA. Of these participants, 59.9% (1,667/2,782) previously had an HIV test. For each general statement about HIV that participants knew prior to participation in the study, the odds of having been tested increased by 19% (OR 1.19; 95%-CI: 1.11-1.27). Participants reporting that HIV is a topic that is discussed in their community had 92% higher odds of having been tested for HIV (OR 1.92; 95%-CI: 1.60-2.31). Migrants living in Germany for less than a year had the lowest odds of having had their last HIV test in Germany (OR 0.17; 95%-CI: 0.11-0.27). Additionally, MisSA 18 to 25 years (OR 0.55; 95%-CI: 0.42-0.73) and participants with varied sexual partners and inconsistent condom use (OR 0.75; 95%-CI: 0.44-0.97) had significantly lower odds of having had their last HIV test in Germany. Through participatory research, we were able to show that knowledge about HIV and discussing HIV in communities increased the odds of having attended HIV testing among MisSA. However, recent migrants and young sexually active people are among the least reached by testing offers in Germany. Community-based interventions may present opportunities to reach such migrants and improve knowledge and increase discussion about HIV.


Copper(II)-catalyzed C-O coupling of aryl bromides with aliphatic diols: synthesis of ethers, phenols, and benzo-fused cyclic ethers.
A highly efficient copper-catalyzed C-O cross-coupling reaction between aryl bromides and aliphatic diols has been developed employing a cheaper, more efficient, and easily removable copper(II) catalyst. A broad range of aryl bromides were coupled with aliphatic diols of different lengths using 5 mol% CuCl2 and 3 equivalents of K2CO3 in the absence of any other ligands or solvents to afford the corresponding hydroxyalkyl aryl ethers in good to excellent yields. In this newly developed protocol, aliphatic diols have multilateral functions as coupling reactants, ligands, and solvents. The resulting hydroxyalkyl aryl ethers were further readily converted into the corresponding phenols, presenting a valuable alternative way to phenols from aryl bromides. Furthermore, it was demonstrated that they are useful intermediates for more advanced molecules such as benzofurans and benzo-fused cyclic ethers.


The channel-activating protease CAP1/Prss8 is required for placental labyrinth maturation.
The serine protease CAP1/Prss8 is crucial for skin barrier function, lung alveolar fluid clearance and has been unveiled as diagnostic marker for specific cancer types. Here, we show that a constitutive knockout of CAP1/Prss8 leads to embryonic lethality. These embryos presented no specific defects, but it is during this period, and in particular at E13.5, that wildtype placentas show an increased expression of CAP1/Prss8, thus suggesting a placental defect in the knockout situation. The placentas of knockout embryos exhibited significantly reduced vascular development and incomplete cellular maturation. In contrary, epiblast-specific deletion of CAP1/Prss8 allowed development until birth. These CAP1/Prss8-deficient newborns presented abnormal epidermis, and died soon after birth due to impaired skin function. We thus conclude that a late placental insufficiency might be the primary cause of embryonic lethality in CAP1/Prss8 knockouts. This study highlights a novel and crucial role for CAP1/Prss8 in placental development and function.


Incisional Hernia After Liver Transplant.
An incisional hernia seriously burdens the quality of life after liver transplant. The incidence of incisional hernia after liver transplant is reported to be 4% to 20%. Here, we evaluated incisional hernias that occurred after adult liver transplant and incisional hernias intentionally made in infant liver transplant procedures. Between December 1988 and May 2016, we performed 536 liver transplant procedures in 515 patients. Demographic features, surgical outcomes, and predisposing factors were evaluated. Of 452 liver transplant patients included, incisional hernias were diagnosed in 29 patients (6.4%; 7 pediatric, 22 adult). Most were males (77%) with Child-Pugh score C cirrhosis (62%), moderate/severe ascites (81%), and serum albumin levels <3.5 g/L (86%). Incisional hernia developed in 16 of 51 patients (31%) with wound infection. Twelve incisional hernias were seen in 40 recipients (30%) with body mass index ≥30 kg/m2. Eight of 45 patients (18%) with repeated surgery had incisional hernias. Five of 22 adult incisional hernias (23%) had primary fascia repair, and 17 (77%) were repaired with Prolene mesh graft (3 sublay, 14 onlay). No other complications and no hernia recurrence were shown during follow-up (range, 8-138 mo). Of 7 pediatric liver transplant patients with intentionally made incisional hernias during liver transplant, 5 patients had primary fascia repair and 2 patients had onlay mesh repair. No complications or recurrence were shown during follow-up (range, 12-60 mo). Repeated surgery, postoperative wound infection, and obesity were found to be predisposing risk factors for incisional hernia development after liver transplant in adults. Abdomen closure in infant liver transplant with large-for-size grafts is a different area of discussion. Here, we suggest that an intentionally made incisional hernia with staged closure of the abdomen is safe and effective for graft and patient survival.


Piperlongumine induces autophagy in biliary cancer cells via reactive oxygen species-activated Erk signaling pathway.
Biliary cancer (BC) is an aggressive neoplasm with high mortality. BC can be categorized into three groups: Intrahepatic cholangiocarcinoma (CCA; also known as bile duct cancer), extrahepatic cholangiocarcinoma and gallbladder cancer. Due to its heterogeneity and aggressiveness, the response to current chemotherapy and radiotherapy methods in patients with BC is poor. Therefore, there is an urgent requirement to develop drugs to treat BC. Piperlongumine (PL), a naturally occurring small molecule isolated from Piper longum L., exhibits anticancer activity by inducing reactive oxygen species (ROS) production. In the present study, the effects of PL on cell proliferation, cell cycle, apoptosis and autophagy in BC cells were investigated. PL induced BC cell death in a concentration‑ and time‑dependent manner by inducing ROS production. PL induced cell cycle arrest in CCA cells (HuCCT‑1) and gallbladder cancer cells (OCUG‑1) cells, but with distinct cell cycle distribution profiles. PL caused G2/M cell cycle arrest in HuCCT‑1 cells, and G0/G1 cell cycle arrest in OCUG‑1 cells. PL induced apoptosis and autophagy; PL treatment induced accumulation of LC3‑II in a concentration‑ and time‑dependent manner. The Erk signaling pathway appeared to be involved in autophagy induction. Application of the ROS scavenger, N‑acetyl‑l‑cysteine, to BC cells attenuated the cell death, cell cycle arrest, apoptosis and autophagy induced by PL treatment. These findings indicated that PL may be a potential agent for BC treatment in the future.


28-way vertebrate alignment and conservation track in the UCSC Genome Browser.
This article describes a set of alignments of 28 vertebrate genome sequences that is provided by the UCSC Genome Browser. The alignments can be viewed on the Human Genome Browser (March 2006 assembly) at http://genome.ucsc.edu, downloaded in bulk by anonymous FTP from http://hgdownload.cse.ucsc.edu/goldenPath/hg18/multiz28way, or analyzed with the Galaxy server at http://g2.bx.psu.edu. This article illustrates the power of this resource for exploring vertebrate and mammalian evolution, using three examples. First, we present several vignettes involving insertions and deletions within protein-coding regions, including a look at some human-specific indels. Then we study the extent to which start codons and stop codons in the human sequence are conserved in other species, showing that start codons are in general more poorly conserved than stop codons. Finally, an investigation of the phylogenetic depth of conservation for several classes of functional elements in the human genome reveals striking differences in the rates and modes of decay in alignability. Each functional class has a distinctive period of stringent constraint, followed by decays that allow (for the case of regulatory regions) or reject (for coding regions and ultraconserved elements) insertions and deletions.


Heart Failure With Preserved Ejection Fraction in the Young.
Heart failure with preserved ejection fraction (HFpEF), traditionally considered a disease of the elderly, may also affect younger patients. However, little is known about HFpEF in the young. We prospectively enrolled 1203 patients with HFpEF (left ventricular ejection fraction ≥50%) from 11 Asian regions. We grouped HFpEF patients into very young (<55 years of age; n=157), young (55-64 years of age; n=284), older (65-74 years of age; n=355), and elderly (≥75 years of age; n=407) and compared clinical and echocardiographic characteristics, quality of life, and outcomes across age groups and between very young individuals with HFpEF and age- and sex-matched control subjects without heart failure. Thirty-seven percent of our HFpEF population was <65 years of age. Younger age was associated with male preponderance and a higher prevalence of obesity (body mass index ≥30 kg/m2; 36% in very young HFpEF versus 16% in elderly) together with less renal impairment, atrial fibrillation, and hypertension (all P<0.001). Left ventricular filling pressures and prevalence of left ventricular hypertrophy were similar in very young and elderly HFpEF. Quality of life was better and death and heart failure hospitalization at 1 year occurred less frequently ( P<0.001) in the very young (7%) compared with elderly (21%) HFpEF. Compared with control subjects, very young HFpEF had a 3-fold higher death rate and twice the prevalence of hypertrophy. Young and very young patients with HFpEF display similar adverse cardiac remodeling compared with their older counterparts and very poor outcomes compared with control subjects without heart failure. Obesity may be a major driver of HFpEF in a high proportion of HFpEF in the young and very young.


Post-training stimulation of the right dorsolateral prefrontal cortex impairs working memory training performance.
Research investigating transcranial direct current stimulation (tDCS) to enhance cognitive training augments both our understanding of its long-term effects on cognitive plasticity as well as potential applications to strengthen cognitive interventions. Previous work has demonstrated enhancement of working memory training while applying concurrent tDCS to the dorsolateral prefrontal cortex (DLPFC). However, the optimal stimulation parameters are still unknown. For example, the timing of tDCS delivery has been shown to be an influential variable that can interact with task learning. In the present study, we used tDCS to target the right DLPFC while participants trained on a visuospatial working memory task. We sought to compare the relative efficacy of online stimulation delivered during training to offline stimulation delivered either immediately before or afterwards. We were unable to replicate previously demonstrated benefits of online stimulation; however, we did find evidence that offline stimulation delivered after training can actually be detrimental to training performance relative to sham. We interpret our results in light of evidence suggesting a role of the right DLPFC in promoting memory interference, and conclude that while tDCS may be a promising tool to influence the results of cognitive training, more research and an abundance of caution are needed before fully endorsing its use for cognitive enhancement. This work suggests that effects can vary substantially in magnitude and direction between studies, and may be heavily dependent on a variety of intervention protocol parameters such as the timing and location of stimulation delivery, about which our understanding is still nascent.


A Latent Gaussian process model for analysing intensive longitudinal data.
Intensive longitudinal studies are becoming progressively more prevalent across many social science areas, and especially in psychology. New technologies such as smart-phones, fitness trackers, and the Internet of Things make it much easier than in the past to collect data for intensive longitudinal studies, providing an opportunity to look deep into the underlying characteristics of individuals under a high temporal resolution. In this paper we introduce a new modelling framework for latent curve analysis that is more suitable for the analysis of intensive longitudinal data than existing latent curve models. Specifically, through the modelling of an individual-specific continuous-time latent process, some unique features of intensive longitudinal data are better captured, including intensive measurements in time and unequally spaced time points of observations. Technically, the continuous-time latent process is modelled by a Gaussian process model. This model can be regarded as a semi-parametric extension of the classical latent curve models and falls under the framework of structural equation modelling. Procedures for parameter estimation and statistical inference are provided under an empirical Bayes framework and evaluated by simulation studies. We illustrate the use of the proposed model though the analysis of an ecological momentary assessment data set.


Interactive Voice Response-An Innovative Approach to Post-Stroke Depression Self-Management Support.
Automated interactive voice response (IVR) call systems can provide systematic monitoring and self-management support to depressed patients, but it is unknown if stroke patients are able and willing to engage in IVR interactions. We sought to assess the feasibility and acceptability of IVR as an adjunct to post-stroke depression follow-up care. The CarePartner program is a mobile health program designed to optimize depression self-management, facilitate social support from a caregiver, and strengthen connections between stroke survivors and primary care providers (PCPs). Ischemic stroke patients and an informal caregiver, if available, were recruited during the patient's acute stroke hospitalization or follow-up appointment. The CarePartner program was activated in patients with depressive symptoms during their stroke hospitalization or follow-up. The 3-month intervention consisted of weekly IVR calls monitoring both depressive symptoms and medication adherence along with tailored suggestions for depressive symptom self-management. After each completed IVR call, informal caregivers were automatically updated, and, if needed, the subject's PCP was notified. Of the 56 stroke patients who enrolled, depressive symptoms were identified in 13 (23 %) subjects. Subjects completed 74 % of the weekly IVR assessments. A total of six subjects did not complete the outcome assessment, including two non-study-related deaths. PCPs were notified five times, including two times for suicidal ideation and three times for medication non-adherence. Stroke patients with depressive symptoms were able to engage in an IVR call system. Future studies are needed to explore the efficacy of an IVR approach for post-stroke self-management and monitoring of stroke-related outcomes.


RBE estimation of proton radiation fields using a DeltaE-E telescope.
A new monolithic silicon DeltaE-E telescope was evaluated in unmodulated and modulated 100 MeV proton beams used for hadron therapy. Compared to a classical microdosimetry detector, which provides one-dimensional information on lineal energy of charged particles, this detector system provides two-dimensional information on lineal energy and particle energy based on energy depositions, collected in coincidence, within the DeltaE and E stages of the detector. The authors investigated the possibility to use the information obtained with the DeltaE-E telescope to determine the relative biological effectiveness (RBE) at defined locations within the proton Bragg peak and spread-out Bragg peak (SOBP). An RBE matrix based on the established in vitro V79 cell survival data was developed to link the output of the device directly to RBE(alpha), the RBE in the low-dose limit, at various depths in a homogeneous polystyrene phantom. In the SOBP of a 100 MeV proton beam, the RBE(alpha) increased from 4.04 proximal to the SOBP to a maximum value of 5.4 at the distal edge. The DeltaE-E telescope, with its high spatial resolution, has potential applications to biologically weighted hadron treatment planning as it provides a compact and portable means for estimating the RBE in rapidly changing hadron radiation fields within phantoms.


Fiber-laser-based femtosecond parametric generator in bulk periodically poled LiNbO(3).
A diode-pumped system for optical parametric generation of wavelength-tunable femtosecond pulses is demonstrated. It comprises an Er-doped fiber mode-locked laser, a fiber chirped-pulse amplifier, and a bulk periodically poled LiNbO(3) (PPLN) optical parametric generator. The parametric generator is pumped at 777 nm with frequency-doubled microjoule pulses from the fiber amplifier and produces 300-fs pulses tunable from 1 to 3microm with output energies up to ~200 nJ. Use of a PPLN nonlinear crystal substantially reduces the pump energies required for efficient parametric generation. Saturated single-pass parametric energy conversion of 38% (internal) has been achieved with only 220 nJ of pump inside the crystal. A parametric generation threshold of 54 nJ is observed, and efficient parametric conversion is obtained with repetition rates up to 200 kHz.


Neural basis of extraordinary empathy and altruistic motivation.
A central evolutionary challenge for social groups is uniting a heterogeneous set of individuals towards common goals. One means by which social groups form and endure is by endowing group members with extraordinary prosocial proclivities, such as ingroup love, towards other group members. Here we examined the neural basis of extraordinary empathy and altruistic motivation in African-American and Caucasian-American individuals using functional magnetic resonance imaging. Our results indicate that empathy for ingroup members is neurally distinct from empathy for humankind, more generally. People showed greater response within anterior cingulate cortex and bilateral insula when observing the suffering of others, but African-American individuals additionally recruit medial prefrontal cortex when observing the suffering of members of their own social group. Moreover, neural activity within medial prefrontal cortex in response to pain expressed by ingroup relative to outgroup members predicted greater empathy and altruistic motivation for one's ingroup, suggesting that neurocognitive processes associated with self identity underlie extraordinary empathy and altruistic motivation for members of one's own social group. Taken together, our findings reveal distinct neural mechanisms of empathy and altruistic motivation in an intergroup context and may serve as a foundation for future research investigating the neural bases of intergroup prosociality, more broadly construed.


Comparison of ε-Aminocaproic Acid and Tranexamic Acid in Reducing Postoperative Transfusions in Total Hip Arthroplasty.
Use of antifibrinolytic agents in total hip arthroplasty (THA) is well supported; however, most studies used tranexamic acid (TXA), whereas few used ε-aminocaproic acid (EACA), a similar antifibrinolytic. This study compares the efficacy and cost per surgery of intraoperative infusion of EACA and TXA in reducing postoperative blood transfusion rates in THA. Retrospective chart review of 1799 primary unilateral THA cases from April 2012 through December 2014 at 5 hospitals within our health care network. In our cohort, 711 received EACA, 445 received TXA, and 643 (control group) received no antifibrinolytic. Both antifibrinolytic groups had significantly fewer patients receiving red blood cell (RBC) transfusions when compared with control group (EACA 6.8% [P < .0001], TXA 9.7% [P < .0001] vs control group 24.7%). Average number of RBC units per patient were similar for EACA and TXA (0.11 units/patient and 0.15 units/patient, respectively), and both were significantly lower than the control group (0.48 units/patient, P < .0001). No significant difference was noted in mean RBC units per patient and percentage of patients transfused between EACA and TXA groups (P = .144, P = .074). Logistic regression showed no difference between EACA and TXA when adjusting for age, gender, higher severity of illness levels, admission hemoglobin, performing surgeon, and hospital. Medication acquisition cost for EACA averaged $2.70 per surgery compared with TXA at $39.58 per surgery. Intraoperative antifibrinolytic use significantly decreases need for postoperative blood transfusions. At our institution, EACA is comparable to TXA in THA for reducing transfusion rates while at a lower cost per surgery.


Exposure of reproductively maturing rainbow trout to a New Zealand pulp and paper mill effluent.
Long-term studies on the reproductive fitness of fish under controlled exposure conditions are necessary to address some of the controversy surrounding the field-based studies of pulp and paper effluent effects. This study undertook effluent exposures of 2+ age rainbow trout that were approximately halfway through gonadal growth. Trout were exposed to a mixed thermomechanical/bleached kraft effluent in 12,000-L flow-through exposure tanks at an environmental research facility located at a pulp and paper mill in Kawerau, New Zealand. Trout were exposed to either upstream river water or 10% effluent in upstream river water and were maintained at a ration of 0.7% of body wet weight during the experiment. Results of the 2-month study indicated that trout survival was not significantly different between effluent-exposed tanks and reference tanks. There was extensive growth during the exposure but no differences were found due to effluent exposure. Gonadal development was not significantly different between treatments. Steroid hormone concentrations in males and females were not affected by effluent exposure. The effluent showed no potential to be estrogenic as indicated by a lack of vitellogenin induction in male trout. Other physiological indicators of energy storage and utilization also showed no significant differences. Modest induction of hepatic 7-ethoxyresorufin-O-deethylase (2.5-fold) was the only detectable biological effect of the exposure. Biliary concentration of effluent-related compounds were typical of pulp mill effluent exposure and further suggested that the source of phytosterols was in fact dietary and not effluent-derived.


Cellular perspectives on the glutamate-monoamine interactions in limbic lobe structures and their relevance for some psychiatric disorders.
Dopaminergic, serotonergic and noradrenergic nuclei form the trimonoamine modulating system (TMMS). This system modulates emotional/motivational activities mediated by the limbic circuitry, where glutamate is the major excitatory neurotransmitter. Two main concepts are the basis of this review. First, since 1950 and the discovery of the antipsychotic activity of the dopamine D2 receptor antagonist chlorpromazine, it appears that drugs that can modulate the TMMS possess therapeutic psychiatric properties. Second, the concept of glutamate/trimonoamine imbalance in the cortico-striato-thalamo-cortical loop that has been so successful in explaining the pathophysiology of Parkinson disease has been applied in the pathophysiology of schizophrenia. This review will focus on the complex interactions between the fast synaptic glutamatergic transmission and the TMMS in specific parts of the limbic lobe and we will try to link these interactions to some psychiatric disorders, mainly depression, schizophrenia and drug addiction.


Herbicide mixtures at high doses slow the evolution of resistance in experimentally evolving populations of Chlamydomonas reinhardtii.
The widespread evolution of resistance to herbicides is a pressing issue in global agriculture. Evolutionary principles and practices are key to the management of this threat to global food security. The application of mixtures of herbicides has been advocated as an anti-resistance strategy, without substantial empirical support for its validation. We evolved experimentally populations of the unicellular green chlorophyte, Chlamydomonas reinhardtii, to minimum inhibitory concentrations (MICs) of single-herbicide modes of action and to pair-wise and three-way mixtures between different herbicides at various total combined doses. Herbicide mixtures were most effective when each component was applied at or close to its MIC. When doses were high, increasing the number of mixture components was also effective in reducing the evolution of resistance. Employing mixtures at low combined doses did not retard resistance evolution, even accelerating the evolution of resistance to some components. At low doses, increasing the number of herbicides in the mixture tended to select for more generalist resistance (cross-resistance). Our results reinforce findings from the antibiotic resistance literature and confirm that herbicide mixtures can be very effective for resistance management, but that mixtures should only be employed where the economic and environmental context permits the applications of high combined doses.


African Mitochondrial DNA Haplogroup L2 Is Associated With Slower Decline of β-cell Function and Lower Incidence of Diabetes Mellitus in Non-Hispanic, Black Women Living With Human Immunodeficiency Virus.
Susceptibility to metabolic diseases may be influenced by mitochondrial genetic variability among people living with human immunodeficiency virus (HIV; PLWH), but remains unexplored in populations with African ancestry. We investigated the association between mitochondrial DNA (mtDNA) haplogroups and the homeostatic model assessments of β-cell function (HOMA-B) and insulin resistance (HOMA-IR), as well as incident diabetes mellitus (DM), among Black women living with or at risk for HIV. Women without DM who had fasting glucose (FG) and insulin (FI) data for ≥2 visits were included. Haplogroups were inferred from genotyping data using HaploGrep. HOMA-B and HOMA-IR were calculated using FG and FI data. Incident DM was defined by a combination of FG ≥ 126 mg/dL, the use of DM medication, a DM diagnosis, or hemoglobin A1c ≥ 6.5%. We compared HOMA-B, HOMA-IR, and incident DM by haplogroups and assessed the associations between HOMA-B and HOMA-IR and DM by haplogroup. Of 1288 women (933 living with HIV and 355 living without HIV), PLWH had higher initial HOMA-B and HOMA-IR than people living without HIV. PLWH with haplogroup L2 had a slower decline in HOMA-B per year (Pinteraction = .02) and a lower risk of incident DM (hazard ratio [HR], 0.51; 95% confidence interval [CI], .32-.82) than PLWH with other haplogroups after adjustments for age, body mass index, combination antiretroviral therapy use, CD4 cell counts, and HIV RNA. The impact of HOMA-IR on incident DM was less significant in those with haplogroup L2, compared to non-L2 (HR, 1.28 [95% CI, .70-2.38] vs 4.13 [95% CI, 3.28-5.22], respectively; Pinteraction < .01), among PLWH. Mitochondrial genetic variation is associated with β-cell functions and incident DM in non-Hispanic, Black women with HIV and alters the relationship between insulin resistance and DM.


Built for jumping: the design of the frog muscular system.
Frogs must generate a high level of mechanical power when they jump. The muscular system of frogs that jump is presumably designed to deliver these high powers. The length changes and activation pattern that muscles undergo during jumping were measured, and isolated muscle bundles were driven through this in vivo pattern. During jumping, muscles generated maximum power. Specifically, the muscle fibers (i) operated at optimal sarcomere lengths, (ii) operated at optimal shortening velocities, and (iii) were maximally activated during power generation. Thus, many different parameters must have evolved in concert to produce a system capable of this explosive jumping movement.


Inefficient control of host gene expression by the 2009 pandemic H1N1 influenza A virus NS1 protein.
In 2009, a novel swine-origin H1N1 influenza A virus emerged. Here, we characterize the multifunctional NS1 protein of this human pandemic virus in order to understand factors that may contribute to replication efficiency or pathogenicity. Although the 2009 H1N1 virus NS1 protein (2009/NS1) is an effective interferon antagonist, we found that this NS1 (unlike those of previous human-adapted influenza A viruses) is unable to block general host gene expression in human or swine cells. This property could be restored in 2009/NS1 by replacing R108, E125, and G189 with residues corresponding to human virus consensus. Mechanistically, these previously undescribed mutations acted by increasing binding of 2009/NS1 to the cellular pre-mRNA processing protein CPSF30. A recombinant 2009 H1N1 influenza A virus (A/California/04/09) expressing NS1 with these gain-of-function substitutions was more efficient than the wild type at antagonizing host innate immune responses in primary human epithelial cells. However, such mutations had no significant effect on virus replication in either human or swine tissue culture substrates. Surprisingly, in a mouse model of pathogenicity, the mutant virus appeared to cause less morbidity, and was cleared faster, than the wild type. The mutant virus also demonstrated reduced titers in the upper respiratory tracts of ferrets; however, contact and aerosol transmissibility of the virus was unaffected. Our data highlight a potential human adaptation of NS1 that seems absent in "classically derived" swine-origin influenza A viruses, including the 2009 H1N1 virus. We discuss the impact that a natural future gain of this NS1 function may have on the new pandemic virus in humans.


Adult age differences in prospective memory in the laboratory: are they related to higher stress levels in the elderly?
To explain age deficits found in laboratory-based prospective memory (PM) tasks, it has recently been suggested that the testing situation per se may be more stressful for older adults, thereby impairing their performance. To test this assumption, subjective and physiological stress levels were assessed at several times during the experiment in 33 younger and 29 older adults. In addition, half of participants were randomized in a condition where they completed a relaxation intervention before performing a time-based PM task. Results confirmed the age deficit in laboratory PM. Subjective and physiological stress levels showed no age difference and no detrimental association with PM. The intervention successfully reduced stress levels in both age groups but had no effect on PM or the age deficit. In conclusion, data suggest that age deficits usually observed in laboratory PM may not be due to higher stress levels in the older adults.


Bayesian segregation analysis of somatic cell scores of Ontario Holstein cattle.
Bayesian segregation analysis using a Gibbs sampling approach was applied to four sets of simulated data and one set of field data to detect evidence of major genes affecting the evaluated trait. The substitution effect of a major gene and its allelic frequency were estimated for each set of data. For two datasets simulated with a model with no major gene effect, the resulting estimates of polygenic variance and heritability agreed with the simulated values and tests for the presence of a major gene were not significant. Analyses of two sets of data simulated with a major gene produced posterior distributions that gave significant evidence of major gene effects but underestimated the substitution values of the major gene. The segregation analysis of field data suggested that a major gene significantly affected somatic cell score (SCS) in the population of Ontario Holstein cattle. The estimated heritability of SCS was approximately 0.16. The major gene variance accounted for about 17% of the total genetic variance and the point estimate of the frequency of the allele having a positive effect on SCS was 0.30. However, the precision of these estimates is questionable based on the simulation results. The effect of the major gene may be underestimated.


γδ T cell subsets play opposing roles in regulating experimental autoimmune encephalomyelitis.
γδ T cells are resident in cerebrospinal fluid and central nervous system (CNS) lesions of multiple sclerosis (MS) patients, but as multifaceted cells exhibiting innate and adaptive characteristics, their function remains unknown. Previous studies in experimental autoimmune encephalomyelitis (EAE) are contradictory and identified these cells as either promoting or suppressing disease pathogenesis. This study examines distinct γδ T cell subsets during EAE and indicates they mediate differential functions in CNS inflammation and demyelination resulting in pathogenesis or protection. We identified two γδ subsets in the CNS, Vγ1(+) and Vγ4(+), with distinct cytokine profiles and tissue specificity. Anti-γδ T cell receptor (TCR) monoclonal antibody (mAb) administration results in activation and downregulation of surface TCR, rendering the cells undetectable, but with opposing effects: anti-Vγ4 treatment exacerbates disease whereas anti-Vγ1 treatment is protective. The Vγ4(+) subset produces multiple pro-inflammatory cytokines including high levels of IL-17, and accounts for 15-20% of the interleukin-17 (IL-17) producing cells in the CNS, but utilize a variant transcriptional program than CD4(+) Th17 cells. In contrast, the Vγ1 subset produces CCR5 ligands, which may promote regulatory T cell differentiation. γδ T cell subsets thus play distinct and opposing roles during EAE, providing an explanation for previous reports and suggesting selective targeting to optimize regulation as a potential therapy for MS.


Reconstruction and Simulation of Neocortical Microcircuitry.
We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm(3) containing ~31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ~8 million connections with ~37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies. VIDEO ABSTRACT.


Longitudinal relationship between diabetes-specific emotional distress and follow-up HbA1c in adults with Type 1 diabetes mellitus.
To examine whether diabetes-specific emotional distress was related to follow-up glycaemic control in adults with Type 1 diabetes mellitus. Adults with Type 1 diabetes mellitus completed the Diabetes Distress Scale and reported sociodemographic information when attending a clinical consultation at a university endocrinology unit. Blood samples to determine baseline HbA1c were taken during consultations. All respondents' HbA1c measurements registered from January 2009 to December 2011 were collected from medical records. The relationship between baseline diabetes-specific emotional distress and HbA1c was examined with linear mixed-effects models in 175 patients with complete data. After controlling for confounders, baseline diabetes-specific emotional distress and glycaemic control were significantly associated (fixed-effect coefficient 0.40, P < 0.001) and the regimen-related distress subscale had the strongest association with glycaemic control (fixed-effect coefficient 0.47, P < 0.001). The two-item measure of diabetes-specific distress had a weaker but still significant association with glycaemic control (fixed-effect coefficient 0.31, P < 0.001). None of these relationships was significant after adjusting for the baseline HbA1c . People with elevated baseline diabetes-specific emotional distress are at risk of prolonged suboptimum glycaemic control; therefore, elevated diabetes-specific emotional distress, especially regimen-related distress, might be an important marker for prolonged suboptimum glycaemic control, and might indicate a need for special attention regarding patient self-management.


Severely Impaired and Dysregulated Cytochrome P450 Expression and Activities in Hepatocellular Carcinoma: Implications for Personalized Treatment in Patients.
This study aims to systematically determine the activities and expressions of cytochrome P450s (CYP) in hepatocellular carcinoma (HCC) patients to support their optimal use in personalized treatment of HCC. Activities of seven major drug-metabolizing CYP enzymes (CYP1A2, 2A6, 2C8, 2C9, 2D6, 2E1, and 3A4) were determined in tumors and pericarcinomatous tissues harvested from 26 patients with hepatitis B virus-positive HCC using probe substrates. Protein and mRNA levels of these CYPs were also measured using isotope label-free LC/MS-MS method and real-time PCR, respectively. Maximal metabolic velocity (Vmax) of CYP probe substrates was decreased by 2.5- to 30-fold in tumor microsomes, accompanied by a corresponding decrease in their protein and mRNA expression levels. However, Km values and turnover numbers of substrates in tumor microsomes were not changed. High correlations between activities and CYP protein levels were also observed, but the correlation between activities and mRNA levels was often poor. There was a major decrease in the degree of correlation in CYP expression in tumor tissues, suggesting that CYP expression levels are greatly disrupted by the tumorigenic process. Our unprecedented systemic study of the effects of HCC on CYPs demonstrated that activities of CYPs were seriously impaired and their expression patterns were severely altered by HCC. We proposed that determination of the CYP protein expression profile by LC/MS-MS in each patient is a promising approach that can be clinically used for individualized treatment of HCC.


A TLR/AKT/FoxO3 immune tolerance-like pathway disrupts the repair capacity of oligodendrocyte progenitors.
Cerebral white matter injury (WMI) persistently disrupts myelin regeneration by oligodendrocyte progenitor cells (OPCs). We identified a specific bioactive hyaluronan fragment (bHAf) that downregulates myelin gene expression and chronically blocks OPC maturation and myelination via a tolerance-like mechanism that dysregulates pro-myelination signaling via AKT. Desensitization of AKT occurs via TLR4 but not TLR2 or CD44. OPC differentiation was selectively blocked by bHAf in a maturation-dependent fashion at the late OPC (preOL) stage by a noncanonical TLR4/TRIF pathway that induced persistent activation of the FoxO3 transcription factor downstream of AKT. Activated FoxO3 selectively localized to oligodendrocyte lineage cells in white matter lesions from human preterm neonates and adults with multiple sclerosis. FoxO3 constraint of OPC maturation was bHAf dependent, and involved interactions at the FoxO3 and MBP promoters with the chromatin remodeling factor Brg1 and the transcription factor Olig2, which regulate OPC differentiation. WMI has adapted an immune tolerance-like mechanism whereby persistent engagement of TLR4 by bHAf promotes an OPC niche at the expense of myelination by engaging a FoxO3 signaling pathway that chronically constrains OPC differentiation.


ER stress inhibits mTORC2 and Akt signaling through GSK-3β-mediated phosphorylation of rictor.
In response to environmental cues, cells coordinate a balance between anabolic and catabolic pathways. In eukaryotes, growth factors promote anabolic processes and stimulate cell growth, proliferation, and survival through activation of the phosphoinositide 3-kinase (PI3K)-Akt pathway. Akt-mediated phosphorylation of glycogen synthase kinase-3β (GSK-3β) inhibits its enzymatic activity, thereby stimulating glycogen synthesis. We show that GSK-3β itself inhibits Akt by controlling the mammalian target of rapamycin complex 2 (mTORC2), a key activating kinase for Akt. We found that during cellular stress, GSK-3β phosphorylated the mTORC2 component rictor at serine-1235, a modification that interfered with the binding of Akt to mTORC2. The inhibitory effect of GSK-3β on mTORC2-Akt signaling and cell proliferation was eliminated by blocking phosphorylation of rictor at serine-1235. Thus, in response to cellular stress, GSK-3β restrains mTORC2-Akt signaling by specifically phosphorylating rictor, thereby balancing the activities of GSK-3β and Akt, two opposing players in glucose metabolism.


Rituximab toxicity in patients with peripheral blood malignant B-cell lymphocytosis.
Infusion related adverse events (AE) with day 1 rituximab in patients with B-cell non-Hodgkin's lymphoma (NHL) are common. The purpose of this study was to evaluate the AE occurring in patients with malignant B-cell lymphocytosis who received rituximab. Patients with a > or = 3 x 10(9)/L absolute lymphocyte count (ALC) receiving rituximab from 1998 to 1999 or participating in a phase I study of rituximab and interleukin-12 were reviewed. The AE occurring on the day of rituximab, the treatment provided (including hospitalization), and the subsequent ALC responses were recorded. Twenty-seven patients were identified; 14 had NHL, one Waldenstrom's macroglobulinemia, and 12 patients had chronic lymphocytic leukemia. The baseline median ALC was 9.58 x 10(9)/L (mean, 49.31; range, 3.56-380.95). All patients received rituximab as an outpatient. There were only two AE > or = grade 3. One patient was hospitalized for 1 day for i.v. fluids to treat an increase in creatinine that occurred with tumor lysis. A second patient developed a pulmonary syndrome five days after day 1 rituximab and required mechanical ventilation, but had no long-term lung toxicity. This study demonstrates that patients with high numbers of circulating blood B-lymphocytes can usually safely receive rituximab as outpatients. Patients who experience a rapid drop in ALC should be monitored closely for tumor lysis and the pulmonary syndrome.


Path integration in mammals and its interaction with visual landmarks.
During locomotion, mammals update their position with respect to a fixed point of reference, such as their point of departure, by processing inertial cues, proprioceptive feedback and stored motor commands generated during locomotion. This so-called path integration system (dead reckoning) allows the animal to return to its home, or to a familiar feeding place, even when external cues are absent or novel. However, without the use of external cues, the path integration process leads to rapid accumulation of errors involving both the direction and distance of the goal. Therefore, even nocturnal species such as hamsters and mice rely more on previously learned visual references than on the path integration system when the two types of information are in conflict. Recent studies investigate the extent to which path integration and familiar visual cues cooperate to optimize the navigational performance.


Phase I clinical trial of cilengitide in children with refractory brain tumors: Pediatric Brain Tumor Consortium Study PBTC-012.
A phase I trial of the antiangiogenesis agent cilengitide (EMD 121974), an alpha v beta 3,5 integrin antagonist, was performed to estimate the maximum-tolerated dose (MTD) and describe dose-limiting toxicities (DLTs) and the incidence and severity of other toxicities when administered to children with refractory brain tumors. Thirty-one assessable patients received intravenous cilengitide over 1 hour twice a week for up to 52 weeks at dosages from 120 to 2,400 mg/m(2). Serial blood and urine samples for clinical pharmacology studies were obtained in a subset of consenting patients. No DLTs were observed, and thus, the MTD was not estimated. Three of 13 patients at the dosage level of 2,400 mg/m(2) experienced grade 3 or 4 intratumoral hemorrhage (ITH) possibly related to the study drug; however, two of the ITH events were asymptomatic and, by the current toxicity criteria, would be classified as grade 1. For patients treated at cilengitide 2,400 mg/m(2), the 6-month cumulative incidence estimate of ITH is 23% (SE = 13%). No ITH was observed at 1,800 mg/m(2). Three patients completed 1 year of protocol therapy; one patient with glioblastoma multiforme demonstrated complete response, and two patients had stable disease (SD). An additional patient had SD for more than 5 months. The phase II dosage of intravenous cilengitide in children with refractory brain tumors is 1,800 mg/m(2). A phase II trial to assess the efficacy of cilengitide therapy for children with refractory brain tumors is being developed by the Children's Oncology Group.


Maternal-fetal intervention and fetal care centers.
The past 2 decades have yielded profound advances in the fields of prenatal diagnosis and fetal intervention. Although fetal interventions are driven by a beneficence-based motivation to improve fetal and neonatal outcomes, advancement in fetal therapies raises ethical issues surrounding maternal autonomy and decision-making, concepts of innovation versus research, and organizational aspects within institutions in the development of fetal care centers. To safeguard the interests of both the pregnant woman and the fetus, the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics make recommendations regarding informed consent, the role of research subject advocates and other independent advocates, the availability of support services, the multidisciplinary nature of fetal intervention teams, the oversight of centers, and the need to accumulate maternal and fetal outcome data.


Public stigma associated with psychosis risk syndrome in a college population: implications for peer intervention.
This study compared stigma associated with the psychosis risk label and diagnostic labels for nonpsychotic and psychotic mental disorders among young adult peers. Urban college respondents (N=153) read an experimental vignette describing a young adult experiencing prodromal symptoms who was randomly assigned a diagnostic label (major depression, generalized anxiety disorder, schizophrenia, or psychosis risk with and without accurate information about the psychosis risk label) and answered questions about stigma toward the individual in the vignette. Compared with labels for nonpsychotic disorders, schizophrenia elicited more negative stereotyping and the at-risk label invoked greater social distance and less willingness to help. Any increased social distance appeared to be reduced by accurate information about the at-risk state. No differences in stigma were found for the psychosis risk and schizophrenia labels. The psychosis risk label alone appeared to evoke greater status loss and discrimination. Accurate information may minimize some stigmatizing attitudes among college peers.


Relationship Between Meeting 24-Hour Movement Guidelines and Cardiometabolic Risk Factors in Children.
The purpose of this study was to evaluate the relationship between adherence to pediatric 24-hour movement guidelines (moderate to vigorous physical activity, sedentary behavior, and sleep) and cardiometabolic risk factors. The sample included 357 white and African American children aged 5-18 years. Physical activity, television viewing, and sleep duration were measured using questionnaires, and the 24-hour movement guidelines were defined as ≥60 minutes per day of moderate to vigorous physical activity on ≥5 days per week, ≤ 2 hours per day of television, and sleeping 9-11 hours per night (ages 5-13 y) or 8-10 hours per night (ages 14-18 y). Waist circumference, body fat, abdominal visceral and subcutaneous adipose tissue, blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, and glucose were measured in a clinical setting. A total of 26.9% of the sample met none of the guidelines, whereas 36.4%, 28.3%, and 8.4% of the sample met 1, 2, or all 3 guidelines, respectively. There were significant associations between the number of guidelines met and body mass index, visceral and subcutaneous adipose tissue, triglycerides, and glucose. There were no associations with blood pressure or high-density lipoprotein cholesterol. Meeting more components of the 24-hour movement guidelines was associated with lower levels of obesity and several cardiometabolic risk factors. Future efforts should consider novel strategies to simultaneously improve physical activity, sedentary time, and sleep in children.


Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia.
Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38. The parallel screening of kinase inhibitors revealed that mouse and human neutrophil viability is dependent on cyclin-dependent kinase (CDK) activity but surprisingly only partially dependent on PI3 kinase and JAK/STAT signaling, revealing dominant pathways contributing to neutrophil viability. Mcl-1 haploinsufficiency sensitized neutrophils to CDK inhibition, demonstrating that Mcl-1 is a direct target for CDK inhibitors. This study reveals a therapeutic window for the kinase inhibitors BEZ235, BMS-3, AZD7762, and (R)-BI-2536 to induce apoptosis of leukemia cell lines whilst maintaining immunocompetence and hemostasis.


[The influence of Aronia melanocapra in experimental pancreatitis].
The administration of anthocyanin dyes from Aronia melanocarpa in the rats before the intraperitoneal injections of PAF and ceruleine have a beneficial effect on the development of the acute experimental pancreatitis. It was revealed the reduction of pancreas swelling and decreasing of lipid peroxidation and adenosine deaminase activity. The examination was carried out on 149, weighing 200-250 g, female and male Wistar rats. They lived in the animal quarters with a stable temperature and humidity being fed with standard fodder (Murigan) and water ad libitum.


Health care professionals' views towards self-management and self-management education for people with type 2 diabetes.
Significant problems with patients engaging with diabetes self-management education (DSME) exist. The role of healthcare professionals (HCPs) has been highlighted, with a lack of enthusiasm, inadequate information provision and poor promotion of available programmes all cited as affecting patients' decisions to attend. However, little is known about HCPs' views towards DSME. This study investigates the views of HCPs towards self-management generally and self-management in the context of DSME more specifically. A qualitative study using semi-structured interviews to investigate HCPs views of type 2 diabetes self-management and DSME. Data were analysed thematically and emergent themes were mapped on to the constructs of Normalisation Process Theory (NPT). Two boroughs in London, UK. Sampling was purposive to recruit a diverse range of professional roles including GPs, practice nurses, diabetes specialist nurses, healthcare assistants (HCAs), receptionists and commissioners of care. Interviews were conducted with 22 participants. The NPT analysis demonstrated that while a self-management approach to diabetes care was viewed by HCPs as necessary and, in principle, valuable, the reality is much more complex. HCPs expressed ambivalence about pushing certain patients into self-managing, preferring to retain responsibility. There was a lack of awareness among HCPs about the content of DSME and benefits to patients. Commitment to and engagement with DSME was tempered by concerns about suitability for some patients. There was little evidence of communication between providers of group-based DSME and HCPs or of HCPs engaging in work to follow-up non-attenders. HCPs have concerns about the appropriateness of DSME for all patients and discussed challenges to engaging with and performing the tasks required to embed the approach within practice. DSME, as a means of supporting self-management, was considered important in theory, but there was little evidence of HCPs seeing their role as extending beyond providing referrals.


Diruthenium(ii)-NNN pincer complex catalysts for transfer hydrogenation of ketones.
Dinuclear ruthenium(ii)-NNN pincer complexes bearing a π linker-supported bis(pyrazolyl-imidazolyl-pyridine) ligand were synthesized and structurally characterized, and they exhibited excellent catalytic activity for the transfer hydrogenation of ketones in refluxing isopropanol, reaching TOF values up to 1.3 × 106 h-1. Compared with the corresponding mononuclear Ru(ii)-NNN pincer complexes, the bimetallic complexes could be applied at concentrations as low as 0.03 mol% Ru and demonstrated remarkably enhanced catalytic activity in the transfer hydrogenation reactions of ketones. The high catalytic activity of the diruthenium(ii) complexes is attributed to the excellent stability and possible cooperativity of the two coordinated Ru(ii) metal centers through the π linker. The present synthetic methodology has established an applicable strategy to construct highly active bimetallic NNN pincer complex catalysts.


Constitutive androstane receptor (Car)-driven regeneration protects liver from failure following tissue loss.
Liver can recover following resection. If tissue loss is too excessive, however, liver failure will develop as is known from the small-for-size-syndrome (SFSS). The molecular processes underlying liver failure are ill-understood. Here, we explored the role and the clinical potential of Nr1i3 (constitutive androstane receptor, Car) in liver failure following hepatectomy. Activators of Car, various hepatectomies, Car(-/-) mice, humanized CAR mice, human tissue and ex vivo liver slice cultures were used to study Car in the SFSS. Pathways downstream of Car were investigated by in vivo siRNA knockdown. Excessive tissue loss causing liver failure is associated with deficient induction of Car. Reactivation of Car by an agonist normalizes all features associated with experimental SFSS. The beneficial effects of Car activation are relayed through Foxm1, an essential promoter of the hepatocyte cell cycle. Deficiency in the CAR-FOXM1 axis likewise is evident in human SFSS. Activation of human CAR mitigates SFSS in humanized CAR mice and improves the culture of human liver slices. Impaired hepatic Car-Foxm1 signaling provides a first molecular characterization of liver that fails to recover after tissue loss. Our findings place deficient regeneration as a principal cause behind the SFSS and suggest CAR agonists may bear clinical potential against liver failure. The unique regenerative capacity of liver has its natural limits. Following tissue loss that is too excessive, such as through extended resection in the clinic, liver failure may develop. This is known as small-for-size-syndrome (SFSS) and represents the most frequent cause of death due to liver surgery. Here we show that deficient induction of the protein Car, a central regulator of liver function and growth, is a cause of liver failure following extended resection; reactivation of Car through pharmacological means is sufficient to prevent or rescue the SFSS.


Triple vs Dual Inhaler Therapy and Asthma Outcomes in Moderate to Severe Asthma: A Systematic Review and Meta-analysis.
The benefits and harms of adding long-acting muscarinic antagonists (LAMAs) to inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) for moderate to severe asthma remain unclear. To systematically synthesize the outcomes and adverse events associated with triple therapy (ICS, LABA, and LAMA) vs dual therapy (ICS plus LABA) in children and adults with persistent uncontrolled asthma. MEDLINE, Embase, CENTRAL, ICTRP, FDA, and EMA databases from November 2017, to December 8, 2020, without language restriction. Two investigators independently selected randomized clinical trials (RCTs) comparing triple vs dual therapy in patients with moderate to severe asthma. Two reviewers independently extracted data and assessed risk of bias. Random-effects meta-analyses, including individual patient-level exacerbation data, were used. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach was used to assess certainty (quality) of the evidence. Severe exacerbations, asthma control (measured using the Asthma Control Questionnaire [ACQ-7], a 7-item list with each item ranging from 0 [totally controlled] to 6 [severely uncontrolled]; minimal important difference, 0.5), quality of life (measured using the Asthma-related Quality of Life [AQLQ] tool; score range, 1 [severely impaired] to 7 [no impairment]; minimal important difference, 0.5), mortality, and adverse events. Twenty RCTs using 3 LAMA types that enrolled 11 894 children and adults (mean age, 52 years [range, 9-71 years]; 57.7% female) were included. High-certainty evidence showed that triple therapy vs dual therapy was significantly associated with a reduction in severe exacerbation risk (9 trials [9932 patients]; 22.7% vs 27.4%; risk ratio, 0.83 [95% CI, 0.77 to 0.90]) and an improvement in asthma control (14 trials [11 230 patients]; standardized mean difference [SMD], -0.06 [95% CI, -0.10 to -0.02]; mean difference in ACQ-7 scale, -0.04 [95% CI, -0.07 to -0.01]). There were no significant differences in asthma-related quality of life (7 trials [5247 patients]; SMD, 0.05 [95% CI, -0.03 to 0.13]; mean difference in AQLQ score, 0.05 [95% CI, -0.03 to 0.13]; moderate-certainty evidence) or mortality (17 trials [11 595 patients]; 0.12% vs 0.12%; risk ratio, 0.96 [95% CI, 0.33 to 2.75]; high-certainty evidence) between dual and triple therapy. Triple therapy was significantly associated with increased dry mouth and dysphonia (10 trials [7395 patients]; 3.0% vs 1.8%; risk ratio, 1.65 [95% CI, 1.14 to 2.38]; high-certainty evidence), but treatment-related and serious adverse events were not significantly different between groups (moderate-certainty evidence). Among children (aged 6 to 18 years) and adults with moderate to severe asthma, triple therapy, compared with dual therapy, was significantly associated with fewer severe asthma exacerbations and modest improvements in asthma control without significant differences in quality of life or mortality.


Flexible Sigmoidoscopy and CT Colonography Screening: Patients' Experience with and Factors for Undergoing Screening-Insight from the Proteus Colon Trial.
Purpose To compare the acceptability of computed tomographic (CT) colonography and flexible sigmoidoscopy (FS) screening and the factors predicting CT colonographic screening participation, targeting participants in a randomized screening trial. Materials and Methods Eligible individuals aged 58 years (n = 1984) living in Turin, Italy, were randomly assigned to be invited to screening for colorectal cancer with FS or CT colonography. After individuals who had died or moved away (n = 28) were excluded, 264 of 976 (27.0%) underwent screening with FS and 298 of 980 (30.4%) underwent CT colonography. All attendees and a sample of CT colonography nonattendees (n = 299) were contacted for a telephone interview 3-6 months after invitation for screening, and screening experience and factors affecting participation were investigated. Odds ratios (ORs) were computed by means of multivariable logistic regression. Results For the telephone interviews, 239 of 264 (90.6%) FS attendees, 237 of 298 (79.5%) CT colonography attendees, and 182 of 299 (60.9%) CT colonography nonattendees responded. The percentage of attendees who would recommend the test to friends or relatives was 99.1% among FS and 93.3% among CT colonography attendees. Discomfort associated with bowel preparation was higher among CT colonography than FS attendees (OR, 2.77; 95% confidence interval [CI]: 1.47, 5.24). CT colonography nonattendees were less likely to be men (OR, 0.36; 95% CI: 0.18, 0.71), retired (OR, 0.31; 95% CI: 0.13, 0.75), to report regular physical activity (OR, 0.37; 95% CI: 0.20, 0.70), or to have read the information leaflet (OR, 0.18; 95% CI: 0.08, 0.41). They were more likely to mention screening-related anxiety (mild: OR, 6.30; 95% CI: 2.48, 15.97; moderate or severe: OR, 3.63; 95% CI: 1.87, 7.04), erroneous beliefs about screening (OR, 32.15; 95% CI: 6.26, 165.19), or having undergone a recent fecal occult blood test (OR, 13.69; 95% CI: 3.66, 51.29). Conclusion CT colonography and FS screening are well accepted, but further reducing the discomfort from bowel preparation may increase CT colonography screening acceptability. Negative attitudes, erroneous beliefs about screening, and organizational barriers are limiting screening uptake; all these factors are modifiable and therefore potentially susceptible to interventions. © RSNA, 2017 Online supplemental material is available for this article.


Segmental lineage restrictions in the chick embryo spinal cord depend on the adjacent somites.
We have investigated whether the developing spinal cord is intrinsically segmented in its rostrocaudal (anteroposterior) axis by mapping the spread of clones derived from single labelled cells within the neural tube of the chick embryo. A single cell in the ventrolateral neural tube of the trunk was marked in situ with the fluorescent tracer lysinated rhodamine dextran (LRD) and its descendants located after two days of further incubation. We find that clones derived from cells labelled before overt segmentation of the adjacent mesoderm do not respect any boundaries within the neural tube. Those derived from cells marked after mesodermal segmentation, however, never cross an invisible boundary aligned with the middle of each somite, and tend to be elongated along the mediolateral axis of the neural tube. When the somite pattern is surgically disturbed, neighbouring clones derived from neuroectodermal cells labelled after somite formation behave like clones derived from younger cells: they no longer respect any boundaries, and are not elongated mediolaterally. These results indicate that periodic lineage restrictions do exist in the developing spinal cord of the chick embryo, but their maintenance requires the presence of the adjacent somite mesoderm.